Cancer Liver Metastases Research Articles

Intra-Arterial Therapies for Liver Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

Performing a systematic review and meta-analysis to assess the evidence of intra-arterial therapies in liver metastatic breast cancer (LMBC) patients. A systemic literature search was performed in PubMed, EMBASE, SCOPUS for studies regarding intra-arterial therapies in LMBC patients. Full text studies of LMBC patients (n ≥ 10) published between January 2010 and December 2020 were included when at least one outcome among response rate, adverse events or survival was available. Response rates were pooled using generalized linear mixed models. A weighted estimate of the population median overall survival (OS) was obtained under the assumption of exponentially distributed survival times. A total of 26 studies (1266 patients) were included. Eleven articles reported on transarterial radioembolization (TARE), ten on transarterial chemoembolization (TACE) and four on chemo-infusion. One retrospective study compared TARE and TACE. Pooled response rates were 49% for TARE (95%CI 32-67%), 34% for TACE (95%CI 22-50%) and 19% for chemo-infusion (95%CI 14-25%). Pooled median survival was 9.2months (range 6.1-35.4months) for TARE, 17.8months (range 4.6-47.0) for TACE and 7.9months (range 7.0-14.2) for chemo-infusion. No comparison for OS was possible due to missing survival rates at specific time points (1 and 2year OS) and the large heterogeneity. Although results have to be interpreted with caution due to the large heterogeneity, the superior response rate of TARE and TACE compared to chemo-infusion suggests first choice of TARE or TACE in chemorefractory LMBC patients. Chemo-infusion could be considered in LMBC patients not suitable for TARE or TACE. 3a.

The Race We Already Lost

In this narrative medicine essay, a resident in medicine and pediatrics learns in her last year of medical school that her physician father has metastatic liver cancer and hopes that for just a day or a little longer the 2 could share the title doctor.

Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. HCC progression and metastasis are closely related to altered mitochondrial metabolism, including mitochondrial stress responses, metabolic reprogramming, and mitoribosomal defects. Mitochondrial oxidative phosphorylation (OXPHOS) defects and reactive oxygen species (ROS) production are attributed to mitochondrial dysfunction. In response to oxidative stress caused by increased ROS production, misfolded or unfolded proteins can accumulate in the mitochondrial matrix, leading to initiation of the mitochondrial unfolded protein response (UPRmt). The mitokines FGF21 and GDF15 are upregulated during UPRmt and their levels are positively correlated with liver cancer development, progression, and metastasis. In addition, mitoribosome biogenesis is important for the regulation of mitochondrial respiration, cell viability, and differentiation. Mitoribosomal defects cause OXPHOS impairment, mitochondrial dysfunction, and increased production of ROS, which are associated with HCC progression in mouse models and human HCC patients. In this paper, we focus on the role of mitochondrial metabolic signatures in the development and progression of HCC. Furthermore, we provide a comprehensive review of cell autonomous and cell non-autonomous mitochondrial stress responses during HCC progression and metastasis.

Effect of ICD‐9‐CM to ICD‐10‐CM coding system transition on identification of common conditions: An interrupted time series analysis

To evaluate the effect of diagnostic coding system transition on the identification of common conditions recorded in Taiwan's national claims database. Using the National Health Insurance Research Database, we estimated the 3-month prevalence of recorded diagnosis of 32 conditions based on the ICD-9-CM codes in 2014-2015 and the ICD-10-CM codes in 2016-2017. Two algorithms were assessed for ICD-10-CM: validated ICD-10 codes in the literature and codes translated from ICD-9-CM using an established mapping algorithm. We used segmented regression analysis on time-series data to examine changes in the 3-month prevalence (both level and trend) before and after the ICD-10-CM implementation. Significant changes in the level were found in 19 and 11 conditions when using the ICD-10 codes from the literature and mapping algorithm, respectively. The conditions with inconsistent levels by both of the algorithms were valvular heart disease, peripheral vascular disease, mild liver disease, moderate to severe liver disease, metastatic cancer, rheumatoid arthritis and collagen vascular diseases, coagulopathy, blood loss anemia, deficiency anemia, alcohol abuse, and psychosis. Nine conditions had significant changes in the trend when using the ICD-10 codes from the literature or mapping algorithm. Less than half of the 32 conditions studied had a smooth transition between the ICD-9-CM and ICD-10-CM coding systems. Researchers should pay attention to the conditions where the coding definitions result in inconsistent time series estimates.

Colorectal Cancer, Liver Metastases and Biotherapies

(1) Background: colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Its first main metastatic diffusion spreads to the liver. Different mechanisms such as the epithelial–mesenchymal transition and angiogenesis are the characteristics of this invasion. At this stage, different options are possible and still in debate, especially regarding the use of targeted therapeutics and biotherapies. (2) Methods: A review of the literature has been done focusing on the clinical management of liver metastasis of colorectal cancer and the contribution of biotherapies in this field. (3) Results: In a clinical setting, surgeons and oncologists consider liver metastasis in CRC into two groups to launch adapted therapeutics: resectable and non-resectable. Around these two entities, the combination of targeted therapies and biotherapies are of high interest and are currently tested to know in which molecular and clinical conditions they have to be applied to impact positively both on survival and quality of life of patients.

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.

MiR-424 Acts as a Novel Biomarker in the Diagnosis of Patients with Hepatocellular Carcinoma

Objective: MicroRNA-424 (MiR-424) is proved to be a tumor suppressor against many malignancies, including hepatocellular carcinoma (HCC). Nevertheless, its role in diagnosing HCC remained poorly understood. The authors' research investigated diagnostic value of serum miR-424 in HCC. Materials and Methods: Relative expression levels of serum miR-424 in HCC patients and healthy individuals were measured via quantitative real-time polymerase chain reaction. χ2 test was applied to analyze the correlation between miR-424 expression and clinical features of HCC cases. Diagnostic value was estimated via plotting a receiver operating characteristic (ROC) curve. Results: Serum miR-424 expression was obviously downregulated in HCC cases in comparison to healthy persons (p < 0.001). miR-424 expression presented strong correlation with tumor node metastasis stage (p = 0.022), Barcelona Clinic Liver Cancer stage (p < 0.001), metastasis (p = 0.037), and vein invasion (p = 0.033). ROC curve analysis manifested an area under the curve of 0.768 with a sensitivity of 75.0% and a specificity of 72.4%, suggesting that serum miR-424 had high diagnostic value in HCC patients. Conclusions: The data suggest that serum miR-424 may represent a biomarker in early detection of HCC.

Macrophage migration inhibitory factor predicts an unfavorable outcome after transarterial chemoembolization for hepatic malignancies.

Transarterial chemoembolization (TACE) is a therapeutic option for patients with intermediate‐stage hepatocellular carcinoma (HCC) or metastatic liver cancers. Identifying those patients who particularly benefit from TACE remains challenging. Macrophage migration inhibitory factor (MIF) represents is an inflammatory protein described in patients with liver cancer, but no data on its prognostic relevance in patients undergoing TACE exist. Here, we evaluate MIF serum concentrations as a potential biomarker in patients undergoing TACE for primary and secondary hepatic malignancies. MIF serum concentrations were measured by multiplex immunoassay in 50 patients (HCC: n = 39, liver metastases: n = 11) before and 1 day after TACE as well as in 51 healthy controls. Serum concentrations of MIF did not differ between patients and healthy controls. Interestingly, in the subgroup of patients with larger tumor size, significantly more patients had increased MIF concentrations. Patients with an objective tumor response to TACE therapy showed comparable concentrations of serum MIF compared to patients who did not respond. MIF concentrations at day 1 after TACE were significantly higher compared to baseline concentrations. Importantly, baseline MIF concentrations above the optimal cutoff value (0.625 ng/ml) turned out as a significant and independent prognostic marker for a reduced overall survival (OS) following TACE: patients with elevated MIF concentrations showed a significantly reduced median OS of only 719 days compared to patients below the cutoff value (median OS: 1430 days, p = 0.021). Baseline MIF serum concentrations are associated with tumor size of intrahepatic malignancies and predict outcome of patients with liver cancer receiving TACE.

New insight into long non-coding RNAs associated with bone metastasis of breast cancer based on an integrated analysis

BackgroundBone is the most common site of metastatic breast cancer, and it is a leading cause of breast cancer-related death. This study aimed to explore bone metastasis-related long non-coding RNAs (lncRNAs) in breast cancer.MethodsFour mRNA datasets and two lncRNA datasets of bone metastasis, lung metastasis and liver metastasis of breast cancer were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) in group of bone metastasis vs lung metastasis and bone metastasis vs liver metastasis, as well as the overlap of the two groups, were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein–protein interaction (PPI) network construction of DEmRNAs were conducted. The cis nearby-targeted DEmRNAs of DElncRNAs were obtained. Quantitative real-time polymerase chain reactions (qRT-PCR) was used to detect the expression levels of selected DEmRNAs and DElncRNAs. LOC641518-lymphoid enhancer-binding factor 1 (LEF1) pair was selected to verify its role in migration and invasion capability of breast cancer cells by wounding healing assay and transwell invasion assay.ResultsA total of 237 DEmRNAs were obtained in bone metastasis compared with both lung metastasis and liver metastasis. A total of three DElncRNAs in bone metastasis compared with both lung metastasis and liver metastasis were obtained. A total of seven DElncRNA-nearby-targeted DEmRNA pairs and 15 DElncRNA-nearby-targeted DEmRNA pairs in group of bone metastasis vs lung metastasis and bone metastasis vs liver metastasis, were detected, respectively. Four cis LncRNA-mRNA interaction pairs were identified, which are LOC641518-LEF1, FLJ35024-Very Low Density Lipoprotein Receptor (VLDLR), LOC285972-Retinoic Acid Receptor Responder 2 (RARRES2) and LOC254896-TNF receptor superfamily member 10c (TNFRSF10C). qRT-PCR using clinical samples from our hospital confirms the bioinformatics prediction. siRNA knocking down LOC641518 down-regulates LEF1 mRNA expression, and reduces the migration and invasion capability of breast cancer cells.ConclusionsWe concluded that four LncRNA-mRNA pairs, including LOC641518-LEF1, may play a central role in breast cancer bone metastasis.

Stereotactic Thermal Ablation of Liver Tumors: 3D Planning, Multiple Needle Approach, and Intraprocedural Image Fusion Are the Key to Success—A Narrative Review

Simple SummaryThermal ablation is a minimally invasive, potentially curative approach for the treatment of primary and secondary liver tumors. Different technologies are available, with radiofrequency ablation (RFA) and microwave ablation (MWA) being the most widely used. Both methods induce an irreverible destruction of the tumor tissue by applying thermal energy. Conventionally, a single ablation probe is placed using ultrasound (US) or computed tomography (CT). Using these standard guidance techniques the creation of necrosis zones to treat large tumors (i.e., >2–3 cm) is hampered by technical limitations. These limitations can be overcome by stereotactic thermal ablation: a multiple needle approach with 3D treatment planning and precise stereotactic needle placement combined with immediate verification of treatment success by means of image fusion. The stereotactic multi-needle technique allows for local curative treatment of multiple and large tumors within a single session. Ultimately, due to the application of these sophisticated tools and advanced techniques, a local curative treatment option can be offered to a higher number of patients suffering of primary and secondary liver tumors. This article provides an overview of the current stereotactic techniques for thermal ablation and summarizes the available clinical evidence for this approach.Thermal ablation is an emerging, potentially curative approach in treating primary and metastatic liver cancer. Different technologies are available, with radiofrequency ablation (RFA) and microwave ablation (MWA) being the most widely used. Regardless of the technique, destruction of the entire tumor, including an adequate safety margin, is key. In conventional single-probe US- or CT-guided thermal ablation, the creation of such large necrosis zones is often hampered by technical limitations, especially for large tumors (i.e., >2–3 cm). These limitations have been overcome by stereotactic RFA (SRFA): a multiple needle approach with 3D treatment planning and precise stereotactic needle placement combined with intraprocedural image fusion of pre- and post-interventional CT scans for verification of treatment success. With these sophisticated tools and advanced techniques, the spectrum of locally curable liver malignancies can be dramatically increased. Thus, we strongly believe that stereotactic thermal ablation can become a cornerstone in the treatment of liver malignancies, as it offers all the benefits of a minimally invasive method while providing oncological outcomes comparable to surgery. This article provides an overview of current stereotactic techniques for thermal ablation, summarizes the available clinical evidence for this approach, and discusses its advantages.

Long Non-coding RNA Signature for Liver Metastasis of Colorectal Cancers.

Colorectal cancer ranks within the top three cancers both in terms of incidence as well as deaths. Metastasis is often the major cause of mortality and liver is the primary and most common site to which colorectal cancers metastasize. We tested the prognostic ability of a long non-coding RNA (lncRNA) signature in liver metastatic colorectal cancers. We first evaluated expression levels of several lncRNAs in eight excised liver metastases from primary colorectal cancers and found significantly upregulated lncRNAs HOTAIR and MALAT1 along with significantly downregulated LOC285194. We further compared the expression levels of HOTAIR, MALAT1 and LOC285194 in primary colorectal tumors at the time of initial diagnosis and correlated them with disease progression and liver metastasis. HOTAIR and MALAT1 were significantly upregulated and LOC285194 was significantly downregulated in twelve patients who were diagnosed with liver metastasis within 5 years of initial diagnosis, compared to the five patients with no metastasis. A positive signature comprising of high HOTAIR/MALAT1 and low LOC285194 also correlated with progression to higher grade tumors. Thus, the lncRNA signature comprising of high HOTAIR/MALAT1 and low LOC285194 could be a prognostic signature for liver metastasis as well as overall poor survival.

Narrative review of 3D navigated stereotactic liver ablation—do we still need a minimally invasive liver surgeon?

: Ablation is an exciting alternative to surgery as a curative intent treatment for primary and metastatic liver cancer. However, conventional techniques have not achieved oncologic outcomes equal to surgery except in a minimal subset of patients. We discuss here our use of a stereotactic technique for RFA and summarize the available clinical evidence for this approach to make oncological outcomes of ablation therapy comparable to surgery. Even with promising results, we are the only institution performing this approach, and similar approaches are only made in a few centers worldwide. The causes for that are multifactorial, but reimbursement of percutaneous ablation seems to be the most significant limiting factor for this technology becoming mainstream. Nonetheless, the question to answer is: will stereotactic liver ablation replace minimally invasive liver resection? In our opinion, stereotactic liver ablation will change the way we treat primary and metastatic liver cancer, but ideally, by adding another viable and consistent minimally invasive option. The objective is offering curative intent treatments to more patients and making open procedures become a last resort option. To get there, surgeons and interventional radiologists have to work together to create the clinical evidence and knowhow to make this a reality.

Lipid Metabolic Reprogramming and Metabolic Stress in Liver Cancer

Recent studies have shown that tumor microenvironment plays an important regulatory role in the growth and metastasis of liver cancer. Metabolic reprogramming represents a series of adaptive metabolic alterations that liver cancer cells undertake when they are under metabolic stress caused by glucose deficiency and hypoxia microenvironment, and lipid reprogramming is an important part of it. Previous studies have revealed a variety of lipid types with altered metabolic patterns in liver cancer cells, and have, to a certain extent, investigated the biological functions and regulatory mechanisms of these lipid metabolic reprogramming processes. However, there are still many lipid metabolic reprogramming processes that have not received thorough investigation, and little is known about their roles and mechanisms in the pathogenesis and development of liver cancer. In addition, how to accomplish the goal of treating liver cancer by targeting key regulatory factors in lipid metabolic reprogramming still remains a major challenge in translational medical research. This paper introduced the sources of lipids and the main functions and driving factors of lipid metabolic reprogramming in liver cancer cells, attempting to provide a theoretical basis and potential therapeutic targets for the treatment of liver cancer through regulating or restricting lipid metabolic reprogramming.

Abstract 13: High-Throughput, Non-Invasive Raman Spectroscopy of Anticancer Nanomedicine for Liver Cancer Therapeutic Intervention

Abstract Purpose: Liver cancer remains one of the most difficult to treat, heterogeneous forms of cancer with poor prognosis. Available current therapies face many limitations. Raman spectroscopy is a promising platform for clinical drug development and surgical interventions for improved patient outcomes. Herein, we present a new insight with a rapid, non-destructive, non-invasive Raman spectroscopy modality based molecular signatures unique to anticancer nanomedicine signifying distinct stratification in liver cancer treated tissues of SCID mice. Methods: The therapeutic intervention was investigated using a high-throughput Raman spectroscopy in ex vivo liver tissues treated with combinatorials; targeted and non-targeted polymeric nanocomplexes encapsulated microtubule inhibitors against metastatic liver cancer in SCID mice. Principal Component Analysis (PCA), Linear Discriminate Analysis (LDA) for multivariate data analysis, and cross validation method was used to extrapolate the high throughput Raman based treatment efficiency study in ex vivo liver tissues. Results: Raman spectral signatures obtained by Raman spectroscopy of liver tissue samples of healthy normal liver versus liver cancer cohorts exhibited complete discrimination of healthy ones from the affected diseased counterparts with high accuracy classification. This could be useful as a liver cancer diagnosis tool. Peculiar Raman profiles with distinct stratification of targeted anticancer nanomedicine combinatorials treated cohort were observed. Interestingly, apoptotic lipid bodies and amide I was the prominent features revealed in anticancer nanomedicine combinatorials treatment cohorts. Conclusion: Our approach is a significant advancement for unique Raman molecular signatures-based targeted anticancer nanomedicine combinatorials therapeutic intervention for liver cancer in tissues. Clinical translation of this proposed modality would define Raman based rapid, high-throughput platform for the clinical drug development and monitoring against liver cancer remains warranted. Citation Format: Radhika Poojari, Mithila Bhujbal, Arti Hole, Murali Krishna Chilakapati. High-Throughput, Non-Invasive Raman Spectroscopy of Anticancer Nanomedicine for Liver Cancer Therapeutic Intervention [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 13.

Effects of Interventional Therapy on Liver Metastases-Measurement of Liver Volume by Abdominal Computed Tomography

Purpose: To evaluate the effects of transhepatic arterial infusion (TAI) with transcatheter arterial embolization (TAE) on liver volume of patients with liver metastases, by liver volumetry using 256-slice CT (iCT 256, Philips Healthcare). Methods: A retrospective analysis of 19 patients with liver metastases, who received combination treatment of TAI with TAE, were conducted. Residual liver volumes (LV) were measured before (LV0), after the first (LV1) and the second treatment (LV2) with iCT 256. Bland-Altman method was used to evaluate the agreements of residual liver volume between two reviewers. Residual liver volume changes were compared by One-Way ANOVA. Results: For the first reviewer, LV0, LV1, LV2 were: 872.67±139.31, 960.63±143.91, 842.13±141.45 cc. LV1 &gt; LV0, but the difference was not significant (P = 0.061). LV2 &lt; LV0, the difference was statistically significant (P = 0.013). LV2 &lt; LV0, and the difference was not statistically significant (P = 0.509). For the second reviewer, LV0, LV1, LV2 were: 909.99±135.46, 996.36±180.10, 845.70±131.632 cc. LV1 &gt; LV0, the difference was not statistically significant (P = 0.083). LV2 &lt; LV1, the difference was statistically significant (P = 0.003). LV2 &lt; LV0, the difference was not statistically significant (P = 0.194). Conclusion: Combination treatment of TAI with TAE did not induce significant liver damage in patients with metastatic liver cancer, and iCT256 volumetry provided a precise measurement of liver volume and may play a critical role in the development of interventional surgery.

Abstract 2638: Developing 3d hydrogel model for patient-derived organoids of metastatic colorectal cancer

Abstract The advances in the development of preclinical models for various cancers have tremendously helped study of the biology and genetics of human cancers as well as for development of therapeutics. Recently, patient-derived organoids (PDOs) have emerged as a robust preclinical platform that can provide insight into the patient specific genetic mechanisms, cancer progression and drug susceptibility. We have developed a novel PDO platform by embedding patient-derived organoids in a 3D hydrogel suspension culture. Our previous studies have shown that, when cultured in hydrogel, spheroids derived from cancer cell lines demonstrated upregulated gene expression signatures in relation to migration and angiogenesis compared to cultures in media, suggesting a more hypoxic, nutrient deficient environment. Given that hypoxia and nutrient deficiency are important feathers of solid tumors, the hydrogel environment could provide a good platform for in vitro study of tumor development and resistance to treatment. In the current study, we embedded PDOs derived from liver metastasis of colorectal cancer into the 3D suspension hydrogel culture. The PDOs adapted well in the hydrogel gel environment. We assessed the response of PDOs in hydrogel to anticancer agents, and compared that to those cultured in media. The PDOs cultured in hydrogel showed significantly elevated resistance to the treatments. The IC50s of chemotherapeutic drugs 5-fluorouracil and oxaliplatin are increased by ~5-10 fold when cultured in hydrogel compared to those in media. Further studies through RNAseq analysis revealed differentially activated signaling pathways. In particular, the levels of the CXC ligand family chemokines are significantly up-regulated in the PDOs cultured in the hydrogel. The CXC ligand family chemokines are important immune stimulants that are known to play key role in the chemotaxis and tumor recruitment of immune cells including neutrophil, T-cell and B-cells. Interestingly, the elevated levels of CXC-ligands have been shown to relate to resistance of colorectal cancer against drug treatment such as 5-fluorouracil. Our hydrogel model could help elucidate the mechanisms behind such resistance. Future study will focus on evaluating how well the hydrogel PDO platform can recapitulate tumor microenvironment and its potential in screening for personalized medicine. Citation Format: He Wei, Eveliina Karelehto, Karen Dubbin, Aimy Sebastian, Robert Warren, Monica Moya, Gaby Loots, Elizabeth Wheeler, Matthew Coleman. Developing 3d hydrogel model for patient-derived organoids of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2638.

Abstract 1927: Cancer cells induce apoptosis in hepatocytes as one of the mechanisms to displace hepatocytes in vessel co-opted colorectal cancer liver metastases

Abstract Vessel co-option in colorectal cancer liver metastases (CRCLM) has been recognized as one of the mechanistic pathways of resistance against anti-angiogenic therapy. The cancer cells are highly motile in co-opted lesions, which move toward and along the pre-existing sinusoidal vessels and hijack them to gain access to nutrient. The movement of cancer cells is accompanied by displacement of the hepatocytes. However, the molecular mechanisms underlying this displacement are unclear yet. To examine whether apoptosis involved in hepatocytes displacement by cancer cells in co-opted lesions, we performed immunohistochemical staining for pro-apoptotic markers, such as cleaved caspase-3 and cleaved PARP-1. We observed overexpression of pro-apoptotic markers in liver parenchyma of co-opted lesions compared to angiogenic lesions, specifically the hepatocytes that are in close proximity to the cancer cells. In vitro, we found that culturing hepatocytes with either colorectal cancer cells or conditioned media of co-opted CRCLM organoids induces apoptosis. Importantly, our results also suggested proprotein convertase subtilisin/kexin type 9 (PCSK-9 or PC-9) as a potential mediator of cancer cells-driven hepatocytes apoptosis. Altogether, these results confirm that cancer cells exploit apoptosis to establish vessel co-option in CRCLM. Citation Format: Miran Rada, Migmar Tsamchoe, Audrey Kapelanski-Lamoureux, Jessica Bloom, Stephanie Petrillo, Sébastien Tabariès, Diane H. Kim, Peter Younan, Alex Gregorieff, Peter Siegel, Anthoula Lazaris, Peter Metrakos. Cancer cells induce apoptosis in hepatocytes as one of the mechanisms to displace hepatocytes in vessel co-opted colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1927.

Major vessel bleeding control experience in laparocopic major hepatectomy

Laparoscopic hepatectomy (LH) is worldwidely spread, because LH needs small incision which cause less pain. But during LH, it is hard to control major bleeding. Patient could be in dangerous situation. So we will propose some tips to make control major bleeding during LH. The first case had 2.5 cm hepatocellular carcinoma in segment 5/6. We planned to laparoscopic right hemihepatectomy. After surgery, he had no special event. And he had discharge, at pod 6. The second case underwent low anterior resection due to rectosigmoid colon cancer 6 years ago. He had 3 cm metastatic colon cancer in liver. We planned to laparoscopic right hemihepatectomy. during surgery, uncontrolled massive bleeding happened, he arrested. So open conversion was done. And he had discharge, at pod 5. In the first case, there was bleeding during ligation of vessel by hemoloc. We couldn't recognized bleeding focus. So more liver parenchymal dissection was done. We found that inferior vena cava (IVC) which is base of right hepatic vein (RHV) inferior wall was laceration. The operative used laparoscopic surgical stapler for division of RHV and bleeding control. In the second case, liver parenchyma was dissection fully and ready to division the RHV. Operator dissect posterior wall of RHV by golden finger and dissector. At this moment, IVC which is base of RHV was laceration. operator tried to control bleeding by suture IVC. But the patient arrested. Open conversion operator was done. We suggest laparoscopic surgical stapler rather than manual suture, during massive bleeding.

Identification of DNA methylation biomarkers for risk of liver metastasis in early-stage colorectal cancer

BackgroundLiver metastases can occur even in CRC patients who underwent curative surgery. While evidence suggested that adjuvant chemotherapy can help to reduce the occurrence of liver metastases for certain patients, it is not a recommended routine as the side effects outweigh the potential benefits, especially in Stage II CRC patients. This study aims to construct a model for predicting liver metastasis risk using differential methylation signals in primary CRC tumors, which can facilitate the decision for adjuvant chemotherapy.MethodsFifty-nine stage I/II and IV CRC patients were enrolled. Primary tumor, adjacent normal tissue, and metastatic tumor tissues were subject to targeted bisulfite sequencing for DNA methylation. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was used to identify potential DMRs for predicting liver metastasis of CRC.ResultsWe identified a total of 241,573 DMRs by comparing the DNA methylation profile of primary tumors of stage II patients who developed metastasis to those who were metastasis-free during the follow up period. 213 DMRs were associated with poor prognosis, among which 182 DMRS were found to be hypermethylated in the primary tumor of patients with metastases. Furthermore, by using the LASSO regression model, we identified 23 DMRs that contributed to a high probability of liver metastasis of CRC. The leave-one-out cross validation (LOOCV) was used to evaluate model predictive performance at an AUC of 0.701. In particular, 7 out of those 23 DMRs were found to be in the promoter region of genes that were previously reported prognostic biomarkers in diverse tumor types, including TNNI2, PAX8, GUF1, KLF4, EVI2B, CEP112, and long non-coding RNA AC011298. In addition, the model was also able to distinguish metastases of different sites (liver or lung) at an AUC of 0.933.ConclusionWe have identified DNA methylation biomarkers associated with the risk of cancer liver metastasis in early-stage CRC patients. A risk prediction model based on those epigenetic markers was proposed for outcome assessment.

Retraction.

Retraction: "Silence of lncRNA HEIH suppressed liver cancer cell growth and metastasis through miR-199a-3p/mTOR axis," by Yongbiao Ma, De Cao, Gaoxue Li, Jingxia Hu, Xin Liu, Jianling Liu, J Cell Biochem. 2019; 17757-17766: The above article, published online on 29 May 2019 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/jcb.29041), has been retracted by agreement between the the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. Several flaws and inconsistencies between results presented and experimental methods described were found, the editors consider the conclusions of this article to be invalid. The authors collaborated in the investigation initially, but were not available for a final confirmation of the retraction.