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Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge in CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early‐onset CRC are characterized by a more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left colon‐sided location of the primary tumor. Among EO‐CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have familial CRC. Most notably, the remaining 50% of EO‐CRC patients have neither hereditary syndromes nor familial CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, heredity and outcome of treatments of EO‐CRC, and provide considerations for future perspectives. The prevalence of hereditary syndromes, familial syndromes and neither hereditary or familial (‘terra incognita’) syndromes among early‐onset colorectal cancer in young individuals. Figures are derived from studies in the text.

Background As screening methods for colorectal cancer (CRC) are limited by uptake and adherence, further options are sought. A blood test might increase both, but none has yet been tested in a screening setting. Objective We prospectively assessed the accuracy of circulating methylated SEPT9 DNA (mSEPT9) for detecting CRC in a screening population. Design Asymptomatic individuals ≥50 years old scheduled for screening colonoscopy at 32 US and German clinics voluntarily gave blood plasma samples before colon preparation. Using a commercially available assay, three independent blinded laboratories assayed plasma DNA of all CRC cases and a stratified random sample of other subjects in duplicate real time PCRs. The primary outcomes measures were standardised for overall sensitivity and specificity estimates. Results 7941 men (45%) and women (55%), mean age 60 years, enrolled. Results from 53 CRC cases and from 1457 subjects without CRC yielded a standardised sensitivity of 48.2% (95% CI 32.4% to 63.6%; crude rate 50.9%); for CRC stages I–IV, values were 35.0%, 63.0%, 46.0% and 77.4%, respectively. Specificity was 91.5% (95% CI 89.7% to 93.1%; crude rate 91.4%). Sensitivity for advanced adenomas was low (11.2%). Conclusions Our study using the blood based mSEPT9 test showed that CRC signal in blood can be detected in asymptomatic average risk individuals undergoing screening. However, the utility of the test for population screening for CRC will require improved sensitivity for detection of early cancers and advanced adenomas. Clinical Trial Registration Number: NCT00855348

BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

ObjectiveThe effect of colonoscopy on colorectal cancer mortality is limited by several factors, among them a certain miss rate, leading to limited adenoma detection rates (ADRs). We investigated the effect of an automatic polyp detection system based on deep learning on polyp detection rate and ADR.DesignIn an open, non-blinded trial, consecutive patients were prospectively randomised to undergo diagnostic colonoscopy with or without assistance of a real-time automatic polyp detection system providing a simultaneous visual notice and sound alarm on polyp detection. The primary outcome was ADR.ResultsOf 1058 patients included, 536 were randomised to standard colonoscopy, and 522 were randomised to colonoscopy with computer-aided diagnosis. The artificial intelligence (AI) system significantly increased ADR (29.1%vs20.3%, p<0.001) and the mean number of adenomas per patient (0.53vs0.31, p<0.001). This was due to a higher number of diminutive adenomas found (185vs102; p<0.001), while there was no statistical difference in larger adenomas (77vs58, p=0.075). In addition, the number of hyperplastic polyps was also significantly increased (114vs52, p<0.001).ConclusionsIn a low prevalent ADR population, an automatic polyp detection system during colonoscopy resulted in a significant increase in the number of diminutive adenomas detected, as well as an increase in the rate of hyperplastic polyps. The cost–benefit ratio of such effects has to be determined further.Trial registration numberChiCTR-DDD-17012221; Results.

Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major ef-forts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the im-provements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complex-ity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the compre-hensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the applica-tion of the resulting dynamic changes to a precision medicine- based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC.

Colorectal Cancer is a complex disease caused by the interaction of hereditary and environmental factors that can be classified based on their importance. Colorectal Cancer Diagnosis and Therapeutic Updates provides comprehensive information about the diagnosis and treatment of colorectal cancer. Chapters first cover the fundamentals of colorectal cancer diagnosis, progressing further towards explaining therapeutic modalities and recent advances in the understanding of the disease. Key Features - 11 organized, reader-friendly chapters that provide a complete overview of colorectal cancer - Covers the colorectal cancer diagnosis, screening and histopathology - Covers multimodal treatment of colorectal cancer, including chemotherapy, radiotherapy and robotic surgery - Covers the management and surveillance of colorectal cancer - Explains the key biochemical mechanisms involved in colorectal cancer treatment - Covers recent information about colorectal cancer theranostics and drug delivery - Includes references for further reading in every chapter The book serves as an introductory reference for medical students and residents on the subject of colorectal cancer. It also serves as a quick reference on the disease for the practicing general physician.

ObjectiveColorectal cancer (CRC) screening has been widely implemented in many countries. However, evidence on participation and diagnostic yield of population-based CRC screening in China is sparse.DesignThe analyses were conducted in the context of the Cancer Screening Program in Urban China, which recruited 1 381 561 eligible participants aged 40–69 years from 16 provinces in China from 2012 to 2015. 182 927 participants were evaluated to be high risk for CRC by an established risk score system and were subsequently recommended for colonoscopy. Participation rates and detection of colorectal neoplasms in this programme were reported and their associated factors were explored.Results25 593 participants undertook colonoscopy as recommended, with participation rate of 14.0%. High level of education, history of faecal occult blood test, family history of CRC and history of colonic polyp were found to be associated with the participation in colonoscopy screening. Overall, 65 CRC (0.25%), 785 advanced adenomas (3.07%), 2091 non-advanced adenomas (8.17%) and 1107 hyperplastic polyps (4.33%) were detected. Detection rates of colorectal neoplasms increased with age and were higher for men. More advanced neoplasms were diagnosed in the distal colon/rectum (65.2%). Several factors including age, sex, family history of CRC, dietary intake of processed meat and smoking were identified to be associated with the presence of colorectal neoplasms.ConclusionThe diagnostic yield was not optimal using colonoscopy screening in high-risk populations given the relatively low participation rate. Our findings will provide important references for designing effective population-based CRC screening strategies in the future.

Immunotherapy is a new and exciting modality of cancer treatments. Its role in gastrointestinal malignancies has been promising, especially in advanced disease. Although various therapies are available for treatment of advanced colorectal cancer, survival rates for these patients remain very poor. The application of immunotherapy in colorectal cancer has shown remarkable results for a subset of patients with mismatch-repair-deficient mutations or microsatellite instability in their tumors. This literature review evaluates the current role of immunotherapy in advanced colorectal cancer, potential challenges clinicians face with immunotherapy-based regimens, and the possible future approach of combined modality immunotherapy.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immunemediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.