bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic inflammation, adjuvant chemotherapy, and survival in stage III colorectal cancer: Results from the ScotScan Colorectal Cancer Collaborative.
Authors: Park James Hugh , Fuglestad Anniken Jorlo , Kostner Anne Helene , Oliwa Agata , Roxburgh Campbell SD , Horgan Paul G. , Graham Janet Shirley , Kersten Christian , McMillan Donald C. 
Published: February 2020

228 Background: The systemic inflammatory response (SIR) is a poor prognostic marker in patients with colorectal cancer (CRC), and predicts poor outcome following adjuvant chemotherapy. Whether this may be influenced by chemotherapy regime is not known. The present study examined the relationship between the pre-operative SIR, adjuvant therapy regime, and survival of patients with stage III CRC in the ScotScan cohort. Methods: Patients with stage III CRC in Scotland (1997-2015, n= 317) and Norway (2000-17, n= 312) were included. The pre-operative SIR was measured using C-reactive protein (CRP≤10mg/L or > 10mg/L). Adjuvant status was categorised as none, 5-fluorouracil-only (5FU or capecitabine), or oxaliplatin-combination (Ox). Relationship with 3 year overall (OS) and cancer-specific survival (CSS) was examined. Results: Rates of Ox were comparable between cohorts (Scotland – 26% vs. Norway 28%), although more patients from Norway received single 5FU (4% vs. 19%, P= 0.005). 36% of each cohort were systemically inflamed. Ox was associated with superior OS (90%) and CSS (92%) when compared to 5FU (77% and 84%) and no therapy (61% and 72%, both P< 0.001). Stratified by SIR, patients with CRP≤10mg/L receiving Ox or 5FU had comparable 3yr OS greater than those receiving none (90% vs. 88% vs. 67%), whereas those with CRP > 10mg/L receiving Ox had superior survival than those receiving 5FU or no therapy (89% vs. 64% vs. 53%, P-for interaction = 0.101). Results were similar for CSS (CRP≤10mg/L: 91% vs. 94% vs. 79%; CRP > 10mg/L: 94% vs. 72% vs. 62%, P-for interaction= 0.01). Although patients receiving Ox were younger and less comorbid, both use of Ox and SIR remained independently associated with OS and CSS. Conclusions: Although selection bias in the choice of adjuvant therapy may confound analysis, this study suggests the SIR may aid in determining response to adjuvant therapy. Whereas non-inflamed patients with stage III CRC may benefit from single 5FU, those with an elevated SIR may benefit greater from more intensive, Ox-based regimes. These results remain to be validated, however support the use of the SIR as a prognostic and predictive biomarker in patients with stage III CRC.
The potential for combined measures of the systemic inflammatory response (SIR) in colon cancer: An analysis of 2,300 patients.
Authors: Golder Allan Matthew , McMillan Donald C. , Mansouri David , Park James Hugh , Roxburgh Campbell SD , Horgan Paul G. 
Published: February 2020

233 Background: The preoperative SIR clearly demonstrates independent prognostic significance following curative resection for colon cancer, independent of TNM stage. SIR can be measured either using acute phase proteins, predominantly the modified Glasgow Prognostic Score (mGPS) or using the differential white cell count, predominantly neutrophil-lymphocyte ratio (NLR) or lymphocyte-monocyte ratio (LMR). The present study investigates the potential to combine these scores to better predict overall/cancer specific survival (OS/CSS). Methods: Patients in the West of Scotland undergoing curative resection for Stage I-III colon cancer from 2011-2015 were identified with survival updated until December 2018. Through uni/multivariate analysis (UVA/MVA) we compared the effect on OS/CSS of the SIR measured using a combination of mGPS and either NLR or LMR with other clinicopathological features. Results: 2312 patients were identified having underwent curative surgery. Median follow up time was 60 months and there were 756 deaths during follow up. On UVA: mGPS (0/1/2), NLR ( < 3/3-5/ > 5) and LMR ( < 2.5/2.5+) were significant for OS and CSS (all p < 0.001). In the multivariate model when a combination of mGPS and NLR were entered, both remained significant for OS (mGPS: HR 1.20, p = 0.002 and NLR: HR 1.23, p = 0.001) and CSS (mGPS: HR 1.25, p = 0.003 and NLR: HR 1.21, p = 0.017) adjusted for age, sex, emergency presentation, site, ASA, TNM stage and margin involvement. With mGPS and LMR in the model similar results were seen for OS (mGPS: HR 1.24, p = 0.005 and LMR: HR 1.49, p = 0.003) and CSS (mGPS: HR 1.20 p = 0.001 and LMR: HR 1.45, p < 0.001). When mGPS and NLR were scored 0/1/2 (mGPS 0/1/2 and NLR < 3/3-5/ > 5) and combined to form a cumulative grade (0/1/2/3/4) this offered better stratification of %OS (86/84/72/61/55) than mGPS (83/75/60) or NLR (86/79/66) alone (all p < 0.001). Similar results were seen for %CSS – mGPS (90/79/71), NLR (91/85/75) and combined grade (92/90/77/71/67). Conclusions: The results of the present study show that the combined use of mGPS and a differential white cell-based score (NLR/LMR) stratify OS/CSS better than a single measure of preoperative SIR alone.
The Reg4-CD44ICD pathway and tumor aggression in early-stage colon adenocarcinoma.
Authors: Sninsky Jared , Bishnupuri Kumar , Gonzalez Ivan , Trikalinos Nikolaos , Chen Ling , Dieckgraefe Brian 
Published: February 2020

234 Background: Reg4, or regenerating islet-derived protein 4, is highly expressed in gastrointestinal malignancies and acts as a mitogenic factor. Our prior work suggests a direct invitro interaction between Reg4 and CD44, a non-kinase transmembrane glycoprotein over-expressed in cancer stem cells. Reg4 is hypothesized to activate CD44 proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study was to demonstrate clinical validity of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with disease recurrence and clinical parameters of aggression. Methods: We constructed a tissue microarray (TMA) consisting of 94 stage II/III matched colon adenocarcinoma patients, 23 of which had recurrent disease after potentially curative treatment. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins with specific antibodies. Spearman’s correlation, Chi-square tests, and Kaplan-Meier analyses were used to identify protein associations with tumor characteristics, recurrence and overall survival. Results: Expression of Reg4, CD44, and CD44ICD was associated with tumor location, size, tumor grade, mismatch repair (MMR) status, and disease recurrence. TMA data analysis supported our proposed mechanism of Reg4-mediated release of CD44ICD into the cytoplasm. A significant correlation was observed between Reg4 and CD44 (r2= 0.23, P = 0.028), CD44 and CD44ICD (r2= 0.36, p = 0.0004), and Reg4 and CD44ICD (r2= 0.45, p = < 0.0001). Reg4 expression was associated with larger tumor size (r2= 0.23, p = 0.026) . No association was observed between Reg4, CD44, or CD44ICD expression with disease recurrence. In patients who recurred, Reg4-positive patients had a median survival of 4 years vs. 7 years for Reg4-negative patients (p = 0.04). Our lab has performed in vitroexperiments with CD44ICD interfering peptides blocking the pro-proliferative effect of Reg4. Conclusions: These results suggest that Reg4-positive tumors, while not at higher risk of recurrence, are associated with decreased survival in established recurrent colon adenocarcinoma. Inhibition of the Reg4-CD44/CD44ICD pathway may be a future therapeutic target.
BRCA mutations in metastatic colorectal cancer (mCRC) and response to chemotherapy.
Authors: Feng Sophie , Al-Showbaki Laith , Krzyzanowska Monika K. , Prince Rebecca M. , Stockley Tracy , Yu Celeste , Bedard Philippe L. , Siu Lillian L. , Chen Eric Xueyu 
Published: February 2020

235 Background: Mutations in BRCA 1/2 are typically associated with breast, ovarian, pancreatic and prostate cancers. BRCA mutations have been reported in colorectal cancer in sporadic case series. Unlike other cancers, the significance of BRCA mutations in mCRC is not known. We report the prevalence and molecular characteristics associated with BRCA 1/2 mutations in mCRC, and investigate the impact of these mutations on chemotherapy response since both oxaliplatin (OX) and irinotecan (IRI) interfere with DNA repair pathways. Methods: The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) database was queried to identify mCRC patients (pts) harbouring BRCA 1/2 mutations. BRCA 1/2 mutations were detected using panel-based next generation sequencing (NGS) on archival tumour tissue. Clinical and molecular variables were collected, together with treatment outcomes. Results: Of 279 mCRC pts within the OCTANE database as of March 2019, 9 pts with BRCA 1/2 mutations were identified (3.2%): 4 BRCA 1 and 5 BRCA 2 mutations. Each patient had a unique variant with 8/9 missense mutations and 1/9 splicing error. Allele frequency ranged from 0.11 to 0.57. RAS or BRAF mutations were present in 67%. Common co-mutations included TP53 (56%), APC (56%), TSC1 (44%), ROS1 (33%) and ATM(33%). 2 pts were mismatch repair deficient. Median age was 48.5 years (range: 31-69 years), 56% males. 5 pts presented with de novo metastatic disease. First line OX-containing chemotherapy was administered to 4 pts, and IRI to 3 pts. 2 pts did not receive chemotherapy (1 had surgery only post-adjuvant OX, and 1 immunotherapy). Overall response rate (ORR) was 71%, with all pts achieving a partial response or stable disease. The median progression-free survival was 7.5 months (range: 1.8- 31.7 months) and median overall survival 68.5 months (range: 10.5- 68.5 months) respectively. Conclusions: BRCA 1/2 mutations are present in a small subset of mCRC pts. Pts with these mutations tend to be younger at diagnosis. BRCA 1/2 mutations are associated with favourable response to first line chemotherapy. Targeting BRCA 1/2 mutations may broaden treatment options for these patients.
KRAS status and survival in multicenter study of RAS mutations (MURAS) in patients with colorectal liver metastases receiving Y90 radioembolization treatment.
Authors: Dendy Case Meaghan , Ghodadra Anish , Novelli Paula M. , Wu Vincent , Ganguli Suvranu , Wildgruber Moritz , Kohler Michael , Robinson Charles , Kim Charles , Wang David S. , Sze Daniel Y. , Kolbeck Kenneth , Russell Lori , Uhlig Johannes , Ludwig Johannes M. , Kim Hyun S. 
Published: February 2020

239 Background: Assessment of the clinical outcome and prognostic factors of patients receiving Y90 radioembolization to treat colorectal liver metastases. Methods: Multi-institution retrospective study of patients with CRLM who received Y-90 radioembolization after undergoing molecular testing was performed. Patients treated between 2008 and 2019 were included from 7 institutions within the United States and Europe. Patient demographics, systemic therapy regimens, tumor characteristics, laboratory values and overall survival were analyzed between patients with differing histopathologic and genomic status. Genomic profiling was obtained for KRAS, BRAF, PIK3CA, AKT, MEK, NRAS and MMR genes. Kaplan-Meier survival estimation and multivariate Cox regression were analyzed. Results: 445 patients treated with Y90 radioembolization fulfilled the inclusion criteria. Of the total cohort, 430 patients were available who had documented KRAS mutation status. Average age at diagnosis was found to be 58.4 years for all patients (57.6% male, 42.4% female). Decreased survival post Y90 treatment was shown in those patients with mutant KRAS. The median survival in patients with mutated KRAS was 5.7 months, as compared to 8.0 months in those patients with wild-type KRAS (p< 0.0001). Patient demographics including age, gender and race were not shown to be significant in overall survival post-Y90 treatment (p-values >0.05). The average number of systemic chemotherapy treatments prior to Y90 was 2.15 and was similar between KRAS groups (mutant vs wild type.) KRAS status persisted as a significant predictor of survival on multivariate analysis (p< 0.0001; HR 2.1 CI: 1.54-2.85). Conclusions: KRAS status is shown as a significant prognostic factor in patients with colorectal liver metastases receiving Y90 radioembolization.
A comparison study of the intratumoral microbiome in younger verses older-onset colorectal cancer (COSMO CRC).
Authors: Weinberg Benjamin Adam , Wang Hongkun , Geng Xue , Shokralla Shadi , Bakhshi Emily , Chaldekas Krysta , Harris Brent T. , Clagett Dionyssia , Marshall John 
Published: February 2020

241 Background: Although colorectal cancer (CRC) incidence has declined overall, CRC in individuals under age 45 has risen dramatically, particularly in the distal colon and rectum (left-sided CRC). The intratumoral microbiome (MB) of young individuals may be responsible. Certain bacteria disrupt colonic luminal integrity and promote inflammation, leading to oncogenic mutations in colonic epithelial cells. Fusobacterium nucleatum ( F. nuc) promotes CRC by suppressing immune response within the tumor microenvironment, activating the β-catenin pathway, and causing chemoresistance due to autophagy. Methods: We compared the intratumoral MB in CRC patients (pts) diagnosed before age 45 and after age 65. Primary and metastatic tumors were included. DNA was extracted from tumors and analyzed using 16S ribosomal gene sequencing. We compared the frequency of F. nuc and other bacterial and fungal DNA in tumors from younger- vs. older-onset CRC pts. Results: Tumors from 18 younger pts (median age 39.2 years) and 13 older pts (median age 72.8 years) underwent analysis. In total, 478 unique bacterial and fungal species were detected. F. nuc was found in tumors of 5 younger pts (28%, 4 left-sided and 1 right-sided primary) and 3 older pts (23%, 1 left-sided and 2 right-sided; P = NS, Fisher’s Exact test). A significant difference was seen in the rate of Moraxella osloensis (11% vs. 46%, P = 0.043, Fisher’s Exact test) in younger vs. older pts. There was no significant difference in MB diversity in younger vs. older pts. Conclusions: F. nuc is present in a greater number of tumors in pts with CRC diagnosed before age 45 than previously thought. Intratumoral bacterial profiling may discover patterns that explain the rising incidence of CRC in younger individuals and might eventually inform the development of novel therapeutics and adaptive cancer screening methods.
Tumor area and microscopic extent of invasion to determine circulating tumor DNA fraction in plasma and detectability of colorectal cancer (CRC).
Authors: Bredno Joerg , Lipson Jafi , Venn Oliver , Gross Samuel , Fields Alexander P. , Beausang John F. , Liu Qinwen , Brooks Jacqueline D. , Chen Xiaoji , Lopatin Rita , Liu Hai , Zhang Nan , Zhang Lori , Wu Tony , Allen Brian , Hartman Anne-Renee , Hubbell Earl , Jamshidi Arash , Aravanis Alex 
Published: February 2020

243 Background: Circulating Cell-free Genome Atlas (CCGA; NCT02889978) is a multi-center, case-control, observational study with longitudinal follow-up to develop a cfDNA assay in which classifiers were trained on whole-genome bisulfite sequencing (WGBS) and targeted methylation (TM) sequencing data for detection of multiple cancer types. Previously, we showed that the fraction of ctDNA fragments (TF) was a stronger predictor of cancer detection than clinical stage and an equivalent predictor for survival. Given that CRC tumors can be described via surface area (TSA) and microscopic tumor extent (microinvasion), CRC was used as a model to examine the biophysical determinants of TF. Methods: Detection of multiple cancers with WGBS at 98% and TM at > 99% specificity, and methods for determining TF, were previously reported. A model to predict the presence of detectable cfDNA fragments for CRC adenocarcinomas of stages I, II, and III included TSA and microinvasion beyond the subserosa. Predictors were combined assuming a linear increase of cfDNA shedding with tumor size, with scaling factors depending on microinvasion. Model parameters were determined for 27 participants (7, 11, 9 for stages I, II, III, resp.) with WGBS and applied to 40 participants (12, 15, 13 for I, II, III, resp.) with TM assay and information on tumor size and microinvasion. Results: CRC detection at stages I/II/III was 33/46, 61/73, 57/74% for WGBS/TM. TF predicted detection with AUC = 97.6. The model predicted TF as TSA multiplied by 3.81*10−6 / mm2 for tumors that invaded beyond the subserosa (p < 0.001). This was 4.4x higher than estimates for tumors below the subserosa. The model trained on the WGBS assay predicted CRC detection in the TM assay with an AUC of 0.844. Conclusions: This model used TSA (number of tumor cells) and microinvasion (bloodstream access) to predict the fraction of CRC ctDNA fragments in blood without needing to account for stage. Tumors not penetrating the subserosa had low ctDNA shedding that likely limited detection. These findings may generalize to other cancer types, providing principles to predict ctDNA shedding and thus cancer detectability based on microinvasion and surface area. Clinical trial information: NCT02889978.
Integrating multiple “omics” analyses, on a triage concept, for effective case selection followed by diagnostic colonoscopy.
Authors: Thyparambil Sheeno P. , You Jin , Liu Kang , Sun Hui , Peng Junjie , Cai Sanjun , Li Yaqi , Bao Pingping , Li Qing , Zhang Yani , Li Zheng , Yang Jingzhi , Yin Ziyu , Yao Xiaoming , Zhu Xiurui , Hao Shiying , Heaton Robert , Schilling James , Sylvester Karl G. , Ling Xuefeng B. ,   OncoPlex Diagnostics
Published: February 2020

244 Background: Implementation of population screening for colorectal cancer (CRC) before colonoscopy can reduce the challenge of the overall capacity of bowel examination and improve survival. Blood based CRC assessment biomarkers, on a triage concept, can lead to improved selection to colonoscopy and cost-effective CRC care. Methods: Innovative multi-omics approaches, with global and targeted LCMS data production (metabolomics, lipidomics, and 2D proteomics) and integrative data analytics, were applied to discover serological biomarkers to assess nonadvanced adenoma and identify stage I/II colorectal bowel lesions. A cohort of 2396 normal, 660 adenoma, 953 stage I, and 101 stage II blood samples, was constructed to discover screening biomarkers to support case finding of patients at high risk for nonadvanced adenoma and stage I/II cancer for subsequent diagnostic colonoscopy. Results: A three-analyte mProbe panel was constructed which outperformed the commercial assays of plasma methylated septin 9 and fecal Cologuard tests. Sensitivity: (1) nonadvanced adenoma–Cologuard 17.2%, mProbe 76.0%; (2) stage I-III-Cologuard 93.3%, stage I-II Septin 9 (ARUP laboratories) 77%, stage I-II mProbe: 92.3%. Specificity–Cologuard 89.8%, Septin 9 (ARUP laboratories) 88%, mProbe 90.7%. Conclusions: mProbe triage concept of a blood-based protein biomarker panel promises the precision to allow future CRC screening, and reduce the low-risk utilization of unnecessary, unpleasant and risk-associated bowel examinations.
The potential in artificial intelligence-driven radiomic signature to predict survival in patients with metastatic colorectal cancer treated with cetuximab-based therapy.
Authors: Dercle Laurent , Lu Lin , Schwartz Lawrence Howard , Qian Min , Tejpar Sabine , Eggleton Peter , Zhao Binsheng , Piessevaux Hubert 
Published: February 2020

247 Background: This analysis was undertaken to forecast survival and enhance treatment decisions for patients (pts) with colorectal cancer (CRC) with liver metastases sensitive to folinic acid, fluorouracil and irinotecan (FOLFIRI) alone [F] or in combination with cetuximab [FC] using simple quantitative radiomic changes between CT scans at baseline and 8 weeks. Methods: We retrospectively analyzed 667 pts with KRAS-unselected metastatic CRC in NCT00154102 treated with F and FC. CT quality was classified as high (HQ) or standard (SQ), and four data sets were created and named by treatment quality. Pts were randomly assigned 1:2 to training or validation sets: FCHQ, 38/78 pts; FCSQ, 62/124 pts; FHQ, 51/78 pts; FSQ, 78/158 pts. A machine-learning signature was trained using data set FCHQ to classify pts as treatment-sensitive or treatment-insensitive using just 4 of 3,499 potential radiomic imaging features. Performance was calibrated/validated using ROC curves. Hazard ratios (HRs) and Cox regression models were used to evaluate association with overall survival (OS). Results: The signature used decrease in tumor heterogeneity plus boundary infiltration to successfully predict sensitivity to FC (FCHQ: AUC, 0.80; FCSQ: AUC, 0.72) but failed with non-cetuximab regimens (FHQ: AUC, 0.59; FSQ: AUC, 0.55). The radiomic signature outperformed existing biomarkers ( KRAS mutational status and tumor shrinkage by RECIST 1.1) for sensitivity to cetuximab-based therapy and was strongly associated with OS in the cetuximab-containing sets FCHQ (HR, 44.3; p = 0.0001) and FCSQ (HR, 6.5; p = 0.005). Conclusions: This signature, derived from simple radiomic analysis of tumor imaging phenotype using only standard-of-care CT scans, appeared to be treatment-specific and was superior to all tested prognostic biomarkers. The signature provided early prediction of sensitivity and survival and could be used to guide treatment continuation decisions.
Effect of weight, obesity, and other co-morbidities on mortality of colon cancer patients.
Authors: Sing Kevin , Tran Valerie , McClish Donna , Matin Khalid 
Published: February 2020

25 Background: There have been reports implicating underweight status as well as obesity with lower survival in colorectal cancer patients, but data has been inconsistent. Methods: In this retrospective observational study, we gathered pre-treatment data on BMI and other co-morbidities from 423 colon cancer patients who underwent surgical resection (stages I to III) or were metastatic at diagnosis (stage IV) at VCU Medical Center from 2005 to 2018 and analyzed their survival outcomes. Results: Compared to patients with a normal BMI, patients with underweight status (BMI < 18.5) have a trend towards higher all-cause mortality (HR 1.66, 95% CI 0.67-4.12). Patients with overweight BMI (25-29.9) and obese BMI ( > 30) have a trend towards improved mortality (HR 0.67, 95% CI 0.46-0.98) (HR 0.75, 95% CI 0.53-1.07) respectively. The p-value was 0.0675. We also found that pre-existing diabetes mellitus is associated with increased all-cause mortality (HR 1.43, CI 1.03 to 1.98, p < 0.05), as well as the use of aspirin at diagnosis (HR 1.60, CI 1.16 to 2.21, p < 0.05). Conclusions: Our results are similar to previous findings that patients with underweight status have worse mortality outcome, suggesting the importance of nutritional status prior to starting treatment. We also found that overweight and obese patients have trends towards improved survival compared to normal weight patients. Future focus can be directed to see whether overweight or obesity status past diagnosis affect survival trends. Aspirin use at diagnosis in our study population is associated with worse mortality outcome; literature is conflicting with outcomes and pre-diagnosis aspirin use. Our findings are similar for both locoregional colon cancers as well as metastatic disease. Research should be directed at seeing what kind of interventions such as nutrition or rehabilitation can be used to ameliorate the increased mortality trend in the underweight status group of patients.