Could Preoperative Unintended Weight Loss Predispose to Postoperative Thrombosis in Patients Undergoing Colorectal Cancer Surgery? An Analysis of the NSQIP Data.

Objective: A significant portion of colorectal cancer patients lose weight preoperatively. Here we examine the influence of pre-operative significant weight loss on venous thromboembolism (VTE) risk and determine whether pre-operative BMI and albumin could influence VTE outcomes in patients who have lost significant weight prior to surgery.Methods: We conducted a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and identified 103,455 colorectal cancer patients undergoing major surgery from 2008 to 2012. Patients were assigned to one of two groups based on whether they lost significant weight preoperatively or not. Simple and stepwise multiple logistic regressions were used to evaluate the association between pre-operative unintended weight loss and 30-days postoperative outcomes. The association between weight loss and postoperative thrombosis was further assessed across several strata.Results: The overall prevalence of pre-operative significant weight loss was 6.8%. Significant weight loss prior to surgery was significantly and independently associated with a higher risk of VTE (adjusted OR 1.23, 95% CI 1.06-1.44), mortality (adjusted OR 1.55, 95% CI 1.35-1.78), composite morbidity (adjusted OR 1.52, 95% CI 1.42-1.62), bleeding (adjusted OR 1.78, 95% CI 1.67-1.91) and return to operation room (adjusted OR 1.29, 95% CI 1.16-1.42). The effect of pre-operative significant weight loss on thromboembolic outcome was evident across patients with a BMI <18.5 kg/m2, 18.5 < BMI < 24.99 and BMI >40kg/m2.Conclusions: Significant weight loss and BMI both need to be measured preoperatively to stratify patients who are at a higher risk of VTE.

Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome.

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.

A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer.

Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.

The Crosstalk between Microbiome and Immune Response in Gastric Cancer.

Gastric cancer is the end result of a complex interplay between host genetics, environmental factors, and microbial factors. The link between gut microbiome and gastric cancer has been attributed to persistent activation of the host's immune system by gut microbiota. The end result of this dysregulated interaction between host epithelium and microbes is a state of chronic inflammation. Gut bacteria can promote anti-tumor immune responses through several mechanisms. These include triggering T-cell responses to bacterial antigens that can cross-react with tumor antigens or cause tumor-specific antigen recognition; engagement of pattern recognition receptors that mediate pro-immune or anti-inflammatory effects or via small metabolites that mediate systemic effects on the host. Here we review the role of the gut microbiome including H. pylori and non-H. pylori gastric bacteria, the immune response, and immunotherapy using checkpoint inhibitors. We also review the evidence for cross talk between the gut microbiome and immune response in gastric cancer.

Exosomal Non Coding RNA in LIQUID Biopsies as a Promising Biomarker for Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with a high mortality rate, especially in those that are diagnosed in late stages of the disease. The current screening blood-based markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), have low sensitivity and specificity. Meanwhile, other modalities are either expensive or invasive. Therefore, recent research has shifted towards a minimally invasive test, namely, liquid biopsy. Exosomes are favorable molecules sought in blood samples, since they are abundant, stable in circulation, and harbor genetic information and other biomolecules that could serve as biomarkers or even therapeutic targets. Furthermore, exosomal noncoding RNAs, such as miRNAs, lncRNAs, and circRNAs, have demonstrated the diagnostic potential to detect CRC at an early stage with a higher sensitivity and specificity than CEA and CA19-9 alone. Moreover, they have prognostic potential that is TNM stage specific and could serve as predictive biomarkers for the most common chemotherapeutic drug and combination regimen in CRC, which are 5-FU and FOLFOX, respectively. Therefore, in this review, we focus on the role of these exosomal noncoding RNAs as diagnostic, prognostic, and predictive biomarkers. In addition, we discuss the advantages and challenges of exosomes as a liquid biopsy target.

Antitumor efficacy of arsenic/interferon in preclinical models of chronic myeloid leukemia resistant to tyrosine kinase inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the standard treatment for chronic myeloid leukemia (CML). Despite their clinical success, TKIs are faced with challenges such as treatment resistance, which may be driven by kinase domain mutations, and frequent disease relapse upon the cessation of treatment. The combination of arsenic trioxide (ATO) and interferon-α (IFN) was previously demonstrated to inhibit proliferation and induce apoptosis in CML cell lines, prolong the survival of primary wild-type CML mice, and dramatically decrease the activity of leukemia-initiating cells (LICs). METHODS: The ATO/IFN combination was tested in vitro on imatinib (IMN)-resistant K562-R and Ar230-R cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays were used to evaluate proliferation and apoptosis, respectively. The acridine orange assay was used to assess autophagy, and quantitative reverse transcription-polymerase chain reaction was used to assess the involvement of the hedgehog (Hh) pathway. In vivo, a retroviral transduction/transplantation T315I BCR-ABL CML mouse model was used to assay the effect of the treatment on survival, tumor burden (histopathology and blood counts), and LIC activity (secondary transplantation). RESULTS: In vitro, ATO/IFN synergized to inhibit proliferation and induce apoptosis of IMN-resistant cells with variant modes of resistance. Furthermore, the preclinical effects of ATO/IFN were associated with induction of autophagy along with inhibition of the Hh pathway. Most remarkably, ATO/IFN significantly prolonged the survival of primary T315I-CML mice and displayed a dramatic impairment of disease engraftment in secondary mice, which reflected decreased LIC activity. CONCLUSIONS: Collectively, the ATO/IFN strategy has been demonstrated to have the potential to lead to durable remissions in TKI-resistant CML preclinical models and to overcome various TKI-specific mechanisms of resistance.

Cross-Roads to Drug Resistance and Metastasis in Breast Cancer: miRNAs Regulatory Function and Biomarker Capability.

Breast cancer and specifically metastatic breast cancer (mBC) constitutes a major health burden worldwide with the highest number of cancer-related mortality among women across the globe. Despite having similar subtypes, breast cancer patients present with a spectrum of aggressiveness and responsiveness to therapy due to cancer heterogeneity. Drug resistance and metastasis contribute to therapy failure and cancer recurrence. Research in the past two decades has focused on microRNAs (miRNAs), small endogenous non-coding RNAs, as active players in tumorigenesis, therapy resistance and metastasis and as novel non-invasive cancer biomarkers. This is due to their unique dysregulated signatures throughout tumor progression and their tumor suppressive/oncogenic roles. Identifying miRNAs signatures capable of predicting therapy response and metastatic onset in breast cancer patients might improve prognosis and offer prolonged median and relapse-free survival rate. Despite the growing reports on miRNAs as novel non-invasive biomarkers in breast cancer and as regulators of breast cancer drug resistance or metastasis, the quest on whether some miRNAs are capable of regulating both simultaneously is inevitable, yet understudied. This chapter will review the role of miRNAs as biomarkers and as active players in inducing/reversing anti-cancer drug resistance, driving/blocking metastasis or regulating both simultaneously in breast cancer.

Gut Microbiome: A Promising Biomarker for Immunotherapy in Colorectal Cancer.

Research has been driven towards finding therapy predictive biomarkers for colorectal cancer (CRC) with a special interest in studying the gut microbiome. Gut microbiome acts not only as a barrier to prevent bacterial invasion and infection, but it also affects the efficacy of hematopoietic-cell transplantation, chemotherapy, and immunotherapy. Recently, immunotherapy, which potentiates the host immune system, has revolutionized cancer therapy in general and CRC treatment specifically by increasing the quality of life and the survival of a subset of patients with this disease. In immunotherapy, the gut microbiome plays an important role in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade, programmed cell death protein 1 (PD-L1) mediation, and T cell stimulation. As such, this review will cover the role of gut microbiome in CRC, summarize approved immunotherapy treatments for CRC, and focus on the potential use of gut microbiome as a biomarker for immunotherapy.

Inflammatory Markers and MicroRNAs: The Backstage Actors Influencing Prognosis in Colorectal Cancer Patients.

BACKGROUND: Colorectal cancer (CRC) remains a deadly disease, afflicting the lives of millions worldwide. The prognosis of CRC patients is best predicted by surgical resection and pathological analysis of specimens. Emerging evidence has attributed a significant role to inflammatory markers and microRNAs (miRNAs) in the prognosis and survival of CRC patients. AIM: Here, we review the literature on inflammatory markers and miRNAs with an established role on survival rates, response to systemic chemotherapy, and other clinic-pathological parameters in CRC patients. RESULTS: Our literature review revealed a critical role of inflammatory markers­specifically, the acute-phase proteins, inflammatory cytokines, and blood cell ratios­on prognostic outcomes in CRC patients. MiRNAs, on the other hand, were useful in predicting prognosis and clinical response and accordingly stratifying CRC patients for optimal drug selection. CONCLUSION: These biomarkers are easily measured in routine blood exams and can be used in adjunct to the tumor-node-metastasis (TNM) staging system to identify high-risk patients and those who are more likely to benefit from chemotherapy and other targeted therapies. However, more prospective studies are needed for the validation of these discussed prognostic and predictive biomarkers.

Ascorbic Acid in Colon Cancer: From the Basic to the Clinical Applications.

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type RAS. We perform a PubMed and Ovid MEDLINE search using ascorbic acid, intravenous vitamin C, KRAS mutation, BRAF mutation and colorectal cancer (CRC) as keywords. At the cellular level, colorectal cancer cells undergo a metabolic shift called the Warburg effect to allow for more glucose absorption and utilization of glycolysis. This shift also allows AA to enter which leads to a disruption in the Warburg effect and a shutdown of the downstream KRAS pathway in mutated KRAS colon cancer cells. At the clinical level, AA is associated with tumour regression in advanced disease and improved tolerability and side effects of standard therapy. Based on these findings, we conclude that further clinical trials are needed on a larger scale to examine the therapeutic benefits of AA in colon cancer.

ATL-derived exosomes modulate mesenchymal stem cells: potential role in leukemia progression.

BACKGROUND: Exosomes are membrane nano-vesicles secreted by a multitude of cells that harbor biological constituents such as proteins, lipids, mRNA and microRNA. Exosomes can potentially transfer their cargo to other cells, implicating them in many patho-physiological processes. Mesenchymal stem cells (MSCs), residents of the bone marrow and metastatic niches, potentially interact with cancer cells and/or their derived exosomes. In this study, we investigated whether exosomes derived from adult T-cell leukemia/lymphoma (ATL) cells act as intercellular messengers delivering leukemia-related genes that modulate the properties of human MSCs in favor of leukemia. We hypothesized that the cargo of ATL-derived exosomes is transferred to MSCs and alter their functional behavior to support the establishment of the appropriate microenvironment for leukemia. RESULTS: We showed that both ATL cells (C81 and HuT-102) and patient-derived cells released Tax-containing exosomes. The cargo of HuT-102-derived exosomes consisted of miR-21, miR-155 and vascular endothelial growth factor. We demonstrated that HuT-102-derived exosomes not only deliver Tax to recipient MSCs, but also induce NF-κB activation leading to a change in cellular morphology, increase in proliferation and the induction of gene expression of migration and angiogenic markers. CONCLUSIONS: This study demonstrates that ATL-derived exosomes deliver Tax and other leukemia-related genes to MSCs and alter their properties to presumably create a more conducive milieu for leukemia. These findings highlight the contribution of leukemia-derived exosomes in cellular transformation and their potential value as biomarkers and targets in therapeutic strategies.

CIRCULATING microRNAs: POTENTIAL BIOMARKERS IN CANCER DETECTION, DIAGNOSIS AND PROGNOSIS.

A large family of small 18-25 nucleotide long non coding RNA molecules now known as microRNA (miRNA) was described two decades ago, and has been recently es- tablished as post-transcriptional gene regulators. miRNAs were shown to be involved in the regulation of diverse phys- iological and developmental processes. Moreover, dysregula- tion of specific miRNAs has been implicated later in several pathologies including cancer. Owing to their presence and stability in body fluids, miRNAs have been investigated as novel circulating non-invasive biomarkers. Accordingly, their role as potential diagnostic, prognostic or predictive biomark- ers for many cancer types has recently emerged. This review tackles the use of circulating miRNAs in cancer detection, diagnosis and prognosis, giving examples using common solid tumors and discussing the advantages of their use, the challenges facing this novel circulating biomarker and recorn- mendatidns to overcome them.

Effects of subinhibitory concentrations of antimicrobial agents on Escherichia coli O157:H7 Shiga toxin release and role of the SOS response.

Treatment of Escherichia coli O157:H7 by certain antimicrobial agents often exacerbates the patient's condition by increasing either the release of preformed Shiga toxins (Stx) upon cell lysis or their production through the SOS response-triggered induction of Stx-producing prophages. Recommended subinhibitory concentrations (sub-MICs) of azithromycin (AZI), gentamicin (GEN), imipenem (IMI), and rifampicin (RIF) were evaluated in comparison to norfloxacin (NOR), an SOS-inducer, to assess the role of the SOS response in Stx release. Relative expression of recA (SOS-inducer), Q (late antitermination gene of Stx-producing prophage), stx1, and stx2 genes was assessed at two sub-MICs of the antimicrobials for two different strains of E. coli O157:H7 using reverse transcription-real-time polymerase chain reaction. Both strains at the two sub-MICs were also subjected to Western blotting for LexA protein expression and to reverse passive latex agglutination for Stx detection. For both strains at both sub-MICs, NOR and AZI caused SOS-induced Stx production (high recA, Q, and stx2 gene expression and high Stx2 production), so they should be avoided in E. coli O157:H7 treatment; however, sub-MICs of RIF and IMI induced Stx2 production in an SOS-independent manner except for one strain at the first twofold dilution below MIC of RIF where Stx2 production decreased. Moreover, GEN caused somewhat increased Stx2 production due to its mode of action rather than any effect on gene expression. The choice of antimicrobial therapy should rely on the antimicrobial mode of action, its concentration, and on the nature of the strain.

Can plasma vitamin C predict survival in stage IV colorectal cancer patients? Results of a prospective cohort study.

Background and Aims: In light of the inconclusive evidence on the association between vitamin C status and colorectal cancer (CRC) outcome, this study assessed the prognostic value of vitamin C in participants with metastatic CRC (mCRC). Methods: Adults with mCRC and cancer-free controls were recruited in this prospective cohort study to allow for comparison of vitamin C levels with healthy individuals from the same population. Sociodemographic, lifestyle, medical variables, BRAF and KRAS mutations, as well as Vitamin C plasma level and food intake were evaluated. Predictors of diminished vitamin C level were assessed via multivariate logistic regression. Mortality and progression free survival (PFS) among mCRC participants were analyzed based on plasma vitamin C level. Results: The cancer group (n = 46) was older (mean age: 60 ± 14 vs. 42 ± 9.6, p = 0.047) and included more males (29% vs. 19%, p < 0.001) than the cancer-free group (n = 45). There was a non-significant difference in the vitamin C intake between the two groups; however, the mean plasma vitamin C level was lower in the cancer group (3.5 ± 3.7 vs. 9.2 ± 5.6 mg/l, p < 0.001). After adjusting for age and gender, the cancer group was more likely to be deficient compared to the cancer-free group [Adjusted Odds Ratio (95%CI): 5.4 (2.1-14)]. There was a non-significant trend for higher mortality in the vitamin C deficient cancer group (31% vs. 12%, p = 0.139). PFS did not differ based on vitamin C deficiency and patients with BRAF and KRAS mutations did not have significant differences in vitamin C levels. Conclusion: mCRC patients have lower plasma vitamin C levels than healthy controls. The trend toward higher mortality in the vitamin C deficient cancer group was not statistically significant. Whether this phenomenon affects survival and response to treatment warrants further exploration in phase III clinical trials.

Genotypes and serotype distribution of macrolide resistant invasive and non-invasive Streptococcus pneumoniae isolates from Lebanon.

BACKGROUND: This study determined macrolide resistance genotypes in clinical isolates of Streptococcus pneumoniae from multiple medical centers in Lebanon and assessed the serotype distribution in relation to these mechanism(s) of resistance and the source of isolate recovery. METHODS: Forty four macrolide resistant and 21 macrolide susceptible S. pneumoniae clinical isolates were tested for antimicrobial susceptibility according to CLSI guidelines (2008) and underwent molecular characterization. Serotyping of these isolates was performed by Multiplex PCR-based serotype deduction using CDC protocols. PCR amplification of macrolide resistant erm (encoding methylase) and mef (encoding macrolide efflux pump protein) genes was carried out. RESULTS: Among 44 isolates resistant to erythromycin, 35 were resistant to penicillin and 18 to ceftriaxone. Examination of 44 macrolide resistant isolates by PCR showed that 16 isolates harbored the erm(B) gene, 8 isolates harbored the mef gene, and 14 isolates harbored both the erm(B) and mef genes. There was no amplification by PCR of the erm(B) or mef genes in 6 isolates. Seven different capsular serotypes 2, 9V/9A,12F, 14,19A, 19F, and 23, were detected by multiplex PCR serotype deduction in 35 of 44 macrolide resistant isolates, with 19F being the most prevalent serotype. With the exception of serotype 2, all serotypes were invasive. Isolates belonging to the invasive serotypes 14 and 19F harbored both erm(B) and mef genes. Nine of the 44 macrolide resistant isolates were non-serotypable by our protocols. CONCLUSION: Macrolide resistance in S. pneumoniae in Lebanon is mainly through target site modification but is also mediated through efflux pumps, with serotype 19F having dual resistance and being the most prevalent and invasive.

miR-126 Decreases Proliferation and Mammosphere Formation of MCF-7 and Predicts Prognosis of ER+ Breast Cancer.

Breast cancer (BC) is a major health burden that affects over one million women each year. It is the most prevalent cancer in women and the number one cancer killer of them worldwide. Of all BC subtypes, estrogen receptor-positive (ER+) BC is the most commonly diagnosed. The objective of this study is to investigate the contribution of miR-126 in the tumorigenesis of ER+ BC. miR-126 was downregulated in ER+ BC tissues from young breast cancer patients, as shown through miRNA microarray analysis and RT-qPCR. Subsequently, the effect of the modulation of miR-126 levels on the proliferation, cell cycle progression, and spheres formation of the ER+ BC cell line, MCF-7, was assessed by MTT assay, PI analysis, and mammosphere formation assay, respectively. miR-126 overexpression significantly decreased MCF-7 proliferation and mammosphere-forming ability, but did not affect cell cycle progression. Then, in silico analysis determined SLC7A5, PLXNB2, CRK, PLK2, SPRED1, and IRS1 as potential targets of miR-126. RT-qPCR data showed that miR-126 overexpression significantly downregulated SLC7A5 and PLXNB2 mRNA levels in MCF-7. Finally, in silico survival analysis showed that high expression of miR-126 or low expression of SLC7A5 correlated with better overall survival (OS) of ER+ BC patients. Overall, our study suggests that miR-126 might play a tumor suppressor role in ER+ BC. miR-126 and SLC7A5 might also be considered potential prognostic biomarkers in ER+ BC.

Neo-adjuvant FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma.

BACKGROUND: Surgery and systemic therapy provide the best option for long-term cancer control in localized resectable pancreas cancer. The present study assessed the efficacy and safety of neoadjuvant treatment with FOLFIRINOX in patients with borderline resectable (BR) and locally advanced (LA) pancreas cancer (PDAC). METHODS: This was a prospective noninterventional observational trial of neoadjuvant FOLFIRINOX in BR and LA PDAC. The primary objective was the R0/R1 surgical resection rate. Secondary objectives included progression free survival (PFS) and overall survival (OS), tolerability, and toxicity. RESULTS: Forty-nine patients were enrolled between 2013 and 2019; the majority had LA disease (59.2%). Median age was 61 years, and median Ca 19-9 level pretreatment was 523.4 µmol/L. Following neoadjuvant FOLFIRINOX, 11 patients (22.5%) underwent surgical resection, the majority of which were BR at diagnosis (72.7%). Median OS and PFS for the entire group were 25 (95% CI: 17.2-32.8) and 12 months (95% CI: 9.7-13.3), respectively. Median PFS in BR patients was 14 (95% CI: 10.5-17.5) compared to 12 months (95% CI: 5.2-18.8) in patients with LA patients. Median OS and PFS were not reached in patients who underwent surgical resection as compared to 22 (95% CI: 18.6-25.4) and 9 months (95% CI: 4.2-13.9) in those who did not, respectively. Grade 3/4 neutropenia, leukopenia, neuropathy, nausea/vomiting, and diarrhea occurred in 6.3%, 2.1%, 10.4%, 4.2%, and 8.3%, respectively. CONCLUSION: Neoadjuvant FOLFIRINOX is an active regimen for patients with LA/BR PDAC with a resection rate of 22.5%. These results are in line with prior data.

Treatment sequencing of metastatic colorectal cancer based on primary tumor location.

Colorectal cancer is a heterogeneous disease with various clinical, molecular, and embryological differences related to the origin of the tumor from the right or left colon. Recent studies have demonstrated that tumor sidedness has both a prognostic and predictive value in metastatic colorectal cancer . Patients whose primary tumor originates from the left side of the colon and whose tumor's genome encodes wild-type RAS and BRAF should be offered cetuximab or panitumumab in the first-line treatment of metastatic disease or in subsequent lines. For tumors originating from the right side of the colon, anti-angiogenic treatment, particularly bevacizumab, is an option for this poor prognostic group until better options become available. Specifically, an aggressive initial approach with FOLFOXIRI plus bevacizumab is a treatment option in right-sided tumors under investigation. This report reviews the available data for the treatment of metastatic colorectal cancer according to the location of the primary tumor and proposes the optimal treatment sequencing strategy incorporating the site of origin of the tumor and molecular information into the decision-making process.

Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction.

Worldwide, colorectal cancer (CRC) is a deadly disease whose death rate ranks second among cancers though its incidence ranks third. Early CRC detection is key and is associated with improved survival outcomes. However, existing tests for CRC diagnosis have several weaknesses thus rendering them inefficient. Moreover, reliable prognostic tests that can predict the overall cancer outcome and recurrence of the disease as well as predictive markers that can assess effectiveness of therapy are still lacking. Thus, shifting to noninvasive liquid biopsy or blood-based biomarkers is vital to improving CRC diagnosis, prognosis, and prediction. Methylated circulating tumor DNA (ctDNA) has gained increased attention as a type of liquid biopsy that is tumor-derived fragmented DNA with epigenetic alterations. Methylated ctDNA are more consistently present in blood of cancer patients as compared to mutated ctDNA. Hence, methylated ctDNA serves as a potential biomarker for CRC that is worth investigating. In this review, we explore what has been reported about methylated ctDNA as a biomarker for CRC diagnosis that can distinguish between CRC patients or those having adenoma and healthy controls as validated specifically through ROC curves. We also examine methylated ctDNA as a biomarker for CRC prognosis and prediction as confirmed through robust statistical analyses. Finally, we discuss the major technical challenges that limits the use of methylated ctDNA for clinical application and suggest possible recommendations to enhance its usage.

A risk progression breast epithelial 3D culture model reveals Cx43/hsa_circ_0077755/miR-182 as a biomarker axis for heightened risk of breast cancer initiation.

mRNA-circRNA-miRNAs axes have been characterized in breast cancer, but not as risk-assessment axes for tumor initiation in early-onset breast cancer that is increasing drastically worldwide. To address this gap, we performed circular RNA (circRNA) microarrays and microRNA (miRNA) sequencing on acini of HMT-3522 S1 (S1) breast epithelial risk-progression culture model in 3D and chose an early-stage population miRNome for a validation cohort. Nontumorigenic S1 cells form fully polarized epithelium while pretumorigenic counterparts silenced for gap junction Cx43 (Cx43-KO-S1) lose epithelial polarity, multilayer and mimic premalignant in vivo mammary epithelial morphology. Here, 121 circRNAs and 65 miRNAs were significantly dysregulated in response to Cx43 silencing in cultured epithelia and 15 miRNAs from the patient cohort were involved in epithelial polarity disruption. Focusing on the possible sponging activity of the validated circRNAs to their target miRNAs, we found all miRNAs to be highly enriched in cancer-related pathways and cross-compared their dysregulation to actual miRNA datasets from the cultured epithelia and the patient validation cohort. We present the involvement of gap junction in post-transcriptional axes and reveal Cx43/hsa_circ_0077755/miR-182 as a potential biomarker signature axis for heightened-risk of breast cancer initiation, and that its dysregulation patterns might predict prognosis along breast cancer initiation and progression.