Liver Metastasis-free Survival Research Articles

Serum inflammatory markers as prognostic marker for nasopharyngeal carcinoma with liver metastasis: a multi-center retrospective study.

This retrospective study investigated the prognostic value of serum inflammatory markers in nasopharyngeal carcinoma (NPC) patients, focusing on their association with overall survival (OS) and liver metastasis-free survival (LMFS). The study included 314 NPC patients treated between 2010 and 2020. Clinical characteristics, treatment methods, and serum inflammatory markers were assessed. Patients were categorized into two groups of with and without liver metastasis. Univariate and multivariate Cox regression and Kaplan-Meier survival analyses were performed to investigate the prognostic value of serum inflammatory markers in NPC patients with and without liver metastasis. In the whole cohort, univariate Cox regression analysis singled out tumor necrosis factor-α (TNF-α) (HR = 1.57, 95% CI 1.44-4.90, p = 0.004) and neutrophil-to-lymphocyte ratio (NLR) (HR = 2.13, 95% CI 1.33-3.99, p = 0.009), which were significantly associated with poorer OS. In patients with liver metastasis, TNF-α and NLR could not independently predict OS. However, high TNF-α levels were independently associated with worse OS in patients without liver metastasis (HR (95% CI) = 2.75 (1.67-8.68), p < 0.001). High NLR levels could independently predict poor OS in both groups with (HR (95% CI) = 1.94 (1.77-6.38), p = 0.010) and without liver metastasis (HR (95% CI) = 1.58 (1.19-7.54), p = 0.009). Ultimately, TNF-α and NLR could not significantly predict LMFS. This study highlights the prognostic significance of TNF-α and NLR in NPC patients, especially in those with liver metastasis. These inflammatory markers could serve as valuable indicators for assessing the prognosis of NPC patients. Further research is warranted to validate their clinical utility and explore potential therapeutic implications.

Non-Alcoholic Fatty Liver Disease May Be a Risk Factor for Liver Metastasis After Radical Surgery for Colorectal Cancer: A Retrospective Study.

Distant metastasis develops in approximately one-third of patients with colorectal cancer (CRC) who undergo radical surgery, and colorectal liver metastasis (CRLM) is the most common form of distant metastasis in CRC. Hepatectomy is the only potentially curative treatment for CRLM, but few patients with metastatic CRC meet the criteria for this radical resection, and the 5-year survival rate is poor. Identifying risk factors for CRLM is critical. Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for CRC. However, the effect of NAFLD on CRC liver metastasis after radical surgery remains unclear. Therefore, we examined the impact of NAFLD-associated hepatic fibrosis on liver metastasis after radical surgery for CRC. We retrospectively analyzed data from 388 patients who underwent curative surgery for CRC at our hospital between April 2008 and March 2015. The patients' clinical results, surgical procedures, postoperative course, and pathological and survival data were collected from the hospital records. The NAFLD fibrosis score was calculated and used to divide the patients into two groups (NAFLD and non-NAFLD). Recurrence was observed in 83/388 (21.4%) patients after a mean follow-up of 65.6 ± 15.1months. Twenty-five patients had liver metastasis: 8 in the NAFLD group (8/45; 17.8%) and 17 in the non-NALFD group (17/343; 5.0%) (p = 0.004). Liver metastasis-free survival was significantly worse in the NAFLD than non-NAFLD group (p < 0.001). NAFLD and cancer stage were independent risk factors for liver metastasis recurrence. NAFLD may be a risk factor for liver metastasis in patients with CRC who undergo curative surgery.

Development and validation of a nomogram to predict liver metastasis for pancreatic ductal adenocarcinoma after radical resection.

This study aimed to develop and externally validate a nomogram for predicting liver metastasis after radical resection in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 247 PDAC patients who underwent radical resection were retrospectively reviewed from January 2015 to March 2022 at Ningbo Medical Centre Lihuili Hospital Eastern Section, and used as a training cohort to develop the nomogram. 83 PDAC patients from the Ningbo Medical Centre Lihuili Hospital Xingning Section were enrolled as the validation cohort. The postoperative liver metastasis was recorded during the follow-up, and the liver metastasis-free survival was defined as the time from operation to the date of liver metastasis diagnosis or death. The nomogram was established based on independent prognostic factors selected by LASSO and multivariate Cox regression model. The performance was assessed using the concordance index (C-index) and calibration curves. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to determine the clinical utility of the nomogram model. From the training cohort of 247 patients, a total of 132 patients developed liver metastasis during the follow-up, the 1-, 2- and 3- year liver metastasis-free survival were 52.4%, 43.5% and 40% respectively. The LASSO and multivariate Cox regression analysis indicated that postoperative CA125 (hazard ratio [HR] = 1.007, p <0.001), tumor differentiation (HR = 1.640, p = 0.010), tumor size (HR = 1.520, p = 0.029), lymph node ratio (HR = 1.897, p = 0.002) and portal/superior mesenteric/splenic vein invasion degree (PV/SMV/SV) (HR = 2.829, p <0.001) were the independent factors of liver metastasis. A nomogram with independent factors was developed and the C-index was 0.760 (95% confidence interval [CI], 0.720-0.799) and 0.739 (95% CI, 0.669-0.810) in the training and validation cohorts, respectively. The areas under curve (AUC) of the nomogram at 1-, 2- and 3-year were 0.815, 0.803 and 0.773 in the training cohort, and 0.765, 0.879 and 0.908 in the validation cohort, respectively, higher than those in TNM stage. Decision curve analysis (DCA) analysis revealed that the nomogram model provided superior net benefit in clinical utility. Liver metastasis-free survival curves showed a significant discriminatory ability for liver metastasis risk based on the nomogram (p <0.001). The nomogram showed high accuracy in predicting liver metastasis for PDAC after radical resection, and may serve as a clinical support tool to guide personalized and prescient intervention.

Long-Term Outcomes for Patients with Multiple Endocrine Neoplasia Type 1 and Duodenopancreatic Neuroendocrine Neoplasms.

Liver metastasis from duodenopancreatic neuroendocrine neoplasms (DP-NENs) is a major cause of mortality in multiple endocrine neoplasia type 1 (MEN1) patients, yet much of their natural history is unknown. This longitudinal, retrospective cohort study analyzed all MEN1 patients with imageable functional (F) and nonfunctional (NF) DP-NENs (1990-2021)for liver metastasis-free survival (LMFS) and overall survival (OS). Of 138 patients, 85 (61.6%) had imageable DP-NENs (28 F, 57 NF), and the mean largest tumor size was 1.8 ± 1.4 cm. Multifocality was present in 32 patients (37.7%). Surgery was performed for 49 patients (57.7%). During an 11-year median follow-up period (IQR, 6-17 years), 23 (27.1%) of the patients had liver metastasis, and 19 (22.4%) patients died. Death was attributed to liver metastasis in 60% of cases. The patients with F-DP-NENs versus NF-DP-NENs more often had liver metastasis (46.4% vs. 15.8%; p = 0.002) but had similar 10-year LMFS (80.9 vs. 87.0%; p = 0.44) and OS (82.7 vs. 94.3%; p = 0.69). The patients with NF-DP-NENs had surgery when their tumors were larger (p < 0.001). Tumor size was not associated with liver metastasis (p = 0.89). The average growth rate was 0.04 cm/year (SE, 0.02 cm/year; p = 0.01) during active surveillance for NF-DP-NENs (n = 38). Liver metastasis developed in four patients with tumors smaller than 2 cm. The risk of liver metastasis was independent of surgery (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.21-2.93; p = 0.72) and death (HR, 0.51; 95% CI, 0.08-3.06; p = 0.46). Although the observed outcomes in this study were better than historical data, small NF-DP-NENs still developed liver metastasis and liver metastasis remains a major cause of death. These results suggest that size as a sole criterion for surgery may be insufficient to predict tumor behavior.

Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.

Hyperglycemia Promotes Liver Metastasis of Colorectal Cancer via Upregulation of Integrin αvβ6.

BackgroundDiabetes is related to higher risk of multiple cancers. This study aimed to explore the effect and mechanism of diabetes on liver metastasis of CRC.Material/MethodsOverall and liver metastasis-free survival in diabetic and non-diabetic CRC patients were compared by Kaplan-Meier analysis. Expression of αvβ6 was detected by immunohistochemistry in clinical specimens. Effects of hyperglycemia on αvβ6 expression in colon cancer cells were assessed by western blot, real-time PCR, and flowcytometry. Effects of hyperglycemia on migration and invasion were demonstrated by Transwell assay. Expression and activity of MMP-9 and MMP-2 were determined by real-time PCR and gelatin zymography. Liver metastatic nodules were counted and β6 expression was detected by western blot in a liver metastasis mouse model.ResultsCRC patients with diabetes had poorer overall and liver metastasis-free survival, and diabetes was associated with higher αvβ6 expression in CRC specimens. Hyperglycemia promoted the invasion and migration of colon cancer cells, and upregulated the expression and activity of MMP-9, which were attenuated by inhibition of αvβ6. Hyperglycemia upregulated the expression of β6 and cell surface expression of αvβ6, which was reduced by ERK inhibitor. The in vitro results were confirmed in vivo in the mouse model.ConclusionsOur study demonstrated the enhancing effect of hyperglycemia on liver metastasis of CRC, and showed that αvβ6 was involved in this process, suggesting that control of glucose levels and inhibition of αvβ6 can reduce the risk of liver metastasis in diabetic CRC patients.

Prognostic Prediction Models for Liver Metastasis and Overall Survival in Colorectal Cancer Patients

Objective The objective of this study was to develop novel prediction models for liver metastasis-free survival (LMFS) and overall survival (OS) in colorectal cancer (CRC) patients following surgically curative resections. We developed novel prediction models for LMFS and OS in CRC patients following surgically curative resections. Using clinicopathologic factors, such models were constructed with concordance indices of 0.811 and 0.776 for LMFS and OS, respectively. Methods Seven hundred seventy-six CRC patients presenting to the Osaka Medical Center for Cancer and Cardiovascular Diseases between January 2004 and December 2010 were retrospectively studied. The exclusion criteria were patients with preoperative treatment, synchronous distant metastasis, noncurative resection, and incomplete postoperative follow-up. Results Based on the analysis of clinicopathologic factors, the following factors had significant correlation with LMFS: preoperative serum carcinoembryonic antigen (pre-CEA), tumor invasion, lymph node metastasis, lymphatic invasion, and venous invasion. Using these variables, a novel prediction model was constructed by the Cox regression model with a concordance index (c-index) of 0.811 for LMFS. The following factors had a significant correlation with OS: age, pre-CEA, preoperative serum carbohydrate antigen 19-9, tumor location, pathologically defined tumor invasion, lymph node metastasis, and venous invasion. Using these variables, a prediction model was constructed with a c-index of 0.776 for OS. These models were validated by external datasets in an independent patient group. Conclusions We demonstrated the utility of a novel personalized prognostic model for liver metastasis, integrating tumor node metastasis factors, pre-CEA, and histologic lymphovascular invasion to predict the prognosis. Such models can help clinicians in treating CRC patients postoperatively.

Downregulated Pancreatic Beta Cell Genes Indicate Poor Prognosis in Patients With Pancreatic Neuroendocrine Neoplasms.

To predict metachronous liver metastasis after pancreatectomy for pancreatic neuroendocrine neoplasms (Pan-NENs). Liver metastasis determines the prognosis of patients with Pan-NENs, but no index exists in the WHO 2017 classification for this prediction. Between April 2014 and March 2018, resected primary tumors from 20 patients with or without simultaneous liver metastasis were examined using genome-wide gene expression analysis. For validation analysis, resected primary tumors from 62 patients without simultaneous liver metastasis were examined for PAX6 expression. Gene expression profiling revealed pancreatic beta cell genes (NES, -2.0; P < 0.001) as the most downregulated set in patients with simultaneous liver metastasis. In the test study, PAX6 was the most valuable index for liver metastasis (log FC, -3.683; P = 0.0096). Multivariate analysis identified PAX6 expression (hazard ratio, 0.2; P = 0.03) as an independent risk factor for metachronous liver metastasis-free survival (mLM-FS). The 5-year mLM-FS of patients with high versus low PAX6 expression was significantly better (95% vs 66%, respectively; P < 0.0001). The 5-year overall survival rate of was also better than in those with high versus low PAX6 expression (100% vs 87%, respectively). Patients with low PAX 6 expression were significantly younger and leaner, had a higher Ki-67 index (P = 0.01, 0.007, 0.008, respectively), and showed a higher mitotic rate than patients with high PAX6 expression. Downregulated pancreatic beta cell genes involving PAX6 in primary tumors may predict mLM and poor overall survival after primary tumor resection in Pan-NEN patients.

Hepatitis B virus infection specially increases risk of liver metastasis in breast cancer patients: a propensity-matched analysis.

BackgroundBreast cancer and hepatitis B virus (HBV) infection are serious public health issues in China. But the effect of HBV infection on breast cancer remains unclear. The objective was to assess whether HBV infection was associated with prognosis of breast cancer.MethodsA retrospective database of 1,924 invasive breast cancer patients from Sun Yat-sen University Cancer Center from 2008 to 2010 was established. Propensity score matching method was applied to balance baseline parameters. Logistic regression was used for identifying the independent risk factors of liver metastasis. Prognostic outcomes were evaluated via Kaplan-Meier analysis and Cox model.ResultsPrimary evaluation of gross data suggested HBV infection was associated with much higher rate of liver metastasis. 642 patients were matched for analysis. The median follow-up time was about 69 months. Patients with HBV surface antigen (HBsAg) (+) had a specially higher risk of liver metastasis aside of other distant organs than those with HBsAg (−). HBsAg (−/+) was identified to be an independent risk factor of liver metastasis [odds ratio (OR), 2.651; 95% confidence intervals (CI), 1.213–5.796; P=0.015]. HBsAg (+) was associated with liver metastasis significantly in stage III or in estrogen receptor (ER) (+) and/or progesterone receptor (PR) (+), human epidermal growth factor receptor-2 (HER-2) (−) subtype. Meanwhile, patients with HBsAg (+) had significant shorter liver metastasis-free survival (LMFS) compared with HBsAg (−) patients (P=0.041). But the difference of overall survival (OS) between the HBsAg (−) and HBsAg (+) groups reached statistically no significance (P=0.425). The multivariate analysis suggested HBsAg (+) could worsen the outcome of LMFS [hazards ratio (HR), 2.450; 95% CI, 1.169–5.135; P=0.018].ConclusionsIn breast cancer, HBsAg (+) was associated with specially a higher rate of liver metastasis and thus worsened the LMFS. HBsAg (−/+) was an independent risk factor of liver metastasis.

Abstract 3687: Colorectal cancer stem cell expressing POU5F1 promotes liver metastasis

Abstract Background: The gene POU5F1, encoding the POU domain, class 5, is a transcription factor and the expression is found in embryonic stem cells. POU5F1 gene controls self-renewal and differentiation, and regulates pluripotency and proliferation in embryonic stem cells. However, the role of POU5F1 in metastatic CRC (mCRC) is not well known. We focused on the relationship between POU5F1 gene expression and liver metastasis of CRC and clarify the role and abilities of POU5F1-positive CRC cells. Methods: The study included 158 patients with CRC who underwent surgery from 2009 to 2011. The correlations between the POU5F1 gene expression and the clinical parameters were assessed, and liver-metastasis-free survival (LMFS) was evaluated in these patients. POU5F1-EGFP-positive cells were established by the construct with lentiviral vector, and we examine their sub-population and ability. The capacity to form liver metastasis in vivo was examined using CRC cell lines and primary cultured CRC cells. Results: In the survival analysis, LMFS was significantly poor in the high POU5F1 expression group compared to the low-expression group (P=0.008). Multivariate analyses showed that POU5F1 expression (P=0.015) and TNM stage (p&amp;lt;0.001) significantly correlated with LMFS. POU5F1-EGFP-positive cells highly expressed stem-cell-associated markers and they had self-renewal and differentiation abilities. POU5F1-high cells actively formed liver metastasis. Conclusion: The POU5F1expression correlated with liver metastasis in CRC patients. POU5F1-positive cells have the self-renewal and differentiation abilities as cancer stem cells. POU5F1 contributes to the ability forming liver metastasis in CRC. Citation Format: Norikatsu Miyoshi, Shiki Fujino, Masaru Sasaki, Kazuhiro Saso, Hidekazu Takahashi, Naotsugu Haraguchi, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Masaki Mori, Yuichiro Doki. Colorectal cancer stem cell expressing POU5F1 promotes liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3687.

Oct4 Gene Expression in Primary Colorectal Cancer Promotes Liver Metastasis.

Purpose The Oct4 gene plays an important role in undifferentiated embryonic stem cells and regulates stem cell pluripotency. The aim of this study was to examine the relationship between Oct4 expression and liver metastasis of colorectal cancer (CRC) in clinical samples and investigate the role and abilities of Oct4-positive CRC cells. Methods The study included 158 patients who underwent surgery for CRC between 2009 and 2011. The correlations between the Oct4 gene expression and the clinical parameters were assessed, and liver metastasis-free survival (LMFS) was evaluated in these patients. Oct4-EGFP-positive cells were established to examine their subpopulation and ability. The capacity to form liver metastasis in vivo was examined using CRC cell lines and primary cultured CRC cells. Results LMFS was significantly poor in the Oct4 high-expression group compared with the low-expression group (P = 0.008). Multivariate analyses showed that Oct4 expression (P = 0.015) and TNM stage (P < 0.001) were significantly correlated with LMFS. Oct4-EGFP-positive cells highly expressed stem cell-associated markers and had self-renewal and differentiation abilities. Oct4-high cells actively formed liver metastasis. Conclusion The Oct4 expression was correlated with liver metastasis in CRC patients. Oct4 expression cells have self-renewal and differentiation abilities like those of cancer stem cells. Oct4 contributed to forming liver metastasis in CRC.

Fatty liver is a risk factor for liver metastasis in Chinese patients with non-small cell lung cancer.

BackgroundThe hepatic microenvironment, which may include chronic inflammation and fibrosis, is considered to contribute to the development of liver metastases. Hepatic steatosis (HS) might cause liver inflammation and fibrosis. However, to date, no studies have investigated the impact of HS on liver metastasis in patients with non-small cell lung cancer (NSCLC).MethodsA retrospective cohort study was performed on patients who received NSCLC treatment at two hospitals affiliated with the Southern Medical University from January 2005 to December 2015. The patients were grouped according to the presence of HS. The clinicopathological features of patients between the two groups were compared. The effect of HS on liver metastasis and overall metastasis was evaluated, adjusting for other confounders using Cox regression analyses.ResultsIn total, 1,873 patients with NSCLC with no distant metastases were included in this study, and 408 (21.8%) patients were diagnosed with HS (at the time of diagnosis or before diagnosis). Liver metastases occurred in 166 (8.9%) patients. Liver metastasis-free survival was significantly worse in the study (HS) group (hazard ratio (HR) 1.42; (95% CI [1.03–1.96]); P = 0.031). Multivariate regression analysis demonstrated that HS was an independent risk factor for liver metastasis (HR 1.43; 95% CI [1.02–2.01]; P = 0.039). However, HS was not associated with overall metastasis of NSCLC (HR 0.99; 95% CI [0.84–1.17]; P = 0.895).ConclusionHepatic steatosis was an independent predictor of liver metastasis from in patients with NSCLC.

Abstract 1067: Tenascin C in colorectal cancer stroma is a predictive marker for liver metastasis and is a potent target of miR-198 as identified by microRNA analysis

Abstract Background: Liver metastasis in colorectal cancer (CRC) is still one of the major determinants of survival. Tumor stroma has important roles in the development of colorectal cancer (CRC) metastasis. MicroRNAs (miRNAs) are known to regulate the expression of genes involved in many physiological conditions, including cancer. Previous studies reported important roles of miRNAs in cancer cells in CRC development and metastasis. However, only few studies have focused on miRNA expression in CRC stroma. In this study, we revealed the miRNA expression profiles in tumor stroma by miRNA array analysis using Laser captured microdissection (LCM) to identify miRNAs and their target genes as novel molecular markers involved in CRC liver metastasis. Methods: Tumor stroma was isolated from formalin-fixed, paraffin-embedded tissues of primary CRCs with or without liver metastasis by LCM, and miRNA expression was analyzed using TaqMan miRNA arrays. Results: Hierarchical clustering classified 16 CRCs into two groups according to the existence of synchronous liver metastasis. Combinatory target prediction identified tenascin C (TNC) as a predicted target of miR-198, one of the top 10 miRNAs downregulated in tumor stroma of CRCs with synchronous liver metastasis. Immunohistochemical analysis of TNC in 139 primary CRCs revealed that a high staining intensity was correlated with synchronous liver metastasis (P&amp;lt;0.001). TNC staining intensities in the tumor stroma of 83 CRC liver metastases revealed a higher staining in liver metastases than in primary CRCs independently of preoperative chemotherapy. Univariate and multivariate analyses revealed that the TNC staining intensity was an independent prognostic factor to predict postoperative overall survival (P=0.005; n=139) and liver metastasis-free survival (P=0.001; n=128). To evaluate the biological link between miR-198 and TNC, we first checked expression levels of miR-198 in the 16 samples in miRNA array data, and compared them with TNC staining intensities. The CRC samples expressing miR-198 tended to have lower levels of TNC expression in comparison with those without miR-198 expression, although the difference was not statistically significant (P=0.237). Next, we transfected a miR-198 mimic or a miR-198 inhibitor into SW620 human colon cancer cells and CCD-18Co human colon fibroblast cells and analyzed the expression change of TNC protein by western blotting. The relative protein expression of TNC was suppressed by treatment with the miR-198 mimic and increased by miR-198 inhibitor. Conclusions: Alterations of miRNAs in CRC stroma appear to form a metastasis-permissive environment that can elevate TNC to promote liver metastasis. TNC in primary CRC stroma has the potential to be a novel biomarker to predict postoperative prognosis. Citation Format: Tomohiro Murakami, Hirotoshi Kikuchi, Hisahito Ishimatsu, Sanshiro Kawata, Amane Hirotsu, Tomohiro Matsumoto, Yusuke Ozaki, Yoshihiro Hiramatsu, Kinji Kamiya, Megumi Baba, Satoshi Baba, Masatoshi Kitagawa, Takanori Sakaguchi, Hiroyuki Konno, Hiroya Takeuchi. Tenascin C in colorectal cancer stroma is a predictive marker for liver metastasis and is a potent target of miR-198 as identified by microRNA analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1067.

Impact of adjuvant hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil with systemic gemcitabine for resectable pancreatic cancer.

360 Background: Despite recent advances in cancer treatment, postoperative recurrence remains an unsolved issue for resectable pancreatic cancer. To prevent hepatic recurrence and prolong postoperative survival, we introduced postoperative adjuvant chemotherapy of high-dose 5-fluorouracil (5-FU) hepatic arterial infusion (HAI) with systemic chemotherapy using gemcitabine in 2006. We retrospectively evaluated the clinical impact of HAI. Methods: A total of 251 patients who underwent pancreatic resection for PC were analyzed. Patients received weekly high-dose 5-FU through the hepatic artery using a port-catheter system (1000 mg/m2 for 5 h) plus concurrent systemic gemcitabine (1000 mg/m2) followed by systemic 3 cycles of gemcitabine or 4 cycles of S-1. Patients were divided into two groups. The patients who completed planned adjuvant chemotherapy of HAI were classified as the completion group (HAI), and the patients who failed to complete HAI or received systemic adjuvant chemotherapy other than HAI were classified as the control group. Results: One hundred thirty-eight patients (55%) completed planned adjuvant chemotherapy of HAI. On the other hand, 28 patients (11%) failed to complete HAI and 85 patients (34%) received systemic adjuvant chemotherapy alone. The reasons for incompletion of HAI were as follows: any recurrence during HAI treatment in 8, poor general condition of patients in 4, hepatic arterial stenosis in 4 and catheter trouble in 3. Initial hepatic metastasis rate was significantly lower in the HAI group than the control group (15.2 vs. 26.3%, p=0.029), and liver metastasis free survival was significantly better in the HAI group than the control group (p=0.001). The HAI group had a better prognosis than the control group (58.1 vs. 26.9M, p &lt; 0.001). Prognostic factor analysis indicated that failure to complete HAI (p &lt; 0.001, HR 1.95), borderline resectable tumor (p = 0.028, HR 1.63), and lymph node metastasis (p = 0.018, HR 1.59) were the independent adverse prognostic factors. Conclusions: Our data demonstrate that HAI can significantly prevent hepatic recurrence and also improve the postoperative prognosis in pancreatic cancer.

CT texture features of liver parenchyma for predicting development of metastatic disease and overall survival in patients with colorectal cancer.

To determine if identifiable hepatic textural features are present at abdominal CT in patients with colorectal cancer (CRC) prior to the development of CT-detectable hepatic metastases. Four filtration-histogram texture features (standard deviation, skewness, entropy and kurtosis) were extracted from the liver parenchyma on portal venous phase CT images at staging and post-treatment surveillance. Surveillance scans corresponded to the last scan prior to the development of CT-detectable CRC liver metastases in 29 patients (median time interval, 6 months), and these were compared with interval-matched surveillance scans in 60 CRC patients who did not develop liver metastases. Predictive models of liver metastasis-free survival and overall survival were built using regularised Cox proportional hazards regression. Texture features did not significantly differ between cases and controls. For Cox models using all features as predictors, all coefficients were shrunk to zero, suggesting no association between any CT texture features and outcomes. Prognostic indices derived from entropy features at surveillance CT incorrectly classified patients into risk groups for future liver metastases (p < 0.001). On surveillance CT scans immediately prior to the development of CRC liver metastases, we found no evidence suggesting that changes in identifiable hepatic texture features were predictive of their development. • No correlation between liver texture features and metastasis-free survival was observed. • Liver texture features incorrectly classified patients into risk groups for liver metastases. • Standardised texture analysis workflows need to be developed to improve research reproducibility.

Tenascin C in colorectal cancer stroma is a predictive marker for liver metastasis and is a potent target of miR-198 as identified by microRNA analysis

Background:Tumour stroma has important roles in the development of colorectal cancer (CRC) metastasis. We aimed to clarify the roles of microRNAs (miRNAs) and their target genes in CRC stroma in the development of liver metastasis.Methods:Tumour stroma was isolated from formalin-fixed, paraffin-embedded tissues of primary CRCs with or without liver metastasis by laser capture microdissection, and miRNA expression was analysed using TaqMan miRNA arrays.Results:Hierarchical clustering classified 16 CRCs into two groups according to the existence of synchronous liver metastasis. Combinatory target prediction identified tenascin C as a predicted target of miR-198, one of the top 10 miRNAs downregulated in tumour stroma of CRCs with synchronous liver metastasis. Immunohistochemical analysis of tenascin C in 139 primary CRCs revealed that a high staining intensity was correlated with synchronous liver metastasis (P<0.001). Univariate and multivariate analyses revealed that the tenascin C staining intensity was an independent prognostic factor to predict postoperative overall survival (P=0.005; n=139) and liver metastasis-free survival (P=0.001; n=128).Conclusions:Alterations of miRNAs in CRC stroma appear to form a metastasis-permissive environment that can elevate tenascin C to promote liver metastasis. Tenascin C in primary CRC stroma has the potential to be a novel biomarker to predict postoperative prognosis.

Fatty liver decreases the risk of liver metastasis in patients with breast cancer: a two-center cohort study.

The influence of hepatic steatosis (HS) on liver metastasis in patients with non-metastatic breast cancer (BC) remains unclear. The aim of this study was to clarify the relationship between HS and liver metastasis in non-metastatic BC patients. Patients who underwent treatment for BC at two affiliated hospitals of Southern Medical University, between January 1, 2005 and December 31, 2015, were retrospectively reviewed. BC patients were divided into the study and control groups based on the presence of HS. The association between HS and liver metastasis was analyzed, adjusting for the confounding factors using Cox regression and propensity score case-match analysis. In total, 1230 female BC patients were included, and 372 (30.2%) patients were diagnosed with HS (at the time of diagnosis BC or before). The cumulative liver metastasis-free survival (MFS) rate was significantly higher in the study group than in the control group (hazard ratio 0.61; 95% confidence interval 0.40-0.94; P=0.024). On multivariate analysis, HS was an independent protective factor for local liver metastasis (HR 0.55; 0.35-0.86; P=0.008). After one-to-one matching of the study group (344) with the control group (344), liver MFS remained significantly better in the study group (HR 0.42; 0.26-0.69; P=0.001). This study indicated that HS may serve as an independent factor to decrease liver metastasis in patients with BC. Additional prospective studies are necessary to validate this finding.

Abstract 4438: MiRNA expression analysis in the tumor stroma predicts Tenascin C to promote colorectal cancer liver metastasis

Abstract Background: Liver is the most common site for colorectal cancer (CRC) metastasis, and mechanisms underlying colorectal liver metastasis need to be explored. The tumor microenvironment consists of many stromal cells which are known to interact with cancer cells and to promote metastasis. Recently many microRNAs (miRNAs) specifically expressed in the stroma is receiving attention. In this study, we analyzed the differences in miRNA expression profiles between peritumoral stroma of CRCs with and without liver metastasis, and sought to identify liver metastasis-promoting molecules that can be regulated by the altered expression of miRNAs in the peritumoral stroma. Materials and methods: The formalin-fixed paraffin-embedded (FFPE) specimens of primary CRCs from 8 patients without metastasis, 4 patients with synchronous liver metastasis and 4 patients with metachronous liver metastasis were used for miRNA array analysis. None of the patients had received any treatment prior to surgery. Tumor stroma was isolated from FFPE samples using laser capture microdissection without contamination of cancer cells, and total RNAs were extracted. The quality of total RNA was assessed, and miRNA expression was analyzed using TaqMan miRNA arrays. Protein expression of Tenascin C (TNC) was immunohistochemically analyzed in 139 primary CRCs. Results: Unsupervised hierarchical clustering classified 16 samples analyzed into two groups according to their miRNA expressions. CRCs with synchronous liver metastasis showed differential miRNA expression profiles from those without liver metastasis or with metachronous liver metastasis. Top10 miRNAs up-regulated in CRCs with synchronous liver metastasis vs. CRCs without liver metastasis or with metachronous liver metastasis were hsa-miR-518b, 618, 186, 520f, 29c, 520e, 155, 30c, 518e and 106b, and those down-regulated in CRCs with synchronous liver metastasis were hsa-miR-302a, 551b, 627, 628-5p, 19a, 372, 302b, 384, 198 and 636. The predictive targets of the top 10 down-regulated miRNAs were analyzed in silico using on-line data base such as .miRDB. TNC was identified as a candidate for metastasis-promoting molecule which can be upregulated in the peritumoral stroma followed by the downregulation of miRNAs. Immunohistochemical analysis revealed that protein expression of TNC was higher in the stroma of primary CRCs with synchronous liver metastasis compared with those without liver metastasis or with metachronous liver metastasis. Furthermore, high expression of TNC protein in the primary CRC stroma was correlated with shorter overall survival and liver metastasis-free survival. Conclusions: Alterations of miRNAs in the CRC stroma appear to create a metastasis permissive environment in which TNC plays an important role. Expression of TNC in primary CRC stroma has the potential to be a novel biomarker to predict the risk of postoperative liver metastasis in CRC patients. Citation Format: Tomohiro Murakami, Hisahito Ishimatsu, Hirotoshi Kikuchi, Amane Hirotsu, Tomohiro Matsumoto, Yusuke Ozaki, Toshiki Kawabata, Yoshihiro Hiramatsu, Kinji Kamiya, Megumi Baba, Takanori Sakaguchi, Hiroyuki Konno. MiRNA expression analysis in the tumor stroma predicts Tenascin C to promote colorectal cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4438. doi:10.1158/1538-7445.AM2017-4438

Soluble HLA-G is a differential prognostic marker in sequential colorectal cancer disease stages.

The expression of HLA-G by tumour cells is an established mechanism to escape recognition and immune mediated destruction, allowing tumour survival, growth and metastasis. However, the prognostic value of soluble HLA-G (sHLA-G) remains unknown. Mucinous carcinoma (MC) is a distinct form of colorectal cancer (CRC) found in 10 to 15% of patients, which has long been associated with poor response to treatment. To investigate the prognostic value of plasma sHLA-G levels in CRC patients, preoperative plasma sHLA-G levels were determined by ELISA in CRC patients (n = 133). In addition, the local expression of HLA-G in tumour biopsies was assessed using tissue microarray analysis (n = 255). Within the high 33rd percentile of sHLA-G levels (265-890 U/mL; n = 44) we observed higher frequency of MC patients (p = 0.012; Chi-square), and higher sHLA-G levels in patients with vascular invasion (p = 0.035; two-tailed t-test). Moreover, MC patients had significantly higher sHLA-G levels compared to those with adenocarcinoma not otherwise specified (p = 0.036; two-tailed t-test). Surprisingly, while stage II patients showed negative correlation between sHLA-G levels and liver metastasis free survival (LMFS) (p = 0.041; R = -0.321), in stage III patients high sHLA-G levels were associated with significantly longer LMFS (p = 0.002), and sHLA-G levels displayed positive correlation with LMFS (p = 0.006; R = 0.409). High HLA-G expression in tumours was associated with poor cancer specific overall survival in stage II to III (p = 0.01), and with shorter LMFS in stage II patients (p = 0.004). Our findings reveal that sHLA-G levels are associated with distinct progression patterns in consecutive disease stages, indicating a potential value as surrogate marker in the differential prognosis of CRC.

Mesenteric Tumor Deposits in Midgut Small Intestinal Neuroendocrine Tumors Are a Stronger Indicator Than Lymph Node Metastasis for Liver Metastasis and Poor Prognosis.

Mesenteric tumor deposits (MTDs) are not included in the American Joint Committee on Cancer (AJCC) staging system for midgut small intestinal neuroendocrine tumors (NETs). We examined the prognostic significance of MTDs associated with midgut NETs. Hematoxylin and eosin slides from 132 resected jejunal/ileal NETs were reviewed for AJCC tumor stage, lymph node (LN) metastasis, MTDs, and hepatic metastases. MTDs were defined as discrete irregular mesenteric tumor nodules discontinuous from the primary tumor. Clinical or pathologic evidence of metastases and survival data were abstracted from electronic medical records. The cohort included 72 male and 60 female patients with a median age of 60 years. LN metastasis, MTDs, and liver metastasis were present in 80%, 68%, and 58% of patients, respectively. Female sex and presence of MTDs were independent predictors of liver metastasis. The odds ratio for hepatic metastasis in the presence of MTDs was 16.68 (95% confidence interval [CI], 4.66-59.73) and 0.81 (95% CI, 0.20-3.26) for LN metastasis. Age, MTDs, and hepatic metastasis were associated with disease-specific survival (DSS) in univariate analysis. Primary tumor histologic grade, pT3/T4 stage, and LN metastasis were not associated with DSS. Multivariate analysis of liver metastasis-free survival stratified by tumor grade showed that MTDs were associated with adverse outcomes. The hazard ratio for MTDs was 4.58 (95% CI, 1.89-11.11), compared with 0.98 (95% CI, 0.47-2.05) for LN metastasis. MTDs, but not LN metastasis, in midgut NETs are a strong predictor for hepatic metastasis and are associated with poor DSS.