Local Ablation Does Not Worsen Perioperative Outcomes After Liver Transplant for Hepatocellular Carcinoma.

OBJECTIVE. Local ablation of hepatocellular carcinoma (HCC) before liver transplant has important advantages, such as preventing disease progression, tumor downstaging, and offering a test of time. However, it might render liver transplant more technically demanding. Thus far, its potential effect on liver transplant outcomes is still unknown, and, therefore, the current study was performed. MATERIALS AND METHODS. Patients who underwent liver transplant for HCC at a single tertiary referral center between 2008 and 2016 were included and retrospectively analyzed. Patients who underwent liver resection and local ablation before liver transplant were excluded. Patients treated with local ablation before liver transplant were compared with those not treated with local ablation, both before and after propensity score matching. In addition, the local ablation group was compared with patients who underwent primary resection before liver transplant. Posttreatment mortality and morbidity were determined, and overall and disease-free survival rates were calculated. RESULTS. In total, 182 patients were included. Twenty-six patients underwent resection but not local ablation before liver transplant. Of the remaining 156 patients, 66 (42%) underwent local ablation before liver transplant and 90 (58%) did not. Perioperative mortality and morbidity were similar in both groups before and after propensity score matching (8% and 74% in the local ablation group vs 10% and 83% in the non-local ablation group, p = 0.60 and 0.17, respectively). In addition, no significant differences in long-term outcomes were observed between the groups before and after propensity score matching. Also, no differences were observed in outcomes in the local ablation group versus the liver resection group. CONCLUSION. Local ablation before liver transplant does not have a negative effect on outcomes after liver transplant for HCC.

Impact of postoperative complications on long-term survival following surgery for T4 colorectal cancer.

BACKGROUND: Postoperative complications (POCs) after the resection of locally advanced colorectal cancer (CRC) may influence adjuvant treatment timing, outcomes, and survival. This study aimed to evaluate the impact of POCs on long-term outcomes in patients surgically treated for T4 CRC. METHODS: All consecutive patients who underwent the resection of T4 CRC at a single centre from 2004 to 2013 were retrospectively analysed from a prospectively maintained database. POCs were assessed using the Clavien-Dindo classification. Patients who developed POCs were compared with those who did not in terms of recurrence-free survival (RFS) and overall survival (OS). RESULTS: The study population comprised 106 patients, including 79 (74.5%) with synchronous distant metastases. Overall, 46 patients (43%) developed at least one POC during the hospital stay, and of those patients, 9 (20%) had severe complications (Clavien-Dindo ≥ grade III). POCs were not associated with OS (65% with POCs vs. 69% without POCs; p = 0.72) or RFS (58% with POCs vs. 70% without POCs; p = 0.37). Similarly, POCs did not affect OS or RFS in patients who had synchronous metastases at diagnosis compared with those who did not. CONCLUSIONS: POCs do not affect the oncological course of patients subjected to the resection of T4 CRC, even in cases of synchronous metastases.

Development of a Safe and Effective Vaccinia Virus Oncolytic Vector WR-Δ4 with a Set of Gene Deletions on Several Viral Pathways.

Despite the effectiveness of classic treatments and available diagnostic tools, cancer continues to be a leading world health problem, with devastating cancer-related death rates. Advances in oncolytic virotherapy have shown promise as potentially effective treatment options in the fight against cancer. The poxviruses have many features that make them an attractive platform for the development of oncolytic vectors, with some candidates currently in clinical trials. Here, we report the design and generation of a new oncolytic vector based on the vaccinia virus Western Reserve (WR) strain. We show that the WR-Δ4 virus, with the combined deletion of four specific viral genes that act on metabolic, proliferation, and signaling pathways (A48R, B18R, C11R, and J2R), has effective anti-tumor capabilities in vivo. In WR-Δ4-infected mice, we observed strong viral attenuation, reduced virus dissemination, and efficient tumor cell growth control in the B16F10 syngeneic melanoma model, with enhanced neutrophil migration and activation of tumor antigen-specific immune responses. This approach provides an alternative strategy toward ongoing efforts to develop an optimal oncolytic poxvirus vector.

Ligation versus no ligation of spontaneous portosystemic shunts during liver transplantation: Audit of a prospective series of 66 consecutive patients.

The management of large spontaneous portosystemic shunt (SPSS) during liver transplantation (LT) is a matter of debate. The aim of this study is to compare the short-term and longterm outcomes of SPSS ligation versus nonligation during LT, when both options are available. From 2011 to 2017, 66 patients with SPSS underwent LT: 56 without and 10 with portal vein thrombosis (PVT), all of whom underwent successful thrombectomy and could have portoportal reconstruction. The SPSS were either splenorenal (n = 40; 60.6%), left gastric (n = 16; 24.2%), or mesenterico-iliac (n = 10; 15.1%). Following portoportal anastomosis, the SPSS was ligated in 36 (54.4%) patients and left in place in 30 (45.5%) patients, based on the effect of the SPSS clamping/unclamping test on portal vein flow during the anhepatic phase. Intraoperatively, satisfactory portal flow was obtained in both groups. Primary nonfunction (PNF) and primary dysfunction (PDF) rates did not differ significantly between the 2 groups. Nonligation of SPSS was significantly associated with a higher rate of postoperative encephalopathy (P < 0.001) and major postoperative morbidity (P = 0.02). PVT occurred in 0 and 3 patients in the ligated and nonligated shunt group, respectively (P = 0.08). A composite end point, which included the relevant complications in the setting of SPSS in LT (ie, PNF and PDF, PVT, and encephalopathy) was present in 16 (44.4%) and 22 (73.3%) patients of the ligated and nonligated shunt group, respectively (P = 0.02). Patient (P = 0.05) and graft (P = 0.02) survival rates were better in the ligated shunt group. In conclusion, the present study supports routine ligation of large SPSS during LT whenever feasible. Liver Transplantation 24 505-515 2018 AASLD.

Transjugular intrahepatic portosystemic shunt as a bridge to non-hepatic surgery in cirrhotic patients with severe portal hypertension: a systematic review.

BACKGROUND: Portal hypertension (PHTN) increases the risk of non-hepatic surgery in cirrhotic patients. This first systematic review analyzes the place of transjugular intrahepatic portosystemic shunt (TIPS) in preparation for non-hepatic surgery in such patients. METHODS: Medline, EMBASE, and Scopus databases were searched from 1990 to 2017 to identify reports on outcomes of non-hepatic surgery in cirrhotic patients with PHTN prepared by TIPS. Feasibility of TIPS and the planned surgery, and the short- and long-term outcomes of the latter were assessed. RESULTS: Nineteen studies (64 patients) were selected. TIPS was indicated for past history of variceal bleeding and/or ascites in 22 (34%) and 33 (52%) patients, respectively. The planned surgery was gastrointestinal tract cancer in 38 (59%) patients, benign digestive or pelvic surgery in 21 (33%) patients and others in 4 (6%) patients. The TIPS procedure was successful in all, with a nil mortality rate. All patients could be operated within a median delay of 30 days from TIPS (mortality rate = 8%; overall morbidity rate = 59.4%). One year overall survival was 80%. CONCLUSIONS: TIPS allows non-hepatic surgery in cirrhotic patients deemed non operable due to PHTN. Further evidence in larger cohort of patients is essential for wider applicability.

Early small bowel perforation due to aflibercept.

In patients with malignancy who receive aflibercept based chemotherapy, gastrointestinal perforation is among the reported adverse events with a prevalence of 1.9%. This complication may lead to mortality up to 10.8%. We here report a case of small bowel perforation that occurred fifteen days after the first cycle of aflibercept in a 58-year old female who had metachronous colorectal liver metastases. Emergency laparotomy was performed and revealed a small bowel perforation without any anastomotic dehiscence. Surgery was followed by uneventful outcome. The use of aflibercept in patients with malignancy may be associated with very early gastrointestinal perforation and this should be known by oncologist and surgeons.

Fusion of Information from 3D Printing and Surgical Robot: An Innovative Minimally Technique Illustrated by the Resection of a Large Celiac Trunk Aneurysm.

The rapid advancement in technological innovations, such as 3D printing and robotic surgery, is a progression that few could imagine just a few years ago. The combination of these technologies namely 3D printing of patient-specific anatomy and robotic surgery is reported here to plan and perform the resection of a large aneurysm of the celiac trunk.

Modulating the physicochemical and structural properties of gold-functionalized protein nanotubes through thiol surface modification.

Biomolecules are advantageous scaffolds for the synthesis and ordering of metallic nanoparticles. Rotavirus VP6 nanotubes possess intrinsic affinity to metal ions, a property that has been exploited to synthesize gold nanoparticles over them. The resulting nanobiomaterials have unique properties useful for novel applications. However, the formed nanobiomaterials lack of colloidal stability and flocculate, limiting their functionality. Here we demonstrate that it is possible to synthesize thiol-protected gold nanoparticles over VP6 nanotubes, which resulted in soluble nanobiomaterials. With this strategy, it was possible to modulate the size, colloidal stability, and surface plasmon resonance of the synthesized nanoparticles by controlling the content of the thiolated ligands. Two types of water-soluble ligands were tested, a small linear ligand, sodium 3-mercapto-1-propanesulfonate (MPS), and a bulky ligand, 5-mercaptopentyl ß-D-glucopyranoside (GlcC5SH). The synthesized nanobiomaterials had a higher stability in suspension, as determined by Z-potential measurements. To the extent of our knowledge, this is the first time that a rational strategy is developed to modulate the particular properties of metal nanoparticles in situ synthesized over a protein bioscaffold through thiol coating, achieving a high spatial and structural organization of nanoparticles in a single integrative hybrid structure.

Characterization of conductive nanobiomaterials derived from viral assemblies by low-voltage STEM imaging and Raman scattering.

New technologies require the development of novel nanomaterials that need to be fully characterized to achieve their potential. High-resolution low-voltage scanning transmission electron microscopy (STEM) has proven to be a very powerful technique in nanotechnology, but its use for the characterization of nanobiomaterials has been limited. Rotavirus VP6 self-assembles into nanotubular assemblies that possess an intrinsic affinity for Au ions. This property was exploited to produce hybrid nanobiomaterials by the in situ functionalization of recombinant VP6 nanotubes with gold nanoparticles. In this work, Raman spectroscopy and advanced analytical electron microscopy imaging with spherical aberration-corrected (Cs) STEM and nanodiffraction at low-voltage doses were employed to characterize nanobiomaterials. STEM imaging revealed the precise structure and arrangement of the protein templates, as well as the nanostructure and atomic arrangement of gold nanoparticles with high spatial sub-Angstrom resolution and avoided radiation damage. The imaging was coupled with backscattered electron imaging, ultra-high resolution scanning electron microscopy and x-ray spectroscopy. The hybrid nanobiomaterials that were obtained showed unique properties as bioelectronic conductive devices and showed enhanced Raman scattering by their precise arrangement into superlattices, displaying the utility of viral assemblies as functional integrative self-assembled nanomaterials for novel applications.

Strategies for specifically directing metal functionalization of protein nanotubes: constructing protein coated silver nanowires.

Biological molecules that self-assemble in the nanoscale range are useful multifunctional materials. Rotavirus VP6 protein self-assembles into tubular structures in the absence of other rotavirus proteins. Here, we present strategies for selectively directing metal functionalization to the lumen of VP6 nanotubes. The specific in situ metal reduction in the inner surface of nanotube walls was achieved by the simple modification of a method previously reported to functionalize the nanotube outer surface. Silver nanorods and nanowires as long as 1.5 µm were formed inside the nanotubes by coalescence of nanoparticles. Such one-dimensional structures were longer than others previously obtained using bioscaffolds. The interactions between silver ions and the nanotube were simulated to understand the conditions that allowed nanowire formation. Molecular docking showed that a naturally occurring arrangement of aspartate residues enabled the stabilization of silver ions on the internal surface of the VP6 nanotubes. This is the first time that such a spatial arrangement has been proposed for the nucleation of silver nanoparticles, opening the possibility of using such an array to direct functionalization of other biomolecules. These results demonstrate the natural capabilities of VP6 nanotubes to function as a versatile biotemplate for nanomaterials.

Oxidative phosphorylation is impaired by prolonged hypoxia in breast and possibly in cervix carcinoma.

It has been assumed that oxidative phosphorylation (OxPhos) in solid tumors is severely reduced due to cytochrome c oxidase substrate restriction, although the measured extracellular oxygen concentration in hypoxic areas seems not limiting for this activity. To identify alternative hypoxia-induced OxPhos depressing mechanisms, an integral analysis of transcription, translation, enzyme activities and pathway fluxes was performed on glycolysis and OxPhos in HeLa and MCF-7 carcinomas. In both neoplasias exposed to hypoxia, an early transcriptional response was observed after 8h (two times increased glycolysis-related mRNA synthesis promoted by increased HIF-1alpha levels). However, major metabolic remodeling was observed only after 24h hypoxia: increased glycolytic protein content (1-5-times), enzyme activities (2-times) and fluxes (4-6-times). Interestingly, in MCF-7 cells, 24h hypoxia decreased OxPhos flux (4-6-fold), and 2-oxoglutarate dehydrogenase and glutaminase activities (3-fold), with no changes in respiratory complexes I and IV activities. In contrast, 24h hypoxia did not significantly affect HeLa OxPhos flux; neither mitochondria related mRNAs, protein contents or enzyme activities, although the enhanced glycolysis became the main ATP supplier. Thus, prolonged hypoxia (a) targeted some mitochondrial enzymes in MCF-7 but not in HeLa cells, and (b) induced a transition from mitochondrial towards a glycolytic-dependent energy metabolism in both MCF-7 and HeLa carcinomas.

Targeting of cancer energy metabolism.

The main purpose of this review is to update and analyze the effect of several antineoplastic drugs (adriamycin, apoptodilin, casiopeinas, cisplatin, clotrimazole, cyclophosphamide, ditercalinium, NSAIDs, tamoxifen, taxol, 6-mercaptopurine, and alpha-tocopheryl succinate) and energy metabolism inhibitors (2-DOG, gossypol, delocalized lipophilic cations, and uncouplers) on tumor development and progression. The possibility that these antineoplastic drugs currently used in in vitro cancer models, in chemo-therapy, or under study in phase I to III clinical trials induce tumor cellular death by altering also metabolite concentration (i.e., ATP), enzyme activities, and/or energy metabolism fluxes is assessed. It is proposed that the use of energy metabolic therapy, as an alternative or complementary strategy, might be a promising novel approach in the treatment of cancer.

Post-conditioning preserves glycolytic ATP during early reperfusion: a survival mechanism for the reperfused heart.

BACKGROUND: Glycolytic activity during the transition period from anaerobic to aerobic metabolism has been demonstrated to be critical for heart recovery in isolated reperfused hearts. The purpose of this work was to investigate the relevance of the glycolytic pathway in preserving the cardiac function of post-conditioned hearts. METHODS: The activation of the glycolytic pathway in post-conditioned hearts was evaluated by measuring GLUT-4 insertion, glucose consumption and lactate production. Iodoacetic acid and 2-deoxy-D-glucose were administrated to the working hearts to evaluate the effect of glycolytic inhibition in the post-conditioning protective effect. RESULTS: Post-conditioning maneuvers applied to isolated rat hearts, after prolonged ischemia and before reperfusion, promoted recovery of cardiac mechanical function with sustained increase of GLUT-4 translocation and activation of the glycolytic pathway during ischemia and early reperfusion. Iodoacetate inhibited the protective effect of post-conditioning, without affecting the mitochondrial oxidative capacity. Glycolysis contribution to maintain mechanical function at early reperfusion was observed in post-conditioned hearts perfused with 2-deoxy-D-glucose and in hearts in which iodoacetate was administered only during reperfusion. CONCLUSION: It is concluded that in the post-conditioned heart, a functional compartmentation of anaerobic energy metabolism, at early reperfusion, plays a significant role in cardiac protection against reperfusion damage.

Energy metabolism transition in multi-cellular human tumor spheroids.

It is thought that glycolysis is the predominant energy pathway in cancer, particularly in solid and poorly vascularized tumors where hypoxic regions develop. To evaluate whether glycolysis does effectively predominate for ATP supply and to identify the underlying biochemical mechanisms, the glycolytic and oxidative phosphorylation (OxPhos) fluxes, ATP/ADP ratio, phosphorylation potential, and expression and activity of relevant energy metabolism enzymes were determined in multi-cellular tumor spheroids, as a model of human solid tumors. In HeLa and Hek293 young-spheroids, the OxPhos flux and cytochrome c oxidase protein content and activity were similar to those observed in monolayer cultured cells, whereas the glycolytic flux increased two- to fourfold; the contribution of OxPhos to ATP supply was 60%. In contrast, in old-spheroids, OxPhos, ATP content, ATP/ADP ratio, and phosphorylation potential diminished 50-70%, as well as the activity (88%) and content (3 times) of cytochrome c oxidase. Glycolysis and hexokinase increased significantly (both, 4 times); consequently glycolysis was the predominant pathway for ATP supply (80%). These changes were associated with an increase (3.3 times) in the HIF-1alpha content. After chronic exposure, both oxidative and glycolytic inhibitors blocked spheroid growth, although the glycolytic inhibitors, 2-deoxyglucose and gossypol (IC(50) of 15-17 nM), were more potent than the mitochondrial inhibitors, casiopeina II-gly, laherradurin, and rhodamine 123 (IC(50) > 100 nM). These results suggest that glycolysis and OxPhos might be considered as metabolic targets to diminish cellular proliferation in poorly vascularized, hypoxic solid tumors.