Majority Of Colorectal Cancer Patients Research Articles

Inhibition of DNMTs increases neoantigen-reactive T-cell toxicity against microsatellite-stable colorectal cancer in combination with radiotherapy

The therapeutic efficacy of immunotherapy is limited in the majority of colorectal cancer patients due to the low mutational and neoantigen burdens in this immunogenically “cold” microsatellite stability-colorectal cancer (MSS-CRC) cohort. Here, we showed that DNA methyltransferase (DNMT) inhibition upregulated neoantigen-bearing gene expression in MSS-CRC, resulting in increased neoantigen presentation by MHC class I in tumor cells and leading to increased neoantigen-specific T-cell activation in combination with radiotherapy. The cytotoxicity of neoantigen-reactive T cells (NRTs) to DNMTi-treated cancer cells was highly cytotoxic, and these cells secreted high IFNγ levels targeting MSS-CRC cells after ex vivo expansion of NRTs with DNMTi-treated tumor antigens. Moreover, the therapeutic efficacy of NRTs further increased when NRTs were combined with radiotherapy in vivo. Administration of DNMTi-augmented NRTs and radiotherapy achieved an ∼50 % complete response and extended survival time in an immunocompetent MSS-CRC animal model. Moreover, remarkably, splenocytes from these mice exhibited neoantigen-specific T-cell responses, indicating that radiotherapy in combination with DNMTi-augmented NRTs prolonged and increased neoantigen-specific T-cell toxicity in MSS-CRC patients. In addition, these DNMTi-augmented NRTs markedly increase the therapeutic efficacy of cancer vaccines and immune checkpoint inhibitors (ICIs). These data suggest that a combination of radiotherapy and epi-immunotherapeutic agents improves the function of ex vivo-expanded neoantigen-reactive T cells and increases the tumor-specific cytotoxic effector population to enhance therapeutic efficacy in MSS-CRC.

The Role of Tumor Parenchymal and Stromal Ratios in Colorectal Cancer.

To evaluate the implications and significant role of parenchymal and stromal ratio in colorectal cancer (CRC). In our review, we involved English studies from common databases such as Web of Science, Scopus, Google Scholar, PubMed, and the Cochrane Library using the following keywords "colorectal cancer", "tumor stromal ratio", "tumor parenchymal ratio", and "prognostic marker" till December 2023. The majority of CRC patients are usually diagnosed at late stages, which may lead to missing out on the chance to get radical therapy. Patients with unfavorable prognosis have epithelial malignant tumors with a high amount of stroma, more than 50% stroma, while tumors with a low amount of stroma, less than 50%, and abundant carcinoma tissue have a better prognosis. Tumor-stromal ratio is a valuable, cheap, and fast modality that provides valuable prognostic data of colorectal carcinoma and other cancers.

P1171 The impact of biological and small molecule therapy on time to colonic resection and cancer rates in patients with Ulcerative Colitis

Abstract Background The expanding medical armamentarium in ulcerative colitis (UC) has contributed to increased control of inflammation. However, simultaneously, postponed colonic resection with an accumulative inflammatory burden might lead to an increased risk of CRC. Recent studies have reported conflicting results regarding the incidence of colorectal cancer (CRC) in UC patients. Aim To analyse the impact of advanced medical therapies (defined as biologicals and small molecules) on time to colonic resection and risk of CRC in UC patients. Methods Consecutive patients ≥18 years with established UC who underwent colonic resection between January 2003 and October 2022 at the Academic Medical Centre Amsterdam or the University Hospital Leuven were included. Primary outcomes were time to colonic resection and CRC rate in colonic specimens, compared between four time periods: P1 (2003-2007), P2 (2008-2012), P3 (2013-2017) and P4 (2018-2022). Secondary outcomes were the effect of advanced medical therapy on time to resection, cancer stage and risk of CRC. CRC was staged according to the AJCC TNM classification (advanced cancer defined as T3/T4, N1/2 or M1). Results A total of 716 patients were included. The usage of advanced medical therapies prior to surgery increased from 38.2% in P1 to 90.2% in P4 (p<0.001). However, this did not result in an increased time to colonic resection (P1: 7 years (2-12) vs P2: 6 years (2-14) vs P3: 7 years (3-14) vs P4: 7 years (2-14), p=0.94). CRC was diagnosed in 72 (10.1%) patients, and this incidence did also not change over time. Time to resection was significantly longer (median 18 years, IQR 10-24) in CRC patients compared to the overall cohort. The majority of CRC patients (64.8%) were diagnosed with advanced cancer, which did not decrease over time. Patients using advanced medical therapies had significantly shorter follow-up compared to therapy-naïve patients (6 years vs. 10 years, p<0.001), which resulted in a decreased risk of CRC (OR 0.17, p=<0.001). However, the finding of an incidental carcinoma rate (i.e. not preoperatively diagnosed) in this group was 18% whereas this was only 4% in patients without advanced medical therapy (p=0.08). Moreover, the incidence of advanced CRC was numerically higher in UC patients who received ≥2 therapies (83.3% vs 61.0%, p=0.14). Conclusion This study demonstrated that in the last two decades, the increased usage of advanced medical therapies did not result in an increased time to resection, nor in a decreased CRC rate in UC patients undergoing colonic resection. A higher incidence of incidental and advanced cancers was seen in patients with ≥2 therapies. Therefore, care should be taken with improved tailored surveillance in this group.

Centrosomal Protein 55 (CEP55) Drives Immune Exclusion and Resistance to Immune Checkpoint Inhibitors in Colorectal Cancer.

Colorectal cancer (CRC) currently ranks as the third most common cancer in the United States, and its incidence is on the rise, especially among younger individuals. Despite the remarkable success of immune checkpoint inhibitors (ICIs) in various cancers, most CRC patients fail to respond due to intrinsic resistance mechanisms. While microsatellite instability-high phenotypes serve as a reliable positive predictive biomarker for ICI treatment, the majority of CRC patients with microsatellite-stable (MSS) tumors remain ineligible for this therapeutic approach. In this study, we investigated the role of centrosomal protein 55 (CEP55) in shaping the tumor immune microenvironment in CRC. CEP55 is overexpressed in multiple cancer types and was shown to promote tumorigenesis by upregulating the PI3K/AKT pathway. Our data revealed that elevated CEP55 expression in CRC was associated with reduced T cell infiltration, contributing to immune exclusion. As CRC tumors progressed, CEP55 expression increased alongside sequential mutations in crucial driver genes (APC, KRAS, TP53, and SMAD4), indicating its involvement in tumor progression. CEP55 knockout significantly impaired tumor growth in vitro and in vivo, suggesting that CEP55 plays a crucial role in tumorigenesis. Furthermore, the CEP55 knockout increased CD8+ T cell infiltration and granzyme B production, indicating improved anti-tumor immunity. Additionally, we observed reduced regulatory T cell infiltration in CEP55 knockout tumors, suggesting diminished immune suppression. Most significantly, CEP55 knockout tumors demonstrated enhanced responsiveness to immune checkpoint inhibition in a clinically relevant orthotopic CRC model. Treatment with anti-PD1 significantly reduced tumor growth in CEP55 knockout tumors compared to control tumors, suggesting that inhibiting CEP55 could improve the efficacy of ICIs. Collectively, our study underscores the crucial role of CEP55 in driving immune exclusion and resistance to ICIs in CRC. Targeting CEP55 emerges as a promising therapeutic strategy to sensitize CRC to immune checkpoint inhibition, thereby improving survival outcomes for CRC patients.

The Composition of Small Extracellular Vesicles (sEVs) in the Blood Plasma of Colorectal Cancer Patients Reflects the Presence of Metabolic Syndrome and Correlates with Angiogenesis and the Effectiveness of Thermoradiation Therapy.

The majority of colorectal cancer patients (CRCPs) develop tumors on the background of "metabolically healthy obesity" or metabolic syndrome. The aim of the work was to study the levels of matrix metalloproteinases (MMPs) and heat shock proteins (HSPs) on the surface of blood plasma CD9-positive and FABP4-positive small extracellular vesicles (sEVs) from CRCPs depending on metabolic status and tumor angiogenesis, as well as to evaluate the sEVs markers as predictors of the effectiveness of thermoradiotherapy. In CRCPs, compared with patients with colorectal polyps (CPPs), the proportion of triple positive EVs and EVs with the MMP9+MMP2-TIMP1+ phenotype increased significantly among FABP4-positive EVs (adipocyte-derived EVs), which in general may indicate the overexpression of MMP9 and TIMP1 by adipocytes or adipose tissue macrophages in CRCPs. The results obtained have prospects for use as markers to clarify cancer risk in CPPs. One can assume that for CRCPs with metabolic syndrome or metabolically healthy obesity, it is the FABP4+MMP9+MMP2-TIMP1- population of circulating sEVs that is the most optimal biomarker reflecting tumor angiogenesis. Determining this population in the blood will be useful in monitoring patients after treatment for the early detection of tumor progression. CD9+MMP9+MMP2-TIMP1- and MMP9+MMP2-TIMP1+ subpopulations of circulating sEVs are the most promising predictors of the efficacy of thermoradiation therapy because their levels at baseline differ significantly in CRCPs with different tumor responses.

Challenges and exploration for immunotherapies targeting cold colorectal cancer.

In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of various tumors, greatly improving clinical efficacy. As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery, chemotherapy, radiotherapy and targeted therapy, the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells, features that are also important when distinguishing malignant tumors from "cold tumors" or "hot tumors". At present, only a small proportion of colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) or who are microsatellite instability-high (MSI-H) can benefit from ICI treatments because these patients have the characteristics of a "hot tumor", with a high tumor mutational burden (TMB) and massive immune cell infiltration, making the tumor more easily recognized by the immune system. In contrast, a majority of CRC patients with proficient MMR (pMMR) or who are microsatellite stable (MSS) have a low TMB, lack immune cell infiltration, and have almost no response to immune monotherapy; thus, these tumors are "cold". The greatest challenge today is how to improve the immunotherapy response of "cold tumor" patients. With the development of clinical research, immunotherapies combined with other treatment strategies (such as targeted therapy, chemotherapy, and radiotherapy) have now become potentially effective clinical strategies and research hotspots. Therefore, the question of how to promote the transformation of "cold tumors" to "hot tumors" and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration. Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.

Abstract P043: A precision medicine gap: limited recognition of colorectal patients eligible for germline testing in molecular residual disease testing setting

Abstract Background: Germline testing for hereditary colorectal cancer (CRC) has traditionally been offered to patients with strong cancer family histories, whose colon tumors revealed mismatch repair deficiency (dMMR), and/or individuals diagnosed with CRC under age 50. Underdiagnosis of hereditary cancer syndromes is often attributed to the complexity or unawareness of family history or phenotypic criteria.1,2 The National Comprehensive Cancer Network (NCCN) guidelines for CRC were recently updated (v. 1.2022) to consider germline multigene panel testing (MGPT) evaluation for all individuals with CRC.3,4 Our goal was to evaluate documentation of MGPT in CRC patients referred for molecular residual disease (MRD) testing. Methods: This retrospective cohort study reviewed clinical data submitted to a commercial laboratory for consecutive CRC patients referred from non-academic medical facilities for MRD testing during a two-month study period. Medical diagnoses, treatment history, family history and germline genetic evaluation status were obtained from the test requisition form and pathology reports. Clinical notes were reviewed in 77/80 cases. Results: Of the 80 patients who met criteria for inclusion, 65/80 (81%) had documented MMR testing of their colorectal tumor. Whereas five had abnormal immunohistochemistry, only two (40%) had documented germline results. 19/80 (24%) met NCCN criteria solely based on a personal CRC diagnosis <50 years, but only 1/19 (5.3%) had documented MGPT. Only 5/80 (6%) of all CRC patients had documented MGPT. Conclusion: Our real-world data from the community oncology precision medicine setting suggests that a majority of CRC patients who received MRD testing and met the prior NCCN criteria for MGPT may not have received evaluation beyond routine MMR status. Process and educational improvements are needed in community health settings to increase access and uptake of germline testing in CRC patients regardless of age at diagnosis or MMR status. Citation Format: Suzanne Schrock-Kelley, Vivienne Souter, Michael Hall, Jeffrey N. Weitzel. A precision medicine gap: limited recognition of colorectal patients eligible for germline testing in molecular residual disease testing setting. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P043.

Immunonutrition of perioperative therapy for colorectal cancer

Abstract Immunonutrition, a modified nutritional formula that involves the addition of glutamine, arginine, omega-3 fatty acids, nucleotides, and other potential compounds to the diet, has proven its potential for use in immunomodulation and protein metabolism improvement. Its clinical benefits include shortening hospital stays and lowering surgical infectious complications in upper gastrointestinal surgery. However, the use of perioperative immunonutrition is rare among colorectal cancer patients undergoing surgical intervention. Colorectal cancer is one of the most common cancers around the world, but its malnutrition rate is not high in comparison with other cancers (eg, gastric cancer or esophageal cancer). Furthermore, the surgical modality for the majority of colorectal cancer patients involves minimal invasive surgery (MIS), which enhances recovery speed. It is an interesting clinical question whether or not perioperative immunonutrition supplementation for colorectal cancer patients undergoing MIS causes extraclinical impacts. The immunomodulation effect of CD4+ T cells has been proven in colorectal patients undergoing elective surgery. In recent years, there have been several prospective randomized studies elucidating the clinical effects of immunonutrition on colorectal cancer patients undergoing surgery in Western countries. These studies have generally found that perioperative immunonutrition was associated with a lower rate of surgical infectious complications even in normo-nourished patients undergoing MIS. The use of perioperative immunonutrition provides clinical benefits according to high-quality studies. However, most results come from Western countries, and its effect needs to be validated in Asian countries.

LncRNA MIR600HG induces the proliferation and invasion of colorectal cancer cells via regulating miR-144-3p/KIF3A

Colorectal cancer (CRC) is a common digestive system malignancy characterized by the high morbidity and mortality rates. Due to the limited therapeutic options, the majority of CRC patients do not receive timely treatment, which has thus increased the risk of tumor recurrence. Long noncoding RNAs (lncRNAs), as the essential regulators, are involved in numerous pivotal physiological and pathological processes in CRC. By qRT-PCR, it could be discovered in this study that MIR600HG expression obviously increased in CRC tissues and cell lines compared with the normal group. Moreover, the high expression of MIR600HG was correlated with tumor size, tumor volume and TNM stage. Overexpression of MIR600HG affected the expression of downstream molecules, such as miR-144-3p and KIF3A, providing the possible mechanisms of MIR600HG in the development and progression of CRC.

Clinical pattern and drug-related problems among colorectal cancer patients at oncology center in Ethiopia: A hospital-based study.

Objective:Despite the fact that cancer patients are highly susceptible to drug-related problems due to the effects of cytotoxic agents, data are limited due to a lack of studies on those patients. Hence, we aimed to investigate drug-related problems among patients diagnosed with colorectal cancer.Method:A registry-based cross-sectional study was conducted on colorectal cancer patients at the Felege Hiwot Comprehensive Specialized Hospital. Socio-demographic and disease-related characteristics, treatment regimens, and drug-related problems were recorded by reviewing medical records. Standard guidelines, protocols, and databases were used to evaluate the occurrence of drug-related problems and the severity of adverse drug reactions. For the analysis, Stata version 16/MP for Windows was used. Logistic regression analysis was employed to investigate the potential-associated factors of drug-related problems. A p-value ⩽ 0.05 was used to declare the statistical significance of each independent variable.Results:A total of 150 colorectal cancer patients were included, with a mean age of 51.4 ± 13.8 years. About 30% and 41.3% had stage II and stage III cancers, respectively. About three-quarters (73.8%) of the patients were given 5-fluorouracil-based combination regimens. The prevalence of drug-related problems was found to be 48.7%, with a mean of 2.12 ± 0.93 drug-related problems. In the Felege Hiwot Comprehensive Specialized Hospital, drug–drug interactions and adverse drug reactions were the most prevalent drug-related problems, which accounted for 50 (32.7%) and 49 (32%) cases, respectively. Being elderly (>50 years old) (p = 0.013), having co-morbidity (p = 0.001), and being on five or more medications (p = 0.002) were independent predictors of drug-related problems.Conclusion:Fluorouracil-based chemotherapy was the most frequently used treatment regimen. Almost, half of the colorectal cancer patients had one or more drug-related problems. About one-third of patients had adverse drug reactions and drug–drug interactions. Furthermore, age, co-morbidity status, and the number of medications used were significantly associated with drug-related problems. Clinical pharmacy services should be implemented to optimize drug therapy because the majority of colorectal cancer patients have one or more drug-related problems.

Wnt/β-Catenin Target Genes in Colon Cancer Metastasis: The Special Case of L1CAM.

Simple SummaryThe Wnt/β-catenin cell–cell signaling pathway is one of the most basic and highly conserved pathways for intercellular communications regulating key steps during development, differentiation, and cancer. In colorectal cancer (CRC), in particular, aberrant activation of the Wnt/β-catenin pathway is believed to be responsible for perpetuating the disease from the very early stages of cancer development. A large number of downstream target genes of β-catenin-T-cell factor (TCF), including oncogenes, were detected as regulators of CRC development. In this review, we will summarize studies mainly on one such target gene, the L1CAM (L1) cell adhesion receptor, that is selectively induced in invasive and metastatic CRC cells and in regenerating cells of the intestine following injury. We will describe studies on the genes activated when the levels of L1 are increased in CRC cells and their effectiveness in propagating CRC development. These downstream targets of L1-signaling can serve in diagnosis and may provide additional targets for CRC therapy.Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell–cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, are common during invasive and metastatic cancer development. The Wnt/β-catenin signaling pathway is an excellent model for studying the role of adhesion-mediated signaling in colorectal cancer (CRC) invasion and metastasis, because β-catenin has a dual role in the cell; it is a major adhesion linker of cadherin transmembrane receptors to the cytoskeleton and, in addition, it is also a key transducer of Wnt signaling to the nucleus, where it acts as a co-transcriptional activator of Wnt target genes. Hyperactivation of Wnt/β-catenin signaling is a common feature in the majority of CRC patients. We found that the neural cell adhesion receptor L1CAM (L1) is a target gene of β-catenin signaling and is induced in carcinoma cells of CRC patients, where it plays an important role in CRC metastasis. In this review, we will discuss studies on β-catenin target genes activated during CRC development (in particular, L1), the signaling pathways affected by L1, and the role of downstream target genes activated by L1 overexpression, especially those that are also part of the intestinal stem cell gene signature. As intestinal stem cells are highly regulated by Wnt signaling and are believed to also play major roles in CRC progression, unravelling the mechanisms underlying the regulation of these genes will shed light on both normal intestinal homeostasis and the development of invasive and metastatic CRC.

STUDY OF THE POSSIBILITIES OF PREOPERATIVE CHEMOTHERAPY IN MULTIPLE METASTASIS OF COLORECTAL CANCER IN THE LIVER

Preoperative chemotherapy (CT) in 35 patients with colorectal cancer (CRC) with liver metastases demonstrated a high frequency of objective effects - in 22 (62.9%) patients, stabilization was noted in 10 (28.6%) cases. With bilobar liver metastases and the use of oxaliplatin-containing regimens, partial regression was 62.9%. Side effects in most cases were clinically insignificant, no deaths were observed. The results obtained demonstrate the possibility of performing extended surgical operations in the majority of CRC patients with multiple liver metastases after preoperative CT.

Tumour suppressor 15-hydroxyprostaglandin dehydrogenase induces differentiation in colon cancer via GLI1 inhibition

Inflammation is an established risk factor for colorectal cancer. We and others have shown that colorectal cancer patients with elevated cysteinyl leukotriene receptor 2 (CysLT2R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) levels exhibit good prognoses. However, both CysLT2R and 15-PGDH, which act as tumour suppressors, are often suppressed in colorectal cancer. We previously reported that leukotriene C4 (LTC4)-induced differentiation in colon cancer via CysLT2R signalling. Here, we investigated the involvement of Hedgehog (Hh)–GLI1 signalling, which is often hyperactivated in colorectal cancer. We found that the majority of colorectal cancer patients had high-GLI1 expression, which was negatively correlated with CysLT2R, 15-PGDH, and Mucin-2 and overall survival compared with the low-GLI1 group. LTC4-induced 15-PGDH downregulated both the mRNA and protein expression of GLI1 in a protein kinase A (PKA)-dependent manner. Interestingly, the LTC4-induced increase in differentiation markers and reduction in Wnt targets remained unaltered in GLI1-knockdown cells. The restoration of GLI1 in 15-PGDH-knockdown cells did not ameliorate the LTC4-induced effects, indicating the importance of both 15-PGDH and GLI1. LTC4-mediated reduction in the DCLK1 and LGR5 stemness markers in colonospheres was abolished in cells lacking 15-PGDH or GLI1. Both DCLK1 and LGR5 were highly increased in tumour tissue compared with the matched controls. Reduced Mucin-2 levels were observed both in zebrafish xenografts with GLI1-knockdown cells and in the cysltr2−/− colitis-associated colon cancer (CAC) mouse model. Furthermore, GLI1 expression was positively correlated with stemness and negatively correlated with differentiation in CRC patients when comparing tumour and mucosal tissues. In conclusion, restoring 15-PGDH expression via CysLT2R activation might benefit colorectal cancer patients.

Gastrointestinal Disasters of Cetuximab in the Treatment of Metastatic Colorectal Cancer: Mechanism and its Effect on Prognosis

Colorectal cancer (CRC) is among the top three cancers worldwide in terms of incidence and associated mortality. Colorectal cancer (CRC) is responsible for more than 880,000 deaths annually. The number of of CRC cases worldwide continues to increase, posing a serious threat to human health. Surgery and chemotherapy are the first treatments for CRC patients. The majority of CRC patients are diagnosed at an advanced stage, as symptoms are usually not apparent and difficult to diagnose in the early stage. The prognosis of metastatic CRC (mCRC) has long been unsatisfactory. Targeted drugs therapy, which targeting at specific genes and proteins, is a new treatment approach to CRC. Cetuximab is one of the most widely studied targeted drugs. By competitively binding to the epithelial growth factor receptor (EGFR), cetuximab inhibits the EGF and binding of the EGF ligand to the EGFR, thereby inhibiting tumor cell growth, invasion, and metastasis and inducing tumor cell apoptosis. The curative effect of cetuximab as a treatment for many kinds of tumors, especially mCRC, has been confirmed. Cetuximab combined with chemotherapy or monotherapy is used as first-line treatment in patients with RAS(rat sarcoma,Ras) wild-type mCRC. However, adverse drug reactions (ADRs) associated with the clinical application of cetuximab are attracting increasing attention, with numerous studies reporting adverse effects of cetuximab on the gastrointestinal system, with these effects having adverse consequences for the prognosis of CRC. In this review, we focus mainly on gastrointestinal disasters on cetuximab treatment for mCRC from three areas: the intestinal mucosal barrier (IMB), gut microbiota (GM)-host immune balance, and bacterial metabolites short chain fatty acids (SCFAs), and the impact of these effects on the prognosis of mCRC. We also make suggestions aimed at aiding oncological understanding of cetuximab as a treatment for mCRC. Keywords: Bacterial metabolites, cetuximab, colorectal cancer, gut microbiota-host immune balance, gastrointestinal disasters

Long Non-coding RNA TDRKH-AS1 Promotes Colorectal Cancer Cell Proliferation and Invasion Through the β-Catenin Activated Wnt Signaling Pathway.

Colorectal cancer (CRC) is a common cancer worldwide, with a lower 5-years survival rate. Recently, long non-coding RNAs (lncRNAs) have been well-studied as the oncogenes or the tumor suppressors in multiple malignancies, including CRC. However, their biological functions and potential mechanisms in human cancer remain unclear. Here, we evaluated the expression of TDRKH-AS1 in CRC tissues and identified its potential targets. We found that TDRKH-AS1 is upregulated in majority of CRC patients, which is also significantly correlated with their malignant characteristics and their dismal prognoses. The high expression of TDRKH-AS1 can promote cancer cell proliferation substantially and invasion based on in vitro experiments. We also recognized that the TDRKH-AS1 targets the β-catenin in the Wnt signaling pathway to exert its carcinogenic activity. TDRKH-AS1 could serve as a promising prognostic predictor and a potential therapeutic target for further early diagnoses and treatments via a non-invasive method.

Gene editing particle system as a therapeutic approach for drug-resistant colorectal cancer

The epidermal growth factor receptor (EGFR) pathway plays an important role in the progression of colorectal cancer (CRC). Anti-EGFR drugs based on antibodies have been widely used for treating CRC through inducing the cell death pathway. However, the majority of CRC patients will inevitably develop drug-resistance during anti-EGFR drug treatment, which is mainly caused by a point mutation in the KRAS oncogene. We developed a nanoliposomal (NL) particle containing the Cas9 protein and a single-guide RNA (sgRNA) complex (Cas9-RNP), for genomic editing of the KRAS mutation. The NL particle is composed of bio-compatible lipid compounds that can effectively encapsulate Cas9-RNP. By modifying the NL particle to include the appropriate antibody, it can specifically recognize EGFR expressing CRC and effectively deliver the gene-editing complexes. The conditions of NL treatment were optimized using a KRAS mutated CRC in vivo mouse model. Mice with KRAS-mutated CRC showed drug resistance against cetuximab, a therapeutic antibody drug. After treating the mice with the KRAS gene-editing NL particles, the implanted tumors showed a dramatic decrease in size. Our results demonstrated that this genomic editing complex has great potential as a therapeutic carrier system for the treatment of drug-resistant cancer caused by a point mutation.

Hubungan antara obesitas dan insiden kanker kolorektal di RSUP Sanglah tahun 2016-2017

Introduction: Colorectal cancer is the third malignant disease in Indonesia. Obesity is one of the risk factors related to colorectal cancer. This research aims to role out relationships between obese and age to the incidence of colorectal cancer at Sanglah General Hospital.Method: Study design using case-control analytic model, covering 274 samples, divided into the group of colorectal cancer (137 persons) and non-cancer samples (137 persons). Secondary data were used for analysis obtained from medical records in year period of 2016-2017 at Sanglah General Hospital. Data were analyzed using Chi-square analysis and risk estimate model.Result: The result showed that the majority of colorectal cancer patients were male (53.3%), meanwhile for non-cancer patients were female (50.4%). The average age of colorectal cancer patients was 54 years old while 42 years for non-colorectal cancer patients. Based on the BMI groups, majority of cancer colorectal patients (62%) belongs to obese, while only 39.4% for non-colorectal cancer patients. Result of analysis showed that there is significant relationship between obese and the incidence of colorectal cancer (p value <0.001), with the risk increase of prevalence by 1.588 times higher for those patients with BMI ≥23.00 kg/m2 (95% CI 1.235-2.040). Result from the Chi-square test also indicated that there is significant relationship between age above 40 years and the incidence of colorectal cancer (p value <0.001).Conclusion: It can be concluded that there is significant relationships between obese and age above 40 years to the incidence of colorectal cancer.

Lebertransplantation beim hepatisch metastasierten kolorektalen Karzinom: aktuelle Datenlage und mögliche Zukunftsszenarien

Colorectal cancer (CRC) is the third most common cancer worldwide. The majority of CRC patients will develop distant metastases during the course of their disease, most of them occurring in the liver. To date, liver resection represents the only curative option. However, due to insufficient liver remnant volume, only a minority of patients with hepatic CRC metastasis are candidates for liver resection. In recent years, various surgical and minimally invasive procedures have been developed for the treatment of non-resectable colorectal liver metastases (NRCRM). Whereas initial reports yielded 5‑year overall survival (OS) rates of less than 20%, results have now significantly improved owing to the ameliorated chemotherapy and refined surgical techniques. Furthermore, liver transplantation (LTX) has surfaced as a promising option for patients with NRCLM. Recent studies report 5‑year OS rates exceeding 50%. Despite this success, wider application of LTX for the treatment of NCRLM is currently hampered by the persisting organ shortage. This ethical dilemma may now be overcome through innovative protocols which allow the use of only a small part of the donor liver for NRCLM patients while the remaining part of the graft is transplanted to a second recipient. This review illustrates the underlying factors which have so far hindered a curative approach for NRCRM patients and highlights recent promising achievements in oncology and transplant medicine.

Design and Synthesis of TASIN Analogues Specifically Targeting Colorectal Cancer Cell Lines with Mutant Adenomatous Polyposis Coli (APC).

Despite advances in targeted anticancer therapies, there are still no small-molecule-based therapies available that specifically target colorectal cancer (CRC) development and progression, the second leading cause of cancer deaths. We previously disclosed the discovery of truncating adenomatous polyposis coli (APC)-selective inhibitor 1 (TASIN-1), a small molecule that specifically targets colorectal cancer cells lines with truncating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene through inhibition of cholesterol biosynthesis. Here, we report a medicinal chemistry evaluation of a collection of TASIN analogues and activity against colon cancer cell lines and an isogenic cell line pair reporting on the status of APC-dependent selectivity. A number of potent and selective analogues were identified, including compounds with good metabolic stability and pharmacokinetic properties. The compounds reported herein represent a first-in-class genotype-selective series that specifically target apc mutations present in the majority of CRC patients and serve as a translational platform toward a targeted therapy for colon cancer.

Incidence and outcome of colorectal cancer in liver transplant recipients: A national, multicentre analysis on 8115 patients.

De novo malignancies after liver transplantation represent one of the leading causes of death in the long-term. It remains unclear whether liver transplant recipients have an increased risk of colorectal cancer and whether this negatively impacts on survival, particularly in those patients affected by primary sclerosing cholangitis and ulcerative colitis. In this national multicentre cohort retrospective study, the incidence of colorectal cancer in 8115 evaluable adult patients undergoing a liver transplantation between 1 January 1990 and 31 December 2010 was compared to the incidence in the general population through standardised incidence ratios. Fifty-two (0.6%) cases of colorectal cancer were identified at a median of 5.6years postliver transplantation, predominantly grade 2 (76.9%) and stage T3 (50%) at diagnosis. The incidence rate of colorectal cancer in the whole liver transplant population was similar to the general UK population (SIR: 0.92), but significantly higher (SIR: 7.0) in the group of patients affected by primary sclerosing cholangitis/ulcerative colitis. One-, five- and ten-year survival rates from colorectal cancer diagnosis were 71%, 48% and 31%, respectively, and the majority of colorectal cancer patients died of cancer-specific causes. Liver transplantation alone is not associated with an increased risk of colorectal cancer development. The primary sclerosing cholangitis/ulcerative colitis liver transplant population showed a significantly higher risk of colorectal cancer development than the general population, with a high proportion of advanced stage at diagnosis and a reduced patient survival.