Liver Metastases In Cancer Patients Research Articles

Abstract 925: Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection

Abstract Introduction: Anti-EGFR monoclonal antibody plus doublet chemotherapy is the mainstay of first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Some of these patients might undergo secondary resection. However, there is no standardized suggestion on whether colorectal cancer liver metastasis patients should keep target therapy after secondary resection. NCCN guidelines suggest chemotherapy only in patients receiving primary liver resection. Whether we could spare the use of target therapy after secondary resection is the main aim of our study. Methods: Using Taiwan's National Health Insurance Research Database, we established a cohort of KRAS wild-type mCRC patients treated with first-line anti-EGFR therapy plus doublet chemotherapy between 2013 and 2018. Secondary surgery was defined as either resection of liver metastases or radiofrequency ablation. Results: 5694 stage IV mCRC patients received anti-EGFR MAb plus doublet chemotherapy as a first-line treatment between 2013 and 2018. 174 patients were enrolled in the final analysis, with 153 continuing anti-EGFR MAb after secondary resection and 21 patients without anti-EGFR MAb. Compared with those who without anti-EGFR therapy after secondary resection, patients who continued anti-EGFR MAb exhibited significantly longer overall survival (OS; median, 43.8 vs. 31.9 months, p = 0.031) but not in time to treatment failure (TTF; median, 22.2 vs. 26.6 months, p = 0.841). The OS benefits of continuing anti-EGFR MAb remained regardless of left-sided or right-sided primary tumors (40.9 vs. 43.0 months, p = 0.980). The patient cohort from 2016 to 2018 showed more prolonged survival than from 2012 to 2015 (not reached vs. 40.450, p = 0.0305). TTF has no statistical difference when considering patient cohort or primary tumor location. In multivariate analyses, continuing first-line anti-EGFR MAb therapy after secondary resection remained an independent predictor of longer OS. Conclusion: For mCRC patients who received secondary resection after first-line anti-EGFR and doublet chemotherapy, continuing anti-EGFR MAb after resection was associated with significantly longer OS regardless of primary tumor sidedness. Citation Format: Yao-Yu Hsieh, Chin-Wen Tsai, T-CARE Group, Yi-Hsieh Liang. Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 925.

Construction and validation of the predictive model for gallbladder cancer liver metastasis patients: a SEER-based study.

The purpose of this present research was to construct a nomograph model to predict prognosis in gallbladder cancer liver metastasis (GCLM) patients so as to provide a basis for clinical decision-making. We surveyed patients diagnosed with GCLM in the Surveillance Epidemiology and the End Results database between 2010 and 2019. They were randomized 7 : 3 into a training set and a validation set. In the training set, meaningful prognostic factors were determined using univariate and multivariate Cox regression analyses, and an individualized nomogram prediction model was generated. The prediction model was evaluated by C-index, calibration curve, ROC curve and DCA curve from the training set and the validation set. A total of 727 confirmed cases were enrolled in the research, 510 in the training set and 217 in the validation set. Factors including bone metastasis, surgery, chemotherapy and radiotherapy were independent prognostic factors for cancer-specific survival (CSS) rates and were employed in the construction of the nomogram model. The C-index for the training set and validation set were 0.688 and 0.708, respectively. The calibration curve exhibited good consistency between predicted and actual CSS rates. ROC curve and DCA of the nomogram showed superior performance at 6 months CSS, 1-year CSS and 2 years CSS in both the training set and validation set. We have successfully constructed a nomogram model that can predict CSS rates in patients with GCLM. This prediction model can help patients in counseling and guide clinicians in treatment decisions.

An elevated preoperative cholesterol-to-lymphocyte ratio predicts unfavourable outcomes in colorectal cancer liver metastasis patients receiving simultaneous resections: a retrospective study

BackgroundTo explore the clinical prognostic utility of the preoperative cholesterol-to-lymphocyte ratio (CLR) in outcomes for colorectal cancer liver metastasis (CRLM) patients receiving simultaneous resection of the primary lesion and liver metastases.MethodsA total of 444 CRLM patients receiving simultaneous resections were enrolled. The optimal cut-off value for CLR was determined using the highest Youden’s index. Patients were divided into the CLR < 3.06 group and the CLR≥3.06 group. Propensity score matching analysis (PSM) and the inverse probability of treatment weighting (IPTW) method were conducted to eliminate bias between the two groups. The outcomes included short-term outcomes and long-term outcomes. Kaplan–Meier curves and log-rank tests were used to analyse progression-free survival (PFS) and overall survival (OS).ResultsIn the short-term outcome analysis, after 1:1 PSM, 137 patients were distributed to the CLR < 3.06 group and CLR≥3.06 group. No significant difference was noted between the two groups (P > 0.1). Compared with patients with CLR < 3.06, patients with CLR≥3.06 had comparable operation times (320.0 [272.5–421.0] vs. 360.0 [292.5-434.5], P = 0.088), blood loss (200.0 [100.0-400.0] vs. 200.0 [150.0-450.0], P = 0.831), postoperative complication rates (50.4% vs. 46.7%, P = 0.546) and postoperative ICU rates (5.8% vs. 11.7%, P = 0.087). In the long-term outcome analysis, Kaplan–Meier analysis showed that compared with patients with CLR < 3.06, patients with CLR≥3.06 had worse PFS (P = 0.005, median: 10.2 months vs. 13.0 months) and OS (P = 0.002, median: 41.0 months vs. 70.9 months). IPTW-adjusted Kaplan–Meier analysis showed that the CLR≥3.06 group had worse PFS (P = 0.027) and OS (P = 0.010) than the CLR < 3.06 group. In the IPTW-adjusted Cox proportional hazards regression analysis, CLR≥3.06 was an independent factor for PFS (HR = 1.376, 95% CI 1.097–1.726, P = 0.006) and OS (HR = 1.723, 95% CI 1.218–2.439, P = 0.002). IPTW-adjusted Cox proportional hazards regression analysis including postoperative complications, operation time, intraoperative blood loss, intraoperative blood transfusion and postoperative chemotherapy revealed that CLR≥3.06 was an independent factor for PFS (HR = 1.617, 95% CI 1.252–2.090, P < 0.001) and OS (HR = 1.823, 95% CI 1.258–2.643, P = 0.002).ConclusionsThe preoperative CLR level predicts unfavourable outcomes in CRLM patients receiving simultaneous resection of the primary lesion and liver metastases and should be taken into consideration when developing treatment and monitoring strategies.

Effects of Continuous Care Combined with Evidence-Based Nursing on Mental Status and Quality of Life and Self-Care Ability in Patients with Liver from Breast Cancer: A Single-Center Randomized Controlled Study.

Objective To explore the multidisciplinary collaborative extended care combined with EBN to improve breast cancer liver metastasis patients' psychological status and self-care ability. Background In the past ten years, the number of breast cancer patients with liver metastases has increased year by year, becoming a global public health problem. Studies have shown that 30% of breast cancer patients with liver metastases show varying degrees of anxiety and depression, and their quality of life is significantly lower than that of the normal population. Multidisciplinary collaborative continuous care can improve the prognosis of breast cancer treatment to a certain extent and is the key to meeting the needs of cancer patients. Materials and Methods The clinical data of 96 patients with liver metastases from breast cancer were selected as the study subjects and divided into a comparison group and an observation group of 48 cases each according to a random number table. Among them, the comparison group implemented evidence-based nursing (EBN) and the observation group implemented multidisciplinary collaborative extended care based on the comparison group. The effects of psychological status, quality of life, self-care ability, and sleep quality were compared between the two groups before and after nursing care. Results After nursing, the sleep quality scores, increased awakening scores, sleep quality that shows weakness because important things are not steady or strong scores, and night terrors scores of the two groups of breast cancer patients with liver the spread of diseases through the body were very much improved, and the sleep quality scores of the instance of watching, noticing, or making a statement group were much lower than those of the comparison group (P < 0.05). After nursing, the fear and stress-related score, depression score, tiredness and distress score, and anger score of the two groups of breast cancer patients with liver (the spread of diseases through the body) were very much improved, and the mental state score of the instance of watching, noticing, or making a statement group was much lower than that of the comparison group (P < 0.05). The scores of self-care skills, self-responsibility, health knowledge, and self-idea of patients in the instance of watching, noticing, or making a statement group after nursing were higher than those in the comparison group (P < 0.05). After nursing, the scores of mental energy, social interaction, emotional restriction, and mental status of patients in (instance of watching, noticing, or making a statement) were much higher than those in the comparison group (P < 0.05). Conclusion Multidisciplinary collaborative continuous nursing combined with EBN can effectively improve the sleep quality and psychological state of patients with breast cancer and liver metastases and improve self-care ability.

Treatment efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization versus regorafenib monotherapy in colorectal cancer liver metastasis patients who fail standard treatment regimens

ObjectiveThis study aimed to evaluate the efficacy and safety of regorafenib plus drug-eluting beads-transarterial chemoembolization (DEB-TACE) versus regorafenib monotherapy in colorectal cancer liver metastases (CRLM) patients who failed standard treatment regimens.MethodsTotally, 76 eligible CRLM patients were analyzed, among which 42 patients received regorafenib monotherapy (as regorafenib group) and 34 patients received regorafenib plus DEB-TACE (as regorafenib plus DEB-TACE group).ResultsObjective response rate (35.3% versus 7.1%, P = 0.002) and disease control rate (76.5% versus 47.6%, P = 0.011) were both increased in regorafenib plus DEB-TACE group compared with regorafenib group; meanwhile, negative conversion rate of carcinoembryonic antigen (66.7% versus 28.6%, P = 0.008) after treatment was elevated in regorafenib plus DEB-TACE group compared with regorafenib group. Notably, progression-free survival (PFS) (median value: 7.6 versus 4.1 months, P < 0.001) and overall survival (OS) (median value: 15.7 versus 9.2 months, P < 0.001) were both higher in regorafenib plus DEB-TACE group compared with regorafenib group. Furthermore, liver function indexes (alanine transaminase, aspartate aminotransferase, and cholinesterase levels) after treatment were all similar between the two groups (all P > 0.05). In addition, the occurrences of upper abdominal distending pain (P < 0.001), nausea and vomiting (P = 0.002) and fever (P = 0.002) were higher in regorafenib plus DEB-TACE group compared with regorafenib group, while the majority of these adverse events were mild and tolerable.ConclusionsRegorafenib plus DEB-TACE is superior to regorafenib monotherapy regarding treatment response, PFS and OS, while induces tolerable post-embolization syndrome in CRLM patients who fail standard treatment regimens.

The Effect of Diffuse Liver Diseases on the Occurrence of Liver Metastases in Cancer Patients: A Systematic Review and Meta-Analysis.

Simple SummaryDiffuse liver diseases have a high incidence among the general population and even higher in patients with a solid cancer. Since many patients with a solid tumor die of liver metastases, the aim of this systematic review of the literature was to explore the correlation between diffuse liver diseases and the risk of having liver metastases at diagnosis or during follow-up. To summarize the results of included studies, a meta-analysis was also conducted. The results of our systematic review should encourage the research community to further investigate the complex relationship between the liver’s microscopic environment and metastases, which may also affect prognosis and response to therapy.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 (n = 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.

A novel prognostic nomogram for colorectal cancer liver metastasis patients with recurrence after hepatectomy.

PurposeWe aimed to construct a nomogram to predict personalized post‐recurrence survival (PRS) among colorectal cancer liver metastasis (CRLM) patients with post‐hepatectomy recurrence.MethodsColorectal cancer liver metastasis patients who received initial hepatectomy and had subsequent recurrence between 2001 and 2019 in Sun Yat‐sen University Cancer Center from China were included in the study. Patients were randomly assigned to a training cohort and a validation cohort on a ratio of 2:1. Univariable analysis was first employed to select potential predictive factors for PRS. Then, the multivariable Cox regression model was applied to recognize independent prognostic factors. According to the model, a nomogram to predict PRS was established. The nomogram's predictive capacity was further assessed utilizing concordance index (C‐index) values, calibration plots, and Kaplan–Meier curves.ResultsAbout 376 patients were finally enrolled, with a 3‐year PRS rate of 37.3% and a 5‐year PRS rate of 24.6%. The following five independent predictors for PRS were determined to construct the nomogram: the largest size of liver metastases at initial hepatectomy, relapse‐free survival, CEA level at recurrence, recurrent sites, and treatment for recurrence. The nomogram displayed fairly good discrimination and calibration. The C‐index value was 0.742 for the training cohort and 0.773 for the validation cohort. Patients were grouped into three risk groups very well by the nomogram, with 5‐year PRS rates of 45.2%, 23.3%, and 9.0%, respectively (p < 0.001) in the training cohort and 36.0%, 9.2%, and 4.6%, respectively (p < 0.001) in the validation cohort.ConclusionA novel nomogram was built and validated to enable the prediction of personal PRS in CRLM patients with post‐hepatectomy recurrence. The nomogram may help physicians in decision making.

The Impact of Tumor Volume in Breast Cancer Liver Metastasis Patients Treated with Stereotactic Radiotherapy – Does Size Matter?

To investigate the relationship between tumor volume and survival in breast cancer liver metastasis (BCLM) patients treated with stereotactic radiotherapy. 39 biopsy proven breast cancer patients whom liver metastasis was treated with stereotactic radiotherapy (SRT) were retrospectively investigated. Patient characteristics, survival and their relation with tumor volume were analyzed. Median age was 47 years (range; 27-78 years). Median tumor size was 1.8 ± 1.1 cm. Median gross tumor volume (GTV) and planning tumor volume (PTV) were 6.8 cc (range, 0.7-55.2 cc) and 38.7 cc (range; 9.3-163.8 cc), respectively. SRT dose prescription was 3 fr x 18 Gy in 37 patients (96%), 3 fr x 20 Gy in 1 patient (2%) and 3 fr x 16 Gy in 1 patient (2%). 13 patients (33%) had solitary liver metastasis while 26 patients (67%) also had other organ metastases beyond liver. Median follow-up for entire cohort was 15.4 months (range; 1-49 months). At last visit 26 patients (67%) had disease progression. Among these patients 25 patients (64%) had distant metastasis while 2 patients (5%) had isolated local recurrence. The 1- and 2- years overall survival (OS) rates were %79.1 and %46.0, respectively. Median OS was 23.8 months (95% CI: 13.3-34.3 months). 1 and 2-years progression-free survival (PFS) rates were 38.1% and 11.5%, respectively. Median PFS was 8.7 months (95%CI: 5.6-11.8 months). 1 and 2-years of local control (LC) per tumor were 92.9% and 85%, respectively. Patients were divided into two groups according to tumor volume £30 cc or >30 cc. 1-year OS was 100% for patients with tumor volume £30 cc while 1-year OS was 34% for patients with tumor volume > 30 cc (p = 0.04). 4 patients developed grad 3 late toxicity. Among them 1 had duodenal ulcer, received medical treatment without any surgical intervention and 3 of them had rib fracture treated with symptomatic medical treatment. SRT is an efficient treatment with optimal LC and low toxicity profile in BCLM patients. Tumor volume of £30 cc had better survival.

Histopathological growth patterns correlate with the immunoscore in colorectal cancer liver metastasis patients after hepatectomy.

Various scoring systems have been proposed to predict the postoperative prognosis of colorectal liver metastasis (CRLM), including the clinical risk score (CRS), the immunoscore and so on. Recently, histopathological growth patterns (HGPs) have been recognized. However, the correlation between HGPs and the immunoscore, and their prognostic values in patients with CRLM after liver resection remain undetermined. In this study, HGPs were retrospectively evaluated in H&E-stained slides from 166 CRLM patients. The immunoscore was calculated according to the densities of immunostained CD3 + and CD8 + cells. A risk score combining HGPs, the immunoscore and the CRS was defined and divided patients into the low-, medium- and high-risk group. Our results showed that the densities of CD3 + and CD8 + cells were higher in the desmoplastic HGP (dHGP) group than in the non-dHGP group, and the proportion of high immunoscores was also higher in the dHGP group (51.9% vs. 33.0%, respectively, P = 0.020). Patients with the dHGP had significantly longer relapse-free survival (RFS) and overall survival (OS) than those with the non-HGP. The low-risk group showed significantly higher 2-year RFS and 5-year OS rates than the other two groups (RFS: 76.2%, 43.7% and 33.1%, respectively; P < 0.001; OS: 89.7%, 54.4% and 33.3%, respectively; P < 0.001). In conclusion, the dHGP correlates with relatively high immunoscores, predicting a favorable prognosis independent of the immunoscore and CRS. A novel risk score combining HGPs, the immunoscore and the CRS may be used for the stratification of CRLM patients' survival.

Synchronous resection of colorectal cancer liver metastasis : propensity score matching of open versus minimally invasive surgery

Introduction: Laparoscopic liver resection is now considered as safe and feasible procedure for primary liver cancer. Apart from that, synchronous open liver resection of colorectal cancer liver metastasis has also demonstrated safety, efficacy and feasibility in several studies. Nevertheless, still oncologic safety and perioperative outcome of synchronous minimally invasive liver resection in colorectal cancer liver metastasis remain unclear. Method: From January 2006 to June 2017, we reviewed synchronous liver resection in colorectal cancer liver metastasis patients in Severance hospital. We exclude hybrid resection, such as primary cancer with laparoscopic approach and liver resection with open approach. Eventually, 391 patients were investigated. Result: Total 66 patients underwent pure minimally invasive approach for liver resection and primary cancer operation. On the other hand, 325 patients was performed open liver resection. Between two group, length of stay(LOS, 14.7 days vs 9.7 days) and imaging liver metastasis lesion numbers( 3.9 vs 1.5) and final pathologic liver metastasis number (3.8 vs 1.4), tumor size (2.8 cm vs 1.9 cm) were statistically higher in open group. In survival analysis, minimally approach for liver resection group was more favorable than open resection group in overall survival (mean 87.9 months vs 110.9 months, p=0.011) and disease free survival( mean 40.6 months vs 59.3 months.p= 0.033). After propensity score matching, LOS of still longer in open resection group in statistically significance. In survival analysis, there were no differences between two groups. Conclusion: Syncrhonous minimally invasive liver resection for colorectal cancer liver metastasis is safe and fesasible with benefit of short LOS. In terms of oncologic outcome, minimally invasive liver resection was not inferior to open liver resection. In selected patients, minimally invasive approach for liver metastasis resection synchronously should be considered.

Abstract 5187: Metastatic lung cancer-derived exosomes stimulate premetastatic niche in liver: Beyond seed soil hypothesis

Abstract Background: Tumor-derived exosomes (TDEs) are small membrane bound extracellular vesicles (EVs) that have the ability to alter their immediate microenvironment (ME) through cell-cell interaction and are known to be critical modulators of pre-metastatic niche. Lung cancer is a highly metastatic disease, with metastases often occurring when the tumor is in a clinically early stage. It is known to metastasize to the liver in the Asian population, but the underlying mechanism still remains unclear. Thus, understanding the role of TDEs in development of liver metastasis and its contributions to improvise the prognostic and therapeutic implications is of great importance. Methodology: Exosomes isolated from serum of lung cancer liver metastasis patients were characterized by nanoparticle tracking analysis, electron microscopy and flow cytometry with antibody directed at CD63. These exosomes were further co-cultured with A549 cells to check for their uptake at various time intervals. Moreover, effect of isolated exosomes was tested on: 1. Cell motility and invasiveness of A549 cells determined by transwell chamber migration assay and scratch assay; 2. Gene expression profiles and cell cycle regulation studies; and 3. Histopathological changes and liver function tests after exosome were intraperitoneally injected in Wistar rats to investigate the early events involved in the metastatic spread. Results: We found that CD63 - FITC labelled exosomes isolated from serum of liver metastatic patients were actively incorporated by A549 cells. The exosome uptake by A549 cells induced migratory/invasive phenotypic and morphologic changes in a concentration and time- dependent manner. Moreover, on further evaluating the effect of TDEs on different phases of cell cycle it was observed that cellular uptake of exosomes was increased during G2/M phase stimulating the cells to enter these cell cycle phases leading to cell proliferation. Further, we observed that E-cadherin, beta catenin, VEGFA, CDKN2A and TGFBR2 were differentially expressed when A549 cells were treated with exosomes demonstrating an important role of these TDEs in altering the tumor microenvironment. Liver function test demonstrated an increase in serum SGPT and SGOT levels whereas when histopathological examination was done the lungs showed patches of pneumonitis and the liver was highly inflamed. Conclusion: Collectively this study indicated that metastatic tumor derived exosomes are capable of increasing the migratory and invasive property of the primary lung cancer cells. Furthermore, our results depict an undisputable role of these exosomes as key modulators in the formation of the pre-metastatic niche required for the colonization of circulating tumor cells (CTCs) ultimately leading to distant metastasis. Thus understanding and targeting tumor derived exosomes could lead to better and novel therapeutic strategies. Citation Format: Kanisha Shah, Dr. Rakesh M. Rawal. Metastatic lung cancer-derived exosomes stimulate premetastatic niche in liver: Beyond seed soil hypothesis [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 5187.

Prognostic significance of 18F-FDG PET/CT in patients with colorectal cancer liver metastases after hepatectomy

IntroductionColorectal cancer liver metastasis (CRLM) can be cured with surgery. To improve survival, optimal selection of CRLM patients should be done cautiously, which may be facilitated by preoperative [F-18] fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). MethodsA total of 245 patients with CRLM between February 2007 and January 2015 were retrospectively studied. All clinical variables, pathological data, and various PET/CT parameters were correlated with disease-free survival (DFS) and overall survival (OS). Metastatic tumor maximum standardized uptake value (SUVmax) and normal liver mean SUV (SUVmean) ratio was selected for group classification. ResultsThe median DFS in months were 24.5 months and median OS were 41.7 months. Multivariate analysis found an increased risk of worse prognosis in DFS for primary colon cancer T3∼T4, N2 stage, neoadjuvant chemotherapy, synchronous metastasis, multiple metastatic tumor number and metastatic tumor SUVmax/normal liver SUVmean ratio >4.3. The DFS rate of each group classified by SUV ratio was 58.1%, 39.0%, and 33.6% vs. 39.3%, 20.8%, and 15.8% at 1, 3, and 5 years (p = 0.017). Patients with multiple tumors and SUV ratio of >4.3 showed worst survival (OS rate: 74.2%, 41.5%, and 24.2%, p = 0.001 at 1, 3, and 5 years, respectively). ConclusionsPET/CT variables can be a valuable prognostic factor in patients with CRLM for the prediction of recurrence. Preoperative PET/CT may improve risk stratification and optimize outcomes of patients with CRLM.

Detection of liver metastases in cancer patients with geographic fatty infiltration of the liver: the added value of contrast-enhanced sonography.

PurposeThe aim of this study is to assess the role of contrast-enhanced ultrasonography (CEUS) in the detection of liver metastases in cancer patients with geographic liver fatty deposition on greyscale ultrasonography (US).MethodsThirty-seven consecutive cancer patients (24 women and 13 men; age, 33 to 80 years; mean, 58.1 years) with geographic liver fatty deposition, but without any detectable focal liver lesion on greyscale US, underwent sulphur hexafluoride-enhanced US. Two readers reported by consensus the presence, size, and location of any detected lesion. All patients underwent magnetic resonance imaging (MRI) as a confirmatory study. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy were calculated.ResultsSeven focal liver lesions (size, 4 to 10 mm; mean, 6.1 mm) were detected in 4/37 patients (10.8%): four metastases (size, 5 to 10 mm; mean, 6.7 mm) were detected both by CEUS and MRI, with one hemangioma and two cysts (size range, 4 to 6 mm; mean, 5.3 mm) detected by MRI only. In 1/37 patients (2.7%), CEUS misdiagnosed geographic fatty change as three metastases. In 32/37 patients (86.5%), no lesions were detected. Sensitivity, specificity, PPV, NPV, and accuracy of CEUS were 100% (95% confidence Interval [CI], 1.000 to 1.000), 97.1% (95% CI, 0.914 to 1.027), 75%, 100%, and 97.3%, respectively. No statistically significant differences were found between CEUS and MRI in the detection of focal liver lesions (P=0.480), whereas both of them performed better than baseline US (P<0.001).ConclusionCEUS improves the detection of liver metastases in cancer patients with geographic liver fatty deposition on greyscale US.

Analysis of circulating tumor cells in colorectal cancer liver metastasis patients before and after cryosurgery

ABSTRACTIn this study, we determined the number of peripheral blood circulating tumor cells (CTCs) pre- and post-cryosurgery in patients with colorectal cancer liver metastasis as a reference for understanding the relevance of any changes to the efficacy of cryosurgery. CTC numbers and CTC-related gene expression were measured in the peripheral blood of 55 patients with colorectal liver metastasis at 1 day before and 7 and 30 d after cryoablation using magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) combined with real-time quantitative PCR (RT-qPCR). The number of CTCs decreased significantly with postoperative time (P < 0.01). Delta cycle threshold values for the CTC-related genes CEA, Ep-CAM, CK18 and CK19 increased significantly after cryoablation. Furthermore, the expression of CEA, Ep-CAM, CK18 and CK19 decreased significantly with time after cryoablation (P < 0.01). RT-qPCR and FACS combined with MACS has significant diagnostic and prognostic value for evaluating the efficacy of cryosurgery in patients with advanced colorectal cancer.

Abstract B090: A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent

Abstract Liver metastases are a major common cause of mortality of patients with different types of cancer due to lack of effective treatment options. Anticancer immunotherapy provides an attractive approach for developing a more effective systemic therapy for patients with metastatic liver cancer. We generated a Toll-like receptor 5 (TLR5) agonistic agent entolimod™ (CBLB502), a pharmacologically optimized derivative of bacterial Salmonella flagellin that is now at advanced stage of clinical development as a medical countermeasure to reduce adverse side effects of radiation therapy. We also found that entolimod, in addition to its radioprotective properties, has anticancer effects against a variety of TLR5-positive tumors and TLR5-negative tumors residing in a TLR5-expressing environment such as the liver in mice. We hypothesized that entolimod can suppress tumor growth in a TLR5-responsive microenvironment such as the liver independently of the TLR5 status of tumor cells. We tested the therapeutic potential of entolimod against TLR5 responsive and non-responsive tumors using mouse triple negative 4T1 breast and CT26 colorectal adenocarcinoma models mimicking clinically occurring development of post-surgery liver metastases in cancer patients. Our results demonstrate that entolimod treatment was efficient in suppressing metastatic growth when injected systemically in both models. Investigating the mechanism of entolimod's antitumor activity we found that several major transcriptional factors, such as NF-κB, STAT-3 and AP-1, are rapidly activated in hepatocytes leading to a short-term neutrophilic infiltration and long-term NK cell accumulation and activation that coordinate CD8+ and CD4+ T cell immunity against liver metastases. This resulted in significant improvement of long-term tumor-free survival and durable, tumor-specific T cell memory. Importantly, unlike other TLR agonists entolimod is safe and does not show signs of septic shock even with systemic administration. Moreover, the results of two phase 1 clinical trials with 150 healthy volunteers and 26 patients with advanced cancers demonstrated good tolerability and safe profile of the response, which supports entolimod's potential as an immunotherapeutic agent. This also suggests that entolimod can be potentially combined with radiation, chemotherapeutic, targeted, and other immunotherapeutic agents to improve the efficacy of anticancer therapy. Citation Format: Craig Brackett, Bojidar Kojouharov, Sandra Gollnick, Andrei Gudkov, Lyudmila Burdelya. A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B090.

Immune evasion mechanisms in colorectal cancer liver metastasis patients vaccinated with TroVax (MVA-5T4).

We have recently reported the results of a phase II trial in which two TroVax [modified vaccinia ankara (MVA) encoding the tumour antigen 5T4] vaccinations were given to patients both pre- and post-surgical resection of liver metastases secondary to colorectal cancer (CRC). 5T4-specific cellular responses were assessed at the entry and 2 weeks after each vaccination by proliferation of fresh lymphocytes and ELISA for antibody responses; 18 from the 19 CRC patients mounted a 5T4-specific cellular and/or humoral response. Here, we present a comparison of individual and between patient responses over the course of the treatments using cryopreserved peripheral blood mononuclear cells (PBMC) samples from the baseline until after the fourth vaccination at 14 weeks. Assays used were proliferation assay with 5T4-Fc fusion protein, overlapping 32mer 5T4 peptides, MVA-LacZ and MVA-5T4 infected autologous monocytes. Responses to 5T4 protein or one or more peptide pools were pre-existing in 12/20 patients and subsequently 10 and 12 patients showed boosted and/or de novo responses, respectively. Cumulatively, 13/20 patients showed proliferative responses by week 14. We also assessed the levels of systemic T regulatory cells, plasma cytokine levels, phenotype of tumour-infiltrating lymphocytes including T regulatory cells and tumour HLA class I loss of expression. More than half of the patients showed phenotypes consistent with relative immune suppression and/or escape highlighting the complexity of positive and negative factors challenging any simple correlation with clinical outcome.

Clinicopathological analysis of colorectal cancer liver metastasis and intrahepatic cholangiocarcinoma: Are they just apples and oranges?

Backgrounds/aims Intrahepatic cholangiocarcinoma and colorectal cancer liver metastasis are the most primary and secondary adenocarcinoma of the liver, respectively. A large-scale long-term comparative study of these two cohort patient is lacking. Methods A total of 166 colorectal cancer liver metastasis patients and 206 intrahepatic cholangiocarcinoma patients who had undergone curative liver resection were retrospectively analysed. Among 206 intrahepatic cholangiocarcinoma, there were 47 intraductal growth type-intrahepatic cholangiocarcinoma and 159 non-intraductal growth type-intrahepatic cholangiocarcinoma. The demographics, clinicopathological data, immunohistochemical study and survival were analysed. Results The intrahepatic cholangiocarcinoma patients were more female-predominated, associated with hepatolithiasis, symptomatic, jaundiced, and with larger tumour size compared with those of colorectal cancer liver metastasis. Prognostic factors of intrahepatic cholangiocarcinoma were pathologic staging, histologic pattern and section margin; whereas prognostic factors of colorectal cancer liver metastasis were rectal origin, differentiation, section margin and bilobar distribution. CK7 and CK20 differentiated majority of intrahepatic cholangiocarcinoma from colorectal cancer liver metastasis, while CDX2 and MUC5AC helped to differentiate inconclusive cases. The 1-, 3-, 5- and 10-year survival rates of colorectal cancer liver metastasis were 77%, 31%, 20% and 14%, compared to 53%, 21%, 13% and 7% of intrahepatic cholangiocarcinoma ( p = .0001). Furthermore, the survival of colorectal cancer liver metastasis was comparable to staged II intrahepatic cholangiocarcinoma ( p = .8866) and intraductal growth type-intrahepatic cholangiocarcinoma ( p = .1915). Conclusions Demographics, precipitating factor, clinical manifestations, and prognostic factors of colorectal cancer liver metastasis and intrahepatic cholangiocarcinoma differed remarkably. High incidence of CDX2 and MUC2 expression in colorectal cancer liver metastasis and intraductal growth type-intrahepatic cholangiocarcinoma might explain their similar cytoarchitecture and survival.

Profile of Plasma Angiogenic Factors Before and After Hepatectomy for Colorectal Cancer Liver Metastases

Circulating angiogenic factors in patients with colorectal cancer liver metastases may promote tumor growth and contribute to liver regeneration after partial hepatectomy. We analyzed blood samples from 26 patients with colorectal cancer liver metastases before and after liver resection and used samples from 20 healthy controls as a reference. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF) were measured, and levels were correlated with recurrence. The median preoperative levels of all four factors were significantly higher and more variable in colorectal cancer liver metastasis patients than in controls. HGF and bFGF levels increased significantly 3 days and 1 month after hepatectomy, respectively, and returned to near preoperative levels at 3 months. Postoperative VEGF and EGF levels remained relatively stably increased over 3 months. After a median follow-up of 19 months, 10 patients (42%) experienced recurrence. Higher preoperative VEGF and HGF levels correlated with subsequent recurrence (P = .018 and .021, respectively), and a preoperative adjusted total value of all four factors accurately identified patients at low, moderate, and high risk of recurrence (P = .034). Patients who experienced disease recurrence also had relatively higher bFGF levels 3 months after operation (P = .035). Plasma angiogenic factors are increased in patients with colorectal cancer liver metastases and remain increased at least 3 months after partial hepatectomy. Measurement of certain factors before and after hepatic resection can predict recurrence. Targeted biological agents may counteract the tumor-promoting effects of these circulating factors on subclinical disease.

18F-fluorodeoxyglucose (FDG)-PET features of focal nodular hyperplasia (FNH) of the liver.

The aim of this paper is to describe the imaging pattern of focal nodular hyperplasia (FNH) by l8F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). Eight consecutive asymptomatic patients with histologic proof of FNH underwent 18F-FDG PET imaging. The lesions were found incidentally. The 18F-FDG PET imaging was performed with a dedicated PET tomograph after intravenous injection of 300-370 MBq 18F-FDG. The 18F-FDG accumulation in the lesions was (semi)quantified by calculating the standardized uptake value (SUV) and SUV has been corrected for the lean body mass (LBM). Eight patients with liver metastases spread from melanoma (n=2) and colorectal carcinoma (n=6) served as controls. The size of the FNH lesions and of the control group ranged from 2.0 to 8.5 cm (mean 4.83 cm +/- 2.37) and from 1.5 to 6 cm (mean 3.28 +/- 1.52), respectively. While in malignant liver lesions the accumulation of 18F-FDG was significantly increased, all FNH lesions showed normal or even decreased accumulation of 18F-FDG. In FNH lesions, SUV ranged between 1.5 and 2.6 (mean 2.12 +/- 0.38), whereas all liver metastases showed an increased SUV ranging between 6.20 and 16.00 (mean 10.07 +/- 3.79). The SUV corrected for LMB (SUVLBM) was similar to the SUV and ranged between 0.9 and 2.2 (mean 1.81 +/- 0.41) for FNH and between 5.9 and 16.3 (mean 9.15 +/- 4.03), respectively. In contrast to liver metastases, there is no increased glucose metabolism in FNH in vivo. The imaging feature of FNH by 18F-FDG-PET imaging is not specific for FNH; however, it may be helpful to differentiate FNH from liver metastases in cancer patients if radiological methods are not diagnostic.