Proteomic Characterization of Circulating Molecular Perturbations Associated With Pancreatic Adenocarcinoma Following Intravenous ω-3 Fatty Acid and Gemcitabine Administration: A Pilot Study.

BACKGROUND: Administration of intravenous ω-3 fatty acid (ω-3FA) in advanced pancreatic adenocarcinoma patients receiving gemcitabine chemotherapy shows disease stabilization and improved progression-free survival. Using high-definition plasma proteomics, the underlying biological mechanisms responsible for these clinical effects are investigated. METHODS AND RESULTS: A pilot study involving plasma that was collected at baseline from 13 patients with histologically confirmed, unresectable pancreatic adenocarcinoma (baseline group) after 1-month treatment with intravenous gemcitabine and ω-3FA (treatment group) and intravenous gemcitabine only (control group) and was prepared for proteomic analysis. A 2-arm study comparing baseline vs treatment and treatment vs control was performed. Proteins were isolated from plasma with extensive immunodepletion, then digested and labeled with isobaric tandem mass tag peptide tags. Samples were then combined, fractionated, and injected into a QExactive-Orbitrap Mass-Spectrometer and analyzed on Proteome Discoverer and Scaffold with ensuing bioinformatics analysis. Selective reaction monitoring analysis was performed for verification. In total, 3476 proteins were identified. Anti-inflammatory markers (C-reactive protein, haptoglobin, and serum amyloid-A1) were reduced in the treatment group. Enrichment analysis showed angiogenesis downregulation, complement immune systems upregulation, and epigenetic modifications on histones. Pathway analysis identified direct action via the Pi3K-AKT pathway. Serum amyloid-A1 significantly reduced (P < .001) as a potential biomarker of efficacy for ω-3FA. CONCLUSIONS: This pilot study demonstrates administration of ω-3FA has potential anti-inflammatory, antiangiogenic, and proapoptotic effects via direct interaction with cancer-signaling pathways in patients with advanced pancreatic adenocarcinoma. Further studies in a larger sample size is required to validate the clinical correlation found in this preliminary study.

Targeted therapy for hepatocellular carcinoma.

The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.

The Effect of Supplementary Omegaven® on the Clinical Outcome of Patients With Advanced Esophagogastric Adenocarcinoma Receiving Palliative Epirubicin, Oxaliplatin, and Capecitabine Chemotherapy: A Phase II clinical trial.

BACKGROUND/AIM: Previous studies have shown anti-proliferative and anti-apoptotic effects of omega-3 fatty acids (Omegaven®) in vitro and in vivo. Whether this effect can be exploited in patients with advanced esophago-gastric adenocarcinoma is unknown. The present study intended to determine the tumour radiological response and toxicity profile of intravenous omega-3 fish oil infusion when combined with standard palliative chemotherapy, and present the effects of this treatment on plasma cytokine biomarkers. MATERIALS AND METHODS: Participants with advanced esophago-gastric adenocarcinoma were enrolled in a phase II single-arm clinical trial of palliative chemotherapy (epirubicin, oxaliplatin, and capecitabine; EOX) coupled with weekly infusion of Omegaven®. Outcomes were compared to those observed in 37 historical control patients who had received EOX alone. Toxicity was graded using the CTCAE v4.03 and radiological response was assessed using RECIST v1.1. Plasma cytokine levels of IL-1, IL-2, IL-6, TNF-α, and VEGF were evaluated by ELISA. RESULTS: Twenty participants were included in the analysis. Radiological responses were as follows: partial response (EOX plus omega-3 group 73% vs. EOX alone 39%, p=0.03), stable disease (EOX plus omega-3 21% vs. EOX alone 39%, p=0.24), and progressive disease (EOX plus omega-3 7% vs. EOX alone 18%, p=0.34). Grade 3 or 4 toxicity was less common (thromboembolism & gastrointestinal) in those who received EOX plus omega-3. This translated into fewer hospital admissions. There were significant reductions in the concentrations of IL-2 (p=0.009), TNF-α (p<0.0001) and VEGF (p=0.002) following each treatment. CONCLUSION: The treatment with supplementary omega-3 fatty acids reduced chemotherapy-related toxicity and resulted in better radiological responses. The combination treatment resulted in a shift towards a favourable anti-inflammatory cytokine profile. These findings should be evaluated in a randomised clinical trial.

Effects of Omegaven®, EPA, DHA and oxaliplatin on oesophageal adenocarcinoma cell lines growth, cytokine and cell signal biomarkers expression.

BACKGROUND: There is limited evidence assessing the effects of omega-3 polyunsaturated fatty acids (PUFAs) on oesophageal adenocarcinoma, both in vitro and in vivo. We evaluated the effects of the omega-3 PUFA and oxaliplatin on OE33 and OE19 cells. METHOD: The two oesophageal cells were treated with Omegaven® (fish oil emulsion), EPA, DHA and oxaliplatin and incubated for up to 144 h. RESULTS: The following inhibitory effects were observed on OE33 cells: EPA reduced cell growth by 39% (p = 0.001), DHA by 59% (p < 0.000) and Oxaliplatin by 77% (p < 0.000). For OE19 cells, the EPA reduced growth by 1% (p = 0.992), DHA by 26% (p = 0.019) and oxaliplatin by 76% (p < 0.000). For both cells, Omegaven® resulted in reduced cell growth at intermediate concentrations (20-40 µM) and increased cell growth at low (10 µM) and high (50 µM) concentrations. DHA, Omegaven® and oxaliplatin were associated with significant downregulation of VEGF and p53 protein, and upregulation of p21 protein. DHA, Omegaven® and Oxaliplatin also led to significant downregulation of the total ERK1/2 and Akt proteins. CONCLUSION: DHA, Omegaven® and oxaliplatin were associated with downregulation of p53 and VEGF in both cells. Of the PUFAs studied, DHA alone or in combination (Omegaven®) had greater in vitro anti-cancer effects than EPA alone.

The impact of an omega-3 fatty acid rich lipid emulsion on fatty acid profiles in critically ill septic patients.

BACKGROUND: Death from sepsis in the intensive therapy unit (ITU) is frequently preceded by the development of multiple organ failure as a result of uncontrolled inflammation. Treatment with omega-3 (n-3) fatty acids (FAs), principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been demonstrated to attenuate the effects of uncontrolled inflammation and may be clinically beneficial in reducing mortality from organ dysfunction. Fish oil (FO) is a source of EPA and DHA. METHODS: A randomized trial investigating the effects of parenteral (intravenous) nutrition providing FO (0.092g EPA+DHA/kg body weight/day) was conducted. Sixty consecutive ITU patients diagnosed with sepsis were randomised to receive either once daily parenteral FO and standard medical care or standard medical care only. RESULTS: Forty one patients (21 received fish oil; 20 controls) consented to blood sampling and blood was taken on days 0, 1, 2, 3, 5, 7, 10 and 13; because of deaths, patient discharge and withdrawal of consent, the number of blood samples available for analysis diminished with time. FA composition of plasma phosphatidylcholine (PC), plasma non-esterified FAs (NEFAs) and peripheral blood mononuclear cells (PBMCs) was determined by gas chromatography. EPA and DHA were rapidly incorporated into all 3 lipid pools investigated. There was a reduction in the arachidonic acid (AA) to EPA+DHA ratio in plasma PC and NEFAs. Fewer patients died in the FO group (13.3% (n=4)) compared with the control group (26.7% (n=8)) but this difference was not significant. A reduction in the AA/(EPA+DHA) ratio in PBMCs and plasma PC was associated with significantly improved survival. Plasma PC, plasma NEFA and PBMC FA profiles are rapidly altered by FO infusion in critically ill septic patients. CONCLUSION: The provision of high dose n-3 FAs resulted in a rapid and significant increase in EPA and DHA and a reduction in AA/(EPA+DHA) ratio. This latter reduction is associated with improved survival.

Targeting pancreatic cancer using a combination of gemcitabine with the omega-3 polyunsaturated fatty acid emulsion, Lipidem™.

SCOPE: Pancreatic cancer remains a disease of poor prognosis, with alternate strategies being sought to improve therapeutic efficacy. Omega-3 fatty acids have shown clinical benefit, and mechanisms of action are under investigation. METHODS AND RESULTS: Proliferation assays, flow cytometry, invasion assays, ELISA and western blotting were used to investigate efficacy of omega-3 fatty acids alone and in combination with gemcitabine. The docosahexanoic acid (DHA)/eicosapentanoic acid (EPA) combination, Lipidem™, in combination with gemcitabine inhibited growth in pancreatic cancer and pancreatic stellate cell (PSC) lines, with PSCs exhibiting greatest sensitivity to this combination. Invasion of pancreatic cancer cells and PSCs in a 3D spheroid model, was inhibited by combination of gemcitabine with Lipidem™. PSCs were required for cancer cell invasion in an organotypic co-culture model, with invasive capacity reduced by Lipidem™ alone. Platelet-derived growth factor (PDGF) is a key cytokine in pro-proliferative and invasion signalling, and thus a critical regulator of interactions between pancreatic cancer cells and adjacent stroma. Platelet-derived growth factor (PDGF-BB) secretion was completely inhibited by the combination of Lipidem™ with gemcitabine in cancer cells and PSCs. CONCLUSION: Lipidem™ in combination with gemcitabine, has anti-proliferative and anti-invasive efficacy in vitro, with pancreatic stellate cells exhibiting the greatest sensitivity to this combination.

A randomized controlled trial investigating the effects of parenteral fish oil on survival outcomes in critically ill patients with sepsis: a pilot study.

INTRODUCTION: Death from sepsis in the intensive care unit (ITU) is frequently preceded by the development of multiple organ failure as a result of uncontrolled inflammation. Treatment with ω-3 has been demonstrated to attenuate the effects of uncontrolled inflammation and may be clinically beneficial. METHOD: A randomized control trial investigating the effects of parenteral ω-3 was carried out. Consecutive patients diagnosed with sepsis were entered into the study and randomized to receive either parenteral ω-3 or standard medical care only. The primary outcome measure was a reduction in organ dysfunction using the Sequential Organ Failure Assessment (SOFA) score as a surrogate marker. The secondary outcome measures were mortality, length of stay, mean C-reactive protein (CRP), and days free of organ dysfunction/failure. RESULTS: Sixty patients were included in the study. The baseline demographics were matched for the two cohorts. Patients treated with parenteral ω-3 were associated with a significant reduction in new organ dysfunction (Δ-SOFA 2.2 ± 2.2 vs. 1.0 ± 1.5, P = .005 and maximum-SOFA 10.1 ± 4.2 vs. 8.1 ± 3.2, P = .041) and maximum CRP (186.7 ± 78 vs. 141.5 ± 62.6, P = .019). There was no significant reduction in the length of stay between cohorts. Patients treated with ω-3 in the strata of less severe sepsis had a significant reduction in mortality (P = .042). CONCLUSION: The treatment of critically ill septic patients with parenteral ω-3 is safe. It is associated with a significant reduction in organ dysfunction. It may be associated with a reduction in mortality in patients with less severe sepsis.

Unsaturated fatty acids differ between hepatic colorectal metastases and liver tissue without tumour in humans: results from a randomised controlled trial of intravenous eicosapentaenoic and docosahexaenoic acids.

INTRODUCTION: Mediators derived from the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid oxidation have been shown to have tumour promoting effects in experimental models, while n-3 PUFAs are thought to be protective. Here we report fatty acid concentrations in hepatic colorectal metastases compared to liver tissue without tumour in humans. METHODS: Twenty patients with colorectal liver metastasis were randomized to receive a 72 h infusion of parenteral nutrition with or without n-3 PUFAs. Histological samples from liver metastases and liver tissue without tumour were obtained from 15 patients at the time of their subsequent liver resection (mean 8 days (range 4-12) post-infusion) and the fatty acid composition determined by gas chromatography. RESULTS: There were no significant differences in fatty acid composition between the two intervention groups. When data from all patients were combined, liver tissue without tumour had a higher content of both n-3 and n-6 PUFAs and a lower content of oleic acid and total n-9 fatty acids compared with tumour tissue (p<0.0001, 0.0002,<0.0001 and <0.0001, respectively). The n-6/n-3 PUFA ratio was found to be higher in tumour tissue than tissue without tumour (p<0.0001). CONCLUSIONS: Hepatic colorectal adenocarcinoma metastases have a higher content of n-9 fatty acids and a lower content of n-6 and n-3 PUFAs than liver tissue without tumour.

Changes in plasma and erythrocyte omega-6 and omega-3 fatty acids in response to intravenous supply of omega-3 fatty acids in patients with hepatic colorectal metastases.

BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are functionally the most important omega-3 polyunsaturated fatty acids (PUFAs). Oral supply of these fatty acids increases their levels in plasma and cell membranes, often at the expense of the omega-6 PUFAs arachidonic acid (ARA) and linoleic acid. This results in an altered pattern of lipid mediator production to one which is less pro-inflammatory. We investigated whether short term intravenous supply of omega-3 PUFAs could change the levels of EPA, DHA, ARA and linoleic acid in plasma and erythrocytes in patients with hepatic colorectal metastases. METHODS: Twenty patients were randomised to receive a 72 hour infusion of total parenteral nutrition with (treatment group) or without (control group) omega-3 PUFAs. EPA, DHA, ARA and linoleic acid were measured in plasma phosphatidylcholine (PC) and erythrocytes at several times points up to the end of infusion and 5 to 12 days (mean 9 days) after stopping the infusion. RESULTS: The treatment group showed increases in plasma PC EPA and DHA and erythrocyte EPA and decreases in plasma PC and erythrocyte linoleic acid, with effects most evident late in the infusion period. Plasma PC and erythrocyte EPA and linoleic acid all returned to baseline levels after the 5-12 day washout. Plasma PC DHA remained elevated above baseline after washout. CONCLUSIONS: Intravenous supply of omega-3 PUFAs results in a rapid increase of EPA and DHA in plasma PC and of EPA in erythrocytes. These findings suggest that infusion of omega-3 PUFAs could be used to induce a rapid effect especially in targeting inflammation.

Reduction in circulating pro-angiogenic and pro-inflammatory factors is related to improved outcomes in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega-3 fish oil.

BACKGROUND: Pancreatic cancer is a rapidly progressive disease which is often only amenable to palliative treatment. Few patients respond to palliative chemotherapy, so surrogate markers indicating which patients are likely to respond to treatment are required. There is a well-established link between pro-inflammatory circulating cytokines and growth factors (CAF), and the development of neoplasia. Agents that may modulate these factors are of interest in developing potential novel therapeutic applications. METHODS: As part of a single-arm phase II trial in patients with advanced pancreatic cancer (APC) treated with gemcitabine and intravenous (i.v.) omega-3 rich lipid emulsion (n-3FA), serum samples were analysed for 14 CAF using a multiplex cytokine array. Baseline serum concentrations were correlated with overall (OS) and progression-free survival (PFS), and changes in concentration correlated with time and outcomes for CAF responders were analysed. RESULTS: Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) concentrations reduced significantly with treatment over time. Low baseline interleukin (IL)-6 and -8 were correlated with improved OS. PDGF responders showed a tendency towards improved OS and FGF responders a significantly improved PFS. DISCUSSION: Treatment with gemcitabine plus i.v. n-3FA may reduce concentrations of CAF which may be associated with an improved outcome. Baseline IL-6 and -8 may be surrogate markers for outcome in patients with APC treated with this regimen.

The autologous normothermic ex vivo perfused porcine liver-kidney model: improving the circuit's biochemical and acid-base environment.

BACKGROUND: The ex vivo porcine liver perfused model isolates the organ from extrinsic regulatory mechanisms, facilitating an improved understanding of the organ physiology and reaction to various conditions. We have assessed the influence of the addition of a porcine kidney to the circuit. METHODS: Eight livers were harvested and perfused for 6 hours. In 5 additional experiments a kidney also was connected in parallel. Hourly arterial blood gases were collected to analyze glucose, acid base, and renal parameters. The primary end point was an evaluation of the influence of the kidney on glucose, pH, and electrolyte levels. RESULTS: In the combined porcine liver-kidney circuit all the parameters significantly improved compared with the liver circuit alone. This was particularly evident for glucose values because normoglycemia was reached by the end of the perfusion, and for pH and electrolyte values that were maintained at initial levels. CONCLUSIONS: The addition of a porcine kidney to the perfusion circuit improves the biochemical milieu. This might produce more consistent and reliable results, particularly during studies requiring a steady-state environment.

Renal effects of microwave ablation compared with radiofrequency, cryotherapy and surgical resection at different volumes of the liver treated.

BACKGROUND: Renal changes after microwave tissue ablation (MTA) were compared with those following hepatic resection, cryotherapy (CRYO), and radiofrequency ablation (RFA). Structural damage producing renal impairment has been assessed directly by examining tissue specimens and by serum analysis for two sensitive biomarkers, retinol binding protein (RBP) and the heat shock protein 70 (HSP-70) for each modality at different ablation volumes. METHODS: Live rats underwent MTA, surgical resection, CRYO or RFA of 15, 33 or 66% of total hepatic volume. Urine and tissue samples were collected at the time of death. Percentage of tubules with casts and glomerular damage, tissue expression of HSP-70 and urine RBP were evaluated and compared. Behaviour of the animals was also assessed by means of five different parameters and combined to produce a response score. RESULTS: All RFA and CRYO rats undergoing 66% died and these animals had >60% of damaged tubuli and 8% of altered glomeruli. No animals treated by MTA or surgical resection died. Cut-off values (those predicting fatal treatments) could be identified for levels of HSP-70 and RBP. CONCLUSIONS: Large volume MTA is associated with a significant reduced renal damage and is well tolerated compared with RFA and CRYO.

Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.

Hepatic microwave ablation: a review of the histological changes following thermal damage.

Microwave (MW) ablation therapy is a local treatment by which tumours are destroyed by coagulation from the passage of MWs into cells. The aim of this review is to examine histological results obtained from preclinical and clinical studies. A literature search was undertaken for all studies focusing on MW therapy and in which lesions were excised for a complete histopathological examination after treatment. Two main zones were described after ablative therapy (central and transitional). Both corresponded to specific microscopic characteristics and evolved over time in a precise manner. No viable cells even up to 6 cm in diameter were demonstrated in 93% of lesions after treatment. Microwave therapy is a reliable technique under a variety of clinical situations. Future investigations are needed to compare MW with other ablative techniques to identify factors that influence the effectiveness of the various techniques and to determine specific indications.

Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences.

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 micromol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M1dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

Local ablation for unresectable liver tumors: is thermal best?

Hepatic resection remains the "gold standard" for patients with resectable disease. Nevertheless, for a variety of reasons this is not feasible for the majority of patients. A wide range of locally ablative techniques has been developed for use in these patients with the aim of improving survival. Unfortunately, as with many recent techniques in surgery, much of the development of these methods, and particularly their introduction clinically, has not been based on sound scientific data. The relative merits and limitations of the more commonly used techniques are discussed, although this lack of prospective, randomized data precludes firm conclusions to be drawn from many of the studies reported. By far the most popular methods now employed, thermal techniques have certain limitations, particularly when treating tumors adjacent to major vascular or biliary structures. The authors believe that this situation represents the "niche" for which ablative techniques may ultimately find their logical application, where a single awkwardly placed metastasis deems a patient unresectable. If such a metastasis can be completely and safely ablated, a potentially curative resection may then become a realistic option. The relatively new, nonthermal technique of hepatic electrolysis has been extensively studied and shown to be safe and effective in close proximity to major intrahepatic veins due to a subtle electrochemical action rather than a rapid "burn". This technique is discussed in the context of other, more traditional thermal methods of ablation.

Chemoprevention of gastrointestinal malignancies.

BACKGROUND: There has been considerable interest in the use of chemical or dietary agents to suppress or inhibit the development of tumours in the early stages of carcinogenesis. This concept is known as chemoprevention and although the potential for such agents is tremendous, evaluating their clinical benefit is beset with difficulties. AIMS: Using selected agents, such as curcumin and indole-3-carbinol, as examples, the present review will discuss the possible mechanisms of chemoprevention and the problems encountered in developing these agents into clinical drugs. METHODS: A review of the published literature from 1985 to the present day was performed using Medline and Web of Science search engines. Key words used were 'gastrointestinal cancer' and 'chemoprevention'. CONCLUSION: A huge number of agents with possible chemopreventive action has been identified. Pilot trials using molecular signatures of cancer activity can be used to select which agents should be included in large-scale phase III clinical trials. Publications concerning chemoprevention are concentrated in the scientific and oncological literature but surgeons with their greater exposure to premalignant gastrointestinal disease need to be aware of current concepts in this rapidly expanding field. This knowledge would allow collaboration between oncologists and surgeons in clinical trials to further evaluate chemopreventive compounds and ascertain their clinical impact.

Electrolysis and other local ablative treatments for non-resectable colorectal liver metastases.

The present paper is a review of the current ablative treatment options for the treatment of colorectal liver metastases. Cryotherapy, microwave coagulation therapy, radiofrequency ablation and laser-induced thermotherapy are discussed. Electrolysis, a novel non-thermal ablative treatment, is described. Potential benefits of electrolysis include the apparent ability to safely and effectively treat lesions abutting major hepatic structures and the lack of a systemic inflammatory reaction following electrolytic ablation. Further studies in animals and humans are needed to confirm this potential and to further refine the methods of electrolytic treatment of colorectal liver metastases.