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    Serum Tumor Markers Combined With Clinicopathological Characteristics for Predicting MMR and KRAS Status in 2279 Chinese Colorectal Cancer Patients: A Retrospective Analysis. Zhao Ning,Cao Yinghao,Yang Jia,Li Hang,Wu Ke,Wang Jiliang,Peng Tao,Cai Kailin Frontiers in oncology Although serum tumor markers (STMs), clinicopathological characteristics and the status of KRAS and MMR play an important role in optimizing the treatment and prognosis of colorectal cancer, their interrelationships remain largely unknown. A retrospective analysis of 2279 patients who tested for KRAS and MMR status, and STM measurements prior to treatment over the past four years was conducted. Of the 784 patients tested for KRAS and 2279 patients tested for MMR status, KRAS mutations and dMMR were identified in 276 patients (35.20%) and 177 patients (7.77%), respectively. Logistic regression analysis demonstrated that right colon, well and moderate differentiation and negative CA19-9 were independent predictors for KRAS mutations. The ROC curve yielded an AUC of 0.609 through the combination of these three factors. Age < 65 was an independent predictive factor for dMMR, along with tumor size > 4.6 cm, right colon, poor differentiation, harvested lymph nodes ≥ 22, no lymph node metastasis, no perineural invasion, negative CEA and positive CA72-4. When the nine criteria were used together, the AUC was 0.849. In summary, both STMs and clinicopathological characteristics were found to be significantly associated with the status of KRAS and MMR. The combination of these two factors possessed a strong predictive power for KRAS mutations and dMMR among CRC patients. 10.3389/fonc.2021.582244
    Prognostic Value of Platelet-to-Lymphocyte Ratio, Neutrophil-to-Lymphocyte Ratio, and Lymphocyte-to-White Blood Cell Ratio in Colorectal Cancer Patients Who Received Neoadjuvant Chemotherapy. Jia Wangqiang,Yuan Long,Ni Hongyan,Xu Benling,Zhao Peng Technology in cancer research & treatment BACKGROUND:The objective of this study was to assess the prognostic value of pretreatment platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-white blood cell ratio (LWR) of CRC patients who received neoadjuvant chemotherapy. METHODS:We analyzed the peripheral blood routine parameters and other clinical data of 145 patients with colorectal cancer who had undergone neoadjuvant chemotherapy between January 2011 and February 2014. Pretreatment blood parameters of 145 patients were collected, and PLR, NLR, and LWR were calculated. The utility of PLR, NLR, and LWR in predicting treatment efficacy and patient survival was statistically evaluated using the chi-square test, log-rank test, Kaplan-Meier curves and logistic regression models, and Cox regression models. RESULTS:Receiver operating characteristic curve showed that the best cutoff values of PLR, NLR, and LWR were 154.31, 3.01, and 0.22, respectively. In univariate analysis, tumor location ( = 0.044), differentiation degree ( = 0.001), lymph node metastasis ( = 0.020), and high PLR ( = 0.042) were significantly correlated with a lower overall response rate (ORR). In addition, clinical stage, lymph node metastasis, and high PLR were correlated with short OS ( < 0.01) and DFS ( < 0.01). Moreover, WBC count was correlated with a short OS. Multivariate analysis showed that tumor location ( = 0.013), differentiation degree ( = 0.001), and lymph node metastasis ( = 0.033) were independent predictors of ORR. In addition, lymph node metastasis independently predicted a shorter OS ( = 0.011). Lymph node metastasis ( = 0.013) and high PLR ( = 0.022) were independent prognostic factors for short DFS. CONCLUSIONS:For CRC patients who received NAC, clinical pathological stage and lymph node metastasis were correlated with lower ORR and survival, while a high PLR that may be of prognostic relevance in CRC patients receiving NAC. 10.1177/15330338211034291
    Predictive Role of Tumor Budding in T1 Colorectal Cancer Lymph Node Metastasis. Huang Li-Bin,Yang Ting-Han,Chen Hai-Ning Gastroenterology 10.1053/j.gastro.2020.12.053
    Preoperative CA19-9: a competitive predictor of recurrence in patients with colorectal cancer liver metastases after hepatectomy. Liu Jia-Ming,Wang Yan-Yan,Liu Wei,Xu Da,Wang Kun,Xing Bao-Cai International journal of colorectal disease PURPOSE:The role of preoperative carbohydrate antigen 19-9 (CA19-9) in colorectal cancer liver metastases (CRLM) patients is still unclear. The present study aimed to explore the prognostic significance of preoperative CA19-9 in those patients. METHODS:A total of 691 CRLM patients were included in this study. X-tile analyses were performed to determine the optimal cut-off values of CA19-9 and carcinoembryonic antigen (CEA). Prognostic predictors were identified by multivariate analyses. RESULTS:The optimal cut-off values of CA19-9 and CEA for 5-year recurrence-free survival (RFS) were 35.24 U/ml and 20.4 ng/ml, respectively. Patients with high-level CA19-9 had significantly worse RFS and overall survival (OS) than those with low-level CA19-9 (P = 0.001 and P = 0.002, respectively). In addition, patients with high-level CA19-9 had poor RFS and OS (P = 0.028 and P = 0.011, respectively) at low-level CEA. Multivariate analyses confirmed that preoperative CA19-9 was an independent predictor for RFS (hazard ratio [HR] 1.295; 95% confidence interval [CI] 1.043-1.607; P = 0.019) but not for OS (HR 1.213; 95% CI 0.902-1.631; P = 0.201). CONCLUSION:CA19-9 is a promising predictor of recurrence for CRLM patients undergoing hepatectomy, and an effective supplement for patients with low-level CEA. 10.1007/s00384-020-03828-z
    Preoperative iron status is a prognosis factor for stage II and III colorectal cancer. Sawayama Hiroshi,Miyamoto Yuji,Mima Kosuke,Kato Rikako,Ogawa Katsuhiro,Hiyoshi Yukiharu,Shimokawa Mototsugu,Akiyama Takahiko,Kiyozumi Yuki,Iwagami Shiro,Iwatsuki Masaaki,Baba Yoshifumi,Yoshida Naoya,Baba Hideo International journal of clinical oncology BACKGROUND:Iron deficiency anemia is represented in colorectal cancer (CRC) patients. Iron surplus load to increase non-transferrin bound iron (NTBI), and NTBI promotes cancer progression and influences microbiota. This study investigated whether preoperative serum iron status was associated with prognosis after CRC resection. METHODS:We evaluated preoperative iron and transferrin saturation (TSAT), which was calculated as iron divided by total iron-binding capacity, in 327 patients who underwent surgery for Stage II-III CRC. Fe < 60 μg/dl and TSAT > 40% were defined as low and high iron, respectively. The associations between iron status and overall survival (OS) were evaluated in univariate and multivariate Cox proportional hazards analysis. RESULTS:Of the 327 patients, 179 (54.7%), 124 (37.9%) and 24 (7.3%) had low, normal and high iron, respectively. In univariate analysis, low iron was associated with shorter OS (hazard ratio [HR] 2.821, 95% confidence interval [CI] 1.451-5.485, P = 0.002). High iron was also associated with shorter OS (HR 3.396, 95% CI 1.359-8.489, P = 0.009). In multivariate analysis, high age (P = 0.002), depth of invasion pT4 (P = 0.012), lymph-node metastasis presence (P = 0.035), low albumin (P = 0.011), low iron (HR 2.282, 95% CI 1.163-4.478, P = 0.016) and high iron (HR 3.757, 95% CI 1.486-9.494 P = 0.005) were independently associated with shorter OS. High iron was associated with the amount of intratumoral Fusobacterium nucleatum compared with normal iron. CONCLUSION:Both low and high preoperative iron in Stage II-III CRC patients were associated with unfavorable OS in univariate and multivariate analyses. 10.1007/s10147-021-01995-9
    A novel risk stratification for predicting prognosis of colorectal cancer patients with bone metastasis. Ma Xiaolong,Guan Xu,Ma Chenxi,Quan Jichuan,Zhao Zhixun,Chen Haipeng,Huang Haiyang,Wei Ran,Liu Zheng,Jiang Zheng,Chen Yinggang,Wang Xishan Journal of gastrointestinal oncology Background:Our understanding in prognosis of bone metastasis (BM) from colorectal cancer (CRC) is limited. We aimed to establish a clinical risk stratification for individually predicting the survival of CRC patients with BM. Methods:A total of 200 CRC patients with BM were included in this study. Survival time from BM diagnosis was estimated using the Kaplan-Meier method. The multivariable COX regression model identified the risk factors on cancer specific survival (CSS). Based on weighted scoring system, the stratification model was constructed to classify patients with BM according to prognostic risk. Discrimination power and calibration ability of risk stratification were measured. Results:The median CSS time was 11 months after BM diagnosis. Lymph node metastasis, Carbohydrate antigen 199 (CA199) levels, bone involvement, Karnofsky Performance Status (KPS) scores, primary tumor resection, bisphosphonates therapy and radiotherapy were identified as predictors of CSS. Four risk groups were stratified according to weighted scoring system, including low risk, medium risk, medium-high risk and high risk group, with 35, 16, 9 and 5 months of median CSS, respectively (P=0.000). The risk stratification displayed good accuracy in predicting CSS, with acceptable discrimination and calibration. Conclusions:This novel risk stratification predicts CSS in CRC patient with BM using easily accessible clinicopathologic factors, which is recommended for use in individualized clinical decision making in patient with BM. 10.21037/jgo-20-586
    Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis. Khan Umama,Chowdhury Sabrina,Billah Md Morsaline,Islam Kazi Mohammed Didarul,Thorlacius Henrik,Rahman Milladur International journal of molecular sciences Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy. 10.3390/ijms22147260
    Development and Validation of a Prognostic Nomogram for Colorectal Cancer Patients With Synchronous Peritoneal Metastasis. Yang Zifeng,Li Yong,Qin Xiusen,Lv Zejian,Wang Huaiming,Wu Deqing,Yuan Zixu,Wang Hui Frontiers in oncology Purpose:Synchronous peritoneal metastasis (S-PM) is considered a poor prognostic factor for colorectal cancer (CRC) and there is no nomogram to predict the survival of these patients. In this study, we aimed to use a multicenter data to identify the factors associated with S-PM of CRC to construct a nomogram for predicting the overall survival (OS) of these patients. Methods:CRC patients with S-PM from two medical centers were enrolled between September 2007 and June 2017. Multivariate analysis was used to identify independent factors associated with OS for the nomogram to predict the 1-, 2-, and 3-year OS rates in the development group. The concordance index (C-index), calibration plot, relative operating characteristic (ROC) curve with area under the curve (AUC) were calculated to evaluate the performance of the nomogram in both the development and an external validation group. Results:277 CRC patients with S-PM in the development group and 68 patients in the validation group were eligible for this study. In multivariate analysis of development group, age, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and chemotherapy were independent variables for OS, based on which the nomogram was built. The C-index of the nomogram in the development and validation group was 0.701 (95% Cl, 0.666-0.736) and 0.716 (95% Cl, 0.622-0.810); demonstrating good discriminative ability. The calibration plots showed satisfactory consistency between actual observation and nomogram-predicted OS probabilities in the development and external validation group. The nomogram showed good predictive accuracy for 1-, 2-, and 3-year OS rates in both groups with AUC >0.70. An online dynamic webserver was also developed for increasing the ease of the nomogram. Conclusions:We developed and validated a predictive nomogram with good discriminative and high accuracy to predict the OS in CRC patients with S-PM. 10.3389/fonc.2021.615321
    Risk scoring system for recurrence after simultaneous resection of colorectal cancer liver metastasis. Wu Yuchen,Guo Tianan,Xu Zhenhong,Liu Fangqi,Cai Sanjun,Wang Lu,Xu Ye Annals of translational medicine Background:The simultaneous resection of synchronous colorectal cancer liver metastasis (SCRLM) has been widely applied. It is necessary to establish a risk scoring system to predict post-operative recurrence, especially in patients with neoadjuvant treatment. Methods:The medical records of 221 patients undergoing simultaneous resection of CRLM were assessed in this study with a further 128 patients allocated to a validation group. All patients in the study group were classified according to their history of neoadjuvant treatment and univariate and multivariate analyses were applied to study independent risk factors. A score model was then generated according to the factors included. Our data set were also applied to validate three other existing scoring models [Fong clinical recurrence score (CRS), Konopke, and Zakaria disease-free survival (DFS) score], and the concordance index was calculated for comparison among these models. Results:CRLM involving more than three nodes positive for a primary tumor was considered an independent risk factor for progression in patients without neoadjuvant treatment and all score models could discretely stratify patients according to disease free survival. In patients receiving neoadjuvant treatment, CRLM involving more than one node and transfusion invasion were major determinants in patients after treatment. However, only our scoring system and Fong's CRS score could discretely discriminate patients. In the validation group, patients were significantly classified with the score system. Conclusions:Existing score models had better values for determining prognosis in patients with SCRLM, especially in those undertaking neoadjuvant treatment. Larger cohorts, along with more detailed clinical features and multicenter validation should be undertaken before utilization. 10.21037/atm-21-2595
    Dietary Melatonin and Glycine Decrease Tumor Growth through Antiangiogenic Activity in Experimental Colorectal Liver Metastasis. Kvietkauskas Mindaugas,Zitkute Viktorija,Leber Bettina,Strupas Kestutis,Stiegler Philipp,Schemmer Peter Nutrients Despite multimodal treatment strategies, clinical outcomes of advanced stage colorectal cancer (CRC) patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Since both melatonin and glycine have anti-cancer activities without relevant side effects, this study was designed to investigate their combined effects in experimental CRC liver metastases. CRC metastasis with CC531 cells were induced in male Wistar rats. Melatonin and glycine alone or their combination were supplemented for 14 days ( = 100). Blood parameters, a micro-computed tomography scan (tumor volume over time), and immunohistochemistry for Ki67 and CD31 expression in tumor tissue were compared between groups. Melatonin and glycine alone significantly reduced the tumor volume by 63.2% ( = 0.002) and 43% ( = 0.044) over time, respectively, while tumor volume increased by 8.7% in the controls. Moreover, treatment with melatonin and glycine alone reduced the tumor proliferation index. Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters. The leukocyte count was significantly increased with melatonin at the end of the experiment ( = 0.012) which was due to a high lymphocytes count. Tumor microvascular density was significantly reduced in all treatment groups. The results of this study suggest an inhibitory function for melatonin and glycine alone in the case of CRC liver metastasis growth by acting as natural antiangiogenic molecules, followed by angiogenesis-dependent cancer proliferation and immunomodulation. 10.3390/nu13062035
    MicroRNA-29b is a Novel Prognostic Marker in Colorectal Cancer. Inoue Akira,Yamamoto Hirofumi,Uemura Mamoru,Nishimura Junichi,Hata Taishi,Takemasa Ichiro,Ikenaga Masakazu,Ikeda Masataka,Murata Kohei,Mizushima Tsunekazu,Doki Yuichiro,Mori Masaki Annals of surgical oncology PURPOSE:Recent studies have suggested that microRNA-29 (miR-29) family members may play important roles in human cancer by regulating cell proliferation, differentiation, apoptosis, migration, and invasion. The present study aimed to investigate the clinical significance and biological function of miR-29b in colorectal cancer (CRC). METHODS:Real-time polymerase chain reaction was used to quantify miR-29b expression. The association between miR-29b and survival was evaluated in 245 patients with CRC. We transfected an miR-29b mimetic into CRC cells to explore the functional role of miR-29b in vitro, based on a proliferation assay, flow cytometry, and Western blotting. RESULTS:In clinical samples of CRC, miR-29b expression was significantly reduced in tumor tissues compared with normal mucosa (p < 0.012). Multivariate survival analyses indicated that miR-29b expression was an independent prognostic factor for disease-free survival (p = 0.026), lymph node metastasis (p = 0.004), and pathological T classification (p = 0.002). In a multivariate analysis of 5-year overall survival, we found a similar association between lymph node metastasis, pathological T classification, venous invasion, and miR-29b expression (p = 0.013). In vitro, low Ki-67-positive staining showed that administration of the mimic-miR-29b reduced proliferation of CRC cells. An Annexin V apoptosis assay and flow cytometric analysis revealed that miR-29b induced apoptosis and arrested the cell cycle at the G1/S transition. Moreover, miR-29b inhibited the expression of MCL1 and CDK6. CONCLUSIONS:Our findings indicated that miR-29b may be a useful, novel, prognostic marker and may play important roles in regulating apoptosis and cell cycle in CRC. 10.1245/s10434-014-4255-8
    Serum microRNA-29a is a promising novel marker for early detection of colorectal liver metastasis. Wang Long-Gang,Gu Jin Cancer epidemiology BACKGROUND:Colorectal cancer (CRC) metastasis occurs in various organs, most frequently in liver. Serological examination including tumor and biochemical markers for liver function evaluation is routinely performed, though its accuracy is not high. MicroRNAs (miRNAs) have been implicated in a variety of human diseases including cancer, and have many characteristics of an ideal biomarker most notably their inherent stability and resilience. Recently, several studies have indicated that circulating miRNAs hold much potential as novel noninvasive biomarkers for cancer and other disease processes. The objective of this study was to investigate the potential of serum miRNAs as novel biomarkers for CRC with liver metastasis. METHODS:This study was divided into three phases: (I) 3 candidate serum miRNAs were detected by using real-time RT-PCR, corresponding 38 CRC patients with liver metastasis and 36 CRC patients without metastasis. (II) Marker validation by real-time RT-PCR on a similar cohort of age- and sex-matched CRC patients without (n=20) and with liver metastasis (n=20). (III) We examined the correlation between the expressions of candidate serum miRNAs with clinical parameters of CRC patients. RESULTS:Serum miR-29a was significantly higher in colorectal liver metastasis (CRLM) patients than in CRC patients. This marker yielded a receiver operating characteristic curve area of 80.3%. At a cutoff value of 0.155, the sensitivity was 75% and the specificity was 75% in discriminating metastatic from non-metastatic patients. In addition, increased levels of miR-29a expression were also observed in colorectal tumors from CRLM patients compared with CRC patients. No significant difference was observed in the levels of serum miR-92a between metastatic and non-metastatic patients. CONCLUSIONS:These findings suggest that serum miR-29a has strong potential as a novel noninvasive biomarker for early detection of CRC with liver metastasis. 10.1016/j.canep.2011.05.002
    A Gene-Related Nomogram for Preoperative Prediction of Lymph Node Metastasis in Colorectal Cancer. Wei Shuxun,Zang Jia,Jia Youpeng,Chen Aona,Xie Yayun,Huang Jian,Li Zheng,Nie Gang,Liu Hui,Liu Fuchen,Gao Wenchao Journal of investigative surgery : the official journal of the Academy of Surgical Research : To develop and validate a gene-related nomogram for predicting the risk of lymph node (LN) metastasis preoperatively in patients with colorectal cancer (CRC). : RNA-seq data of 581 CRC and 51 normal cases with clinical features were downloaded from TCGA database. In the evaluation cohort with 381 CRC cases, the LASSO regression was used to reduce dimensionality of gene signatures extracted to build gene score. A gene-related nomogram was performed based on the multivariable logistic regression analysis. The performance of the nomogram was assessed by the discrimination, calibration, and clinical usefulness not only in the evaluation, but also in the validation cohort with 200 CRC cases. : A total of 12,590 differentially expressed genes were selected, in which 59 candidates associated with LN metastasis in differentially expressed genes set were screened by LASSO to form the gene score. Based on the analysis of multivariate logistic regression, the gene-related nomogram showed good calibration and discrimination not only in the evaluation cohort (concordance-index 0.93; 95%CI 0.91-0.96), but also in the validation cohort (concordance-index 0.70; 95%CI 0.63-0.78). The decision curve analysis of the gene-related nomogram also provides constructive guidance for the design of operation plan, preoperatively. : The presented genes nomogram may predict the LN metastasis in CRC patients, preoperatively. And 59 hub genes were defined related to LN metastasis of CRC, which can serve as treatment targets for the further study. Preoperative biopsy and gene analysis are needed to develop the operation plan in clinical practice. 10.1080/08941939.2019.1569738
    Association of albumin-bilirubin score in patients with colorectal cancer receiving later-line chemotherapy with regorafenib. Watanabe Daichi,Fujii Hironori,Yamada Yunami,Matsuhashi Nobuhisa,Makiyama Akitaka,Iihara Hirotoshi,Takahashi Takao,Kiyama Shigeru,Kobayashi Ryo,Yoshida Kazuhiro,Suzuki Akio International journal of clinical oncology BACKGROUND:Regorafenib is recognized as a later-line standard treatment in patients with metastatic colorectal cancer (mCRC). In this study, we examined the association of the albumin-bilirubin (ALBI) score in patients with mCRC receiving later-line chemotherapy with regorafenib. PATIENTS AND METHODS:We retrospectively analyzed data from patients with mCRC treated with regorafenib in a later line between January 2013 and December 2019. Patients were divided into a Normal-ALBI group (ALBI grade 1) and a High-ALBI group (ALBI grades 2 and 3). Primary endpoint was median overall survival (OS) and secondary endpoints were median time to treatment failure (TTF) and incidence of adverse events (AEs). RESULTS:Data from 60 patients were analyzed (Normal-ALBI group: 32 patients and High-ALBI group: 28 patients). Median OS [10.23 vs. 3.70 months, hazard ratio (HR): 1.79, 95% confidence interval (CI) 1.02-3.13, p = 0.041] and median TTF (2.27 vs. 1.78 months, HR: 1.78, 95%CI 1.02-3.09, p = 0.042) were significantly longer in the Normal-ALBI group than High-ALBI group. On Cox proportional hazard analysis, ALBI score was significantly correlated with OS. The incidence of liver dysfunction (grade ≥ 2) was significantly higher in the High-ALBI than the Normal-ALBI group (42.9% vs. 15.6%, p = 0.041), whereas other AEs were comparable between the two groups. CONCLUSION:ALBI was strongly associated with the prognosis of patients with mCRC treated with regorafenib and with the occurrence of liver-related adverse events. These findings may imply that patients with a high ALBI score should not be treated with regorafenib. 10.1007/s10147-021-01910-2
    Prognostic Significance of the Immunological Indices in Patients Who Underwent Complete Resection of Pulmonary Metastases of Colorectal Cancer. Okazaki Yuki,Shibutani Masatsune,Wang E N,Nagahara Hisashi,Fukuoka Tatsunari,Iseki Yasuhito,Kashiwagi Shinichiro,Tanaka Hiroaki,Maeda Kiyoshi,Hirakawa Kosei,Ohira Masaichi In vivo (Athens, Greece) BACKGROUND/AIM:The neutrophil-to-lymphocyte ratio (NLR) and the density of tumor-infiltrating lymphocytes (TILs) have been reported as immunological prognostic factors for various cancers. We evaluated the association between the prognosis and the immunological status in patients who underwent complete resection of pulmonary metastases of colorectal cancer (CRC). PATIENTS AND METHODS:We evaluated the associations between the NLR before the resection of pulmonary metastases and the relapse-free survival (RFS) or overall survival (OS), or between the density of TILs in the pulmonary metastasis and the RFS or OS. RESULTS:The RFS and OS were significantly worse in the NLR-High group than in the NLR-Low group. The RFS was significantly longer in the CD3TILs-High group than in the CD3TILs-Low group. CONCLUSION:The NLR and the density of TILs may have prognostic significance in patients who undergo complete resection of pulmonary metastases of CRC. 10.21873/invivo.12354
    A 20-year single center experience in the surgical treatment of colorectal liver metastasis. Tsalis Konstantinos,Ioannidis Orestis,Cheva Angeliki,Antigoni Savvala Natalia,Antoniou Nikolaos,Parpoudi Styliani,Kyziridis Dimitrios,Tatsis Dimitrios,Konstantaras Dimitrios,Kitsikosta Loukiani,George Pramateftakis Manousos,Kotidis Efstathios,Avgerinos Antonios,Mantzoros Ioannis Journal of B.U.ON. : official journal of the Balkan Union of Oncology PURPOSE:To present our experience in the treatment of patients with liver metastases from colorectal cancer. METHODS:The surgical and histopathological records of our department dating from 1st January 1997 to 31 December 2016 were examined, searching for patients who have undergone surgical treatment of colorectal liver metastasis. RESULTS:A total of 90 patients with colorectal liver metastases were treated in the last 20 years in our department. Their mean age was 65.28 years and 54 (60%) were male. The primary tumor was in the colon in 71 patients (78.9%) and in 19 (21.1%) patients in the rectum. Thirty-six (40%) patients presented with synchronous metastatic liver disease, from which 27 were subjected to simultaneous resection, 2 underwent a liver-first approach and 7 were subjected to resection of primary tumor first. Regarding the number of metastases 67 (74.4%) patients had single metastasis, 12 (13.3%) had 2 lesions, 4 (4.4%) had 3 lesions and 7 (7.8%) had 4-8 lesions. In-hospital and 30-day mortality was 3.85%. Median survival was 41 months. CONCLUSION:Surgical resection is the treatment of choice for the management of liver metastasis from colorectal cancer and can be safely performed. Follow up of patients with colorectal cancer is imperative as metachronous metastasis presents in a significant percentage of patients with negative locoregional lymph nodes of the primary tumor. The order of resection doesn't seem to alter outcome in synchronous metastasis. Recurrence is common and re-resection if feasible is the only chance of cure.
    Applicability of postoperative carcinoembryonic antigen levels in determining post-liver-resection adjuvant chemotherapy regimens for colorectal cancer hepatic metastasis. Chiang Jy-Ming,Hung Hsin-Yuan,You Jeng-Fu,Chiang Sum-Fu,Lee Chen-Fang,Chou Hong-Shiue,Lee Wei-Chen,Chan Kun-Ming Medicine Liver resection (LR) is the standard procedure for treating colorectal cancer (CRC) hepatic metastasis; however, LR associated with a high recurrence incidence. This study aimed to determine an optimal post-LR adjuvant chemotherapeutic strategy to improve overall long-term patient outcomes. A retrospective study of 490 patients who had undergone curative LR for CRC hepatic metastasis was performed. Patients who underwent post-LR adjuvant chemotherapy demonstrated high overall survival (OS) rates (hazard ratio [HR] = 0.58, P = .002) but not high recurrence-free survival (RFS) rates (HR = 1.02, P = .885). Moreover, OS was significantly longer in patients who underwent 5-fluorouracil + leucovorin (5-FU/LV; HR = 0.63, P = .039), oxaliplatin-based chemotherapy (HR = 0.45, P < .001), or irinotecan-based chemotherapy with bevacizumab (HR = 0.64, P = .040) than in those who did not. Among patients with carcinoembryonic antigen (CEA) levels of <5 ng/mL at 1 month after LR, significant differences were noted only in those who underwent 5-FU/LV (HR = 0.58, P = .035) and oxaliplatin-based chemotherapy (HR = 0.38, P < .001). In conclusion, perioperative CEA levels are crucial in prognosis and treatment of patients with CRC hepatic metastasis after LR. Additionally, certain regimens of adjuvant chemotherapy alongside post-LR CEA levels may provide beneficial results. 10.1097/MD.0000000000017696
    Proteomic analysis to identify biomarkers in the primary tumour that predict response to neoadjuvant chemotherapy in liver metastases. Sutton Paul,Evans Jonathan,Jones Robert,Malik Hassan,Vimalachandran Dale,Palmer Daniel,Goldring Chris,Kitteringham Neil Lancet (London, England) BACKGROUND:Colorectal cancer is the fourth commonest cancer in the UK, and the second commonest cause of cancer-related death. A knowledge of the biological phenotype of colorectal liver metastases would be invaluable to inform clinical decision making; however, deriving this information from the metastatic lesions is not feasible until after resection. We aimed to use proteomic analysis to identify biomarkers in the primary tumour that predict response to neoadjuvant chemotherapy in liver metastases. METHODS:Fresh tissue from both primary colorectal tumour and liver metastases from 17 patients was subjected to proteomic analysis using isobaric tagging for relative quantification. Data were analysed with Protein Pilot (Ab Sciex, Framingham, MA, USA), with stratification of patients into those showing low or high response to chemotherapy permitting the identification of potential predictive biomarkers. These markers were subsequently validated by immunohistochemistry on a tissue microarray of 63 patients. FINDINGS:We identified 5768 discrete proteins. Five of them predicted histopathological response to fluorouracil-based chemotherapy regimens, of which the FAD binding protein NQO1 was subsequently validated by immunohistochemistry. When compared with the chemotherapeutic agent alone, knockdown of the corresponding gene with small interfering RNA decreased cell viability when co-incubated with fluorouracil (77·1% vs 46·6%, p=0·037) and irinotecan (41·7% vs 24·4%, p=0·006). Similar results were also seen after inhibition of protein activity by pretreating cells with dicoumarol. INTERPRETATION:These results show that proteomic sequencing of matched metastatic colorectal cancer samples is feasible, with high protein coverage. The high degree of similarity between the primary and secondary proteomes suggests that primary tissue is predictive of the metastatic phenotype. NQO1 expression in the primary tumour predicts response to neoadjuvant chemotherapy in the liver metastases, and inhibition of this protein at both genetic and functional levels improves chemosensitivity. FUNDING:Cancer Research UK. 10.1016/S0140-6736(15)60410-X
    Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer. Russo Mariangela,Siravegna Giulia,Blaszkowsky Lawrence S,Corti Giorgio,Crisafulli Giovanni,Ahronian Leanne G,Mussolin Benedetta,Kwak Eunice L,Buscarino Michela,Lazzari Luca,Valtorta Emanuele,Truini Mauro,Jessop Nicholas A,Robinson Hayley E,Hong Theodore S,Mino-Kenudson Mari,Di Nicolantonio Federica,Thabet Ashraf,Sartore-Bianchi Andrea,Siena Salvatore,Iafrate A John,Bardelli Alberto,Corcoran Ryan B Cancer discovery UNLABELLED:How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient. SIGNIFICANCE:Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance. 10.1158/2159-8290.CD-15-1283
    Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer. Hur Keun,Toiyama Yuji,Okugawa Yoshinaga,Ide Shozo,Imaoka Hiroki,Boland C Richard,Goel Ajay Gut BACKGROUND AND AIMS:Distant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis. METHODS:MiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation. RESULTS:MiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls. CONCLUSIONS:High levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC. 10.1136/gutjnl-2014-308737
    PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis. Nguyen Alexander,Loo Jia Min,Mital Rohit,Weinberg Ethan M,Man Fung Ying,Zeng Zhaoshi,Paty Philip B,Saltz Leonard,Janjigian Yelena Y,de Stanchina Elisa,Tavazoie Sohail F The Journal of clinical investigation Colorectal cancer metastasis to the liver is a major cause of cancer-related death; however, the genes and pathways that govern this metastatic colonization event remain poorly characterized. Here, using a large-scale in vivo RNAi screen, we identified liver and red blood cell pyruvate kinase (PKLR) as a driver of metastatic liver colonization. PKLR expression was increased in liver metastases as well as in primary colorectal tumors of patients with metastatic disease. Evaluation of a murine liver colonization model revealed that PKLR promotes cell survival in the tumor core during conditions of high cell density and oxygen deprivation by increasing glutathione, the primary endogenous antioxidant. PKLR negatively regulated the glycolytic activity of PKM2, the major pyruvate kinase isoenzyme known to regulate cellular glutathione levels. Glutathione is critical for metastasis, and we determined that the rate-limiting enzyme of glutathione synthesis, GCLC, becomes overexpressed in patient liver metastases, promotes cell survival under hypoxic and cell-dense conditions, and mediates metastatic liver colonization. RNAi-mediated inhibition of glutathione synthesis impaired survival of multiple colon cancer cell lines, and pharmacological targeting of this metabolic pathway reduced colonization in a primary patient-derived xenograft model. Our findings highlight the impact of metabolic reprogramming within the niche as metastases progress and suggest clinical potential for targeting this pathway in colorectal cancer. 10.1172/JCI83587
    Treatment of colorectal peritoneal metastases requires multidisciplinary efforts. Goéré Diane,Gelli Maximiliano The Lancet. Oncology 10.1016/S1470-2045(16)30490-9
    Cancer: Therapy for colorectal cancer liver metastases: understanding resistance. Ray Katrina Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2016.183
    Improving treatment of liver metastases by targeting nonangiogenic mechanisms. Emblem Kyrre E,Jain Rakesh K Nature medicine 10.1038/nm.4228
    Tumor Deposits in Colorectal Cancer: Improving the Value of Modern Staging-A Systematic Review and Meta-Analysis. Nagtegaal Iris D,Knijn Nikki,Hugen Niek,Marshall Helen C,Sugihara Kenichi,Tot Tibor,Ueno Hideki,Quirke Philip Journal of clinical oncology : official journal of the American Society of Clinical Oncology Purpose Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The role of tumor deposits (TDs) in staging remains debated. We have assessed the relation of TDs with metastatic pattern to evaluate whether TDs might add significant new information to staging. Methods We performed a systematic literature search that was focused on the role of TDs in CRC. Studies with neoadjuvant-treated patients were excluded. Data on stage, histologic factors, and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TDs, lymph node metastases (LNMs), and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. Results Of 10,106 included patients with CRC, 22% presented with TDs. TDs are invariably associated with poor outcome. Presence of TDs was associated with presence of LNMs and EMVI. In a pairwise comparison, effects of TD were stronger than those of both LNMs and EMVI. In the logistic regression model, TDs in combination with LNMs is the strongest predictor for liver (odds ratio [OR], 5.5), lung (OR, 4.3) and peritoneal metastases (OR, 7.0). Presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. Conclusion We have shown that TDs are not equal to LNMs or EMVI with respect to biology and outcome. We lose valuable prognostic information by allocating TDs into nodal category N1c and only considering TDs in the absence of LNMs. Therefore, we propose that the number of TDs should be added to the number of LNMs to derive a final N stage. 10.1200/JCO.2016.68.9091
    Hepatic atrophy following preoperative chemotherapy predicts hepatic insufficiency after resection of colorectal liver metastases. Yamashita Suguru,Shindoh Junichi,Mizuno Takashi,Chun Yun Shin,Conrad Claudius,Aloia Thomas A,Vauthey Jean-Nicolas Journal of hepatology BACKGROUND & AIMS:For patients with colorectal liver metastases (CLM) undergoing major hepatectomy, extensive preoperative chemotherapy has been associated with increased morbidity and mortality. The impact of extensive chemotherapy on total liver volume (TLV) change is unclear. The aims of the current study were twofold: (1) to determine the change of TLV following preoperative chemotherapy in patients undergoing resection for CLM and (2) to investigate the correlations among TLV change, postoperative hepatic insufficiency (PHI), and death from liver failure. METHODS:Clinicopathological features of patients with CLM who underwent preoperative chemotherapy and curative resection were reviewed (2008-2015). TLV change (degree of atrophy) was defined as the percentage difference of TLV (estimated by manual volumetry)/standardized liver volume (SLV) ratio: ([Pre-chemotherapy TLV]-[Post-chemotherapy TLV])×100÷SLV (%). Receiver operating characteristic (ROC) analysis was performed to decide the accurate cut-off value of degree of atrophy to predict PHI. The Cox proportional hazard model was performed to identify the predictors of severe degree of atrophy and PHI. RESULTS:The study cohort consisted of 459 patients, of which 154 patients (34%) underwent extensive preoperative chemotherapy (≥7 cycles). ROC analysis identified the degree of atrophy ≥10% as an accurate cut-off to predict PHI, which was significantly correlated with ≥7 cycles of preoperative chemotherapy. Four factors independently predicted PHI: standardized future liver remnant ≤30% (odds ratio [OR] 4.03, p=0.019), high aspartate aminotransferase-to-platelet ratio index (OR 5.27, p=0.028), degree of atrophy ≥10% (OR 43.5, p<0.001), and major hepatic resection (OR 5.78, p=0.005). Degree of atrophy ≥10% was associated with increased mortality from liver failure (0% [0/374] vs. 15% [13/85], p<0.001). CONCLUSION:Extensive preoperative chemotherapy induced significant atrophic change of TLV. Degree of atrophy ≥10% is an independent predictor of PHI and death in patients with CLM undergoing preoperative chemotherapy and resection. LAY SUMMARY:Extensive preoperative chemotherapy for patients with colorectal liver metastases (CLM) could induce hepatic atrophy. A higher degree of atrophy is an independent predictor of postoperative hepatic insufficiency and death in patients with CLM undergoing preoperative chemotherapy and resection. 10.1016/j.jhep.2017.01.031
    The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Zhai Weiwei,Lim Tony Kiat-Hon,Zhang Tong,Phang Su-Ting,Tiang Zenia,Guan Peiyong,Ng Ming-Hwee,Lim Jia Qi,Yao Fei,Li Zheng,Ng Poh Yong,Yan Jie,Goh Brian K,Chung Alexander Yaw-Fui,Choo Su-Pin,Khor Chiea Chuen,Soon Wendy Wei-Jia,Sung Ken Wing-Kin,Foo Roger Sik-Yin,Chow Pierce Kah-Hoe Nature communications Hepatocellular carcinoma (HCC) has one of the poorest survival rates among cancers. Using multi-regional sampling of nine resected HCC with different aetiologies, here we construct phylogenetic relationships of these sectors, showing diverse levels of genetic sharing, spanning early to late diversification. Unlike the variegated pattern found in colorectal cancers, a large proportion of HCC display a clear isolation-by-distance pattern where spatially closer sectors are genetically more similar. Two resected intra-hepatic metastases showed genetic divergence occurring before and after primary tumour diversification, respectively. Metastatic tumours had much higher variability than their primary tumours, suggesting that intra-hepatic metastasis is accompanied by rapid diversification at the distant location. The presence of co-existing mutations offers the possibility of drug repositioning for HCC treatment. Taken together, these insights into intra-tumour heterogeneity allow for a comprehensive understanding of the evolutionary trajectories of HCC and suggest novel avenues for personalized therapy. 10.1038/ncomms14565
    A distinct role for Lgr5 stem cells in primary and metastatic colon cancer. de Sousa e Melo Felipe,Kurtova Antonina V,Harnoss Jonathan M,Kljavin Noelyn,Hoeck Joerg D,Hung Jeffrey,Anderson Jeffrey Eastham,Storm Elaine E,Modrusan Zora,Koeppen Hartmut,Dijkgraaf Gerrit J P,Piskol Robert,de Sauvage Frederic J Nature Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5 cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5 cells that continuously attempt to replenish the Lgr5 CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease. 10.1038/nature21713
    Indocyanine green fluorescence imaging in colorectal surgery: overview, applications, and future directions. Keller Deborah S,Ishizawa Takeaki,Cohen Richard,Chand Manish The lancet. Gastroenterology & hepatology Indocyanine green fluorescence imaging is a surgical tool with increasing applications in colorectal surgery. This tool has received acceptance in various surgical disciplines as a potential method to enhance surgical field visualisation, improve lymph node retrieval, and decrease the incidence of anastomotic leaks. In colorectal surgery specifically, small studies have shown that intraoperative fluorescence imaging is a safe and feasible method to assess anastomotic perfusion, and its use might affect the incidence of anastomotic leaks. Controlled trials are ongoing to validate these conclusions. The number of new indications for indocyanine green continues to increase, including innovative options for detecting and guiding management of colorectal metastasis to the liver. These advances could offer great value for surgeons and patients, by improving the accuracy and outcomes of oncological resections. 10.1016/S2468-1253(17)30216-9
    Surgery: KRAS mutations and hepatic recurrence after treatment of colorectal liver metastases. Brudvik Kristoffer Watten,Vauthey Jean-Nicolas Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2017.129
    Analysis of persistence and antibiotic response in colorectal cancer. Bullman Susan,Pedamallu Chandra S,Sicinska Ewa,Clancy Thomas E,Zhang Xiaoyang,Cai Diana,Neuberg Donna,Huang Katherine,Guevara Fatima,Nelson Timothy,Chipashvili Otari,Hagan Timothy,Walker Mark,Ramachandran Aruna,Diosdado Begoña,Serna Garazi,Mulet Nuria,Landolfi Stefania,Ramon Y Cajal Santiago,Fasani Roberta,Aguirre Andrew J,Ng Kimmie,Élez Elena,Ogino Shuji,Tabernero Josep,Fuchs Charles S,Hahn William C,Nuciforo Paolo,Meyerson Matthew Science (New York, N.Y.) Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with and its associated microbiome-including , , and species-is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors. In situ hybridization analysis revealed that is predominantly associated with cancer cells in the metastatic lesions. Mouse xenografts of human primary colorectal adenocarcinomas were found to retain viable and its associated microbiome through successive passages. Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced load, cancer cell proliferation, and overall tumor growth. These observations argue for further investigation of antimicrobial interventions as a potential treatment for patients with -associated colorectal cancer. 10.1126/science.aal5240
    Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer. Ishaque Naveed,Abba Mohammed L,Hauser Christine,Patil Nitin,Paramasivam Nagarajan,Huebschmann Daniel,Leupold Jörg Hendrik,Balasubramanian Gnana Prakash,Kleinheinz Kortine,Toprak Umut H,Hutter Barbara,Benner Axel,Shavinskaya Anna,Zhou Chan,Gu Zuguang,Kerssemakers Jules,Marx Alexander,Moniuszko Marcin,Kozlowski Miroslaw,Reszec Joanna,Niklinski Jacek,Eils Jürgen,Schlesner Matthias,Eils Roland,Brors Benedikt,Allgayer Heike Nature communications Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3' UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3' UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy. 10.1038/s41467-018-07041-z
    Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Zeng Zhicheng,Li Yuling,Pan Yangjian,Lan Xiaoliang,Song Fuyao,Sun Jingbo,Zhou Kun,Liu Xiaolong,Ren Xiaoli,Wang Feifei,Hu Jinlong,Zhu Xiaohui,Yang Wei,Liao Wenting,Li Guoxin,Ding Yanqing,Liang Li Nature communications Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis. 10.1038/s41467-018-07810-w
    Hepatocytes direct the formation of a pro-metastatic niche in the liver. Lee Jae W,Stone Meredith L,Porrett Paige M,Thomas Stacy K,Komar Chad A,Li Joey H,Delman Devora,Graham Kathleen,Gladney Whitney L,Hua Xia,Black Taylor A,Chien Austin L,Majmundar Krishna S,Thompson Jeffrey C,Yee Stephanie S,O'Hara Mark H,Aggarwal Charu,Xin Dong,Shaked Abraham,Gao Mingming,Liu Dexi,Borad Mitesh J,Ramanathan Ramesh K,Carpenter Erica L,Ji Ailing,de Beer Maria C,de Beer Frederick C,Webb Nancy R,Beatty Gregory L Nature The liver is the most common site of metastatic disease. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver. The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6-STAT3-SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets. 10.1038/s41586-019-1004-y
    Total circulating cell-free DNA as a prognostic biomarker in metastatic colorectal cancer before first-line oxaliplatin-based chemotherapy. Hamfjord J,Guren T K,Dajani O,Johansen J S,Glimelius B,Sorbye H,Pfeiffer P,Lingjærde O C,Tveit K M,Kure E H,Pallisgaard N,Spindler K-L G Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Metastatic colorectal cancer (mCRC) is a heterogeneous disease where prognosis is dependent both on tumor biology and host factors. Total circulating cell-free DNA (cfDNA) has shown to harbor prognostic information in mCRC, although less is known about the biological correlates of cfDNA levels in this patient group. The primary objective was to evaluate the prognostic value of pretreatment cfDNA in patients receiving the first-line oxaliplatin-based chemotherapy for mCRC, by using a predefined upper limit of normal (ULN) from a cohort of presumed healthy individuals. The secondary objective was to model cfDNA levels as a function of predefined tumor and host factors. PATIENTS AND METHODS:This was a retrospective post hoc study based on a prospective multicenter phase III trial, the NORDIC-VII study. DNA was purified from 547 plasma samples and cfDNA quantified by a droplet digital PCR assay (B2M, PPIA) with controls for lymphocyte contamination. Main clinical end point was overall survival (OS). RESULTS:cfDNA was quantified in 493 patients, 54 were excluded mainly due to lymphocyte contamination. Median cfDNA level was 7673 alleles/ml (1050-1 645 000) for B2M and 5959 alleles/ml (555-854 167) for PPIA. High cfDNA levels were associated with impaired outcome; median OS of 16.6 months for levels above ULN and 25.9 months for levels below ULN (hazard ratio = 1.83, 95% confidence interval 1.51-2.21, P < 0.001). The result was confirmed in multivariate OS analysis adjusting for established clinicopathological characteristics. A linear regression model predicted cfDNA levels from sum of longest tumor diameters by RECIST, the presence of liver metastases and systemic inflammatory response as measured by interleukin 6 (F(6, 357) = 62.7, P < 0.001). CONCLUSION:cfDNA holds promise as a minimally invasive and clinically relevant prognostic biomarker in mCRC before initiating first-line oxaliplatin-based chemotherapy and may be a complex entity associated with tumor burden, liver metastases and systemic inflammatory response. TRIAL REGISTRATION:ClinicalTrials.gov, NCT00145314. 10.1093/annonc/mdz139
    Quantitative evidence for early metastatic seeding in colorectal cancer. Hu Zheng,Ding Jie,Ma Zhicheng,Sun Ruping,Seoane Jose A,Scott Shaffer J,Suarez Carlos J,Berghoff Anna S,Cremolini Chiara,Falcone Alfredo,Loupakis Fotios,Birner Peter,Preusser Matthias,Lenz Heinz-Josef,Curtis Christina Nature genetics Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain. The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01 cm). We validated the association between early drivers and metastasis in an independent cohort of 2,751 colorectal cancers, demonstrating their utility as biomarkers of metastasis. This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis. 10.1038/s41588-019-0423-x
    Rapid evolution and biogeographic spread in a colorectal cancer. Alves Joao M,Prado-López Sonia,Cameselle-Teijeiro José Manuel,Posada David Nature communications How and when tumoral clones start spreading to surrounding and distant tissues is currently unclear. Here we leveraged a model-based evolutionary framework to investigate the demographic and biogeographic history of a colorectal cancer. Our analyses strongly support an early monoclonal metastatic colonization, followed by a rapid population expansion at both primary and secondary sites. Moreover, we infer a hematogenous metastatic spread under positive selection, plus the return of some tumoral cells from the liver back to the colon lymph nodes. This study illustrates how sophisticated techniques typical of organismal evolution can provide a detailed, quantitative picture of the complex tumoral dynamics over time and space. 10.1038/s41467-019-12926-8
    Prostaglandin E Induces miR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression. Cen Bo,Lang Jessica D,Du Yuchen,Wei Jie,Xiong Ying,Bradley Norma,Wang Dingzhi,DuBois Raymond N Gastroenterology BACKGROUND & AIMS:Prostaglandin E (PGE) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE on colorectal cancer (CRC) development. METHODS:We incubated LS174T colorectal cancer cells with PGE or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative polymerase chain reaction, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NOD-scidIL-2Rg mice were given injections of LS174T cells, and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes. RESULTS:We identified miRNA 675-5p (miR675-5p) as the miRNA most highly up-regulated by incubation of colorectal cancer cells with PGE. PGE increased expression of miR675-5p by activating expression of Myc, via activation of protein kinase B, also known as (AKT), nuclear factor κB, and β-catenin. PGE increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE formed more liver and lung metastases in mice than control LS174T cells. We identified a 3' untranslated region in the TP53 messenger RNA that bound miR675-5p; binding resulted in loss of the p53 protein. Expression of miR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC. CONCLUSIONS:We found that treatment of mice with PGE increased CRC cells invasive activity and ability to form liver and lung metastases. PGE down-regulates expression of p53 by increasing expression of miR675-5p, which binds to and prevents translation of TP53 messenger RNA. These findings provide insight into the mechanisms by which PGE promotes tumor development and progression. Strategies to target PGE might be developed for treatment of CRC. 10.1053/j.gastro.2019.11.013
    Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy. Shi Liangrong,Wang Junjun,Ding Nianhua,Zhang Yi,Zhu Yibei,Dong Shunli,Wang Xiaohui,Peng Changli,Zhou Chunhui,Zhou Ledu,Li Xiaodong,Shi Hongbing,Wu Wei,Long Xueyin,Wu Changping,Liao Weihua Nature communications Radiofrequency ablation (RFA) promotes tumor antigen-specific T cell responses and enhances the effect of immunotherapy in preclinical settings. Here we report that the existence of remnant tumor masses due to incomplete RFA (iRFA) is associated with earlier new metastases and poor survival in patients with colorectal cancer liver metastases (CRCLM). Using mouse models, we demonstrate that iRFA promotes tumor progression and hinders the efficacy of anti-PD-1 therapy. Immune analysis reveals that iRFA induces sustained local inflammation with predominant myeloid suppressor cells, which inhibit T cell function in tumors. Mechanistically, tumor cell-derived CCL2 is critical for the accumulation of monocytes and tumor-associated macrophages (TAMs). The crosstalk between TAMs and tumor cells enhances the CCL2 production by tumor cells. Furthermore, we find that administration of a CCR2 antagonist or the loss of CCL2 expression in tumor cells enhances the antitumor activity of PD-1 blockade, providing a salvage alternative for residual tumors after iRFA. 10.1038/s41467-019-13204-3
    Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases. Milette Simon,Hashimoto Masakazu,Perrino Stephanie,Qi Shu,Chen Michely,Ham Boram,Wang Ni,Istomine Roman,Lowy Andrew M,Piccirillo Ciriaco A,Brodt Pnina Nature communications Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8 T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease. 10.1038/s41467-019-13571-x
    Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Bridgewater John A,Pugh Siân A,Maishman Tom,Eminton Zina,Mellor Jane,Whitehead Amy,Stanton Louise,Radford Michael,Corkhill Andrea,Griffiths Gareth O,Falk Stephen,Valle Juan W,O'Reilly Derek,Siriwardena Ajith K,Hornbuckle Joanne,Rees Myrddin,Iveson Timothy J,Hickish Tamas,Garden O James,Cunningham David,Maughan Timothy S,Primrose John N, The Lancet. Oncology BACKGROUND:The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS:New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m administered intravenously over 2 h and oral capecitabine 1000 mg/m twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m every 2 weeks with regimen one and three or a loading dose of 400 mg/m followed by a weekly infusion of 250 mg/m with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS:Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION:Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING:Cancer Research UK. 10.1016/S1470-2045(19)30798-3
    ASCO 2020 Gastrointestinal Cancers Symposium. Pinion Sheila The lancet. Gastroenterology & hepatology 10.1016/S2468-1253(20)30045-5
    Plasticity in Motion: Shape-Shifting Lgr5Cells Initiate Colorectal Cancer Metastasis. Ganesh Karuna Cell stem cell In this issue of Cell Stem Cell, Fumagalli et al. (2020) employ intravital microscopy of colorectal cancer organoid xenografts to investigate the cell of origin of metastases. While tumor-initiating cells are Lgr5, most disseminated cancer cells are Lgr5 and seed liver metastases in which Lgr5 cells then appear, showing that bidirectional plasticity of phenotypic states drives metastasis. 10.1016/j.stem.2020.03.007
    Nano Codelivery of Oxaliplatin and Folinic Acid Achieves Synergistic Chemo-Immunotherapy with 5-Fluorouracil for Colorectal Cancer and Liver Metastasis. Guo Jianfeng,Yu Zhuo,Das Manisit,Huang Leaf ACS nano FOLFOX, the combinational strategy of folinic acid (FnA), 5-fluorouracil (5-Fu), and oxaliplatin (OxP), has been used as standard treatment of colorectal cancer (CRC) for decades. Despite the improved survival, patients still suffer from drawbacks such as low efficacy, high toxicity, and long course of treatment. New strategies to address these issues are needed to further clinical benefits. In this study, a nanoprecipitate (CHNOPt) was formed by the active form of OxP ([Pt(DACH)(HO)]) and FnA, which was formulated into an aminoethyl anisamide targeted PEGylated lipid nanoparticle within microemulsions using nanoprecipitation technique. The resultant formulation (namely Nano-Folox) significantly promoted the blood circulation and tumor accumulation of platinum drug and FnA in an orthotopic CRC mouse model. Emerging evidence indicates that OxP can not only provide anticancer cytotoxic effects but also induce immunogenic cell death (a type of apoptosis that primes anticancer immune responses). Consequently, Nano-Folox demonstrated favorable chemo-immunotherapeutic activities in orthotopic CRC mice. In addition, when compared to FOLFOX the significantly stronger chemo-immunotherapeutic responses were achieved by the combination of Nano-Folox and 5-Fu without showing toxicity. Moreover, the anti-PD-L1 monoclonal antibody enhanced Nano-Folox/5-Fu for decreased liver metastases in mice. These results indicate the potential of Nano-Folox-based combination strategy for the treatment of CRC. 10.1021/acsnano.0c01676
    Mapping the spreading routes of lymphatic metastases in human colorectal cancer. Zhang Chong,Zhang Lin,Xu Tianlei,Xue Ruidong,Yu Liang,Zhu Yuelu,Wu Yunlong,Zhang Qingqing,Li Dongdong,Shen Shuohao,Tan Dongfeng,Bai Fan,Zhang Haizeng Nature communications Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). How tumor cells disseminate within the lymphatic network remains largely unknown. Here, we analyze the subclonal structure of 94 tumor samples, covering the primary tumors, lymph node metastases (LNMs), and liver metastases from 10 CRC patients. We portray a high-resolution lymphatic metastatic map for CRC by dividing LNMs into paracolic, intermediate, and central subgroups. Among the 61 metastatic routes identified, 38 (62.3%) are initiated from the primary tumors, 22 (36.1%) from LNMs, and 1 from liver metastasis (1.6%). In 5 patients, we find 6 LNMs that reseed 2 or more LNMs. We summarize 3 diverse modes of metastasis in CRC and show that skip spreading of tumor cells within the lymphatic network is common. Our study sheds light on the complicated metastatic pattern in CRC and has great clinical implications. 10.1038/s41467-020-15886-6
    Hepatic metastases resection after cetuximab: are we missing something? Ulusakarya Ayhan,Innominato Pasquale F,Bouchahda Mohamed,Levi Francis A,Adam René The Lancet. Oncology 10.1016/S1470-2045(20)30144-3
    Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer. Shen Ying,Wang Xiaohong,Lu Junyan,Salfenmoser Martin,Wirsik Naita Maren,Schleussner Nikolai,Imle Andrea,Freire Valls Aida,Radhakrishnan Praveen,Liang Jie,Wang Guoliang,Muley Thomas,Schneider Martin,Ruiz de Almodovar Carmen,Diz-Muñoz Alba,Schmidt Thomas Cancer cell Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher in liver metastases than in primary colorectal tumors. Highly activated metastasis-associated fibroblasts increase tissue stiffness, which enhances angiogenesis and anti-angiogenic therapy resistance. Drugs targeting the renin-angiotensin system, normally prescribed to treat hypertension, inhibit fibroblast contraction and extracellular matrix deposition, thereby reducing liver metastases stiffening and increasing the anti-angiogenic effects of bevacizumab. Patients treated with bevacizumab showed prolonged survival when concomitantly treated with renin-angiotensin inhibitors, highlighting the importance of modulating the mechanical microenvironment for therapeutic regimens. 10.1016/j.ccell.2020.05.005
    Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial. Tang Wentao,Ren Li,Liu Tianshu,Ye Qinghai,Wei Ye,He Guodong,Lin Qi,Wang Xiaoying,Wang Mingliang,Liang Fei,Cui Yuehong,Xu Jianmin Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:To assess the effects of bevacizumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) as first-line treatment of mutant unresectable colorectal liver metastases. METHODS:From October 2013 to December 2017, patients with mutant unresectable liver-limited metastases from colorectal cancer were randomly assigned to receive mFOLFOX6 plus bevacizumab (arm A) or mFOLFOX6 alone (arm B). The resectability of liver metastases was determined by a local multidisciplinary team. The primary end point was the actual rate of patients converted to R0 resection for liver metastases. Secondary end points included tumor response, survival, and toxicity. The block randomization method was used. RESULTS:The intention-to-treat population comprised 241 patients. A total of 121 patients were randomly assigned to arm A and 120 to arm B. The median follow-up time was 37.0 months for all patients. The R0 resection rates for liver metastases were 22.3% (27 of 121 patients) in arm A and 5.8% (7 of 120 patients) in arm B, with a significant difference ( < .01). Patients in arm A had significantly better objective response rates (54.5% 36.7%; < .01), median progression-free survival (9.5 5.6 months; < .01) and median overall survival (25.7 20.5 months; = .03) compared with those in arm B. The addition of bevacizumab was associated with more frequent proteinuria (9.9% 3.3%; = .04) and hypertension (8.3% 2.5%; < .05). CONCLUSION:For patients with initially unresectable mutant colorectal liver metastases, bevacizumab combined with mFOLFOX6 increased the resectability of liver metastases and improved response rates and survival compared with mFOLFOX6 alone. 10.1200/JCO.20.00174
    Modern therapeutic approaches for the treatment of malignant liver tumours. Petrowsky Henrik,Fritsch Ralph,Guckenberger Matthias,De Oliveira Michelle L,Dutkowski Philipp,Clavien Pierre-Alain Nature reviews. Gastroenterology & hepatology Malignant liver tumours include a wide range of primary and secondary tumours. Although surgery remains the mainstay of curative treatment, modern therapies integrate a variety of neoadjuvant and adjuvant strategies and have achieved dramatic improvements in survival. Extensive tumour loads, which have traditionally been considered unresectable, are now amenable to curative treatment through systemic conversion chemotherapies followed by a variety of interventions such as augmentation of the healthy liver through portal vein occlusion, staged surgeries or ablation modalities. Liver transplantation is established in selected patients with hepatocellular carcinoma but is now emerging as a promising option in many other types of tumour such as perihilar cholangiocarcinomas, neuroendocrine or colorectal liver metastases. In this Review, we summarize the available therapies for the treatment of malignant liver tumours, with an emphasis on surgical and ablative approaches and how they align with other therapies such as modern anticancer drugs or radiotherapy. In addition, we describe three complex case studies of patients with malignant liver tumours. Finally, we discuss the outlook for future treatment, including personalized approaches based on molecular tumour subtyping, response to targeted drugs, novel biomarkers and precision surgery adapted to the specific tumour. 10.1038/s41575-020-0314-8
    Integrated Omics of Metastatic Colorectal Cancer. Li Chen,Sun Yi-Di,Yu Guan-Yu,Cui Jing-Ru,Lou Zheng,Zhang Hang,Huang Ya,Bai Chen-Guang,Deng Lu-Lu,Liu Peng,Zheng Kuo,Wang Yan-Hua,Wang Qin-Qin,Li Qing-Run,Wu Qing-Qing,Liu Qi,Shyr Yu,Li Yi-Xue,Chen Luo-Nan,Wu Jia-Rui,Zhang Wei,Zeng Rong Cancer cell We integrate the genomics, proteomics, and phosphoproteomics of 480 clinical tissues from 146 patients in a Chinese colorectal cancer (CRC) cohort, among which 70 had metastatic CRC (mCRC). Proteomic profiling differentiates three CRC subtypes characterized by distinct clinical prognosis and molecular signatures. Proteomic and phosphoproteomic profiling of primary tumors alone successfully distinguishes cases with metastasis. Metastatic tissues exhibit high similarities with primary tumors at the genetic but not the proteomic level, and kinase network analysis reveals significant heterogeneity between primary colorectal tumors and their liver metastases. In vivo xenograft-based drug tests using 31 primary and metastatic tumors show personalized responses, which could also be predicted by kinase-substrate network analysis no matter whether tumors carry mutations in the drug-targeted genes. Our study provides a valuable resource for better understanding of mCRC and has potential for clinical application. 10.1016/j.ccell.2020.08.002
    Liver transplantation for secondary liver tumours: The difficult balance between survival and recurrence. Line Pål-Dag,Dueland Svein Journal of hepatology Assessing the balance between survival and recurrence after transplantation for secondary liver tumours should be based on the type of cancer in question. For neuroendocrine liver metastases, high recurrence rates are clearly related to reduced long-term survival. For colorectal liver metastases, experience to date indicates that pulmonary recurrence alone has a modest impact on survival outcomes. Further studies focusing on this group of patients will be important for the development of this field of transplant oncology. Liver transplantation for secondary liver tumours should be implemented in accordance with stringent transplant criteria and preferably in the context of prospective trials. Expansion of the donor pool by utilising extended criteria donors and partial liver transplantation could be considered for this indication. 10.1016/j.jhep.2020.08.015
    Contrast-enhanced ultrasound can guide the therapeutic strategy by improving the detection of colorectal liver metastases. Sawatzki Mikael,Güller Ulrich,Güsewell Sabine,Husarik Daniela B,Semela David,Brand Stephan Journal of hepatology BACKGROUND & AIMS:CT may miss up to 30% of cases of colorectal liver metastases (CRLMs). We assessed the impact of contrast-enhanced ultrasound (CEUS) on the detection of CRLMs and on changes to the therapeutic strategy; additionally, we assessed the accuracy of CEUS in differentiating unclear focal liver lesions (FLLs) compared to staging-CT. METHODS:We prospectively analyzed all patients with newly diagnosed and histologically confirmed colorectal cancer (CRC) at our tertiary gastroenterological center between December 2015 and May 2019. CEUS was performed in a total of 296 patients without CRLMs after staging-CT using the contrast agent (SonoVue®). Standard of reference was obtained by MRI or histology to diagnose CRLMs missed by CT. Benign FLLs were confirmed by MRI or follow-up CT (mean follow-up interval: 18 months). RESULTS:Eight additional CRLMs were detected by CEUS (overall 2.7%; sensitivity 88.9%, specificity 99.0%, positive predictive value 100%, negative predictive value 99.6%). All patients with CRLMs detected only by CEUS were in tumor stage T3/T4 (4.0% additionally detected CRLMs). The number needed to screen to detect 1 additional CRLM by CEUS was 37 in all patients and 24.5 in T3/T4-patients. When results were reviewed by a board-certified radiologist and oncologist, the therapeutic strategy changed in 6 of these 8 patients. Among the 62 patients (20.9%) with unclear FLLs after staging-CT, CEUS determined the dignity (malignant vs. benign) of 98.4% of the FLLs. CONCLUSION:Overall, CEUS detected 2.7% additional CRLMs (including 4.0% in tumor stage T3/T4) with a significant impact on the oncological therapeutic strategy for 75% of these patients. Patients with tumor stage T3/T4 would particularly benefit from CEUS. We propose CEUS as the first imaging modality for CT-detected lesions of unknown dignity. LAY SUMMARY:In patients with newly diagnosed colorectal cancer, contrast-enhanced ultrasound (CEUS) detected additional liver metastases after computed tomography (CT). In the majority of these patients, the oncological therapy was changed after obtaining the CEUS results. After staging-CT, 21% of hepatic lesions remained unclear. In these cases, CEUS was accurate to either reveal or exclude liver metastasis in nearly all patients and could reduce costs (e.g., number of MRI scans). 10.1016/j.jhep.2020.09.036
    Long-Term Oncologic Outcomes After Laparoscopic Versus Open Resection for Colorectal Liver Metastases : A Randomized Trial. Aghayan Davit L,Kazaryan Airazat M,Dagenborg Vegar Johansen,Røsok Bård I,Fagerland Morten Wang,Waaler Bjørnelv Gudrun Maria,Kristiansen Ronny,Flatmark Kjersti,Fretland Åsmund Avdem,Edwin Bjørn, Annals of internal medicine BACKGROUND:Despite the recent worldwide dissemination of laparoscopic liver surgery, no high-level evidence supports the oncologic safety of this approach. OBJECTIVE:To evaluate long-term oncologic outcomes after laparoscopic versus open liver resection in patients with colorectal metastases. DESIGN:A single-center, assessor-blinded, randomized controlled trial (OSLO-COMET [Oslo Randomized Laparoscopic Versus Open Liver Resection for Colorectal Metastases Trial]). (ClinicalTrials.gov: NCT01516710). SETTING:Oslo University Hospital, the only provider of liver surgery for the 3 million inhabitants of southeastern Norway. PARTICIPANTS:Patients with resectable colorectal liver metastases were randomly assigned to have open or laparoscopic liver resection. INTERVENTION:From February 2012 to January 2016, a total of 280 patients were included in the trial (laparoscopic surgery:  = 133; open surgery:  = 147). MEASUREMENTS:The primary outcome was postoperative morbidity within 30 days. Five-year rates of overall and recurrence-free survival were predefined secondary end points. RESULTS:At a median follow-up of 70 months, rates of 5-year overall survival were 54% in the laparoscopic group and 55% in the open group (between-group difference, 0.5 percentage point [95% CI, -11.3 to 12.3 percentage points]; hazard ratio, 0.93 [CI, 0.67 to 1.30];  = 0.67). Rates of 5-year recurrence-free survival were 30% in the laparoscopic group and 36% in the open group (between-group difference, 6.0 percentage points [CI, -6.7 to 18.7 percentage points]; hazard ratio, 1.09 [CI, 0.80 to 1.49];  = 0.57). LIMITATION:The trial was not powered to detect differences in secondary end points and was not designed to address a noninferiority hypothesis for survival outcomes. CONCLUSION:In this randomized trial of laparoscopic and open liver surgery, no difference in survival outcomes was found between the treatment groups. However, differences in 5-year overall survival up to about 10 percentage points in either direction cannot be excluded. This trial should be followed by pragmatic multicenter trials and international registries. PRIMARY FUNDING SOURCE:The South-Eastern Norway Regional Health Authority. 10.7326/M20-4011
    Summary for Patients: Laparoscopic Versus Open Surgery for Colorectal Liver Metastases. Annals of internal medicine 10.7326/P20-0012
    Contrast-enhanced ultrasound of the liver in colorectal cancer: A useful tool in the right patient. Piscaglia Fabio,Sansone Vito,Tovoli Francesco Journal of hepatology 10.1016/j.jhep.2020.11.044
    Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS): A Randomized Clinical Trial. Kanemitsu Yukihide,Shitara Kohei,Mizusawa Junki,Hamaguchi Tetsuya,Shida Dai,Komori Koji,Ikeda Satoshi,Ojima Hitoshi,Ike Hideyuki,Shiomi Akio,Watanabe Jun,Takii Yasumasa,Yamaguchi Takashi,Katsumata Kenji,Ito Masaaki,Okuda Junji,Hyakudomi Ryoji,Shimada Yasuhiro,Katayama Hiroshi,Fukuda Haruhiko, Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases. PATIENTS AND METHODS:This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat. RESULTS:Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm. CONCLUSION:Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases. 10.1200/JCO.20.02447
    Genomic evolution and diverse models of systemic metastases in colorectal cancer. Chen Hai-Ning,Shu Yang,Liao Fei,Liao Xue,Zhang Hongying,Qin Yun,Wang Zhu,Luo Maochao,Liu Qiuluo,Xue Zhinan,Cao Minyuan,Zhang Shouyue,Zhang Wei-Han,Hou Qianqian,Xia Xuyang,Luo Han,Zhang Yan,Yang Lie,Hu Jian-Kun,Fu Xianghui,Liu Bo,Hu Hongbo,Huang Canhua,Peng Yong,Cheng Wei,Dai Lunzhi,Yang Li,Zhang Wei,Dong Biao,Li Yuan,Wei Yuquan,Xu Heng,Zhou Zong-Guang Gut OBJECTIVE:The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing. DESIGN:Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells. RESULTS:Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in , which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of enhances the metastatic potential of CRC cells. CONCLUSION:Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis. 10.1136/gutjnl-2020-323703
    Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver. Bertocchi Alice,Carloni Sara,Ravenda Paola Simona,Bertalot Giovanni,Spadoni Ilaria,Lo Cascio Antonino,Gandini Sara,Lizier Michela,Braga Daniele,Asnicar Francesco,Segata Nicola,Klaver Chris,Brescia Paola,Rossi Elio,Anselmo Achille,Guglietta Silvia,Maroli Annalisa,Spaggiari Paola,Tarazona Noelia,Cervantes Andres,Marsoni Silvia,Lazzari Luca,Jodice Maria Giovanna,Luise Chiara,Erreni Marco,Pece Salvatore,Di Fiore Pier Paolo,Viale Giuseppe,Spinelli Antonino,Pozzi Chiara,Penna Giuseppe,Rescigno Maria Cancer cell Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases. 10.1016/j.ccell.2021.03.004
    Creatine promotes cancer metastasis through activation of Smad2/3. Zhang Liwen,Zhu Zijing,Yan Huiwen,Wang Wen,Wu Zhenzhen,Zhang Fei,Zhang Qixiang,Shi Guizhi,Du Junfeng,Cai Huiyun,Zhang Xuanxuan,Hsu David,Gao Pu,Piao Hai-Long,Chen Gang,Bu Pengcheng Cell metabolism As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers. 10.1016/j.cmet.2021.03.009
    Liver metastases. Tsilimigras Diamantis I,Brodt Pnina,Clavien Pierre-Alain,Muschel Ruth J,D'Angelica Michael I,Endo Itaru,Parks Rowan W,Doyle Majella,de Santibañes Eduardo,Pawlik Timothy M Nature reviews. Disease primers Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), pancreatic cancer, melanoma, lung cancer and breast cancer, although CRC is the most common primary cancer that metastasizes to the liver. Interactions between tumour cells and the tumour microenvironment play an important part in the engraftment, survival and progression of the metastases. Various cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, parenchymal hepatocytes, dendritic cells, resident natural killer cells as well as other immune cells such as monocytes, macrophages and neutrophils are implicated in promoting and sustaining metastases in the liver. Four key phases (microvascular, pre-angiogenic, angiogenic and growth phases) have been identified in the process of liver metastasis. Imaging modalities such as ultrasonography, CT, MRI and PET scans are typically used for the diagnosis of liver metastases. Surgical resection remains the main potentially curative treatment among patients with resectable liver metastases. The role of liver transplantation in the management of liver metastasis remains controversial. Systemic therapies, newer biologic agents (for example, bevacizumab and cetuximab) and immunotherapeutic agents have revolutionized the treatment options for liver metastases. Moving forward, incorporation of genetic tests can provide more accurate information to guide clinical decision-making and predict prognosis among patients with liver metastases. 10.1038/s41572-021-00261-6