bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diffusion kurtosis imaging in predicting the chemotherapeutic response of colorectal liver metastases: The result of the FDZL-MRinCLM study.
Authors: Li Wenhua , Guo Weijian , Zhang Huan , Chen Zhiyu , Zhang Wen , Tong Tong 
Published: May 2020

e16034 Background: Colorectal liver metastatic (CLM) patients are a special population who have potential of cure with effective conversion treatment. The conventional radiological imaging commonly evaluates the response 6-8 weeks after the medication. A response marker for earlier prediction could avoid further use of ineffective drugs and guide the medical change for optimal regimen. This study is to evaluate the feasibility of early parameter change assessed by functional MR in predicting clinical response to chemotherapy and investigate its prognostic value in CLM patients. Methods: From August 2016, CLM patients were consecutively enrolled and examined by functional MRI with diffusion kurtosis imaging (DKI) sequence of liver at baseline and one cycle after the initiation of chemotherapy. The whole-lesion histogram and texture analyses of DKI was analyzed and features were extracted from the inline-generated parametric maps included K and D. The primary endpoint of the study was the DKI-predicted ORR of liver metastases, and the secondary endpoint were the DKI-predicted PFS and OS. The efficacy response was assessed by the RECIST Version 1.1 every two cycles of treatment. The association between the baseline DKI parameters, value change ratio (delta-DKI parameters = (Valuebaseline-Valuecycle1)/ Valuebaseline) and ORR and survival were examined. Results: Up to Dec 2019, one-hundred consecutively enrolled patients (65 Male, 35 Female, Age from 30-75 years old) received the treatment (FOLFOX 13, XELOX 53, FOLFIRI 34) and complete the liver functional MRI scanning. A total of 42 responding (CR+PR) and 58 nonresponding (SD+PD) patients were evaluated. Lower baseline D values (D-mean, D-std and D-median, P < 0.005), higher baseline K values (K-mean, K-median, P < 0.005), lower delta-D values (delta-D-DiffEntropy, P = 0.000) and higher delta-K value (delta-K-median, P = 0.022) were significantly associated with a higher ORR, and the combination of all the significant parameters yielded an AUC of 0.834 (sensitivity 76.19%, specificity 77.59%) in predicting the early efficacy of CLMs. Patients with higher delta-D-diffEntropy value showed a longer PFS (9.0 vs 5 mons, P = 0.002) and OS (30.5 vs 14.8 mons, P = 0.032). Conclusions: The baseline value and early parameter change in DKI might be a good predictive marker for the chemotherapeutic response of CLMs, and the early increase of D value in liver metastases could be a promising factor for survival of patients undergoing standard chemotherapy. Clinical trial information: NCT03088163 .
The role of Systemic Inflammation Score (SIS) in BRAF(V600) mutant metastatic colorectal cancer (mCRC).
Authors: Martinez Lago Nieves , Covela Rúa Marta , Brozos Elena , Fernandez Montes Ana , de La Camara Gomez Juan , Méndez Méndez Carlos , Jorge Fernández Mónica , Cousillas Castiñeira Antia ,   Galician Research Group on Digestive Tumors (GITuD)
Published: May 2020

e16051 Background: Multiple studies have reported prognostic association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLT) and albumin levels in patients (pts) with colorectal cancer. However, it is unknown the prognostic impact in patients with BRAF(V600) mutant metastatic colorectal cancer (mCRC). Methods: Observational, retrospective, multicentric study pts with BRAF V600mt mCRC treated at 9 university Spanish hospitals in NW Spain, belonging to GITuD Group. Demographic, clinic, pathological characteristics, overall survival (OS) and progression free survival (PFS) data were retrospectively collected and analyzed. We calculated a Systemic Inflammation Score (SIS) summing the number of risk factors that each patient had: albumin levels <3.6 g/dL, Hemoglobin levels <12.5, Neutrophil to Lymphocyte ratio (NLR) >3 and Platelet to lymphocyte ratio (PLR) >175. Results: We recorded data from 71 pts between November 2010 to June 2018. Median age was 62.0 years (range 31-83y), 54.9% female, 73.2% ECOG PS0-1, 49.3% right-sided, 37.3% high grade, 70.4% synchronous presentation, 64.8% primary tumor resection. Median OS was 11.9 months (m) (95% CI, 9.7-14.0 (m)). Pts with higher NLR (>3) had a significantly lower OS: 7.8 vs 13.7 (m) HR 1.934 (95% CI 1.2-3.3) p = 0.014, which was also true for pts with low Hb (<12.5g/dL): OS 9.0 vs 13.0 (m) (HR 1.767,95% CI 1.1-3.0 p = 0.035) and low albumin (<3.6 g/dL): OS 4.9 vs 12.5 (m) (HR 2.142; 95% CI 1.1-4.5, p = 0.040). Pts. with higher PLR (>175) was associated with a non-significant trend worse OS: 5.7 vs 13.5 (m) (HR 1.555; 95% CI 0.9-2.7, p = 0.102). SIS was associated with a worse prognosis: median OS 0/1/2/3/4 factors were 16.7 vs. 11.0 vs. 11.4 vs. 4.8 vs. 4.0 (m) (p = 0.006). Pts with SIS = 0 had significantly higher OS: 16.7 vs 9.0 (m) (HR 0.357; 95% CI 0.3-0.9; p = 0.027). First-line PFS was 4.4 (m) (95% CI, 3.2-5.7 months). First line PFS according type of treatment: Bev+Triplet-CT/Bev+Doublet-CT/antiEGFR+Doublet-CT/Doublet-CT: 8.0 vs 4.8 vs 2.9 vs 2.1 (m) (p = 0.091). BEV based CT was associated with a prolonged first line PFS: median 5.2 vs. 2.3 (m) (HR 0.562; 95% CI, 0.3-0.9; p = 0.033). BEV based CT was associated with prolonged first-line PFS in SIS Score 1-4: 4.8 vs. 2.3 (m) (HR 0.426; 95% CI 0.2-0.8; p = 0.009). Nevertheless, we don’t identify differences in first-line PFS in SIS Score 0: 7.0 vs 2.1 (m) (HR 0.803; 95% CI 0.3-2.5; p = 0.700). Conclusions: SIS identifies a population with a worse prognosis and subsidiary of improvement in First-line PFS with BEV based CT.
Utility of circulating tumor DNA in genomic profiling of colorectal cancer with peritoneal metastasis.
Authors: Ma Tenghui , Cao Weiguo , Huang Jin , Song Yuguang , Zhu Lingjun , Liu Lianke , Zhao Yun-Bo , Bai Jun , Liang Li , Ma Fei , Yuan Mingming , Chen Rongrong , Wang Hui 
Published: May 2020

e16057 Background: Patients (pts) with peritoneal metastatic (PM) colorectal cancer (CRC) have significantly poorer prognosis than those with other metastases. In this study, we aim to investigate genomic profiles of PM-CRC and metastatic CRC without peritoneal involvement (non-PM-CRC) and PM-CRC with other organ involvement (PM-CRC+) using circulating tumor DNA (ctDNA)-based sequencing. Methods: A total of 169 pts with metastatic CRC were enrolled irrespective of treatment history, including 53 pts with non-PM-CRC, 47 pts with PM-CRC, and 69 pts with PM-CRC+. Matched tumor-normal next-generation sequencing of 1021 cancer-related genes was performed on ctDNA and white blood cells derived from plasma samples. The differences of mutation number were examined with student t test, and the differences of mutation detection rate were examined with two tailed Fisher’s exact test. p≤0.05 was considered statistically significant. Results: Somatic mutations were identified in 96% of pts with non-PM-CRC, 77% of pts with PM-CRC, and 97% of pts with PM-CRC+. The number of somatic mutations observed in the PM-CRC cohort was significantly lower than that in the other cohorts with the median value of 2 in the PM-CRC cohort, 9 in the non-PM-CRC cohort, and 7 in the PM-CRC+ cohort (p = 0.0002 and p < 0.0001, respectively). The most frequently mutated genes in these cohorts was listed in Table. The detection rate of APC and TP53 mutations in the PM-CRC cohort was significantly lower than the other cohorts. Significant differences were also observed when comparing TCF7L2 mutations in the non-PM-CRC and the other cohorts, LRP1B mutations in the PM-CRC cohort and PM-CRC+ cohort, and NOTCH4 and PCK1 mutations in the non-PM-CRC and PM-CRC+ cohorts. In addition, BRAF mutations were more commonly observed in the PM-CRC cohort (13%) than the other cohorts (8% for non-PM-CRC cohort, 4% for PM-CRC+ cohort) (p = 0.51 and 0.16, respectively). Conclusions: Pts with PM-CRC exhibit a distinct molecular profile compared with non-PM-CRC and PM-CRC+, which may be helpful to explain their relatively poor prognosis and potentially be used in the early diagnosis of PM. [Table: see text]
The mutational landscape of the adjacent paracancerous tissues confirmed the safe margin of 2-5cm in colorectal cancer resection.
Authors: Gu Jin , Yao Jianfei , Song Lele , Huang Dandan , Gao Zhaoya , Gao Qingkun , Niu Pengfei , Zeng Qingmin , Wang Yanzhao , Wang Denglin , Liu Danni , Jing Zhang , Lei Fuming 
Published: May 2020

e16060 Background: Margin of 2-5cm is regarded as the safe margin in surgical resection of colorectal cancer (CRC) by macroscopic pathological examinations. However, whether 2-5cm is safe has never been verified by molecular evidence. Methods: We systematically analyzed the mutational profile of 35 CRC tissues and paired adjacent paracancerous tissues 2-3cm and 5cm adjacent to the cancer margin by whole-exome sequencing. Results: The number of SNV/INDEL mutations in the adjacent 2-3cm and 5cm tissues was much less than that in cancer. The number of common SNV/INDEL mutations between cancer and the adjacent tissues ranged from 0 to 2. Although TP53, APC and KRAS SNV/INDEL mutations exhibited the highest frequency in CRC, the APC SNV/INDEL mutations were observed in only one adjacent 5cm tissue, and no TP53 or KRAS SNV/INDEL mutations were observed in any adjacent tissues. We further determined the potential driver gene mutations in adjacent tissues by searching databases including COSMIC CGC, IntOGen, OncoKB, TCGA and Vogelstein databases. A certain mutation was determined as a driver gene mutation if all five databases predict it to be a driver gene mutation. As a result, 9 SNV/INDEL driver gene mutations (1 ATM, 1 BRCA1, 1 BRCA2, 1 MET, 1 NF1, 3 PTEN and 1 STAG2 mutations) were found in the adjacent 2-3cm group, and 9 SNV/INDEL driver gene mutations (1 APC, 1 ARID1A, 1 FBXW7, 3 PTEN, 2 STAG2 and 1 BRCA2 mutations) were found in the adjacent 5cm group. No common SNV/INDEL driver gene mutations were found between cancer tissues and the paired 2-3cm or 5cm tissues, suggesting the driver gene mutations predicted in adjacent normal tissues may not be cancer-relevant. Conclusions: We established the mutational landscape of the adjacent 2-3cm and 5cm tissues to CRC, and found almost no key driver gene SNV/INDEL mutations in adjacent tissues. No common SNV/INDEL driver gene mutations were found between cancer and the adjacent tissues, supporting a safe resection with a margin at 2 to 5cm.
Presence of circulating tumor cells is more significant than tumor stage in characterizing cellular local immunity in colorectal cancer.
Authors: Sitkovskaya Anastasia O. , Kit Oleg I. , Zlatnik Elena Yu. , Novikova Inna A. , Sagakyants Aleksandr B. , Ulianova Elena P. , Shulgina Oksana G. , Kolesnikov Vladimir E. , Oganyan Nairi B. , Pavlov Vladislav K. , Karasev Timofey S. , Dzhenkova Elena A. , Shaposhnikov Alexander V. , Snezhko Aleksandr V. , Tolmakh Roman E. , Fomenko Yuriy A. , Petrov Dmitry S. 
Published: May 2020

e16073 Background: The purpose of the study was a correlation analysis of parameters of local immunity and markers of the epithelial-mesenchymal transition (EMT) with the number of circulating tumor cells (CTCs) in patients with stage II-IV colorectal cancer (CRC). Methods: The study included 60 patients newly diagnosed with stage II-IV CRC. CTCs were detected with the Cell Search System (Janssen Diagnostics, LLC) prior to surgery. CTC≤3 were considered negative, CTC > 3 – positive. After surgery, IHC analysis of tumor infiltration with immune system cells was performed with monoclonal antibodies for human CD3, CD4, CD8, CD20 and CD56; expression of EMT-associated proteins (E-cadherin, N-cadherin) was measured. All patients were informed of the goal of the study and provided informed consent. Results: CTC-negative patients with later cancer stages showed the loss of connection between the local levels of CD4+ and CD8+, and in stage IV - between CD3+ and CD4+. Starting from stage III, a negative correlation was observed between the expressions of E- and N-cadherin, not associated with the studied indices of local cellular immunity. The presence of CTCs in all 3 investigated stages of CRC, apparently, causes the loss of many connections between the indicators of the 3 units of local cellular immunity. While negative correlations were revealed between T-, B- and NK-cells in CTC-negative status, in CTC+ their number decreased to 1. An important positive correlation was between local levels of CD3+ and CD8+, indicating the predominance of cytotoxic T cells in the tumor and detected at all stages in CTC-negative patients, losing significance in the presence of CTCs regardless of the stage. In stage II, the only correlation (inverse one) was observed between the parameters of local (CD4+) immunity and the expression of cadherins (E-cadherin), which probably reflected the presence of immunosuppressive and growth-stimulating Tregs fraction among these cells. Conclusions: In general, the presence of CTCs was more significant for the number and nature of interconnections of cellular parameters of the local immunity than the tumor stage.
Associations between oncogenic risk markers and clinical outcomes among black and white colorectal cancer patients.
Authors: Starks Victoria , Mitchell Edith P. 
Published: May 2020

e16078 Background: Blacks have a 25% higher incidence of colorectal cancer compared to their white societal counterparts1. Additionally, the overall mortality rate among black colorectal cancer patients is 50% higher than that of whites2. However, little is known about the biomarkers prevalent among blacks and their possible correlation to treatment response and patient outcomes. Objective: The objective of this study is to explore disease trends that may unveil a correlation between molecular markers, pathologic stage at presentation and poor clinical outcomes among black colorectal cancer patients. Methods: De-identified patient data was obtained from The Oncology Data Services Department (Cancer Registry) of TJUH. The population cohort (n = 836) included newly diagnosed colorectal cancer patients treated at TJUH from 2000-2019, & included information regarding patient race, sex, age at presentation, stage at presentation, histological code, tumor markers: KRAS, NRAS, BRAF, MS1, treatment received, surgical findings: tumor size, lymph node involvement, presence of distant metastases at first surgery, response to chemotherapy & disease-free survival. Results: Findings reveal a higher prevalence of BRAF mutations among whites compared to blacks within this population, while black patients were diagnosed later according to AJCC pathological stage at presentation. Future analysis of this cohort will further divide the population by age ( < 50, 50-65, & > 65). This facet of the study will explore relationships between age & stage at presentation among patients of different races. Conclusions: Both oncogenic risk markers and AJCC stage at presentation differ between black and white colorectal cancer patients within this population. Additional analysis regarding age at presentation will further inform us as to how these findings may contribute to the comparatively higher incidence and mortality rates among black colorectal cancer patients. Researchers should continue to explore possible etiologies for the prevalent racial disparities seen among black colorectal cancer patients.
Clinical utility of germline genetic testing after tumor genomic testing in colorectal cancer patients.
Authors: Ngo Nhu , Lincoln Stephen E , Das Kingshuk , Pineda Alvarez Daniel Esteban , Yang Shan , Michalski Scott T. , Nielsen Sarah M. , Esplin Edward D. , Nussbaum Robert Luke 
Published: May 2020

e16089 Background: Practice guidelines support genomic and biomarker testing of colorectal cancer (CRC) to inform treatment options in advanced disease and to screen for MMR deficiency/MSI/Lynch syndrome. As yet, guidelines for follow-up germline testing are not well established. In 2019 ESMO recommended reflex germline testing when pathogenic variants (PV) were found in any of 27 cancer susceptibility genes (CSG) in tumor samples (PMID 31050713). The CSGs were chosen because PV in these genes were clinically actionable and had “germline conversion rates” (GCR) of > 10% (proportion of tumor-detected PV that were germline). We examined the utility of germline testing in a cohort of CRC patients who had prior tumor sequencing. Methods: We reviewed somatic & germline PV in an unselected consecutive series of CRC patients who were referred for germline testing and had prior tumor testing. We determined the GCR for genes with pathogenic germline variants (PGV) and compared our results to ESMO data. Results: 66 of 238 (27%) patients harbored PGV. 15% of PGV were not reported in the tumor assay. High GCR for BRCA1/2 (30%), MMR genes (40%), PALB2 (57%), and BRIP1 (67%) were in keeping with ESMO. Low GCR for APC (1.4%) and TP53 (3%) were similar to ESMO, and reflective of high somatic mutation rates in these genes. We noted high GCR for CHEK2 (75%) and ATM (24%), two genes not included in ESMO guidelines due to their intermediate penetrance. Conclusions: ESMO guidelines provide a key starting point for when reflex germline testing should be pursued after tumor testing. In our study 27% (65/238) of patients had PGV that conferred potential eligibility for targeted therapy or clinical trials. For CRC, finding PV in MMR genes, BRCA1/2, and other relevant CSGs should prompt follow-up germline testing. In cases with APC PV in tumor, ESMO recommended reflex germline testing only in patients < 30 yo, where the GCR was > 10%. Our study suggests that reflex germline testing after tumor sequencing yields clinically actionable results. [Table: see text]
The effectiveness of colorectal cancer screening for cancer survivors.
Authors: Liu Chia-Jen , Lai Tzu-Yu , Yeh Chiu-Mei , Tsai Chun-Kuang , Chen Po-Min , Liu Jin-Hwang , Chiou Tzeon-Jye , Teng Chung-Jen 
Published: May 2020

e16091 Background: Colorectal cancer (CRC) is one of the highest-incident neoplasms in many countries. Although the incidence of CRC is increasing gradually, the mortality rate has not increased due to early detection and multidisciplinary treatment. CRC screening programs, including colonoscopy and fecal occult blood tests, have been reducing CRC-related mortality worldwide. In Taiwan, the CRC screening program uses a biennial fecal immunochemical test (FIT) as the initial screening tool. FIT-positive participants receive a colonoscopy as a CRC confirmation examination. Cancer survivors have a higher incidence of secondary primary malignancies. Methods: We conducted a nationwide population-based study in Taiwan. The cancer survivors with FIT in the Nationwide Colorectal Cancer Screening (NCCS) Program between January 2010 and September 2014 were enrolled as the study group. The patients aged under 50, diagnosed with CRC before the FIT were excluded. The screening participants without a cancer history were served as the comparison group. The primary endpoint was CRC diagnosis within six months after a FIT. The cancer diagnosis was identified by using Taiwan Cancer Registry. The ratios of positive FIT, confirmatory colonoscopy, and CRC diagnosis in the cancer survivors and the comparison cohort were calculated and compared. Analyses were adjusted for participants’ characteristics by using multilevel logistic regression models. Results: We identified 288,919 cancer survivors who participated in the NCCS Program. Of them, 41.1% were male and the median age was 59 (interquartile ranges 54–64). There were 417,907 FITs performed in the study cohort. The FIT positive rates were 11.3% and 7.4% in the study and comparison groups, respectively (OR 1.59 95% CI 1.57–1.60). Of the FIT positive participants, 50.5% and 52.3% received confirmatory colonoscopy or the related examinations within six months, respectively (OR 0.93 95% CI 0.91–0.95). Then 3.0% and 4.4% of those receiving confirmatory colonoscopy were diagnosed with CRC in the study and comparison groups, respectively (OR 0.68 95% CI 0.63–0.74). After adjustment for age, sex, income, a family history of CRC, and comorbidities, the cancer survivors in this screening program had a similar rate of CRC diagnosis compared with those without antecedent malignancies (adjusted OR: 0.97, 95% CI 0.87–1.08). Conclusions: Although the cancer survivors had a higher rate of positive FIT, the CRC diagnosed by the screening did not increase. We further identified the risk factors associated with CRC in the cancer survivors.
Cell-free DNA and exoDNA analysis in metastatic colorectal cancer patients (mCRC).
Authors: Galvano Antonio , Castiglia Marta , Guarini Aurelia , Gristina Valerio , Cutaia Sofia , Bazan Viviana , Russo Antonio , Carreca Ignazio UGO 
Published: May 2020

e16093 Background: Liquid biopsy is a growing field in translational cancer research. Two of the most studied liquid biopsy biomarkers are cell-free DNA (cfDNA) and exosomes, nano-sized vesicles that transport protein and nucleic acids including DNA (exoDNA). Therefore, both cfDNA and exoDNA are potentially useful to investigate the molecular landscape of tumor with a minimally invasive approach. Here we investigate the prognostic and predictive role of both cfDNA and exoDNA in mCRC using Next Generation Sequencing (NGS) analysis. Methods: From July 2017 to September 2018, samples of 40 mCRC patients were collected at the Medical Oncology of the AOUP Paolo Giaccone of Palermo. Blood samples were collected in EDTA-tubes before chemotherapy infusion (T1), at the first instrumental evaluation (T2) and every 2-3 months (T3). Plasma was used to isolate cfDNA and exosomes using the QIAamp Circulating Nucleic Acid and ExoEasy Maxi Kit respectively. ExoDNA was isolated through the QIAamp DNA micro kit. NGS analysis was conducted on IonS5 with AmpliSeq Cancer Hotspot Panel v2, which includes hotspot regions of 50 cancer-related genes. Results: Patients with cfDNA concentration > 0.47ng/μl have worse PFS compared with those with < 0.47 ng/μl cfDNA level. NGS analysis from 16 cfDNA samples showed a total of 292 mutations, with a median of 5 non-synonymous mutations in T1 vs. 8 non-synonymous mutations in T2 sample. We report an inverse and significant correlation between non-synonymous mutations count and disease-specific survival (DSS). Only 2 cfDNA samples carried KRAS mutations, despite it were previously reported in 5 paired tissue samples. An interesting result emerged from exoDNA sequencing of CRC20. KRAS mutation was identified in T1 exoDNA but not in the paired cfDNA samples, suggesting that exoDNA is able to intercept KRAS mutation earlier than cfDNA. Conclusions: cfDNA analysis could be a useful tool for better patients’ stratification. exoDNA could allow an early interception of disease recurrence that could be explained by the ability of exosomes to protect their cargo from degradation.