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    Arginase as a useful factor for the diagnosis of colorectal cancer liver metastases. Mielczarek M,Chrzanowska A,Scibior D,Skwarek A,Ashamiss F,Lewandowska K,Barańczyk-Kuźma A The International journal of biological markers The present work is a continuation of studies on arginase as a marker in the diagnosis of colorectal cancer liver metastases (CRCLM). The purpose of the study was the evaluation of the arginase test in comparison with other colorectal cancer tests such as CEA, CA 19-9 and biochemical markers of liver function such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The studies were conducted on blood serum from 85 patients with CRCLM obtained one to two days before tumor resection. The control group comprised 140 healthy blood donors and 81 patients with various non-malignant gastrointestinal diseases. Raised arginase activity was observed in serum of 85% of CRCLM patients, whereas elevated levels of CEA and CA 19-9 were found in 63% and 42% of patients, respectively. The combination of CEA or CA 19-9 with the arginase assay improved their sensitivity, but the sensitivity of the combined parameters was not higher than that of the arginase test itself. AST and ALT activities were increased in about 30% of CRCLM patients. The specificity of the arginase test calculated for 221 control subjects was 76%. It can thus be concluded that the determination of serum arginase activity can be helpful in the diagnosis of patients with colorectal cancer liver metastases.
    Preoperative Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Perioperative Liver-Related Complications Following Liver Resection for Colorectal Cancer Metastases. Amptoulach S,Gross G,Sturesson C,Rissler P,Kalaitzakis E Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society BACKGROUND AND AIMS:There are limited data on the potential role of preoperative non-invasive markers, specifically the aspartate-to-alanine aminotransferase ratio and the aspartate aminotransferase-to-platelet ratio index, in predicting perioperative liver-related complications after hepatectomy for colorectal cancer metastases. METHODS:Patients undergoing liver resection for colorectal cancer metastases in a European institution during 2003-2010 were retrospectively enrolled. Relevant data, such as neoadjuvant chemotherapy, preoperative liver function tests, and perioperative complications, were collected from medical records. The nontumorous liver parenchyma in the surgical specimens of 31 patients was re-evaluated. RESULTS:Overall, 215 patients were included. In total, 40% underwent neoadjuvant chemotherapy and 47% major resection, while 47% had perioperative complications (6% liver-related). In multivariate regression analysis, the aspartate aminotransferase-to-platelet ratio index was independently associated with liver-related complications (odds ratio: 1.149, p = 0.003) and perioperative liver failure (odds ratio: 1.155, p = 0.012). The latter was also true in the subcohort of patients with neoadjuvant chemotherapy (odds ratio: 1.157, p = 0.004) but not in those without such therapy (p = 0.062). The aspartate-to-alanine aminotransferase ratio was not related to liver-related complications (p = 0.929). The area under the receiver operating characteristics curve for the aspartate aminotransferase-to-platelet ratio index as a predictor of liver-related complications was 0.857 (p = 0.008) in patients with neoadjuvant chemotherapy. Increasing aspartate aminotransferase-to-platelet ratio index was observed with an increase in degrees of sinusoidal obstruction syndrome (p = 0.01) but not for fibrosis (p = 0.175) or steatosis (p = 0.173) in the nontumorous liver in surgical specimens. CONCLUSION:The preoperative aspartate aminotransferase-to-platelet ratio index, but not the aspartate-to-alanine aminotransferase ratio, predicts perioperative liver-related complications following hepatectomy due to colorectal cancer metastases, in particular after neoadjuvant chemotherapy. The aspartate aminotransferase-to-platelet ratio index is related to sinusoidal obstruction syndrome in the nontumorous liver. 10.1177/1457496916683094
    Abnormal Liver Function Induced by Space-Occupying Lesions Is Associated with Unfavorable Oncologic Outcome in Patients with Colorectal Cancer Liver Metastases. Jiang Zheng,Li Chunxiang,Zhao Zhixun,Liu Zheng,Guan Xu,Yang Ming,Li Xiaofu,Yuan Dawei,Qiu Songbo,Wang Xishan BioMed research international An early prediction of prognosis for patients with colorectal liver metastasis (CRLM) may help us determine treatment strategies. Liver function reflects the effect of the overall metastatic burden. We investigated the prognostic value of liver function in CRLM patients. In our study, patients with abnormal LFTs (liver function tests) had a poorer prognosis than did those with normal LFTs ( < 0.05). A multivariate analysis revealed that LFTs was an independent prognostic factor for CRLM. For those patients with abnormal LFTs, novel prognostic contour maps were generated using LFTs, and no positive correlation exists between the values of survival duration and abnormal LFTs. Additionally, the MTVR (metastatic tumor volume ratio) was measured directly by magnetic resonance imaging and was shown to be highly correlated to LFTs by a Pearson correlation analysis. A multivariate logistic regression analysis also demonstrated that the MTVR and hepatectomy were independently predictive of abnormal LFTs. The space-occupying effect of metastatic lesions can cause abnormal LFTs, resulting in a poor prognosis. Biochemical analyses of LFTs at the initial diagnosis of CRLM enable the stratification of patients into low- and high-risk groups; it may help clinicians determine promising treatment strategies. 10.1155/2018/9321270
    Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Köhne C H,Cunningham D,Di Costanzo F,Glimelius B,Blijham G,Aranda E,Scheithauer W,Rougier P,Palmer M,Wils J,Baron B,Pignatti F,Schöffski P,Micheel S,Hecker H Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Patients with metastatic colorectal cancer are usually offered systemic chemotherapy as palliative treatment. A multivariate analysis was performed in order to identify predictors and their constellation that allow a valid prediction of the outcome in patients treated with 5-fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS:A total of 3825 patients treated with 5-FU within 19 prospective randomised and three phase II trials were separated into learning (n = 2549) and validation (n = 1276) samples. Data were analysed by tree analysis using the recursive partition and amalgamation method (RECPAM). A predictor could only enter the RECPAM analysis if the number of patients with missing values was < 33.3% within a node, and the minimal node size was set to 50 patients. Twenty-three potential predictors were grouped into subsets of laboratory variables (11 parameters), tumour-related variables (seven parameters) and clinical variables (five parameters). In the first step, tree analysis was performed separately for each predictor subset. The selected prognostic parameters of the resulting partial models (the 'winners') were entered into the general model. The classification rule from the data of the learning set was applied to the independent validation set. RESULTS:Winners of the subgroup analysis for laboratory variables were: platelets > or = 400 x 10(9)/l, alkaline phosphatase > or = 300 U/l, white blood cell (WBC) count > or = 10 x 10(9)/l and haemoglobin < 11 x 10(9)/l, and all predicted a worse outcome. Negative predictors within the subgroup of tumour parameters were: number of tumour sites more than one or more than two, presence of liver metastases or peritoneal carcinomatosis, which predicted a worse outcome. Furthermore, presence of lung metastases, a primary rectal cancer and presence of lymph node metastases all predicted a better outcome in the multivariate setting. Among the clinical parameters only performance status of ECOG 0 or 1 predicted better outcome. In the final regression tree, three risk groups could be identified: low risk group (n = 1111) with a median survival of 15 months for patients with ECOG 0/1 and only one tumour site; intermediate risk group (n = 904) with a median survival of 10.7 months for patients with ECOG 0/1 and more than one tumour site and alkaline phosphatase < 300 U/l or patients with ECOG > 1, WBC count < 10 x 10(9)/l and only one tumour site; high risk group (n = 534) with a median survival of 6.1 months for patients with ECOG 0/1 and more than one tumour site and alkaline phosphatase of > or = 300 U/l or patients with ECOG > 1 and more than one tumour site or WBC count > 10 x 10(9)/l. The median survival times for the good, intermediate and high risk groups in the validation sample were 14.7, 10.5 and 6.4 months, respectively. CONCLUSIONS:Patients can be divided into at least three risk groups depending on the four baseline clinical parameters: performance status, WBC count, alkaline phosphatase and number of metastatic sites. Any molecular or biological marker should be validated against these clinical parameters and decisions for more or less intensive treatments may be studied separately in these three risk groups. Also, clinical trials should be stratified according to the three risk groups. 10.1093/annonc/mdf034
    Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives. Zeng Xuezhen,Ward Simon E,Zhou Jingying,Cheng Alfred S L Cancers A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver-resident cells including Kupffer cells, hepatic stellate cells, and liver-sinusoidal endothelial cells are co-opted by the recruited cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis-prone liver immune microenvironment should open new immuno-oncology avenues for liver metastasis intervention. 10.3390/cancers13102418
    Development and validation of risk and prognostic nomograms for bone metastases in Chinese advanced colorectal cancer patients. Annals of translational medicine BACKGROUND:Bone metastases (BM) from colorectal cancer (CRC) are often accompanied by extraosseous metastases, resulting in a dismal prognosis. The present study aimed to determine the risk factors for BM in metastatic CRC (mCRC) and the prognostic factors for CRC patients with BM. METHODS:The study was based on a training cohort of 214 mCRC patients (of which, 101 patients had BM) from our center, and a validation cohort of 511 mCRC patients (of which, 173 patients had BM) from another institute. Risk and prognostic nomograms for BM were developed using univariate and multivariate analyses. The goodness of fit, discrimination, and calibration performance of the nomograms were assessed by R, concordance statistics (C-statistics), and the calibration curve. The results were internally validated using bootstrap resampling in the training cohort, and externally validated in the validation cohort. RESULTS:The novel BM risk nomogram comprised seven variables [degree of tumor differentiation, N-stage, serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), liver metastasis, and lung metastasis]. It showed good performance, with an R of 0.447 and a C-statistic of 0.846 [95% confidence interval (CI), 0.793 to 0.898] in the training cohort, and an R of 0.325 and a C-statistic of 0.792 (95% CI, 0.750 to 0.834) in the validation cohort. The optimal cutoff value to identify individuals at low or high risk was 56% probability, with a sensitivity of 71.3% and a specificity of 89.4%. The prognostic nomogram included five factors (tumor differentiation, number of extra-BM organs, number of BM lesions, ALP, and LDH), and had an R of 0.284 and a C-statistic of 0.723 (95% CI, 0.657 to 0.789) in the training set. This nomogram was externally validated in the validation cohort, with an R of 0.182 and a C-statistic of 0.682 (95% CI, 0.638 to 0.726). CONCLUSIONS:The developed and validated risk and prognostic nomograms showed good performance for predicting the occurrence of BM in mCRC as well as the prognosis of CRC patients with BM. The risk nomogram can be used as a cost-effective preliminary screening tool prior to bone scanning. 10.21037/atm-21-2550
    Nomogram for predicting occurrence and prognosis of liver metastasis in colorectal cancer: a population-based study. Tang Mingshuang,Wang Hongmei,Cao Yitong,Zeng Ziqian,Shan Xuefeng,Wang Lihua International journal of colorectal disease PURPOSE:This study aimed to investigate the prevalence, risk, and prognostic factors for synchronous liver metastasis (LM) in colorectal cancer (CRC) and to construct nomogram for predicting occurrence and prognosis of synchronous LM. METHODS:A total of 203,998 CRC patients who were registered in the SEER database between 2010 and 2016 were included. Logistic regression was used to analyze risk factors and Kaplan-Meier was used to estimate the overall survival of CRC patients with LM. Potential prognostic factors were identified by multivariable Cox regression. For predicting the risk for development and prognosis in CRC patients with LM, we constructed nomogram and the predictive performance was estimated by the receiver operating characteristics cure, the concordance index, and calibration curve. RESULTS:In total, 15.3% of the CRC patients (N = 31,288) had synchronous LM. Male gender, black, uninsured status, left colon, T4/T1, and bone and lung metastases were positively associated with synchronous LM risk. The 1-year, 3-year, and 5-year overall survival rate was 49.1%, 18.4%, and 9.2%, respectively. Older age, male gender, black, uninsured status, poor histological differentiation, lymphatic metastasis, T4/T1, positive carcinoembryonic antigen, and lung, bone, and brain metastases were associated with the overall survival. Nomogram was constructed to predict the development and prognosis of synchronous LM and both of them were proved to have good calibration and discrimination. CONCLUSION:LM is highly prevalent in CRC patients. Nomogram basing on the risk and prognostic factors for synchronous LM was proved to have good performance for predicting the probability of LM occurrence and prognosis. 10.1007/s00384-020-03722-8
    The Effect of Diffuse Liver Diseases on the Occurrence of Liver Metastases in Cancer Patients: A Systematic Review and Meta-Analysis. Monelli Filippo,Besutti Giulia,Djuric Olivera,Bonvicini Laura,Farì Roberto,Bonfatti Stefano,Ligabue Guido,Bassi Maria Chiara,Damato Angela,Bonelli Candida,Pinto Carmine,Pattacini Pierpaolo,Giorgi Rossi Paolo Cancers This systematic review with meta-analysis aimed to assess the effect of diffuse liver diseases (DLD) on the risk of synchronous (S-) or metachronous (M-) liver metastases (LMs) in patients with solid neoplasms. Relevant databases were searched for systematic reviews and cross-sectional or cohort studies published since 1990 comparing the risk of LMs in patients with and without DLD (steatosis, viral hepatitis, cirrhosis, fibrosis) in non-liver solid cancer patients. Outcomes were prevalence of S-LMs, cumulative risk of M-LMs and LM-free survival. Risk of bias (ROB) was assessed using the Newcastle-Ottawa Scale. We report the pooled relative risks (RR) for S-LMs and hazard ratios (HR) for M-LMs. Subgroup analyses included DLD, primary site and continent. Nineteen studies were included ( = 37,591 patients), the majority on colorectal cancer. ROB appraisal results were mixed. Patients with DLD had a lower risk of S-LMs (RR 0.50, 95% CI 0.34-0.76), with a higher effect for cirrhosis and a slightly higher risk of M-LMs (HR 1.11 95% CI, 1.03-1.19), despite a lower risk of M-LMs in patients with vs without viral hepatitis (HR 0.57, 95% CI 0.40-0.82). There may have been a publication bias in favor of studies reporting a lower risk for patients with DLD. DLD are protective against S-LMs and slightly protective against M-LMs for viral hepatitis only. 10.3390/cancers13092246
    AKP and GGT level can provide an early prediction of first-line treatment efficacy in colorectal cancer patients with hepatic metastases. Gong Zhe,Zhang Xiaowei,Geng Qirong,Li Wenhua,Huang Mingzhu,Chen Zhiyu,Sheng Xuedan,Zhang Wen,Guo Weijian Biomarkers in medicine It is important to early evaluate or predict the efficacy to avoid ineffective treatment for most colorectal cancer (CRC) patients with liver metastases. The medical records of 440 patients with histologically confirmed primary CRC admitted to the Fudan University Shanghai Cancer Center were reviewed. High baseline serum alkaline phosphatase (AKP) and γ-glutamyl transferase (GGT) is associated with worse overall survival. In patients with a high serum AKP and GGT a decreased percentage had high objective response rate and better progression-free survival. Measuring the changes of serum AKP or GGT in CRC patients with hepatic metastases before and after the first cycle of treatment is a convenient, fast and economical way to early predict antitumor treatment efficacy. 10.2217/bmm-2020-0667
    Liver transplantation for colorectal liver metastasis. Simoneau Eve,D'Angelica Michael,Halazun Karim J Current opinion in organ transplantation PURPOSE OF REVIEW:The aim of this review is to discuss existing data on liver transplantation for colorectal liver metastasis, emerging controversies, and future directions. RECENT FINDINGS:Contemporary experience with transplanting patients with liver metastasis from colon cancer is mainly derived from European centers, with a large proportion being from a single institution (SECA study), made possible in part by a relatively high donor pool. The initial results prove to be encouraging by demonstrating an overall survival advantage over unresectable patients with liver-limited disease managed with chemotherapy only. Recurrence patterns, however, suggest a need for better patient selection and treatment sequencing optimization. In North America, the main barriers in establishing similar protocols result from national liver graft shortage, which represents an issue of competing resources when indications have yet to be well defined. Evolving strategies in transplantation, such as the utilization of marginal liver grafts and living donor liver transplantation might constitute potential solutions. SUMMARY:Evidence suggests a potential survival benefit of liver transplantation for a subset of patients with unresectable liver-limited CRLM. Further prospective trials are needed to clarify the role and feasibility of this treatment strategy in oncotransplantation. 10.1097/MOT.0000000000000623
    Association between hepatitis B virus infection and colorectal liver metastasis: a meta-analysis. Liu Rongqiang,Kong Weihao,Deng Mingbin,Lin Guozhen,Dai Tianxing,Ye Linsen Bioengineered The paper aims to assess the association between Hepatitis B Virus infection and colorectal liver metastasis by conducting a meta-analysis. The relevant studies were searched until 24 July 2020, Studies that assessed the correlation between HBV infection and CRLM were recruited. A random effects model was applied to calculate the odds ratio (OR) with 95% confidence interval (CI). All data analyses were performed by STATA 12.0 software. Ten studies involving 17529 participants were included in the study. The results shown that there was obvious association between HBV infection and CRLM (OR: 0.51, 95% CI: 0.28-0.91). The study type and case-control rate may be the main causes of heterogeneity. In addition, HBV infection had no association with extrahepatic metastasis or prognosis of patients with CRLM. Sensitivity analyses confirmed that the results were stable, and Egg's test indicated that there was no publication bias. Patients with HBV infection have the reduced risk of CRLM. 10.1080/21655979.2021.1890871
    mSEPT9 Can Monitor the Response and Predict the Prognosis of Stage IV Colorectal Cancer Patients with Liver Metastasis Undergoing Potentially Curative Surgery. Liu Weijun,Hu Pinghai,Liu Jun,Chen Lei The Journal of surgical research BACKGROUND:Stage IV colorectal cancer (CRC) patients with liver metastasis undergoing potentially curative surgery represent a subgroup of patients with a relatively good prognosis. In this study, we aimed to evaluate the performance of mSEPT9 to monitor response to treatment and predict prognosis. METHODS:In total, we recruited 51 stage IV CRC patients with liver metastasis, including 20 patients who underwent simultaneous surgery and 31 patients who underwent staged surgery. We measured the blood levels of mSEPT9 and CEA prior to surgery and then seven days after surgery. RESULTS:mSEPT9 and CEA were detected prior to surgery in 92.2% (47/51) and 70.6% (36/51) of patients, respectively. Following simultaneous and staged surgery, levels of mSEPT9 fell significantly by 923-fold (P<0.001) and 11-fold (P<0.001), respectively. Levels of CEA also fell significantly by 17-fold (P<0.001) and 1.7-fold (P<0.01) following simultaneous and staged surgery, respectively. The mean percentage reduction of mSEPT9 levels after simultaneous surgery (12.3%) was significantly lower than that of staged surgery (33.8%) (P<0.001) while the mean percentage reduction of CEA levels after simultaneous surgery (35.5%) were significantly lower than that of staged surgery (64.6%) (P<0.05). The levels of mSEPT9 in the blood were quantitatively correlated with tumor burden. Survival analysis showed that patients who tested negative for mSEPT9 pre- and post-surgery had a better survival rate than those who tested positive, thus suggesting that mSEPT9 can act as a prognostic indicator. CONCLUSIONS:mSEPT9 showed good quantitative efficacy, higher applicability, and sensitivity, than CEA in assessing treatment response and prognosis prediction in patients with stage IV CRC and liver metastasis. 10.1016/j.jss.2021.06.008
    Laparoscopic liver resection for bilobar multiple metachronous liver metastases in patient with rectal cancer. Lee Seung Jae,Choi In Seok,Moon Ju Ik,Yeon Hee Jin Annals of hepato-biliary-pancreatic surgery Introduction:Laparoscopic liver resection (LLR) of multiple colorectal liver metastases (CRLM) is challenging but has become more practical recently due to progression in operative technique. We aimed to present laparoscopic detection of multiple CRLM using intraoperative ultrasonography (IOUSG) and LLR for scattered CRLM. Methods:A 65-year-old male was admitted with multiple liver metastases during follow-up for mid-rectal cancer. The patient had already undergone laparoscopic lower anterior resection 6 months ago and had completed the sixth adjuvant chemotherapy with capecitabine. Magnetic resonance imaging presented metastatic tumor about 5 cm in size in segment 6 of liver and multiple small metastases in segment 3, 4, 5, 7, and 8 of liver. The surgery was performed in supine position and five trocars were inserted. After detection of tumors using IOUSG to mark the site of the tumors, we performed bisegmentectomy about tumors of segment 5 and 6, and 3 tumorectomy of liver about tumors of segment 3, 4, and 7 + 8. Immediately after surgery, all specimens were cut to check whether the tumors were included and whether the resection margin was sufficient. Results:The operative time was 350 minutes and estimated blood loss was 80 mL. Pringle maneuver was performed 5 times in 15 minutes. All tumor resection margin were grossly confirmed as negative. There were no immediate postoperative complications. The patient was discharged on the day 7 of postoperative hospital stay. Conclusions:LLR is safe and feasible technique even for bilobar multiple CRLM. 10.14701/ahbps.VP-2
    IL-1α and colorectal cancer pathogenesis: Enthralling candidate for anti-cancer therapy. Cheng Kim Jun,Mejia Mohammed Elsa Haniffah,Khong Tak Loon,Mohd Zain Shamsul,Thavagnanam Surendran,Ibrahim Zaridatul Aini Critical reviews in oncology/hematology Inflammation has been well-established as a hallmark of colorectal cancer (CRC). Interleukin-1 alpha (IL-1α) is one of the primary inflammatory mediators driving the pathogenesis of inflammation-associated CRC. This systematic review presents the roles of IL-1α in the pathogenesis of the disease. Bibliographic databases PubMed, Science Direct, Scopus and Web of Science were systematically searched for articles that addresses the relationship between IL-1α and colorectal cancer. We highlighted various mechanisms by which IL-1α promotes the pathogenesis of CRC including enhancement of angiogenesis, metastasis, resistance to therapy, and inhibition of tumour suppressive genes. We also discussed the potential mechanisms by which IL-1α expression is induced or secreted in various studies. Beyond these, the systematic review also highlights several potential therapeutic strategies which should be further explored in the future; to target IL-1α and/or its associated pathways; paving our way in finding effective treatments for CRC patients. 10.1016/j.critrevonc.2021.103398
    Cumulative perioperative lymphocyte/C-reactive protein ratio as a predictor of the long-term outcomes of patients with colorectal cancer. Okugawa Yoshinaga,Toiyama Yuji,Fujikawa Hiroyuki,Kawamura Mikio,Yasuda Hiromi,Yokoe Takeshi,Mochiki Ikuyo,Okita Yoshiki,Ohi Masaki,Nakatani Kaname Surgery today PURPOSE:Systemic inflammatory response influences cancer development and perioperative surgical stress can affect the survival of patients with colorectal cancer (CRC). We developed a system to cumulatively assess perioperative inflammatory response and compare the prognostic value of various cumulative inflammatory and nutritional markers in patients with CRC. METHODS:We assessed perioperative cumulative markers using the trapezoidal area method in 307 patients who underwent surgery for CRC and analyzed the results statistically. RESULTS:The cumulative lymphocyte to C-reactive protein (CRP) ratio (LCR) predicted survival more accurately than other well-established markers (sensitivity: 80.0%, specificity: 69.3%; area under the curve (AUC): 0.779; P  <  0.001). A low cumulative LCR was correlated with factors associated with disease development, including undifferentiated histology, advanced T stage, lymph node metastasis, distant metastasis, and advanced TNM stage classification. A decreased cumulative LCR was an independent prognostic factor for both overall survival (OS) (Hazard Ratio (HR):5.21, 95% confidence interval [CI] 2.42-11.2; P  <  0.0001) and disease-free survival (DFS) (HR: 1.88, 95% CI 1.07-3.31; P  =  0.02), and its prognostic significance was verified in a different clinical setting. The cumulative LCR was correlated negatively with the intraoperative bleeding volume (P  <  0.0001, R  =  0.4). Combined analysis of cumulative and preoperative LCR could help stratify risk for the oncological outcomes of CRC patients. CONCLUSIONS:The findings of this study demonstrate the value of the cumulative LCR in the postoperative management of patients with CRC. 10.1007/s00595-021-02291-9
    First-in-Human PET Imaging and Estimated Radiation Dosimetry of l-[5-C]-Glutamine in Patients with Metastatic Colorectal Cancer. Cohen Allison S,Grudzinski Joe,Smith Gary T,Peterson Todd E,Whisenant Jennifer G,Hickman Tiffany L,Ciombor Kristen K,Cardin Dana,Eng Cathy,Goff Laura W,Das Satya,Coffey Robert J,Berlin Jordan D,Manning H Charles Journal of nuclear medicine : official publication, Society of Nuclear Medicine Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Noninvasive imaging via PET may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. l-[5-C]-glutamine (C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of C-glutamine for oncologic PET imaging. Nine patients with confirmed metastatic colorectal cancer underwent PET/CT imaging. Patients received 337.97 ± 44.08 MBq of C-glutamine. Dynamic PET acquisitions that were centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. After the dynamic acquisition, a whole-body PET/CT scan was acquired. Volume-of-interest analyses were performed to obtain estimates of organ-based absorbed doses of radiation. C-glutamine was well tolerated in all patients, with no observed safety concerns. The organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. PET using C-glutamine appears safe for human use and allows noninvasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment. 10.2967/jnumed.120.261594
    Outcomes following synchronous liver resection, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases: A bi-institutional study. Flood Michael P,Waters Peadar S,Kelly Michael E,Shields Conor,Conneely John,Ramsay Robert,Michael Michael,Loveday Benjamin,Warrier Satish K,Mulsow Jurgen,Heriot Alexander G Surgical oncology PURPOSE:Synchronous liver resection, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal liver (CRLM) and peritoneal metastases (CRPM) has traditionally been contraindicated. However, latest practice promotes specialist, multidisciplinary-led consideration for select patients. This study aimed to evaluate the perioperative and oncological outcomes of synchronous resection in the management of CRLM and CRPM from two tertiary referral centres. METHOD:This bi-institutional, retrospective, cohort study included patients undergoing simultaneous liver resection, CRS and HIPEC for metastatic colorectal cancer from 2013 to 2020. Patients treated with ablative liver techniques, staged operative approaches and extra abdominal disease were excluded. Overall survival (OS) and disease-free survival (DFS) rates were assessed. Univariate and multivariate analyses identified variables associated with survival and major morbidity (Clavien-Dindo grade III/IV). RESULTS:Twenty-three patients were included. The median peritoneal carcinomatosis index (PCI) was 9 (range 0-22). There were two major liver resections and 21 minor resections. CC-0 resections were achieved in all patients. Major morbidity occurred in 7 patients. There were no deaths at 90 days. PCI was independently associated with morbidity (p = 0.04). PCI >10 (p = 0.069), major morbidity (p = 0.083) and presence of KRAS mutation (p = 0.052) approached significance for poor OS. Median follow up was 21 months (4-54 months). Median OS was 37 months, 3-year survival 54%, and median DFS 18 months. CONCLUSION:Synchronous liver resection, cytoreductive surgery and HIPEC is feasible in selected patients with low-volume CRPM and CRLM. Increasing PCI is associated with postoperative major morbidity, and should be considered during operative planning. 10.1016/j.suronc.2021.101553
    The impact of primary tumor location on prognosis after colorectal lung metastasectomy. Sponholz Stefan,Oguzhan Selma,Mese Mesut,Schirren Moritz,Kirschbaum Andreas,Schirren Joachim International journal of colorectal disease PURPOSE:Currently, right colon cancer (RCC), left colon cancer (LCC), and rectal cancer (REC) are typically seen as different tumor entities. It is unknown if this subdivision by primary tumor location has an influence on the survival of patients with colorectal pulmonary metastasectomy (PM). METHODS:We retrospectively analyzed our prospective database of 233 patients operated on for colorectal lung metastases between 1999 and 2014. Differences in the patient characteristics and the primary tumor and metastatic tumor burden were analyzed using χ2-tests. The long-term survival after PM of the three groups was analyzed with the Kaplan-Meier method and log-rank tests. RESULTS:In total, PM was performed for 37 patients with RCC, 57 patients with LCC, and 139 patients with REC. Patients with LCC were significantly more likely to have UICC stage IV primary tumor (44.2% LCC vs. 37.5% RCC vs. 22.8% REC, p = 0.012) and significantly more likely to have a history of additional liver metastases (45.6% LCC vs. 32.4% RCC vs. 27.3% REC, p = 0.046). The 5-year survival rates after PM for patients with RCC, LCC, and REC were 47, 66, and 39%, respectively (p = 0.001). The median survival times of patients with RCC, LCC, and REC were 55 months (95% CI: 42.2-66.8), 108 months (95% CI: 52.7-163.3), and 44 months (95% CI: 50.4-63.6), respectively. CONCLUSIONS:This study demonstrated a prognostic impact of the primary tumor localization in patients undergoing PM for colorectal lung metastases. Nevertheless, long-term survival was achievable in all groups. 10.1007/s00384-021-03907-9
    Preliminary Analysis of Liquid Biopsy after Hepatectomy for Colorectal Liver Metastases. Mason Meredith C,Tzeng Ching-Wei D,Tran Cao Hop S,Aloia Thomas A,Newhook Timothy E,Overman Michael J,Kopetz Scott E,Vauthey Jean-Nicolas,Chun Yun Shin Journal of the American College of Surgeons BACKGROUND:Liquid biopsies are increasingly tested in patients with colorectal cancer to assess tumor burden, response to therapy, and prognosis. The significance of liquid biopsy results after resection of colorectal liver metastases (CLMs) is not well-defined. STUDY DESIGN:Sixty-three patients undergoing CLM resection between 2016 and 2018 had plasma drawn postoperatively for liquid biopsy evaluation. Next-generation sequencing analysis was performed to detect somatic mutations in 70 genes. RESULTS:Liquid biopsy after CLM resection was positive in 42 of 63 patients (67%). Eleven patients (18%) had 1 gene mutation, 14 patients (22%) had 2 to 3 mutations, and 17 patients (27%) had 4 or more mutations. The most common mutation was APC, detected in 32 patients (76%), followed by TP53 (74%) and KRAS (38%). Two-year overall survival rate from date of liver resection was significantly worse among patients with a positive liquid biopsy (70% vs 100%; p = 0.005), particularly for those with 4 or more gene mutations detected, whose 2-year overall survival rate was 41%. Sixteen of the 63 patients underwent serial liquid biopsies, resulting in 100 liquid biopsies with matched serum CEA and CT scan results. Metastases were identified in 74 CT scans, which correlated with positive liquid biopsy in 77% of samples (p < 0.001) and CEA > 3 ng/mL in 45% of samples (p < 0.22). CONCLUSIONS:Liquid biopsy results provide information about disease burden and prognosis that is complementary to serum CEA and CT imaging. A positive liquid biopsy after CLM resection is associated with worse overall survival, particularly when multiple gene mutations are detected. 10.1016/j.jamcollsurg.2021.02.011
    The prognosis of radiofrequency ablation versus hepatic resection for patients with colorectal liver metastases: A systematic review and meta-analysis based on 22 studies. Yang Gang,Wang Guan,Sun Ji,Xiong Yongfu,Li Weinan,Tang Tao,Li Jingdong International journal of surgery (London, England) BACKGROUND:Though hepatic resection (HR) is the standard local therapy for patients with colorectal cancer liver metastases (CRLMs), currently, radiofrequency ablation (RFA) may play an alternative role for elderly and vulnerable patients with various organ dysfunctions. This study aims to compare the prognosis of RFA and HR in treatment of CRLMs. METHODS:A systematic search of PubMed, Embase, Cochrane Library and Web of Science up to October 1, 2020 was conducted for relevant studies that compared the prognosis of RFA with HR in the treatment of CRLMs. The primary outcomes were 30-day mortality, long-term recurrence, overall survival (OS) and disease-free survival (DFS). The secondary outcomes were various factors of OS, recurrence-free survival (RFS), survival, recurrence and complication. RESULTS:A total of 22 studies including 4385 CRLM patients were identified. There was no significant difference between RFA and HR in 30-day mortality, with a pooled OR of 0.88 (95% CI 0.34-2.29; P = 0.80). CRLM patients undergoing RFA experienced significantly higher incidences of marginal and intrahepatic recurrence than HR, with pooled ORs of 7.09 (95% CI 4.56-11.2; 1251 pts) and 2.02 (95% CI 1.24-3.28; 1038 pts). In addition, RFA showed lower 1-, 3- and 5-yr OS rate than HR with pooled ORs of 0.39, 0.40 and 0.60 respectively. A lower 5-yr DFS rate was also found in RFA than HR group, with a pooled OR of 0.74 (95% CI 0.56-0.97; P = 0.03; 1231 pts). Multivariable analysis showed that tumor size, multiple tumors, age, primary node positive and metachronous metastasis were independent factors of OS, and multiple tumors was also an independent factor of RFS. CONCLUSIONS:Though the 30-day mortality of RFA was equal to HR, RFA showed a higher recurrence rate and poor long-term survival outcomes for CRLM patients. Tumor size, multiple tumors, age, primary node positive and metachronous metastasis were independent factors of survival. However, the results were limited because of the inequality baseline characteristics between the comparative groups. Randomized or propensity score matching studies should be performed to clarify the effectiveness of RFA and to determine target populations that benefit most from RFA in the future. 10.1016/j.ijsu.2021.105896
    Survival outcome and prognostic factors for colorectal cancer with synchronous bone metastasis: a population-based study. Li Xiaofen,Hu Wangxiong,Sun Hongna,Gou Hongfeng Clinical & experimental metastasis Prognostic factors of synchronous bone metastatic colorectal cancer (CRC) are still undetermined. We aimed to investigate survival outcome and prognostic factors of patients with synchronous bone metastatic CRC. Information of patients with synchronous bone metastatic CRC were obtained from the Surveillance, Epidemiology, and End Results (SEER) and West China Hospital (WCH) databases. Cases from SEER database composed construction cohort, while cases from WCH database were used as validation cohort. A novel nomogram was constructed to predict individual survival probability based on Cox regression model. The performance of the nomogram was internally and externally validated using calibration curves and concordance index (C-index). Three hundred and eighty-one patients from SEER database were eligible. The median disease specific OS was 9.0 months (95% confidence interval [CI]: 7.3-10.7 months). Multivariate Cox analysis identified seven independent prognostic factors including histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis. A novel nomogram was established based on these variables. In the internal validation, the C-index (0.72, 95% CI 0.69-0.75) and calibration curve indicated well performance of this nomogram at predicting survival outcome in bone metastatic CRC. In the external validation, the C-index was 0.57 (95% CI 0.46-0.68). The prognosis of synchronous bone metastatic CRC is very poor. Histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis are independent prognostic factors. Further study is warranted to confirm the practicality of the prognostic nomogram. 10.1007/s10585-020-10069-5
    Long-term outcome for colorectal liver metastases: combining hepatectomy with intraoperative ultrasound guided open microwave ablation versus hepatectomy alone. Dai Yunzhu,Zhang Yuanping,He Wei,Peng Chuan,Qiu Jiliang,Zheng Nan,Li Huifang,Liu Wenwu,Zheng Yun,Li Binkui,Yuan Yunfei,Zou Ruhai International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group OBJECTIVE:To compare the long-term outcome of combining hepatectomy with intraoperative ultrasound (IOUS)-guided open microwave ablation (MWA) versus hepatectomy alone in patients with colorectal cancer liver metastases (CRLM). METHOD:A retrospective analysis of patients with CRLM who underwent hepatectomy alone (HT group; 380 patients) or hepatectomy combined with IOUS-guided open MWA (HT + MWA group; 57 patients) from April 2002 to September 2018 was conducted at our center. A propensity score-matched (PSM) analysis was used to reduce data bias between the two groups. RESULTS:The overall survival (OS) and disease-free survival (DFS) were not significantly different between the two groups after matching. Although intrahepatic recurrence was more frequent in the HT + MWA group in both the whole and matched cohort, the two groups exhibited similar rates of extrahepatic recurrence as well as concomitant intra- and extrahepatic recurrence. A higher number of CRLM (>3), larger maximum-size and absence of response to induction chemotherapy were independent risk factors for OS. CONCLUSION:The oncological outcomes of hepatectomy combined with intraoperative open ablation was not significantly different to hepatectomy alone and should be considered as a safe and fair option for patients with difficultly resectable CRLM. 10.1080/02656736.2021.1892835
    Patients with colorectal cancer and brain metastasis: The relevance of extracranial metastatic patterns predicting time intervals to first occurrence of intracranial metastasis and survival. Thurmaier Johannes,Heinemann Volker,Engel Jutta,Schubert-Fritschle Gabriele,Wiedemann Max,Nüssler Natascha C,Ruppert Reinhard,Kleeff Jörg,Schepp Wolfgang,Löhe Florian,Karthaus Meinolf,Neumann Jens,Kumbrink Jörg,Taverna Francesco,Stahler Arndt,Heinrich Kathrin,Westphalen Christoph Benedikt,Holch Julian W,Kirchner Thomas,Michl Marlies International journal of cancer The aim of the study was to investigate the predictive impact of extracranial metastatic patterns on course of disease and survival in patients with colorectal cancer (CRC) and brain metastasis (BM). A total of 228 patients (134 male [59%], 94 female [41%]) with histologically proven CRC and BM were classified into different groups according to extracranial metastatic patterns. Time intervals to metastatic events and survival times from initial CRC diagnosis, extracranial and intracranial metastasis were analyzed. Extracranial organs mostly affected were liver (102 of 228 [44.7%]) and lung (96 of 228 [42.1%]). Liver and lung metastases were detected in 31 patients (13.6%). Calculated over the entire course of disease, patients with lung metastasis showed longer overall survival (OS) than patients with liver metastasis or patients without lung metastasis (43.9 vs 34.6 [P = .002] vs 35.0 months [P = .002]). From the date of initial CRC diagnosis, lung metastasis occurred later in CRC history than liver metastasis (24.3 vs 7.5 months). Once lung metastasis was diagnosed, BM occurred faster than in patients with liver metastasis (15.8 vs 26.0 months; Δ 10.2 months). Accordingly, OS from the diagnosis of liver metastasis was longer than from lung metastasis (27.1 vs 19.6 months [P = .08]). Once BM was present, patients with lung metastasis lived longer than patients with liver metastasis (3.8 vs 1.1 months [P = .028]). Shortest survival times in all survival categories analyzed revealed patients with concurrent liver and lung metastasis. Patients with CRC and BM form a heterogeneous cohort where extracranial metastasis to liver or lungs predicts survival. 10.1002/ijc.33364
    Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: A systematic review. Bolhuis Karen,Kos Milan,van Oijen Martijn G H,Swijnenburg Rutger-Jan,Punt Cornelis J A European journal of cancer (Oxford, England : 1990) BACKGROUND:There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases. METHODS:Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected. RESULTS:Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22-57% and 11-38%, respectively. CONCLUSIONS:Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted. 10.1016/j.ejca.2020.09.037
    MRI Findings of Liver Parenchyma Peripheral to Colorectal Liver Metastasis: A Potential Predictor of Long-term Prognosis. Nakai Yudai,Gonoi Wataru,Kurokawa Ryo,Nishioka Yujiro,Abe Hiroyuki,Arita Junichi,Ushiku Tetsuo,Hasegawa Kiyoshi,Abe Osamu Radiology Background Gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI is superior to CT in the detection of colorectal liver metastases (CRLMs) smaller than 10 mm. However, few studies have used MRI findings to predict patients' long-term prognosis. Purpose To investigate the relationship between Gd-EOB-DTPA-enhanced MRI findings in the liver parenchyma peripheral to CRLM and both pathologic vessel invasion and long-term prognosis. Materials and Methods This retrospective study included patients who underwent Gd-EOB-DTPA-enhanced MRI before curative surgery for CRLM, without neoadjuvant chemotherapy, between July 2008 and June 2015. Early enhancement, reduced Gd-EOB-DTPA uptake, and bile duct dilatation peripheral to the CRLM at MRI were evaluated by three abdominal radiologists. All tumor specimens were reevaluated for the presence or absence of portal vein, hepatic vein, and bile duct invasion. Predictors of recurrence-free survival (RFS) and overall survival (OS) after surgery were identified with Cox proportional hazard model with the Bayesian information criterion. Previously reported prognosticators were selected for multivariable analyses. The median follow-up period was 60 months (range, 9-127 months). Results Overall, 106 patients (mean age, 65 years ± 12 [standard deviation]; 68 men) with 148 CRLMs were evaluated. Bile duct dilatation peripheral to the tumor was associated with pathologic portal vein invasion (sensitivity, 12 of 50 [24%]; specificity, 89 of 98 [91%]; = .02), bile duct invasion (sensitivity, eight of 19 [42%]; specificity, 116 of 129 [90%]; = .001), poor RFS ( = .03; hazard ratio [HR] = 2.4 [95% confidence interval {CI}: 1.3, 4.2]), and poor OS ( = .01; HR = 2.4 [95% CI: 1.2, 4.9]). For RFS and OS, early enhancement and reduced Gd-EOB-DTPA uptake peripheral to the CRLM were eliminated by means of variable selection in the multivariable analysis, but the combination of these findings with bile duct dilatation provided a predictor of poor OS ( = .001; HR = 3.3 [95% CI: 1.6, 6.8]). Conclusion MRI signal intensity changes peripheral to the colorectal liver metastasis were predictors of long-term prognosis after curative surgery without neoadjuvant chemotherapy. © RSNA, 2020 See also the editorial by Bashir in this issue. 10.1148/radiol.2020202367
    Long-term Results of Surgery for Colorectal Liver Metastases in Terms of Primary Tumour Location and Clinical Risk Factors. Treska Vladislav,Skala Martin,Prochazkova Kristyna,Svejdova Aneta,Petrakova Tereza,Sebek Jakub,Riha Ivan,Rosendorf Jachym,Polak Robert,Skalicky Tomas,Liska Vaclav In vivo (Athens, Greece) BACKGROUND/AIM:The aim of the study was to evaluate the influence of primary tumour location and clinical risk factors for long-term results of surgery for colorectal liver metastases (CLMs). PATIENTS AND METHODS:Overall survival (OS) and recurrence-free survival (RFS) were evaluated in 636 patients. Patients were divided by tumour location (right-/left-sided colorectal cancer: RCRC/LCRC; rectal cancer), and age, gender, number and size of CLMs, type of liver surgery and interval from primary operation were evaluated. RESULTS:One-, 3- and 5-year OS and RFS were independent of primary tumour location (p<0.59). CLM diameter was negatively associated with OS for the whole cohort (p<0.002), and RCRC (p<0.03) and LCRC (p<0.04) groups, as well as for RFS of those with LCRC (p<0.04). CLM number was negatively associated with RFS for the whole cohort (p<0.0001), RCRC (p<0.02), LCRC (p<0.0001) and RC (p<0.02). Radiofrequency ablation and combined procedures led to worse OS for the whole cohort (p<0.03), and to worse RFS for the whole cohort (p<0.0003) and for those with LCRC (p<0.03). A shorter interval between primary colorectal cancer surgery and CLMs procedure was risky for poor OS and RFS of patients with CLMs from RCRC (p<0.05), LCRC (p<0.05) and RC (p<0.02). CONCLUSION:Primary tumour location together with clinical risk factors are important for long-term results of surgery CLMs. 10.21873/invivo.12087
    Hepatic arterial infusion of oxaliplatin plus systemic chemotherapy and targeted therapy for unresectable colorectal liver metastases. Boilève Alice,De Cuyper Astrid,Larive Alicia,Mahjoubi Linda,Najdawi Milan,Tazdait Mélodie,Gelli Maximiliano,Tselikas Lambros,Smolenschi Cristina,Malka David,Pignon Jean-Pierre,Ducreux Michel,Boige Valérie European journal of cancer (Oxford, England : 1990) BACKGROUND:Hepatic arterial infusion (HAI) combined with systemic chemotherapy has shown promising results in patients with unresectable colorectal liver metastases (CRLM), even after failure to systemic therapy. Addition of systemic targeted therapies has been investigated with controversial results regarding tolerance, especially with HAI-floruxidine when combined with systemic bevacizumab. Our study aimed to analyse feasibility, safety and efficacy of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies. METHODS:Between 2005 and 2016, single-centre consecutive patients with unresectable CRLM who received at least one cycle of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies (cetuximab/panitumumab or bevacizumab) were analysed. RESULTS:A total of 89 patients (median age 55 years (range, 26-76 years) who previously received a median number of one systemic chemotherapy regimen (range, 0-5) including oxaliplatin in 78% of cases were included. Median number of HAI-oxaliplatin cycles was 9 (range, 1-28) combined with systemic chemotherapy and targeted therapies (LV5FU2 [63%], FOLFIRI [36%]) plus anti-EGFR (30%), or bevacizumab (70%). Grade 3/4 toxicities included neutropenia (40%), HAI-related abdominal pain (43%) and neurotoxicity (12%). The intent-to-treat objective response rate was 42%, and 45% had stable disease, allowing complete CRLM resection/ablation in 27% of patients. After a median follow-up of 72 months, median overall and progression-free survival was 20 and 9 months, respectively. CONCLUSION:Addition of targeted therapy to systemic chemotherapy combined with HAI-oxaliplatin is feasible, safe and shows promising activity, even after systemic chemotherapy failure. 10.1016/j.ejca.2020.07.022
    Serum Gamma Glutamyl transferase is a predictor of recurrence after R0 hepatectomy for patients with colorectal cancer liver metastases. Therapeutic advances in medical oncology OBJECTIVES:Gamma glutamyl-transpeptidase (GGT) has been shown as a prognostic marker in many cancers. The aim of this study was to explore whether serum GGT could predict tumor recurrence in patients with liver-confined colorectal cancer liver metastases (CRCLM) undergoing R0 resection. METHODS:We reviewed patients who had underwent liver surgery for CRCLM. Patients with liver-only metastases that underwent R0 resection were included. Pre-operative serum GGT were classified into either high or low using a cut-off value of 33 U/L for female and 51 U/L for male. Relapse-free survival (RFS) was compared in relation to GGT and other clinicopathological factors. RESULTS:Of the 350 patients included, 108 (30.9%) had a high serum GGT. Patients with metachronous liver metastases, number of metastases ⩾2, size of the largest metastasis ⩾3 cm, or a history of neoadjuvant chemotherapy had a higher GGT level ( = 0.001, 0.027, 0.001, and 0.002, respectively). In survival analyses, patients with a high GGT had a shorter RFS than those with a low GGT, with a median RFS of 11.8 30.3 months ( < 0.001). RFS was also associated with the number of metastases, size of the largest metastasis and the delivery of neoadjuvant chemotherapy. In multivariate analysis, GGT remained an independent prognostic factor of RFS. CONCLUSIONS:Our study demonstrates that the serum GGT level before liver surgery is an adverse prognostic factor of RFS for patients with liver-confined CRCLM. 10.1177/1758835920947971
    Metabolic Parameters as Predictors for Progression Free and Overall Survival of Patients with Metastatic Colorectal Cancer. Nemeth Zsuzsanna,Wijker Wouter,Lengyel Zsolt,Hitre Erika,Borbely Katalin Pathology oncology research : POR We tested the prognostic relevance of metabolic parameters and their relative changes in patients with metastatic colorectal cancer (mCRC) treated with monoclonal antibody and chemotherapy. SUV (standardized uptake volume), SAM (standardized added metabolic activity) and TLG (total lesion glycolysis) are assessed with F-fluorodeoxyglucosepositron emission tomography and computed tomography (FDG-PET/CT) to evaluate total metabolic activity of malignant processes. Our purpose was to investigate the change of glucose metabolism in relation to PFS (progression free survival) and OS (overall survival). Fifty-three patients with mCRC with at least one measurable liver metastasis were included in this prospective, multi-center, early exploratory study. All patients were treated with first-line chemotherapy and targeted therapy. Metabolic parameters, like SUV, SAM, normalized SAM (NSAM) and TLG were assessed by FDG-PET/CT, carried out at baseline (scan-1) and after two therapeutic cycle (scan-2). Our results suggested neither SUVmax nor TLG have such prognostic value as NSAM in liver metastases of colorectal cancer. The parameters after the two cycles of chemotherapy proved to be better predictors of the clinical outcome. NSAM after two cycles of treatment has a statistically significant predictive value on OS, while SAM was predictive to the PFS. The follow up normalized SAM after 2 cycles of first line oncotherapy was demonstrated to be useful as prognostic biomarkers for OS in metastatic colorectal cancer. We should introduce this measurement in metastatic colorectal cancer if there is at least one metastasis in the liver. 10.1007/s12253-020-00865-5
    Integrative microphysiological tissue systems of cancer metastasis to the liver. Clark Amanda M,Allbritton Nancy L,Wells Alan Seminars in cancer biology The liver is the most commonly involved organ in metastases from a wide variety of solid tumors. The use of biologically and cellularly complex liver tissue systems have shown that tumor cell behavior and therapeutic responses are modulated within the liver microenvironment and in ways distinct from the behaviors in the primary locations. These microphysiological systems have provided unexpected and powerful insights into the tumor cell biology of metastasis. However, neither the tumor nor the liver exist in an isolated tissue situation, having to function within a complete body and respond to systemic events as well as those in other organs. To examine the influence of one organ on the function of other tissues, microphysiological systems are being linked. Herein, we discuss extending this concept to tumor metastases by integrating complex models of the primary tumor with the liver metastatic environment. In addition, inflammatory organs and the immune system can be incorporated into these multi-organ systems to probe the effects on tumor behavior and cancer treatments. 10.1016/j.semcancer.2020.06.010
    IL6 Modulates the Immune Status of the Tumor Microenvironment to Facilitate Metastatic Colonization of Colorectal Cancer Cells. Toyoshima Yujiro,Kitamura Hidemitsu,Xiang Huihui,Ohno Yosuke,Homma Shigenori,Kawamura Hideki,Takahashi Norihiko,Kamiyama Toshiya,Tanino Mishie,Taketomi Akinobu Cancer immunology research It is unknown as to how liver metastases are correlated with host immune status in colorectal cancer. In this study, we found that IL6, a proinflammatory cytokine produced in tumor-bearing states, promoted the metastatic colonization of colon cancer cells in association with dysfunctional antitumor immunity. In IL6-deficient mice, metastatic colonization of CT26 cells in the liver was reduced, and the antitumor effector function of CD8 T cells, as well as IL12 production by CD11c dendritic cells, were augmented IL6-deficient mice exhibited enhanced IFN-AR1-mediated type I interferon signaling, which upregulated PD-L1 and MHC class I expression on CT26 cells. injection of anti-PD-L1 effectively suppressed the metastatic colonization of CT26 cells in but not in mice. Finally, we confirmed that colorectal cancer patients with low IL6 expression in their primary tumors showed prolonged disease-free survival. These findings suggest that IL6 may be a promising target for the treatment of metastasis in colorectal cancers by improving host immunity. 10.1158/2326-6066.CIR-18-0766
    Estimation of the future remnant liver function is a better tool to predict post-hepatectomy liver failure than platelet-based liver scores. Chapelle T,Op de Beeck B,Driessen A,Roeyen G,Bracke B,Hartman V,Huyghe I,Morrison S,Ysebaert D,Francque S European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology INTRODUCTION:Recently, there has been increasing interest in the preoperative prediction and prevention of post-hepatectomy liver failure (PHLF). This is a particular concern in colorectal liver metastases (CRLM), when surgery follows potentially hepatotoxic chemotherapy. Platelet-based liver scores (PBLS) such as APRI and FIB-4 are predictive of chemotherapy-associated liver injury (CALI) and PHLF. Estimation of the future liver remnant function (eFLRF) by combining Tc-Mebrofenin Hepatobiliary Scintigraphy (HBS) with future liver remnant volume ratio (FLRV%), is predictive of PHLF and related mortality. We hypothesized that a HBS based formula was a better predictor for PHLF than PBLS in chemotherapy-pretreated CRLM. METHODS:Between 2012 and 2016, 140 patients underwent liver resection for CRLM following systemic therapy. HBS, FLRV%, eFLRF and PBLS were calculated and compared for their value in predicting PHLF. RESULTS:eFLRF and FLRV% had a better predictive value for PHLF than HBS alone and APRI and FIB-4 (AUC = 0.800, 0.843 versus 0.652, 0.635 and 0.658 respectively). In a subgroup analysis (Oxaliplatin all, Oxaliplatin ≥ 6 cycles, Irinotecan all and Irinotecan ≥ 6 cycles), eFLRF was the only factor predictive for PHLF in all subgroups (all: p ≤ 0.05). Prediction of HBS for chemotherapy associated steato-hepatitis (CASH) reached almost significance (p = 0.06). FIB-4 was predictive for sinusoidal obstruction syndrome (SOS) (p = 0.011). Only weak correlation was found between HBS and PBLS. CONCLUSION:eFLRF is a better predictor of PHLF than PBLS or HBS alone. PBLS seem to measure other aspects of liver function or damage than HBS. 10.1016/j.ejso.2017.08.009
    Introduction of the resection severity index as independent risk factor limiting survival after resection of colorectal liver metastases. Gwiasda Jill,Schrem Harald,Kaltenborn Alexander,Mahlmann Jan,Mix Heiko,Lehner Frank,Kayser Nicolas,Klempnauer Jürgen,Kulik Ulf Surgical oncology BACKGROUND:The purpose of this study is to evaluate the influence of the recently introduced resection severity index (RSI) in patients with liver resection for hepatocellular carcinoma on survival after resection of colorectal liver metastases. The RSI quantifies pre-operatively the liver cellular damage, liver synthetic function and loss of organ parenchyma. METHODS:All consecutive patients who underwent liver resection for metastases of colorectal cancer (CLM) between 2000 and 2015 were included in this study. Risk factors limiting survival were analyzed using univariable and multivariable Cox regression analyses. RESULTS:The median survival after liver resection for CLM was 3.0 years. Significant independent risk factors for mortality were the RSI (p = 0.029; hazard ratio (HR): 1.088, 95%-confidence interval (95%-CI): 1.009-1.174), age at resection in years (p = 0.001; HR: 1.017, 95%-CI: 1.007-1.027), pre-operative hemoglobin level (p = 0.041; HR: 0.932, 95%-CI: 0.891-0.997), the cecum as location of primary CRC (p < 0.001; HR: 2.023, 95%-CI: 1.403-2.833), adjuvant chemotherapy (p < 0.001; HR: 1.506, 95%-CI: 1.212-1.878), local relapse of the primary tumor (p = 0.027; HR: 1.591, 95%-CI: 1.057-2.297), the units of intra-operatively transfused packed red blood cells (p < 0.001; HR: 1.068, 95%-CI: 1.033-1.104), the size of the largest metastasis (p = 0.002; HR: 1.005, 95%-CI: 1.002-1.008) and the metastasis' distance to the resection margin (p = 0.014; HR: 0.984, 95%-CI: 0.972-0.997). CONCLUSION:The RSI is an independent prognostic factor for survival after liver resection for CLM. Besides the extent of liver resection certain primary tumor characteristics have to be taken into account to ensure long-term survival. 10.1016/j.suronc.2017.08.002
    The Evaluation of Liver Function and Surgical Influence by ICGR15 after Chemotherapy for Colorectal Liver Metastases. Hiwatashi Kiyokazu,Ueno Shinichi,Sakoda Masahiko,Iino Satoshi,Minami Koji,Mori Shinichiro,Kita Yoshiaki,Baba Kenji,Kurahara Hiroshi,Mataki Yuko,Maemura Kosei,Shinchi Hiroyuki,Natsugoe Shoji Journal of Cancer Background; Approximately 60% of patients with colorectal cancer develop liver metastasis at some point after diagnosis. The aim of this study is to investigate whether the evaluation of ICGR15 preoperatively is a useful clinical indicator of hepatic injury following chemotherapy and to investigate the influence of multiple chemotherapies on liver function. Results; Mean ICGR15 values were higher in patients ≥65 years (P = 0.047) and in patients with ≥3 cycles (P = 0.022) and ≥6 cycles (P = 0.001) of systemic chemotherapy. ICGR15 values tended to be higher in patients with postoperative complications (P = 0.085). Patients receiving systemic chemotherapy for ≥6 cycles had higher levels of AST (P = 0.003), ALT (P = 0.015), and alkaline phosphatase (ALP) (P = 0.041). Patients receiving systemic chemotherapy for ≥3 cycles had higher levels of AST (P = 0.015) and ALP (P = 0.015). Conclusions; Because the pathological diagnosis is usually established only after operation, preoperative evaluation such as the identification of sinusoidal injury is difficult. Based on this study, higher ICGR15 values may provide an indication of surgical complications and be a predictor of liver dysfunction following frequent cycles of chemotherapy. Hepatectomy should be performed with the utmost care in such patients, and the number of cycles of preoperative chemotherapy should probably be as low as possible. 10.7150/jca.13759
    TNF Receptor-2 Facilitates an Immunosuppressive Microenvironment in the Liver to Promote the Colonization and Growth of Hepatic Metastases. Ham Boram,Wang Ni,D'Costa Zarina,Fernandez Maria Celia,Bourdeau France,Auguste Patrick,Illemann Martin,Eefsen Rikke Loevendahl,Høyer-Hansen Gunilla,Vainer Ben,Evrard Maximilien,Gao Zu-Hua,Brodt Pnina Cancer research Successful colonization by a cancer cell of a distant metastatic site requires immune escape in the new microenvironment. TNF signaling has been implicated broadly in the suppression of immune surveillance that prevents colonization at the metastatic site and therefore must be blocked. In this study, we explored how TNF signaling influences the efficiency of liver metastasis by colon and lung carcinoma in mice that are genetically deficient for the TNF receptor TNFR2. We found a marked reduction in liver metastases that correlated with a greatly reduced accumulation at metastatic sites of CD11b(+)GR-1(+) myeloid cells with enhanced arginase activity, identified as myeloid-derived suppressor cells (MDSC). Reduced infiltration of MDSC coincided with a reduction in the number of CD4(+)FoxP3(+) T regulatory cells in the tumors. Reconstitution of TNFR2-deficient mice with normal bone marrow, or adoptive transfer of TNFR2-expressing MDSC into these mice, was sufficient to restore liver metastasis to levels in wild-type mice. Conversely, treatment with TNFR2 antisense oligodeoxynucleotides reduced liver metastasis in wild-type mice. Clinically, immunohistochemical analysis of liver metastases from chemotherapy-naïve colon cancer patients confirmed the presence of CD33(+)HLA-DR(-)TNFR2(+) myeloid cells in the periphery of hepatic metastases. Overall, our findings implicate TNFR2 in supporting MDSC-mediated immune suppression and metastasis in the liver, suggesting the use of TNFR2 inhibitors as a strategy to prevent metastatic progression to liver in colon, lung, and various other types of cancer. 10.1158/0008-5472.CAN-14-3173
    Evaluation of Liver Biomarkers as Prognostic Factors for Outcomes to Yttrium-90 Radioembolization of Primary and Secondary Liver Malignancies. Henrie Adam M,Wittstrom Kristina,Delu Adam,Deming Paulina Cancer biotherapy & radiopharmaceuticals The objective of this study was to examine indicators of liver function and inflammation for prognostic value in predicting outcomes to yttrium-90 radioembolization (RE). In a retrospective analysis, markers of liver function and inflammation, biomarkers required to stage liver function and inflammation, and data regarding survival, tumor response, and progression after RE were recorded. Univariate regression models were used to investigate the prognostic value of liver biomarkers in predicting outcome to RE as measured by survival, tumor progression, and radiographic and biochemical tumor response. Markers from all malignancy types were analyzed together. A subgroup analysis was performed on markers from patients with metastatic colorectal cancer. A total of 31 patients received RE from 2004 to 2014. Median survival after RE for all malignancies combined was 13.6 months (95% CI: 6.7-17.6 months). Results from an exploratory analysis of patient data suggest that liver biomarkers, including albumin concentrations, international normalized ratio, bilirubin concentrations, and the model for end-stage liver disease score, possess prognostic value in predicting outcomes to RE. 10.1089/cbr.2015.1842
    Elevated serum angiopoietin-like protein 2 correlates with the metastatic properties of colorectal cancer: a serum biomarker for early diagnosis and recurrence. Toiyama Yuji,Tanaka Koji,Kitajima Takahito,Shimura Tadanobu,Kawamura Mikio,Kawamoto Aya,Okugawa Yoshinaga,Saigusa Susumu,Hiro Junichiro,Inoue Yasuhiro,Mohri Yasuhiko,Goel Ajay,Kusunoki Masato Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:Angiopoietin-like protein 2 (ANGPTL2) is a mediator of chronic inflammation and inflammatory carcinogenesis. The biologic and clinical significance of ANGPTL2 remains unknown in human cancer. Therefore, we investigated the function of ANGPTL2 and evaluated its clinical significance in both primary tumors and matched sera in patients with colorectal cancer. EXPERIMENTAL DESIGN:A colorectal cancer cell line was transfected with siRNA against ANGPTL2 for the assessment of its function. We examined ANGPTL2 expression in colorectal cancer tissues (n = 195) by immunohistochemistry. Finally, we screened serum ANGPTL2 levels from 32 colorectal cancers and 23 normal controls (NC), and validated these results in serum samples obtained from 195 colorectal cancers and 45 NCs by ELISA. RESULTS:Knockdown of ANGPTL2 in vitro significantly inhibited cell proliferation, migration, and invasion, whereas it enhanced anoikis. ANGPTL2 was overexpressed in colorectal cancer tissues, and was significantly associated with advanced T stage, lymph node, and liver metastasis. Likewise, serum ANGPTL2 levels in colorectal cancers were significantly higher than NCs (P < 0.01), and allowed distinguishing of colorectal cancers from NCs with high accuracy (AUC = 0.837). The subsequent validation step confirmed that serum ANGPTL2 levels in colorectal cancers were significantly higher than in NCs (P < 0.0001), and had a high AUC value (0.885) for distinguishing colorectal cancers from NCs. High serum ANGPTL2 was significantly associated with advanced T stage, lymph node and liver metastasis, early relapse, and poor prognosis in colorectal cancers. CONCLUSION:Serum ANGPTL2 is a novel diagnostic and recurrence-predictive biomarker in patients with colorectal cancer. 10.1158/1078-0432.CCR-14-0007
    Regional Therapies for Colorectal Liver Metastases: Systematic Review and Clinical Practice Guideline. Karanicolas P,Beecroft J R,Cosby R,David E,Kalyvas M,Kennedy E,Sapisochin G,Wong R,Zbuk K, Clinical colorectal cancer BACKGROUND:Resection is the foundation for cure for colorectal cancer (CRC) liver metastases; however, only 20% of patients are suitable for surgery. Those suitable would be considered for resection or local therapies before being considered for regional therapies. Noncurative treatment is usually systemic chemotherapy. For patients with liver-only or liver-predominant metastases that are unresectable, regional therapies [conventional transarterial chemoembolization (cTACE), drug-eluting bead transarterial chemoembolization (DEB-TACE), and transarterial radioembolization (TARE)] may be considered. We review the current evidence for regional therapies for CRC liver metastases. PATIENTS AND METHODS:Literature searches (January 2000 to March 2019 or January 2010 to March 2019 depending on the specific systematic review question) were conducted, including Medline, Embase, Cochrane Library, and 2018 American Society of Clinical Oncology (ASCO) abstracts. RESULTS:A total of 4100 articles were identified; 15 studies were included in the review. There were no comparative data regarding the resectable population. There was either insufficient evidence (cTACE or DEB-TACE) or evidence against (TARE) the addition of regional therapies to systemic therapy in the first line in the unresectable population. There was either no evidence (cTACE) or weak evidence (DEB-TACE or TARE) for the addition of regional therapies with or without systemic therapy in the second line or later in the unresectable population. CONCLUSION:Limited evidence supports the delivery of percutaneous regional therapies in patients with unresectable CRC liver metastases. There are strong data demonstrating positive effects of TARE within the liver, but they do not translate to a benefit in patient-important outcomes. DEB-TACE appears to offer a survival benefit in the second-line setting, although the evidence is limited by small sample size and larger trials are needed. 10.1016/j.clcc.2020.09.008
    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. 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. 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. 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