Colorectal Carcinoma Liver Metastases Research Articles

N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.

CD133 + cell infusion in patients with colorectal liver metastases going to be submitted to a major liver resection (CELLCOL): A randomized open label clinical trial

BackgroundTreatment of liver metastases of colorectal carcinoma is surgical resection. However, only 10–15% of the patients in this context will be candidate for curative resection arising other 10–13% after response to neoadyuvant chemotherapy. In order to perform the liver metastases surgery, it is necessary to have a sufficient remnant liver volume (RLV) which allows maintaining an optimal liver function after resection.Studies on liver regeneration have determined that CD133 + stem cells are involved in liver hypertrophy developed after an hepatectomy with encouraging results. As presented in previous studies, CD133 + stem cells can be selected from peripheral blood after stimulation with G-CSF, being able to obtain a large number of them. We propose to treat patients who do not meet criteria for liver metastases surgery because of insufficient RLV (<40%) with CD133 + cells together with portal embolization, in order to achieve enough liver volume which avoids liver failure. Methods/Design: The aim of this study is to evaluate the effectiveness of preoperative PVE plus the administration of CD133 + mobilized from peripheral blood with G-CSF compared to PVE only. Secondary aims areto compare the grade of hypertrophy, speed and changes in liver function, anatomopathological study of hypertrophied liver, to determine the safety of the treatment and analysis of postoperative morbidity and surveillance. Study designProspective randomized longitudinal phase IIb clinical trial, open, to evaluate the efficacy of portal embolization (PVE) together with the administration of CD133 + cells obtained from peripheral blood versus PVE alone, in patients with hepatic metastasis of colorectal carcinoma (CCRHM). DiscussionThe number of CD133 + obtained from peripheral blood after G –CSF stimulation will be far greater than the number obtained with direct puncture of bone marrow. This will allow a greater intrahepatic infusion, which could have a direct impact on achieving a larger and quicker hypertrophy. Consequently, it will permit the treatment of a larger number of patients with an increase on their survival. Trial registrationClinicalTrials.gov, ID NCT03803241.

Histologic features and genomic alterations of primary colorectal adenocarcinoma predict growth patterns of liver metastasis.

BACKGROUNDDifferent histological growth patterns (HGPs) of colorectal carcinoma (CRC) liver metastasis are associated with patients’ prognosis and response to antiangiogenic therapy. However, the relationship between HGPs of liver metastasis and clinicopathological and genomic characteristics of primary cancer has not been well established.AIMTo assess whether certain clinicopathological and genomic features of primary CRC could predict the HGPs of liver metastasis.METHODSA total of 29 patients with paired resections of both primary CRC and liver metastasis were divided into two groups: A (15 cases with desmoplastic liver metastasis) and B (14 cases with replacement liver metastasis). Clinical information was obtained from patients’ charts. Mismatch repair proteins, BRAFV600E, and PD-L1 were evaluated by immunohistochemistry. Five cases were selected randomly from each group for whole exome sequencing (WES) analysis.RESULTSIn the primary tumor, expanding growth pattern, low tumor budding score (TBS), and Crohn’s disease-like response (CDR) were associated with desmoplastic liver metastasis and better overall survival, whereas infiltrating growth pattern alone of primary carcinoma could predict the replacement liver metastasis and worse overall survival (P < 0.05). On WES analysis, primary carcinoma with desmoplastic liver metastasis showed mutations in APC (4/5); TP53 (3/5); KRAS, PIK3CA, and FAT4 (2/5); BRCA-1, BRCA2, BRAF, and DNAH5 (1/5), whereas primary carcinoma with replacement liver metastasis showed mutations in APC and TP53 (3/5); KRAS, FAT4, DNH5, SMAD, ERBB2, ERBB3, LRP1, and SDK1 (1/5).CONCLUSIONThe HGPs, TBS, and CDR of primary CRC as well as the presence of specific genetic mutations such as those in PIK3CA could be used to predict the HGPs of liver metastasis, response to therapy, and patients’ prognosis.

Expression of endothelial progenitor cells and vascular endothelial growth factor according to genomic instability in colorectal liver metastases

Introduction: Increased numbers of endothelial progenitor cells and high level of vascular endothelial growth factor may indicate on higher tumor propensity to angiogenesis. The study aimed to evaluate the possible role of genomic instability in stimulation of angiogenesis in liver metastases of colorectal carcinoma. Methods: Among 80 randomly selected patients liver metastases, 70% and 30% were recognized as microsatellite stable and unstable, respectively. Samples of 2 ml of fresh blood were collected preoperatively. The cell fraction positive to CD309 (EPCS) was enumerated by flow cytometer and expressed as the percentage of WBC. Serum samples for evaluation of the vascular endothelial growth factor (VEGF) concentration were collected simultaneously for ELISA. A P-value < 0.05 was adopted as statistically significant in multiparametric analysis to reveal the association of genomic instability and of angiogenesis. A control group of 36 volunteers (18 F, 18 M, ma 38) was also measured. Results: The expression of EPCs and VEGF were significantly higher in MSI-H than MSS patients (0.01% versus 0.004% for EPCs, P< 0.008; 420.9 versus 300.2 pg/ml for VEGF). Multiparametric analysis showed angiogenesis nine times more active in MSI-H patients (OR=9.1, P< 0.01). They were characterized by more frequent metastases in both liver lobes (OR=32.8 P< 0.001) and metastases outside the liver (OR=8.3 P< 0.01). Conclusions: Patients with CRC metastases with MSI-H have high circulating numbers of EPCs and serum levels of VEGF. This may facilitate they regrowth. The data does point to the potential utility of anti-angiogenesis therapy in MSI-H metastatic disease.

Effect of inflammation on tumor progression of liver metastases of colorectal carcinoma in an experimental model

Effect of inflammation on tumor progression of liver metastases of colorectal carcinoma in an experimental model

Integrating Systemic Therapies into the Multimodality Treatment of Resectable Colorectal Liver Metastases.

Colorectal carcinoma (CRC) is one of the most common cancers worldwide. A considerable proportion of CRC patients may present with metastatic disease either at upfront presentation (synchronous with the primary) or following diagnosis and treatment of the primary tumor (metachronous). Management of CRC liver metastases is a challenging endeavor which frequently necessitates proper assessment of patient- and disease-related factors. There is an opportunity within the management of CRC liver metastases to incorporate multiple treatment modalities (including surgery, other locoregional treatments, and systemic therapy). The current review aims to provide an updated overview on the optimal management strategy for CRC patients with liver metastases with a specific focus on the integration of systemic and/or locoregional treatments among patients with resectable or potentially resectable disease.

Vascularization of colorectal carcinoma liver metastasis: insight into stratification of patients for anti-angiogenic therapies.

Current treatment for metastatic disease targets angiogenesis. With the increasing data demonstrating that cancer cells do not entirely rely on angiogenesis but hijack the existing vasculature through mechanisms such as co‐option of existing blood vessels, identification of targets has become of utmost importance. Our study looks at the vasculature of chemonaïve and treated colorectal carcinoma liver metastases (CRCLMs) to obtain a basic understanding of the microvessel density, type of vasculature (mature versus immature), and correlation with histopathological growth patterns that demonstrate unique patterns of angiogenesis. We performed immunohistochemistry on chemonaïve sections of desmoplastic histopathological growth pattern (DHGP) and replacement histopathological growth patterns (RHGP) lesions with CD31 [endothelial cell (EC) marker] and CD34/Ki67 double staining, which denotes proliferating ECs. The CD31 stains demonstrated a lower microvascular CD31 +ve capillary density in the DHGP versus RHGP lesions; and integrating both immunostains with CD34/Ki67 staining on serial sections revealed proliferating vessels in DHGP lesions and co‐option of mature existing blood vessels in RHGP lesions. Interestingly, upon treatment with chemotherapy and bevacizumab, the RHGP lesions showed no necrosis whereas the DHGP lesions had almost 100% necrosis of the cancer cells and in most cases there was a single layer of viable cancer cells, just under or within the desmoplastic ring. The survival of these cells may be directly related to spatial location and possibly a different microenvironment, which may involve adhesion to different extracellular matrix components and/or different oxygen/nutrient availability. This remains to be elucidated. We provide evidence that DHGP CRCLMs obtain their blood supply via sprouting angiogenesis whereas RHGP lesions obtain their blood supply via co‐option of existing vasculature. Furthermore current treatment regimens do not affect RHGP lesions and although they kill the majority of the cancer cells in DHGP lesions, there are cells surviving within or adjacent to the desmoplastic ring which could potentially give rise to a growing lesion.

Colorectal cancer patients before resection of hepatic metastases. Impact of (18)F-FDG PET on detecting extrahepatic disease.

Evaluation of the role of FDG-PET in comparison to conventional staging methods for detecting extrahepatic tumour deposits prior to resection of liver metastases. In our prospective study, 58 patients (24 women, 34 men; age 33-81 years) with liver metastases of colorectal carcinoma underwent FDG-PET. Images were acquired in 3D-mode including transmission scans and reconstructed iteratively. For conventional staging all patients underwent abdominal ultrasound, helical computed tomography (CT) of the thorax and abdomen, and colonoscopy/rectoscopy. A preliminary therapeutic decision was established without knowledge of the FDG-PET findings. Thereafter, it was revised or confirmed according to the results of FDG-PET. In 3/58 patients extrahepatic tumour deposits were concordantly identified with both conventional staging methods and FDG-PET. However, in one case, both conventional methods and FDG-PET were false positive regarding pulmonary metastases. In 12/58 patients, nothing but FDG-PET detected extrahepatic tumour masses, which were later confirmed either by histology or follow-up. Our study suggests that in 21% of patients exclusively FDG-PET is an appropriate diagnostic tool to reveal extrahepatic metastases or local recurrence of colorectal carcinoma. Our results demonstrate that FDG-PET provides relevant additional information for accurate therapeutic planning as compared to the conventional combination of staging methods. Therefore, FDG-PET has to exert a decisive influence on the decision for resection of hepatic metastases.

Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors.

Background & Aims: Primary tumors of colorectal carcinoma (CRC) with liver metastasis might gain some liver-specific characteristics to adapt the liver micro-environment. This study aims to reveal potential liver-like transcriptional characteristics associated with the liver metastasis in primary colorectal carcinoma.Methods: Among the genes up-regulated in normal liver tissues versus normal colorectal tissues, we identified “liver-specific” genes whose expression levels ranked among the bottom 10% (“unexpressed”) of all measured genes in both normal colorectal tissues and primary colorectal tumors without metastasis. These liver-specific genes were investigated for their expressions in both the primary tumors and the corresponding liver metastases of seven primary CRC patients with liver metastasis using microdissected samples.Results: Among the 3958 genes detected to be up-regulated in normal liver tissues versus normal colorectal tissues, we identified 12 liver-specific genes and found two of them, ANGPTL3 and CFHR5, were unexpressed in microdissected primary colorectal tumors without metastasis but expressed in both microdissected liver metastases and corresponding primary colorectal tumors (Fisher's exact test, P < 0.05). Genes co-expressed with ANGPTL3 and CFHR5 were significantly enriched in metabolism pathways characterizing liver tissues, including “starch and sucrose metabolism” and “drug metabolism-cytochrome P450”.Conclusions: For primary CRC with liver metastasis, both the liver metastases and corresponding primary colorectal tumors may express some liver-specific genes which may help the tumor cells adapt the liver micro-environment.

Laparoscopic liver resection in metastatic colorectal cancer treatment: comparison with long-term results using the conventional approach.

BackgroundLaparoscopic liver resections (LLRs) have been shown to be both feasible and safe. However, no randomised control studies have been performed to date comparing results with those of the open surgery approach.Main aimTo analyse LLR long-term results and compare them with a similar group of open resections in patients with colorectal carcinoma liver metastasis (CRCLM).MethodsRetrospective study on a prospective database. All patients with anatomopathological diagnosis of CRCLM resected between July 2007 and July 2015.ResultsTwenty-two open resections and 18 laparoscopic resections which presented favourable lesions for laparoscopic approach were analysed. Postoperative grade III morbidity was similar in both groups (p = 0.323). Disease-free survival at 1, 3, and 8 years in the laparoscopy group (n =16) was 81%, 58%, and 58%, respectively, while in the open surgery group (n = 17) it was 64%, 37%, and 19% respectively; no differences were found (p = 0.388). Global survival in the laparoscopy group was 93%, 60%, and 40%, respectively, and 88%, 74.5%, and 58.7%, respectively, in the open surgery group; no differences were found (p = 0.893) with a 37 months average follow-up.ConclusionLLR in patients with technically favourable CRCLM had similar morbidity to open resections and resection margins were not compromised because of laparoscopy.

Pathological factors and prognosis of resected liver metastases of colorectal carcinoma: implications and proposal for a pathological reporting protocol.

Colorectal cancer is a leading cause of death worldwide. The liver is the most common site of distant metastases, and surgery is the only potentially curative treatment, although the recurrence rate following surgery is high. In order to define prognosis after surgery, many histopathological features have been identified in the primary tumour. In turn, pathologists routinely report specific findings to guide oncologists on the decision to recommend adjuvant therapy. In general, the pathological report of resected colorectal liver metastases is limited to confirmation of the malignancy and details regarding the margin status. Most pathological reports of a liver resection for colorectal liver metastasis lack information on other important features that have been reported to be independent prognostic factors. We herein review the evidence to support a more detailed pathological report of the resected liver specimen, with attention to: the number and size of liver metastases; margin size; the presence of lymphatic, vascular, perineural and biliary invasion; mucinous pattern; tumour growth pattern; the presence of a tumour pseudocapsule; and the pathological response to neoadjuvant chemotherapy. In addition, we propose a new protocol for the evaluation of colorectal liver metastasis resection specimens.

Abstract 2846: Identify urinary biomarkers for colorectal carcinoma liver metastasis

Abstract Colorectal cancer (CRC) is the third leading prevalent cause of death from cancer in adults, and more than one third of CRC patients are accompanied by liver metastasis. The disease begins as a benign adenomatous polyp, and it subsequently develops into an advanced adenoma and gradually progresses to an invasive cancer. The driving factors behind CRC comprise a series of successive accumulated gene mutations that follow the order “APC-KRAS-TP53-DCC”. Moreover, urine is an important display window for tumor-derived exosomes. Here, to explore the roles of TP53 in CRC and identify novel urinary biomarkers for colorectal cancer metastatic to the liver, a comprehensive proteomic analysis of exosomal proteins from HCT116 TP53-wild type (WT), TP53-knockout (KO) and constructed TP53 (R273H)-mutant (MT) cells, as well as urine samples from CRC patients with and without liver metastasis was performed using the isobaric tag for relative and absolute quantitation (iTRAQ)-2D-LC-MS/MS strategy. The exosomes from the MT and KO cells exhibited significantly reduced sizes compared with the WT cells. A total of 3437 protein groups with ≥2 matched peptides were identified. Specifically, hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) was consistently down-regulated in the exosomes from the MT and KO cells. Functional studies demonstrated that low HGS levels were responsible for the decreased exosome size. TP53 regulated HGS expression and thus HGS-dependent exosome formation. Furthermore, the HGS expression was gradually increased concomitant with CRC carcinogenesis and was an independent poor prognostic factor. In addition, HGS was one of the differentially expressed urine proteins between CRC liver metastasis and healthy individuals. In conclusion, HGS mediates TP53-regulated exosome formation. HGS may serve as a novel histological and urinary prognostic biomarker and a candidate target for therapeutic interventions in CRC. Citation Format: Meng Cai, Yulin Sun, Jiajia Gao, Lina Zhao, Fang Liu, Wei Sun, Zhixiang Zhou, Xiaohang Zhao. Identify urinary biomarkers for colorectal carcinoma 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 2846. doi:10.1158/1538-7445.AM2017-2846

Predictive factors of long-term colorectal cancer survival after ultrasound-controlled ablation of hepatic metastases

Background and objectiveThe risk factors associated to long-term survival were assessed in patients with liver metastases of colorectal carcinoma undergoing ablative therapies. Patients and methodsSingle-centre cohort study, retrospectively analyzed and prospectively collected consecutive patients with unresectable metastatic liver disease of colorectal carcinoma treated with ablative therapies between 1996 and 2013. Factors associated with survival time were identified using Cox's proportional hazard model with time-dependent covariates. A forward variable selection based on Akaike information criterion was performed. Relative risk and 95% confidence intervals for each factor were calculated. Statistical significance was set as p<0.05. ResultsSeventy-five patients with liver metastases of colorectal cancer, with a mean age of 65.6 (10.3) underwent 106 treatments. Variables selected were good quality of life (RR 0.308, 95% CI 0.150–0.632) and tumour extension (RR 3.070, 95% CI 1.776–5.308). The median overall survival was 18.5 months (95% CI 17.4–24.4). The survival prognosis in median was 13.5 vs. 23.4 months for patients with and without tumour extension, and 23.0 vs. 12.8 months for patients with good and fair or poor quality of life, respectively. ConclusionsGood quality of life and tumour extension were the only statistically significant predictors of long-term survival in patients of colorectal carcinoma with liver metastatic disease undergoing ablative treatment with ultrasound.

Predicting Treatment Response of Colorectal Cancer Liver Metastases to Conventional Lipiodol-Based Transarterial Chemoembolization Using Diffusion-Weighted MR Imaging: Value of Pretreatment Apparent Diffusion Coefficients (ADC) and ADC Changes Under Therapy.

To use absolute pretreatment apparent diffusion coefficients (ADC) derived from diffusion-weighted MR imaging (DWI) to predict response to repetitive cTACE for unresectable liver metastases of colorectal carcinoma (CRLM) at 1 and 3months after start of treatment. Fifty-five metastases in 34 patients were examined with DWI prior to treatment and 1 month after initial cTACE. Treatment was performed in 4-week intervals. Response was evaluated at 1 and 3months after start of therapy. Metastases showing a decrease of ≥30% in axial diameter were classified as responding lesions. One month after initial cTACE, seven lesions showed early response. There was no significant difference in absolute pretreatment ADC values between responding and non-responding lesions (p=0.94). Three months after initial cTACE, 17 metastases showed response. There was a significant difference (p=0.021) between absolute pretreatment ADC values of lesions showing response (median 1.08×10-3mm2/s) and no response (median 1.30×10-3mm2/s). Pretreatment ADC showed fair diagnostic value to predict response (AUC 0.7). Lesions showing response at 3months also revealed a significant increase in ADC between measurements before treatment and at one month after initial cTACE (p<0.001). Applying an increase in ADC of 12.17%, response at 3months after initial cTACE could be predicted with a sensitivity and specificity of 77 and 74%, respectively (AUC 0.817). Furthermore, there was a strong and significant correlation (r=0.651, p<0.001) between percentage change in size after third cTACE and percentage change in ADC. In patients with CRLM, ADC measurements are potential biomarkers for assessing response to cTACE.

Factores predictivos de supervivencia a largo plazo del cáncer colorrectal tras la ablación de metástasis hepáticas con control ultrasonográfico

Background and objectiveThe risk factors associated to long-term survival were assessed in patients with liver metastases of colorectal carcinoma undergoing ablative therapies. Patients and methodsSingle-centre cohort study, retrospectively analysed and prospectively collected consecutive patients with unresectable metastatic liver disease of colorectal carcinoma treated with ablative therapies between 1996 and 2013. Factors associated with survival time were identified using Cox's proportional hazard model with time-dependent covariates. A forward variable selection based on Akaike information criterion was performed. Relative risk and 95% confidence intervals for each factor were calculated. Statistical significance was set as P<.05. ResultsSeventy-five patients with liver metastases of colorectal cancer, with a mean age of 65.6 (10.3) underwent 106 treatments. Variables selected were good quality of life (RR 0.308, 95% CI 0.150-0.632) and tumour extension (RR 3.070, 95% CI 1.776-5.308). The median overall survival was 18.5 months (95% CI 17.4-24.4). The survival prognosis in median was 13.5 vs. 23.4 months for patients with and without tumour extension, and 23.0 vs. 12.8 months for patients with good and fair or poor quality of life, respectively. ConclusionsGood quality of life and tumour extension were the only statistically significant predictors of long-term survival in patients of colorectal carcinoma with liver metastatic disease undergoing ablative treatment with ultrasound.

Randomized controlled Phase III study comparing hepatic arterial infusion with systemic chemotherapy after curative resection for liver metastasis of colorectal carcinoma: JFMC 29–0003

The feasibility and efficacy of adjuvant hepatic arterial infusion (HAI) in preventing the development of liver metastases in patients with advanced colon carcinoma have not been validated. The aim of this randomized controlled study was to compare the feasibility of HAI and the protective effect against liver metastasis after curative resection to those of systemic chemotherapy. Between July 2000 and June 2003, 91 patients were enrolled. Patients were randomly assigned to receive 5-fluorouracil (5-FU) via continuous venous infusion (CVI) or intra-hepatic arterial weekly high-dose 5-FU (WHF). The primary endpoint was overall survival (OS). In the WHF group, the cumulative failure rate of hepatic arterial catheterization was 16.7% at 6 months. The occurrence of grade 3 adverse events was comparable between the groups. The 5-year OS rates were 59.0% in the CVI group and 34.9% in the WHF group (P = 0.164). CVI tended to show a protective effect against liver metastasis regarding the 5-year liver-specific cumulative recurrence rate: CVI, 45.0% vs. WHF, 68.3%; P = 0.037). HAI therapy has a certain protective effect against liver metastasis after curative resection in patients with colorectal cancer. However, this therapy did not contribute to any marked improvement in their overall survival.

MCAM and LAMA4 Are Highly Enriched in Tumor Blood Vessels of Renal Cell Carcinoma and Predict Patient Outcome.

The structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, offering an opportunity to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, we performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. We identified a panel of genes consistently upregulated by tumor blood vessels, of which melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes. This result was subsequently confirmed by immunohistochemical analysis of MCAM and LAMA4 expression in RCC and colorectal carcinoma blood vessels. Strong MCAM and LAMA4 expression was also shown to predict poor survival in RCC, but not in colorectal carcinoma. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF, which is highly abundant in this disease. Lastly, MCAM monoclonal antibodies specifically localized to vessels in a murine model of RCC, offering an opportunity for endothelial-specific targeting of anticancer agents. Overall, our findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting. Cancer Res; 76(8); 2314-26. ©2016 AACR.

MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma.

ObjectiveMetastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases.MethodsWe analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE) tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR.ResultsAll three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01). MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01). No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01).ConclusionIn the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases.

Irreversible electroporation in the treatment of locally advanced pancreas and liver metastases of colorectal carcinoma.

Aim of the studyIrreversible electroporation is a new, non-thermal ablation technique in the treatment of parenchymal organ tumors which uses short high voltage pulses of electricity in order to induce apoptosis of targeted cells. In this paper the application of this method of treatment in locally advanced pancreatic cancer (LAPC) and liver cancer is analyzed.Material and methodsBetween 04.2014 and 09.2014 two patients with LAPC and one with colorectal liver metastasis (CRLM) were qualified for treatment with irreversible electroporation. Both patients remained under constant observation and control. PubMed/Medline, Embase and Google Scholar databases were searched and eight original reports on irreversible electroporation of pancreatic and liver tumors based on the biggest groups of patients were found.ResultsTwo patients with LAPC and one with CRLM were qualified for ablation with irreversible electroporation. In all three patients a successful irreversible electroporation (IRE) procedure of the whole tumor was conducted. In the minimum seven-month follow-up 100% local control was achieved – without progression.In the literature review the local response to treatment ranged from 41% to 100%. The event-free survival rate in six-month observation was 94%.ConclusionsAblation with irreversible electroporation is a new non-thermal ablation technique which has been demonstrated, both in the previously published studies and in the cases described in this paper, as a safe and efficient therapeutic method for patients with LAPC and CRLM.

Parenchymal-sparing liver surgery in patients with colorectal carcinoma liver metastases.

Liver resection is the treatment of choice for patients with colorectal liver metastases (CLM). However, major resections are often required to achieve R0 resection, which are associated with substantial rates of morbidity and mortality. Maximizing the amount of residual liver gained increasing significance in modern liver surgery due to the high incidence of chemotherapy-associated parenchymal injury. This fact, along with the progressive expansion of resectability criteria, has led to the development of a surgical philosophy known as "parenchymal-sparing liver surgery" (PSLS). This philosophy includes a variety of resection strategies, either performed alone or in combination with ablative therapies. A profound knowledge of liver anatomy and expert intraoperative ultrasound skills are required to perform PSLS appropriately and safely. There is a clear trend toward PSLS in hepatobiliary centers worldwide as current evidence indicates that tumor biology is the most important predictor of intrahepatic recurrence and survival, rather than the extent of a negative resection margin. Tumor removal avoiding the unnecessary sacrifice of functional parenchyma has been associated with less surgical stress, fewer postoperative complications, uncompromised cancer-related outcomes and higher feasibility of future resections. The increasing evidence supporting PSLS prompts its consideration as the gold-standard surgical approach for CLM.