Bridging horizons beyond CIRCULATE-Japan: a new paradigm in molecular residual disease detection via whole genome sequencing-based circulating tumor DNA assay.

Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.

A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening.

BACKGROUND: Colorectal cancer is the third most diagnosed cancer in adults in the United States. Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality. METHODS: We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions. RESULTS: The clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3). Sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3). A total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3). Specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7). CONCLUSIONS: In an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. (Funded by Guardant Health; ECLIPSE ClinicalTrials.gov number, NCT04136002.).

CXCL5 and CXCL14, but not CXCL16 as potential biomarkers of colorectal cancer.

Experts emphasize that colorectal cancer (CRC) incidence and mortality are increasing. That is why its early detection is of the utmost importance. Patients with cancer diagnosed in earlier stages have a better prognosis and a chance for faster implementation of treatment. Consequently, it is vital to search for new parameters that could be useful in its diagnosis. Therefore, we evaluated the usefulness of CXCL5, CXCL14 and CXCL16 in serum of 115 participants (75 CRC patients and 40 healthy volunteers). Concentrations of all parameters were measured using Luminex. CRP (C-reactive protein) levels were determined by immunoturbidimetry, while levels of classical tumor markers were measured using CMIA (Chemiluminescence Microparticle Immunoassay). Concentrations of CXCL5 were statistically higher in the CRC group when compared to healthy controls. The diagnostic sensitivity, specificity, positive and negative predictive value, and area under the ROC curve (AUC) of CXCL5 and CXCL14 were higher than those of CA 19-9. Obtained results suggest the usefulness of CXCL5 and CXCL16 in the determination of distant metastases and differentiation between TNM (Tumor-Node-Metastasis) stages, as well as the usefulness of CXCL14 and CRP combination in CRC detection (primary or recurrence). However, further studies concerning their role in CRC progression are crucial to confirm and explain their diagnostic utility and clinical application as biomarkers.

Actitudes e imágenes sociales sobre el cribado de cáncer colorrectal. Una aproximación exploratoria mediante grupos de discusión / Attitudes and social images regarding colorectal cancer screening. An exploratory approach through discussion groups

Fundamentos: El programa de cribado de cáncer colorrectal (CCR) mediante el test de sangre oculta en heces (SOH) ha alcanzado una implementación elevada en España, aunque la participación sigue sin encontrarse en cifras óptimas. A su vez, los datosdisponibles ofrecen diferencias de participación significativas, tanto entre CC. AA. como entre distintos grupos sociodemográficos, loque plantea diferentes problemas de equidad. Este estudio buscó realizar un análisis exploratorio, desde una perspectiva cualitativa,sobre las actitudes, percepciones e imágenes sociales que la población objeto del cribado de cáncer colorrectal tenía sobre el mismo,así como las barreras y elementos de mejora a partir de estas. Métodos: Este estudio se diseñó mediante un enfoque de investigación cualitativa a partir de la realización de cuatro grupos dediscusión, durante el mes de mayo de 2022, a un total de veintiséis personas (igual número de hombres y mujeres) con edades decincuenta a sesenta y nueve años, residentes en la Comunidad de Madrid, Cataluña, Andalucía y País Vasco (en grandes y pequeñasciudades), con diferentes niveles formativos y distintas experiencias previas de participación en el programa de cribado de CCR. Resultados: Se detectaron distintas conceptualizaciones de la prevención, pero ninguna que englobe el cáncer (y especialmente el colorrectal) como elemento a incorporar en las prácticas cotidianas, ya que su aparición se asocia fundamentalmente al azar.Sumado al desconocimiento del CCR frente a otros tipos (mama o próstata), se percibieron diferentes barreras de carácter actitudinala la participación en un programa de cribado de CCR, como fueron el rechazo a formar parte del colectivo de más edad (diana de laprueba), el miedo a la espera por los resultados, la falta de fiabilidad o la sensación de poder postergar el momento...(AU)

Backgorund: The screening for colorectal cancer (CRC) through the fecal occult blood test (FOBT) has achieved high implementation in Spain, although participation rates are still not optimal. At the same time, available data show significant differencesin participation both among autonomous communities and among different sociodemographic groups, which raises various equityissues. This study aimed to conduct an exploratory analysis from a qualitative perspective on the attitudes, perceptions, and socialimages that the target population for colorectal cancer screenings holded regarding them, as well as the barriers and areas forimprovement identified through these. Methods: This study was designed using a qualitative research approach, through the conduct of four focus groups in May 2022, witha total of twenty-six participants (equal number of men and women) aged fifty to sixty-nine years. The participants were residents of theCommunity of Madrid, Catalonia, Andalusia, and the Basque Country (in both large and small cities), with varying educational levels anddifferent previous experiences of participation in the CRC screening program. Results: Different conceptualizations of prevention were identified, but none that encompassed cancer (especially colorectalcancer) as an element to be incorporated into daily practices since its occurrence is primarily associated with chance. In addition tothe lack of knowledge about CRC compared to other types of cancer (such as breast or prostate cancer), various attitudinal barriersto participation in the CRC screening program were perceived. These included the rejection of being part of the older age group(targeted by the test), fear of waiting for the results, lack of reliability, or the sense of being able to postpone the moment...(AU)

Systematic analyzing a five- miRNA panel and its diagnostic value of plasma expression in colorectal cancer.

BACKGROUND: Aberrant expression of miRNAs have been implicated in cancers, but the role of miRNAs in colorectal cancer (CRC) remains need to be elucidated. This study aimed to identify miRNAs that related to colorectal cancer (CRC) pathogenesis and determine the diagnostic value. METHODS: Three GEO datasets (GSE128449, GSE35602 and GSE49246) with 131 samples were used to screen miRNAs that differential expression between tumor and control tissues. The expression of the identified miRNAs was validated in 50 clinical tissue samples and the GSE35834 dataset. The clinical significance of these miRNAs was analyzed in the TCGA dataset and clinical tissue samples. The expression of miRNAs in tissues and plasma samples were tested by RT-PCR assay in clinical samples, and their diagnostic value was determined. RESULTS: The analysis of three GEO datasets revealed that miR-595 and miR-1237 were upregulated, while miR-126, miR-139, and miR-143 were downregulated in CRC tissues compared to control tissues. The differential expression of the five miRNAs in CRC tissues was confirmed using clinical tissue samples and GEO databases. There was no significant correlation between the TNM stage and tumor stage of CRC and any of the five miRNAs. Plasma expression of the miRNAs differed significantly between CRC and non-cancer patients, and each miRNA had moderate diagnostic value for CRC. Combining the five miRNAs provided better diagnostic potential for CRC than a single miRNA. CONCLUSIONS: This study demonstrated that five miRNAs were related to the pathogenesis of CRC, but independent of the stage of CRC; Plasma expression of these miRNAs have moderate diagnostic value, and combination of these miRNAs showed better diagnostic ability in CRC.

The role of heavy metals in the development of colorectal cancer.

OBJECTIVE: To investigate the relationship among 18 heavy metals, microsatellite instability (MSI) status, ERCC1, XRCC1 (rs25487), BRAF V600E and 5 tumor markers and their role in the development of colorectal cancer (CRC). METHODS: A total of 101 CRC patients and 60 healthy controls were recruited in the present study. The levels of 18 heavy metals were measured by ICP-MS. MSI status and the genetic polymorphism were determined by PCR (FP205-02, Tiangen Biochemical Technology Co., Ltd., Beijing, China) and Sanger sequencing. Spearman's rank correlation was used to analyze the relationship among various factors. RESULTS: The level of selenium (Se) was lower in the CRC group compared with the control group (p < 0.01), while vanadium (V), arsenic (As), tin (Sn), barium (Ba) and lead (Pb) were higher (p < 0.05), chromium (Cr) and copper (Cu) were significantly higher (p < 0.0001) in the CRC group than those in the control group. Multivariate logistic regression analysis indicated that Cr, Cu, As and Ba were the risk factors for CRC. In addition, CRC was positively correlated with V, Cr, Cu, As, Sn, Ba and Pb, but negatively correlated with Se. MSI was positively correlated with BRAF V600E, but negatively correlated with ERCC1. BRAF V600E was positively correlated with antimony (Sb), thallium (Tl), CA19-9, NSE, AFP and CK19. XRCC1 (rs25487) was found to be positively correlated with Se but negatively correlated with Co. The levels of Sb and Tl were significantly higher in the BRAF V600E positive group compared to the negative group. The mRNA expression level of ERCC1 was significantly higher (P = 0.035) in MSS compared to MSI. And there was a significant correlation between XRCC1 (rs25487) polymorphism and MSI status (P<0.05). CONCLUSION: The results showed that low level of Se and high levels of V, As, Sn, Ba, Pb, Cr, and Cu increased the risk of CRC. Sb and Tl may cause BRAF V600E mutations, leading to MSI. XRCC1 (rs25487) was positively correlated with Se but negatively correlated with Co. The expression of ERCC1 may be related to MSS, while the XRCC1 (rs25487) polymorphism is related to MSI.

Anesthetic­specific lncRNA and mRNA profile changes in blood during colorectal cancer resection: A prospective, matched­case pilot study.

Prometastatic and antitumor effects of different anesthetics have been previously analyzed in several studies with conflicting results. Thus, the underlying perioperative molecular mechanisms mediated by anesthetics potentially affecting tumor phenotype and metastasis remain unclear. It was hypothesized that anesthetic­specific long non­coding RNA (lncRNA) expression changes are induced in the blood circulation and play a crucial role in tumor outcome. In the present study, high­throughput sequencing and quantitative PCR were performed in order to identify lncRNA and mRNA expression changes affected by two therapeutic regimes, total intravenous anesthesia (TIVA) and volatile anesthetic gas (VAG) in patients undergoing colorectal cancer (CRC) resection. Total blood RNA was isolated prior to and following resection and characterized using RNA sequencing. mRNA­lncRNA interactions and their roles in cancer­related signaling of differentially expressed lncRNAs were identified using bioinformatics analyses. The comparison of these two time points revealed 35 differentially expressed lncRNAs in the TIVA­group, and 25 in the VAG­group, whereas eight were shared by both groups. Two lncRNAs in the TIVA­group, and 23 in the VAG­group of in silico identified target­mRNAs were confirmed as differentially regulated in the NGS dataset of the present study. Pathway analysis was performed and cancer relevant canonical pathways for TIVA were identified. Target­mRNA analysis of VAG revealed a markedly worsened immunological response against cancer. In this proof­of­concept study, anesthesic­specific expression changes in lncRNA and mRNA profiles in blood were successfully identified. Moreover, the data of the present study provide the first evidence that anesthesia­induced lncRNA pattern changes may contribute further in the observed differences in CRC outcome following tumor resection.

Comparison between Clinical Utility of CXCL-8 and Clinical Practice Tumor Markers for Colorectal Cancer Diagnosis.

Owing to the high incidence and mortality rates of colorectal cancer (CRC), novel biomarkers for CRC diagnosis are critically needed. Therefore, this study is aimed at exploring the clinical utility of serum C-X-C motif chemokine 8 (CXCL-8) for CRC diagnosis and progression compared to the routinely used biomarkers, carcinoembryonic antigen (CEA), and carbohydrate antigen-19-9 (CA19-9). This study included 227 patients with CRC, 110 patients with colorectal adenoma (CA), and 123 healthy participants, who were recruited from the Fujian Medical University Union Hospital from July 1, 2019 to October 31, 2020. Serum concentrations of CXCL-8, CEA, and CA19-9 were detected using enzyme-linked immunosorbent assay and chemiluminescent microparticle immunoassay. Clinicopathological features of patients with CRC were collected and analyzed. The diagnostic efficacy of CXCL-8, CEA, and CA19-9 for CRC was evaluated using receiver operating characteristic (ROC) curves. We found that the serum concentrations of CXCL-8, CEA, and CA19-9 were significantly higher in patients with CRC than those in patients with CA and healthy controls. The diagnostic sensitivity of CXCL-8 alone was higher than those of CEA and CA19-9 both and when combined; thus, CXCL-8 may be better at discriminating patients with CRC from healthy controls and patients with CA. Moreover, combining CXCL-8 with CEA or CA19-9 improved their respective diagnostic performances in distinguishing patients with CRC from CA patients and healthy participants. Notably, we also found that serum concentrations of CXCL-8 were positively correlated with metastases and tumor size. Therefore, our study suggests that serum CXCL-8 may serve as an improved biomarker for CRC diagnosis compared to the traditional tumor markers CEA and CA19-9. Moreover, our findings indicate the potential efficacy of serum CXCL-8 levels as a CRC prognostic biomarker.

Expression Levels and Clinical Significance of Serum miR-497, CEA, CA24-2, and HBsAg in Patients with Colorectal Cancer.

The objective of the current study was to look at the levels of blood micro ribonucleic acid- (miR-) 497, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 24-2, and hepatitis B surface antigen (HBsAg) in patients with colorectal cancer (CRC), as well as the clinical importance of these markers in CRC patients. The serum levels of miR-497, CEA, CA24-2, and HBsAg were compared between 60 patients with CRC (observation group) and another 60 patients with colorectal polyps (control group). The 4 indicators in patients with lymph node metastasis and liver metastasis were compared. The diagnostic effects of 4 detection methods and the combined detection were analyzed, and the influence of 4 indicators on the 5-year cumulative survival rate of patients was discussed. The results showed that the serum levels of miR-497 and HBsAg were lower, and the levels of CEA and CA24-2 were higher in the observation group (P < 0.05). The combined detection had the best diagnostic effect, and CEA alone had the best prediction effect. The serum level of miR-497 was significantly lower in patients with lymphatic metastasis, with the significantly higher levels of CEA and CA24-2 (P < 0.05). The HBsAg level of patients with liver metastases was greatly lower than that of patients without liver metastases (P < 0.05). The 5-year cumulative survival rate of patients with high levels of CEA and CA24-2 was significantly lower than that of patients with low level of CEA. The 5-year cumulative survival rate was lower in patients with low level of HBsAg, but the difference was small. The 5-year cumulative survival rate of patients with elevated serum miR-497 was observably lower. In conclusion, combined detection could diagnose CRC more accurately. Serum miR-497, CEA, and CA24-2 were important in the diagnosis of lymph node metastasis of CRC. HBsAg did a better job of predicting liver metastases in CRC patients. High level of CEA significantly reduced the cumulative survival rate of CRC patients and could predict the long-term survival rate of patients. Serum levels of miR-497, CEA, CA24-2, and HBsAg played a positive role in the diagnosis and evaluation of CRC and could identify lymph node and liver metastases, having a high clinical guidance value.

Irinotecan dose reduction in metastatic colorectal cancer patients with homozygous UGT1A1*28 polymorphism: a single-center case series.

OBJECTIVE: The UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity, which may increase the risk of severe toxicity in patients who receive standard-dose irinotecan, such as severe neutropenia and diarrhea. This real-world study assessed the optimal irinotecan dose in terms of efficacy and toxicity in metastatic colorectal cancer (mCRC) patients homozygous for the UGT1A1*28 polymorphism and receiving FOLFIRI plus bevacizumab or cetuximab as first-line therapy. METHODS: We analyzed toxicity and treatment outcomes in seven mCRC patients who were homozygous for UGT1A1*28 and received FOLFIRI plus bevacizumab or cetuximab, with an initial irinotecan dose of 120 mg/m2. RESULTS: Six of the seven patients tolerated 120 mg/m2 irinotecan without requiring dose reductions in subsequent cycles. The overall response and disease control rates were 43.0% (3/7) and 71.4% (5/7), respectively. The median progression-free survival and overall survival were 11.0 and 33.0 months, respectively. Only one severe adverse event, grade III neutropenia (2.5%), was observed. CONCLUSIONS: mCRC patients homozygous for the UGT1A1*28 allele can tolerate irinotecan at an initial dose of 120 mg/m2 with favorable oncological outcomes and toxicity profiles. Further prospective studies are warranted to optimize irinotecan-based chemotherapy in these patients.

The Level of LINE-1 mRNA Is Increased in Extracellular Circulating Plasma RNA in Patients with Colorectal Cancer.

We performed a comparative quantitative analysis of LINE-1 mRNA levels in extracellular total plasma RNA in patients with colon cancer and practically healthy donors. Quantitative multiplex PCR with reverse transcription was used to assess the level of LINE-1 and 18S rRNA mRNA in extracellular total plasma RNA. The median of LINE-1 mRNA values in colon cancer patients (4.95) was significantly higher than in healthy donors (2.3) (p=0.037). It was shown for the first time that the level of LINE-1 mRNA in total RNA from blood plasma can be determined in the format of a liquid biopsy and serve as a new potential non-invasive marker of colon cancer.

Modified Shenlingbaizhu Decoction represses the pluripotency of colorectal cancer stem cells by inhibiting TGF-ß mediated EMT program.

BACKGROUND: The Modified Shenlingbaizhu Decoction (MSD) utilizes various phytomedicines has been applied to treat colorectal cancer (CRC). Colorectal cancer stem cells (CSCs) have proven to be tightly associated with CRC progression and metastasis. The mechanism of MSD's inhibitory effect on CSCs has not been determined. PURPOSE: To figure out how MSD inhibits the pluripotency of CSCs and impedes the EMT program. METHODS: The ingredients of MSD extracts were characterized by high-performance liquid chromatography (HPLC). BALB/c-nu mice were transplanted into EGFP labeled SW480 CRC cells and the tumor weight and volume were recorded before and after various doses of MSD treatment. The concentration of TGF-ß1 was quantified with an Enzyme-linked immunosorbent assay. To delineate the logical relationship between EMT and CSCs regulated by MSD, TGF-ß/Smad inhibitor and activator were adopted in tumor-bearing mice and diverse CRC cell lines. Cancer stem cell markers were analyzed by flow cytometry. In vitro analysis of cell motility and viability were done using CCK-8, wound healing, and invasion assay. Immunohistochemistry (IHC) and western blotting (WB) were used for detecting protein expression. The collected results were statistically analyzed with GraphPad Prism 8.0. RESULTS: MSD treatment significantly reduced the size of colorectal cancer tumors and lowered the serum content of TGF-ß1 in mice. Importantly, MSD markedly reduced the expression of pluripotent factors and depressed CD133+ stem cells in the tumor tissues. The TGF-ß/Smad inhibitor neutralized the EMT signaling and lowered the pluripotency by dephosphorylation of SMAD2/3. Similarly, MSD attenuated the pluripotency by limiting TGF-ß/Smad signaling-induced EMT in vivo. MSD inhibited colorectal cancer cell proliferation, migration, and invasion. CONCLUSIONS: MSD inhibits the growth of colorectal cancer. It dampens the pluripotency of CSCs by repressing the TGF-ß-induced EMT program.

Potential roles of serum ATPase and AMPase in predicting diagnosis of colorectal cancer patients.

Colorectal cancer (CRC) is a common gastrointestinal cancer with high incidence and mortality rates. CRC may be associated with regulation of circulating nucleotides. This study aimed to evaluate the serum levels of nucleotide-metabolizing enzymes (ATPase and AMPase) in patients with CRC and to explore the clinical diagnostic value of these enzymes. The gene set variation analysis (GSVA) score of the ATP-adenosine signature was calculated using tumor samples from The Cancer Genome Atlas (TCGA). ATP-adenosine signaling plays a central role in CRC progression. A total of 135 subjects, including 87 patients with CRC and 48 healthy controls, were included. The serum levels of ATPase and AMPase in the CRC group were significantly higher than those in the control group (P < 0.05). Furthermore, ATP and AMP hydrolysis levels significantly increased in the advanced CRC group (P < 0.05). ATP and AMP hydrolysis was decreased by the ENTPDase inhibitors (POM-1 and ARL67156) and CD73 inhibitor (APCP). The sensitivities of ATPase and AMPase were 95.4% and 75.9%, respectively, which were higher than those of CEA (67.8%) and CA19-9 (72.4%). The specificities of ATPase and AMPase were 69.9% and 73.9%, respectively, which were higher than that of CA19-9 (47.8%). The combination of CEA, ATPase, and AMPase demonstrated high sensitivity (92.0%) and specificity (87.0%). Collectively, ATPase and AMPase activities are upregulated in CRC with considerable diagnostic significance. The combination of CEA, ATPase, and AMPase may provide a novel approach for CRC screening.

Combination of serum CST4 and DR-70 contributes to early diagnosis of colorectal cancer.

BACKGROUND: Early diagnosis is of great significance for the prognosis of colorectal cancer (CRC) patients. Either serum cystatin S (CST4) or DR-70 has been demonstrated to play an important role on the diagnosis for CRC, however, the diagnostic performances of individual and combined detection of serum CST4 and DR-70 for the patients with CRC at early stage have still not been clarified up to now. METHODS: The performances of CST4 and DR-70 were evaluated by ELISA for the early diagnosis of CRC with 288 retrospective serum samples. A training set comprised of 64 patients with early CRC, 64 patients with colorectal benign lesions (CBL), and 64 healthy controls (HC) was used to develop the predictive model for early CRC. And then, data obtained from an independent validation set was applied to evaluate and validate the predictive model. RESULTS: In the training set, the levels of CST4 and DR-70 in early CRC group were significantly higher than that in CBL group/HC group (P < 0.001); serum CST4 presented the AUC of 0.927 for early CRC patients, with 57.8% sensitivity at 95.3% specificity; serum DR-70 presented the AUC of 0.725 for early CRC patients, with 29.7% sensitivity at 95.3% specificity; combination of serum CST4 and DR-70 presented the AUC of 0.941, with 68.8% sensitivity at 93.8% specificity. Additionally, the combination of serum CST4 and DR-70 showed the AUC of 0.940 for early CRC patients, with 71.9 % sensitivity at 89.1% specificity in the validation set. CONCLUSIONS: Both serum CST4 and DR-70 present the diagnostic value for the patients with early CRC, and the combination of CST4 and DR-70 contributes to the further improvement of the early diagnosis for CRC.

Association between long noncoding RNA rs944289 and rs7990916 polymorphisms and the risk of colorectal cancer in a Chinese population.

Long non-coding RNAs (LncRNAs) play vital roles in the tumorigenesis of many cancers. Single nucleotide polymorphisms (SNPs) of the lncRNA also play vital roles in tumorigenesis. We explored lncRNA rs944289 and rs7990916 polymorphisms and analyzed the relationship between these lncRNA polymorphisms with the colorectal cancer (CRC) risk in a Chinese population. We recruited 1003 CRC patients from the Affiliated People's Hospital of Jiangsu University and the Fujian Medical University Union Hospital from October 2014 to August 2017. Genomic DNA was extracted using a DNA Kit from lymphocytes of peripheral blood and the genotyping was performed with a SNPscan method. We found that the rs944289 TT homozygote was associated with the decreased CRC risk in the overall population. LncRNA rs944289 TT decreased the CRC risk in the subgroup of female, male, age ≥ 61, without alcohol intake, smoking and BMI ≥ 24 by logistic regression. The subgroup analysis revealed that lncRNA rs7990916 was not associated with CRC risk except for age < 61. Logistic regression analysis revealed that lncRNA rs944289 TT homozygote was associated with the increased risk of rectum cancer (TT vs. CC + CT: adjusted OR = 1.29, 95% CI 1.10-1.66, P = 0.041) or colon cancer. In summary, we proved that lncRNA rs944289 might be significantly related to the decreased CRC risk in the Chinese Han populations and lncRNA rs7990916 was not associated with the CRC risk except for patients of age < 61. In the future, studies with larger samples should be conducted to validate our results.

Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer.

Immune checkpoint inhibitors have shown great promise in treating patients with mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). Although single-agent pembrolizumab has been approved for first-line treatment of dMMR/MSI-H metastatic CRC, combination therapy with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibition (ipilimumab/nivolumab) has reported higher response rates. It is unclear whether patients who progress on PD-1 inhibition will respond to CTLA-4 blockade. Here, we report a case series of three patients with dMMR/MSI-H mCRC, where a durable and ongoing response to nivolumab with ipilimumab was achieved after initial progression with pembrolizumab monotherapy. Blood-based biomarkers such as carcinoembryonic antigen and CA 19-9 were employed to assess treatment response and monitor disease progression along with circulating tumor DNA (ctDNA). Our findings indicate ctDNA's potential to accurately monitor response to therapy and detect disease progression, as validated by standard imaging. This case series demonstrates that CTLA-4 rescue is worthy of additional investigation as a treatment strategy after progression on PD-1 blockade in patients with dMMR/MSI-high mCRC. Our data support the utilization and expansion of clinical studies with combination therapies and using ctDNA kinetics as early dynamic marker for therapy response assessment.

Colorimetric immunosensor constructed using 2D metal-organic framework nanosheets as enzyme mimics for the detection of protein biomarkers.

The simple and sensitive detection of protein is of great significance in biological research and medical diagnosis. However, the commonly-used methods, such as enzyme-linked immunosorbent assay (ELISA), usually rely on signal tags labeled on the antibody, which limits the sensitivity and stability. Herein, we have designed and constructed a colorimetric immunosensor in this work for the analysis of protein by taking advantage of 2D metal-organic framework (2D-MOF) nanomaterials as enzyme mimics. The nanomaterial shows a strong peroxidase mimetic activity, and good selectivity after it is modified with a specific aptamer. Therefore, taking carcinoembryonic antigen (CEA) as an example, this immunosensor achieves a good detection performance with a linear range from 1 pg mL-1 to 1000 ng mL-1 and a limit of detection (LOD) of 0.742 pg mL-1. Moreover, the sensor can successfully distinguish the human serum of colorectal cancer patients from healthy people, which suggests that this sensor has great potential in clinical applications. More importantly, the mass production, low cost, stability and ease of transport of the MOFs nanomaterials, as well as the ability for visual detection will make this sensor suitable for point-of-care (POC) testing in remote or resource-poor areas.

AGA Clinical Practice Update on Approach to the Use of Noninvasive Colorectal Cancer Screening Options: Commentary.

The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update Commentary is to review the available evidence and provide expert advice regarding the approach to using noninvasive colorectal cancer (CRC) screening options, including evidence for their effectiveness, selection of individuals for whom these tests are appropriate, implications of a positive non-colonoscopy screening test, and opportunities to enhance the quality of noninvasive CRC screening programs. This Clinical Practice Update was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. This expert commentary reflects recently published studies in this field, as well as the experiences of the authors who are gastroenterologists with high-level expertise in CRC screening and prevention.

Circulating Cell Free DNA Integrity Index as a Biomarker for Response to Chemotherapy in Patients with Metastatic Colorectal Carcinoma.

OBJECTIVE: Assessing plasma Cell Free DNA (cfDNA) integrity index as a biomarker for response prediction and early response evaluation in mCRC patients receiving chemotherapy, in comparison to Carcinoembryonic antigen (CEA) and Carbohydrate antigen 19-9 (CA19-9), to be used as an additional tool to computed tomography (CT). METHODS: CEA, CA19-9, cfDNA concentration and cfDNA integrity index (ALU 247/115) measurements were conducted on 86 subjects divided into 43 healthy volunteers and 43 mCRC patients, before starting chemotherapy and then after 6-12 weeks of therapy initiation (3-4 cycles FOLFOX) at first response assessment. Plasma cfDNA integrity index was calculated as the ratio of long to short DNA fragments (ALU 247/115) amplified and detected by real-time PCR. Serum CEA and CA19-9 were measured by chemiluminescent immunometric assay. RESULTS: Baseline cfDNA integrity index was statistically significantly different between responders and non-responders (p=0.03). It was found that at cut off 0.608, sensitivity was 73.7%, specificity was 66.7% and diagnostic accuracy=69.77%. Markers with statistical significant difference between responders and non-responders after chemotherapy were CEA % change (p=0.035), CA19-9 (p=0.024), cfDNA integrity index (p=0.035) and cfDNA integrity index % change (p<0.001). Among these markers, cfDNA integrity index % change had the best sensitivity (84.2%), specificity (95.2%) and diagnostic accuracy (90.7%) at cut off -17.827%. CONCLUSION: Baseline cfDNA integrity index can be used as a potential marker to predict response to chemotherapy. cfDNA integrity index (ALU 247/115) % change rather than its absolute value is superior to CEA, CA19-9, cfDNA concentration and their % changes in early assessment of response to chemotherapy.