Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Contribution of mitochondria to injury of hepatocytes and liver tissue by hyperthermia.

OBJECTIVE: The aim of this study was to investigate functional changes of liver mitochondria within the experimentally modeled transition zone of radiofrequency ablation and to estimate possible contribution of these changes to the energy status of liver cells and the whole tissue. MATERIALS AND METHODS: Experiments were carried out on mitochondria isolated from the perfused liver and isolated hepatocytes of male Wistar rats. Hyperthermia was induced by changing the temperature of perfusion medium in the range characteristic for the transition zone (38-52°C). After 15-min perfusion, mitochondria were isolated to investigate changes in the respiration rates and the membrane potential. Adenine nucleotides extracted from isolated hepatocytes and perfused liver subjected to hyperthermic treatment were analyzed by HPLC. RESULTS: Hyperthermic liver perfusion at 42-52°C progressively impaired oxidative phosphorylation in isolated mitochondria. Significant inhibition of the respiratory chain components was observed after perfusion at 42°C, irreversible uncoupling became evident after liver perfusion at higher temperatures (46°C and above). After perfusion at 50-52°C energy supplying function of mitochondria was entirely compromised, and mitochondria turned to energy consumers. Hyperthermia-induced changes in mitochondrial function correlated well with changes in the energy status and viability of isolated hepatocytes, but not with the changes in the energy status of the whole liver tissue. CONCLUSIONS: In this study the pattern of the adverse changes in mitochondrial functions that are progressing with increase in liver perfusion temperature was established. Results of experiments on isolated mitochondria and isolated hepatocytes indicate that hyperthermic treatment significantly and irreversibly inhibits energy-supplying function of mitochondria under conditions similar to those existing in the radiofrequency ablation transition zone and these changes can lead to death of hepatocytes. However, it was not possible to estimate contribution of mitochondrial injury to liver tissue energy status by estimating only hyperthermia-induced changes in adenine nucleotide amounts on the whole tissue level.

Percutaneous Transhepatic Biliary Stenting with Uncovered Self-Expandable Metallic Stents in Patients with Malignant Biliary Obstruction - Efficacy and Survival Analysis.

BACKGROUND: The aim of this study was to assess short- and long-term outcomes of malignant biliary obstruction (MBO) treatment by percutaneous transhepatic biliary stenting (PTBS) with uncovered selfexpandable metallic stents (SEMS), and to identify predictors of survival. MATERIAL/METHODS: A nine-year, single-centre study from a prospectively collected database included 222 patients with inoperable MBO treated by PTBS with uncovered nitinol SEMS. RESULTS: Technical and clinical success rates were 95.9% and 82.4%, respectively. The total rate of postprocedural complications was 14.4%. The mean durations of the primary and secondary stent patency were 114.7±15.1 and 146.4±21.2 days, respectively. The 30-day mortality rate was 15.3% with no procedure-related deaths. The mean estimated length of survival was 143.3±20.6 days. Independent predictors increasing the risk of death included higher than 115 µmol/L serum bilirubin 2-5 days after biliary stenting (HR 3.274, P=0.019), distal (non-hilar) obstruction of the bile ducts (HR 3.711, P=0.008), Bismuth-Corlette type IV stricture (HR 2.082, P=0.008), obstruction due to gallbladder cancer (HR 31.029, P=0.012) and only partial drainage of liver parenchyma (HR 4.158, P=0.040). CONCLUSIONS: PTBS with uncovered SEMS is an effective and safe method for palliative treatment of MBO. Serum bilirubin higher than 115 µmol/L 2-5 days after the procedure has a significant negative impact on patients' survival. Lower survival is also determined by distal bile duct obstruction, Bismuth- Corlette type IV stricture, biliary obstruction caused by gallbladder cancer and when only partial liver drainage is applied.

Radiofrequency ablation of liver tumors (II): clinical application and outcomes.

Radiofrequency ablation is one of the alternatives in the management of liver tumors, especially in patients who are not candidates for surgery. The aim of this article is to review applicability of radiofrequency ablation achieving complete tumor destruction, utility of imaging techniques for patients' follow-up, indications for local ablative procedures, procedure-associated morbidity and mortality, and long-term results in patients with different tumors. The success of local thermal ablation consists in creating adequate volumes of tissue destruction with adequate "clear margin," depending on improved delivery of radiofrequency energy and modulated tissue biophysiology. Different volumes of coagulation necrosis are achieved applying different types of electrodes, pulsing energy sources, utilizing sophisticated ablation schemes. Some additional methods are used to increase the overall deposition of energy through alterations in tissue electrical conductivity, to improve heat retention within the tissue, and to modulate tolerance of tumor tissue to hyperthermia. Contrast-enhanced computed tomography, magnetic resonance imaging, ultrasound or positron emission tomography are applied to control the effectiveness of radiofrequency ablation. The long-term results of radiofrequency ablation are controversial.

Radiofrequency ablation of liver tumors (I): biological background.

Majority of patients suffering from liver tumors are not candidates for surgery. Currently, minimal invasive techniques have become available for local destruction of hepatic tumors. Radiofrequency ablation is based on biological response to tissue hyperthermia. The aim of this article is to review available biological data on tissue destruction mechanisms. Experimental evidence shows that tissue injury following thermal ablation occurs in two distinct phases. The initial phase is direct injury, which is determined by energy applied, tumor biology, and tumor microenvironment. The temperature varies along the ablation zone and this is reflected by different morphological changes in affected tissues. The local hyperthermia alters metabolism, exacerbates tissue hypoxia, and increases thermosensitivity. The second phase - indirect injury - is observed after the cessation of heat stimulus. This phase represents a balance of several promoting and inhibiting mechanisms, such as induction of apoptosis, heat shock proteins, Kupffer cell activation, stimulation of the immune response, release of cytokines, and ischemia-reperfusion injury. A deeper understanding of the underlying mechanisms may possibly lead to refinements in radiofrequency ablation technology, resulting in advanced local tumor control and prolonged overall survival.

Apoptosis is activated in an early period after radiofrequency ablation of liver tissue.

BACKGROUND/AIMS: Hyperthermia induced apoptosis may lead to tumor cell death thus expanding the volume of non-viable tissue and warrant a "safety margin" of at least 10mm to exclude the possibility of tumor recurrence. We carried out an experimental study to investigate the cellular injury produced by radiofrequency ablation in the area surrounding the ablated tissue and to describe early apoptotic processes in the transition zone following radiofrequency ablation procedure in a porcine liver model. METHODOLOGY: Nine anesthetized pigs underwent laparotomy and local thermal ablation of the liver parenchyma. The ablated tissue and the surrounding parenchyma were investigated for apoptosis applying Western blot analysis and immunohistochemistry. RESULTS: The active (cleaved) caspase-3 17-kDa subunit was detected in the transition zone one hour after ablative procedure at a distance of 9-10 mm from the rim of the necrosis zone. In contrast analysis of tissues in necrosis zone and in surrounding normal liver parenchyma revealed no markers of apoptotic activity. CONCLUSION: We determined that apoptosis, leading to further cell death, is activated in the majority of cells in the transition zone, thus supporting the hypothesis that the "safety margin" of 10 mm is encompassed by the indirect thermal effect.

Monitoring changes in heart tissue temperature and evaluation of graft function after coronary artery bypass grafting surgery.

Thermography is a relatively new contact-free method used in experimental and clinical studies and in cardiovascular surgery to investigate the myocardium and coronary artery function. Objects of complex study included mongrel dogs and patients with coronary artery disease who underwent cardiac surgery. For active dynamic thermography, we used a thermovision camera "A20V" (FLIR Systems, USA). Our data indicate that both experimental and clinical study performed on beating hearts could be an important approach to interoperation inspection of autovenous graft function. An infrared camera also can be successfully used to determine the extent of ischemic damage to the myocardium, heart, and blood vessels during surgery as a significant prognostic tool for evaluating outcome after cardiac operation.

Finite element modeling of cooled-tip probe radiofrequency ablation processes in liver tissue.

Finite element model of radiofrequency ablation (RFA) with cooled-tip probe in liver has been developed by employing COMSOL Multiphysics software. It describes coupled electric, thermal and sodium chloride solution infiltration flow phenomena taking place during ablation processes. Features of hydraulic capacity, saturation of the tissue by infiltration, and dependency of electrical conductivity on the damage integral of the tissue have been supplied to the model. RFA experiments have validated the model. Physical parameters describing hydraulic capacity and hydraulic conductivity in the tissue, as well as, the relation of electrical conductivity against the value of damage integral have been determined.