Transarterial Radioembolization for Hepatic Metastases of Pancreatic Adenocarcinoma: A Systematic Review.

PURPOSE: To assess the safety and effectiveness of transarterial radioembolization (TARE) in the treatment of hepatic metastases from pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: A systematic search of the Embase and MEDLINE databases was conducted using keywords and Medical Subject Headings terms related to TARE and hepatic metastases from PDAC. Observational studies and clinical trials reporting overall survival (OS), hepatic progression-free survival (hPFS), or tumor response after TARE were included. RESULTS: Eight studies, comprising 145 patients with metastatic PDAC, met the inclusion criteria. No randomized controlled trials were identified, and 4 studies were prospective. Forty-four (30.3%) patients underwent previous pancreatic resection, and 66 (45.5%) had extrahepatic metastases at the time of TARE. Most studies (n = 6) used resin microspheres for TARE. The pooled disease control rate was 69.4% at a median of 3 months. The median OS from the time of TARE ranged from 3.7 to 9 months. The median hPFS ranged from 2.4 to 5.2 months. There were 31 Grade 3-4 biochemical toxicities and 4 treatment-related deaths. CONCLUSIONS: The role of TARE in patients with hepatic metastases from PDAC remains unclear owing to low patient numbers, limited prospective data, and heterogeneity in the study design. Further prospective studies are required to evaluate the role of TARE in carefully selected patients with liver-only metastatic disease.

Donor Hepatic Steatosis and Outcome After Liver Transplantation: a Systematic Review.

BACKGROUND: There is increasing need to expand availability of donor liver grafts, including steatotic livers. Steatotic liver is associated with poor outcome post-transplantation but with conflicting results in the literature. The aim of this systematic review was to evaluate the impact of steatotic livers on liver transplantation outcomes. METHODS: An electronic search of OVID Medline and Embase databases was performed to identify clinical studies that reported outcomes of steatotic livers in liver transplantation. Data were extracted, and basic descriptive statistics were used to summarise data pooled from individual clinical studies. RESULTS: Ninety-two articles were identified, of which 34 met the inclusion criteria, and stratified analysis were performed. There was a lack of standardised definition of primary non-function or impaired primary function amongst the studies and description of type of steatosis. Severely (>60%) steatotic grafts are associated with increased risk of poor graft function, whilst moderate-severe (>30%) steatotic grafts are associated with decreased graft survival. CONCLUSIONS: Available evidence showed increased risk of poor graft outcome in moderate-severe steatotic livers. A large prospective multi-centred trial will be required to identify the true risks of steatotic livers. Consistent definition of primary non-function/impaired primary function and description of type of steatosis is also required.

Impact of ischemic preconditioning on outcome in clinical liver surgery: a systematic review.

BACKGROUND: Ischemia-reperfusion injury is a major cause of post-liver-surgery complications. Ischemic preconditioning (IPC) has been demonstrated to protect against ischemia-reperfusion injury. Clinical studies have examined IPC in liver surgery but with conflicting results. This systematic review aimed to evaluate the effects of IPC on outcome in clinical liver surgery. METHODS: An electronic search of OVID Medline and Embase databases was performed to identify studies that reported outcomes in patients undergoing liver surgery subjected to IPC. Basic descriptive statistics were used to summarise data from individual clinical studies. RESULTS: 1093 articles were identified, of which 24 met the inclusion criteria. Seven topics were selected and analysed by subgroup. There were 10 studies in cadaveric liver transplantation, 2 in living-related liver transplantation, and 12 in liver resection. IPC decreases hepatocellular damage in liver surgery as determined by transaminases but does not translate to any significant clinical benefit in orthotopic liver transplant or liver resection. CONCLUSIONS: Available clinical evidence does not support routine use of IPC in liver surgery as it does not offer any apparent benefit in perioperative outcome. Further clinical studies will need to be carried out to determine the subset of patients that will benefit from IPC.

Mitochondrial dysfunction in steatotic rat livers occurs because a defect in complex i makes the liver susceptible to prolonged cold ischemia.

Steatotic livers are susceptible to cold ischemia, which is thought to be secondary to mitochondrial dysfunction. Ischemic preconditioning (IPC) has been reported to improve liver function in the setting of warm ischemia/reperfusion injury, but the effect of IPC on steatotic liver mitochondrial function (MF) with cold ischemia has not been previously evaluated. We aimed to evaluate MF with various severities of hepatic steatosis after various durations of cold ischemia storage with or without IPC. Male Sprague-Dawley rats were fed a normal diet or a high-fat/high-sucrose diet for 1, 2, or 4 weeks to induce mild (<30%), moderate (30%-60%), or severe (>60%) macrovesicular steatosis, respectively. Liver MF was tested with high-resolution respirometry after 1.5, 4, 8, 12, 18, and 24 hours of cold ischemia. Rats in each group (n = 10) underwent 10 minutes of IPC or no IPC before cold ischemia. The baseline (time 0) respiration was similar for lean and severely steatotic livers despite decreased mitochondrial complex I (C-I) activity in severely steatotic livers. Hepatic steatosis was associated with increased C-I-mediated leaks and decreased respiratory control ratios (RCRs) after cold ischemia. Mildly, moderately, and severely steatotic livers showed significantly lower RCRs after 8, 1.5, and 1.5 hours of cold ischemia, respectively, in comparison with lean livers. IPC restored RCRs in mildly steatotic livers to levels comparable to those in lean livers for up to 24 hours of cold ischemia via the attenuation of C-I-mediated leaks, but it had no beneficial effect on moderately and severely steatotic livers. In conclusion, steatotic livers exhibited apparent mitochondrial dysfunction through an alteration in C-I activity, and this made them more susceptible to prolonged cold ischemia. The clinically based IPC protocol used here restored MF in cases of mild hepatic steatosis by attenuating C-I-mediated leaks after prolonged cold ischemia, but it did work not in livers with moderate or severe steatosis.

Impact of ischaemic preconditioning on experimental steatotic livers following hepatic ischaemia-reperfusion injury: a systematic review.

BACKGROUND: Steatotic livers are vulnerable to the deleterious effects of ischaemia-reperfusion injury (IRI) that occur after hepatic surgery. Ischaemic preconditioning (IPC) has been shown to abrogate the effects of IRI in patients undergoing hepatic surgery. Experimental studies have suggested that IPC may be beneficial in steatotic livers subjected to IRI. OBJECTIVE: The aim of this systematic review was to evaluate the effects of IPC on steatotic livers following hepatic IRI in experimental models. METHODS: An electronic search of the OVID Medline and EMBASE databases was performed to identify studies that reported clinically relevant outcomes in animal models of hepatic steatosis subjected to IPC and IRI. RESULTS: A total of 1093 articles were identified, of which 18 met the inclusion criteria. There was considerable heterogeneity in the type of animal model, and duration and type of IRI. Increased macrovesicular steatosis (> 30%) was associated with a poor outcome following IRI. Ischaemic preconditioning was found to be beneficial in > 30% steatotic livers and provided for decreased histological damage, improved liver function findings and increased survival. CONCLUSIONS: Experimental evidence supports the use of IPC in steatotic livers undergoing IRI. These findings may be applicable to patients undergoing liver surgery. However, clinical studies are required to validate the efficacy of IPC in this setting.

Ob/ob mouse livers show decreased oxidative phosphorylation efficiencies and anaerobic capacities after cold ischemia.

BACKGROUND: Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. METHODS: Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. RESULTS: Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I-fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. CONCLUSIONS: Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers.

Additive effect of pretransplant obesity, diabetes, and cardiovascular risk factors on outcomes after liver transplantation.

The effects of pretransplant obesity, diabetes mellitus (DM), coronary artery disease (CAD), and hypertension (HTN) on outcomes after liver transplantation (LT) are controversial. Questions have also been raised about the appropriateness of the body mass index (BMI) for assessing obesity in patients with end-stage liver disease. Both issues have implications for organ allocation in LT. To address these questions, we undertook a cohort study of 202 consecutive patients (2000-2010) undergoing LT at a national center in New Zealand. BMI and body fat percentage (%BF) values (dual-energy X-ray absorptiometry) were measured before transplantation, and the methods were compared. The influence of pretransplant risk variables (including obesity, DM, CAD, and HTN) on the 30-day postoperative event rate, length of hospital stay, and survival were analyzed. There was agreement between the calculated BMI and the measured %BF for 86.0% of the study population (κ coefficient = 0.73, 95% confidence interval = 0.61-0.85), and this was maintained across increasing Model for End-Stage Liver Disease scores. Obesity was an independent risk factor for the postoperative event rate [count ratio (CR) = 1.03, P < 0.001], as was DM (CR = 1.4, P < 0.001). Obesity with concomitant DM was the strongest predictor of the postoperative event rate (CR = 1.75, P < 0.001) and a longer hospital stay (5.81 days, P < 0.01). Independent metabolic risk factors had no effect on 30-day, 1-year, or 5-year patient survival. In conclusion, BMI is an adequate tool for assessing obesity-associated risk in LT. Early post-LT morbidity is highest for patients with concomitant obesity and DM, although these factors do not appear to influence recipient survival.

Hepatic mitochondrial function analysis using needle liver biopsy samples.

BACKGROUNDS AND AIM: Current assessment of pre-operative liver function relies upon biochemical blood tests and histology but these only indirectly measure liver function. Mitochondrial function (MF) analysis allows direct measurement of cellular metabolic function and may provide an additional index of hepatic health. Conventional MF analysis requires substantial tissue samples (>100 mg) obtained at open surgery. Here we report a method to assess MF using <3 mg of tissue obtained by a Tru-cut® biopsy needle making it suitable for percutaneous application. METHODS: An 18G Bard® Max-core® biopsy instrument was used to collect samples. The optimal Tru-cut® sample weight, stability in ice-cold University of Wisconsin solution, reproducibility and protocol utility was initially evaluated in Wistar rat livers then confirmed in human samples. MF was measured in saponin-permeabilized samples using high-resolution respirometry. RESULTS: The average mass of a single rat and human liver Tru-cut® biopsy was 5.60±0.30 and 5.16±0.15 mg, respectively (mean; standard error of mean). Two milligram of sample was found the lowest feasible mass for the MF assay. Tissue MF declined after 1 hour of cold storage. Six replicate measurements within rats and humans (n = 6 each) showed low coefficient of variation (<10%) in measurements of State-III respiration, electron transport chain (ETC) capacity and respiratory control ratio (RCR). Ischemic rat and human liver samples consistently showed lower State-III respiration, ETC capacity and RCR, compared to normal perfused liver samples. CONCLUSION: Consistent measurement of liver MF and detection of derangement in a disease state was successfully demonstrated using less than half the tissue from a single Tru-cut® biopsy. Using this technique outpatient assessment of liver MF is now feasible, providing a new assay for the evaluation of hepatic function.

The impact of hepatic steatosis on hepatic ischemia-reperfusion injury in experimental studies: a systematic review.

BACKGROUND: The impact of hepatic steatosis on outcome following hepatic ischemia-reperfusion injury (IRI) remains controversial with conflicting clinical results. A number of experimental studies have been published examining the relationship between hepatic steatosis and IRI. This systematic review evaluates these experimental studies. METHODS: An electronic search of the Medline and Embase databases (January 1946 to June 2012) was performed to identify studies that reported relevant outcomes in animal models of hepatic steatosis subjected to IRI. RESULTS: A total of 1314 articles were identified, of which 33 met the predefined criteria and were included in the study. There was large variation in the type of animal model, duration, and type of IRI and reporting of histological findings. Increased macrovesicular steatosis (>30%) was associated with increased histological damage, liver function derangement, and reduced survival. Increased duration of warm or cold ischemia had a negative impact on all outcomes measured. Microvesicular steatosis did not influence outcome. CONCLUSIONS: Findings from this systemic review support the hypothesis that livers with >30% macrovesicular steatosis are less tolerant of IRI. Clinically, it is likely that these findings are applicable to patients undergoing hepatic resection, but further studies are required to confirm these data.

STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma.

The MYC protooncogene is associated with the pathogenesis of most human neoplasia. Conversely, its experimental inactivation elicits oncogene addiction. Besides constituting a formidable therapeutic target, MYC also has an essential function in normal physiology, thus creating the need for context-specific targeting strategies. The analysis of post-translational MYC activity modulation yields novel targets for MYC inactivation. Specifically, following regulatory network analysis in human B-cells, we identify a novel role of the STK38 kinase as a regulator of MYC activity and a candidate target for abrogating tumorigenesis in MYC-addicted lymphoma. We found that STK38 regulates MYC protein stability and turnover in a kinase activity-dependent manner. STK38 kinase inactivation abrogates apoptosis following B-cell receptor activation, whereas its silencing significantly decreases MYC levels and increases apoptosis. Moreover, STK38 knockdown suppresses growth of MYC-addicted tumors in vivo, thus providing a novel viable target for treating these malignancies.

Development of a swine model of secondary liver tumor from a genetically induced swine fibroblast cell line.

AIM: Metastatic disease is the most common liver tumor. Although alternative therapies have been developed for non-surgical candidates, those therapies lacked ideal testing prior to clinical application because of a paucity of large animal models. The purpose of the present study was to develop a model for secondary liver tumor in a large animal. MATERIAL AND METHODS: Fibroblasts were isolated from swine ear lobules and then transfected with amphotrophic retroviruses encoding human or murine genetic material (hTERT, p53(DD), cyclinD-1, CDK4(R24C), Myc (T58A), Ras(G12V)). Transformed cell lines were finally inoculated subcutaneously (s.c.) into: 1) immunodeficient mice (nude), 2) immunocompetent mice (wild type), 3) immunosuppressed swine (under tacrolimus or corticosteroids), 4) immunocompetent swine, and 5) into the liver and portal circulation of swine under steroid-based immunosuppression. RESULTS: In the murine model, tumor growth was evident in 100% of the nude mice (n=5), with a peak size of 20 mm (15.22+/-4.5 mm; mean+/-SD) at the time of sacrifice (3 weeks). Tumor growth was evident in 71% of the wild mice (n=21), with a peak size of 7.8 mm (4.19+/-1.1 mm) by the third week of growth. In the swine model, tumor growth was evident in 75% (3/4 ears; n=2) of swine under tacrolimus-based immunosuppression versus 50% of swine under steroids-based immunosuppression (n=2). Tumor growth was slow in two animals, while in one animal the tumor was larger with a peak growth of 42 mm at 3 weeks. The tumor pattern in the ear lobules was characterized by slow growth, with a peak size of 6-8 mm in the immunocompetent swine at 3 weeks. All tumors were shown to be malignant by histology. In contrast, inoculums of the transformed fibroblast cell line in swine livers showed no evidence of tumor growth at 3 weeks. CONCLUSIONS: Development of a transformed swine fibroblast cell line was successful, resulting in an in vivo malignant tumor. Cell line inoculums had tumorigenic properties in nude mice, wild-type mice, and immunosuppressed swine, as judged by uncontrolled cell growth, invasion of surrounding tissue, neoangiogenesis, and invasion of normal vasculature, resulting in the formation of tumor nodules. Such properties were not observed in swine upon inoculation into the liver/portal circulation.

Genetic induction of tumorigenesis in swine.

The transition from basic to clinical cancer research for a number of experimental therapeutics is hampered by the lack of a genetically malleable, large animal model. To this end, we genetically engineered primary porcine cells to be tumorigenic by expression of proteins known to perturb pathways commonly corrupted in human cancer. Akin to human cells, these porcine cells were quite resistant to transformation, requiring multiple genetic changes. Moreover, the transformed porcine cells produced tumors when returned to the isogenic host animal. The ability to now rapidly and reproducibly genetically induce tumors of sizes similar to those treated clinically in a large mammal similar to humans in many respects will provide a robust cancer model for preclinical studies dependent on generating large tumors.

Poliosis associated with treatment of fungal endophthalmitis.

PURPOSE: To report a case of poliosis arising from treatment with topical medications. DESIGN: Interventional case report. METHODS: A 37-year-old man was treated for fungal endophthalmitis arising from Aspergillus fumigatus keratitis with penetrating keratoplasty, lensectomy and vitrectomy together with systemic and prolonged topical medications. RESULTS: Recovery was complicated by retinal detachment, elevated intraocular pressure and bullous keratopathy. Unilateral poliosis developed eight months following keratoplasty and has persisted over 2(1)/(2) years. CONCLUSIONS: Topical medications are implicated in causing the poliosis.

Palliative care for patients with a failed liver transplant.

The aim of liver transplantation is to cure the patient with acute or chronic liver disease. While this is often achieved, some patients will experience continued acute rejection of their transplanted liver (graft), established chronic rejection or disease recurrence. In these circumstances, it is necessary to re-assess the patient for treatment by re-transplantation but, with an increased mortality rate, the decision to proceed with this treatment must be carefully considered by the healthcare team, the patient and their family. For patients with diseases which are associated with a high risk of recurrence, quality of life as well as long-term prognosis are the principal aims of care. Integral to the decision to re-transplant is the ethical issue of allocating scarce organs where there is a reduced chance of graft and patient survival. The focus of the healthcare team in a liver transplant unit is commonly curative but, when caring for a patient with graft failure, the team must consider and, when appropriate, facilitate the palliative care approach.