Emerging Therapeutic Targets for Portal Hypertension.

PURPOSE OF REVIEW Portal hypertension is responsible of the main complications of cirrhosis, which carries a high mortality. Recent treatments have improved prognosis, but this is still far from ideal. This paper reviews new potential therapeutic targets unveiled by advances of key pathophysiologic processes. RECENT FINDINGS Recent research highlighted the importance of suppressing etiologic factors and a safe lifestyle and outlined new mechanisms modulating portal pressure. These include intrahepatic abnormalities linked to inflammation, fibrogenesis, vascular occlusion, parenchymal extinction, and angiogenesis; impaired regeneration; increased hepatic vascular tone due to sinusoidal endothelial dysfunction with insufficient NO availability; and paracrine liver cell crosstalk. Moreover, pathways such as the gut-liver axis modulate splanchnic vasodilatation and systemic inflammation, exacerbate liver fibrosis, and are being targeted by therapy. We have summarized studies of new agents addressing these targets. SUMMARY New agents, alone or in combination, allow acting in complementary mechanisms offering a more profound effect on portal hypertension while simultaneously limiting disease progression and favoring regression of fibrosis and of cirrhosis. Major changes in treatment paradigms are anticipated

Endoplasmic Reticulum and Mitochondria Contacts Correlate with the Presence and Severity of NASH in Humans.

The interaction between the mitochondria and the endoplasmic reticulum (ER) is essential for hepatocyte function. An increase in ER-mitochondria contacts (ERMCs) is associated with various metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and its progressive form non-alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. However, the role of ERMCs in the progression of NAFL to NASH is still unclear. We assessed whether ERMCs could correlate with NAFLD severity. We used a proximity ligation assay to measure the abundance of ERMCs in liver biopsies from patients with biopsy-proven NAFLD (n = 48) and correlated the results with histological and metabolic syndrome (MetS) features. NAFLD patients were included according to inclusion and exclusion criteria, and then assigned to NAFL (n = 9) and NASH (n = 39) groups. ERMCs density could discriminate NASH from NAFL (sensitivity 61.5%, specificity 100%). ERMCs abundance correlated with hepatocellular ballooning. Moreover, the density of ERMCs increased with an increase in the number of MetS features. In conclusion, ERMCs increased from NAFL to NASH, in parallel with the number of MetS features, supporting a role for this interaction in the pathophysiology of NASH

Mechanobiology of portal hypertension.

The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues and organs in a dynamic balance characterized by constant remodelling and adaptative processes. Environmental mechanical properties can be interpreted as a complex set of information and instructions that cells read continuously, and to which they respond. In cirrhosis, chronic inflammation and injury drive liver cells dysfunction, leading to excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion and parenchymal extinction. These pathological events result in marked remodelling of the liver microarchitecture, which is cause and result of abnormal environmental mechanical forces, triggering and sustaining the long-standing and progressive process of liver fibrosis. Multiple mechanical forces such as strain, shear stress, and hydrostatic pressure can converge at different stages of the disease until reaching a point of no return where the fibrosis is considered non-reversible. Thereafter, reciprocal communication between cells and their niches becomes the driving force for disease progression. Accumulating evidence supports the idea that, rather than being a passive consequence of fibrosis and portal hypertension (PH), mechanical force-mediated pathways could themselves represent strategic targets for novel therapeutic approaches. In this manuscript, we aim to provide a comprehensive review of the mechanobiology of PH, by furnishing an introduction on the most important mechanisms, integrating these concepts into a discussion on the pathogenesis of PH, and exploring potential therapeutic strategies

Fluorescence‐based bowel anastomosis perfusion evaluation: results from the IHU‐IRCAD‐EAES EURO‐FIGS registry

Background Anastomotic leakage (AL) is one of the dreaded complications following surgery in the digestive tract. Near-infrared fluorescence (NIRF) imaging is a means to intraoperatively visualize anastomotic perfusion, facilitating fluorescence image-guided surgery (FIGS) with the purpose to reduce the incidence of AL. The aim of this study was to analyze the current practices and results of NIRF imaging of the anastomosis in digestive tract surgery through the EURO-FIGS registry. Methods Analysis of data prospectively collected by the registry members provided patient and procedural data along with the ICG dose, timing, and consequences of NIRF imaging. Among the included upper-GI, colorectal, and bariatric surgeries, subgroup analysis was performed to identify risk factors associated with complications. Results A total of 1240 patients were included in the study. The included patients, 74.8% of whom were operated on for cancer, originated from 8 European countries and 30 hospitals. A total of 54 surgeons performed the procedures. In 83.8% of cases, a pre-anastomotic ICG dose was administered, and in 60.1% of cases, a post-anastomotic ICG dose was administered. A significant difference (p < 0.001) was found in the ICG dose given in the four pathology groups registered (range: 0.013–0.89 mg/kg) and a significant (p < 0.001) negative correlation was found between the ICG dose and BMI. In 27.3% of the procedures, the choice of the anastomotic level was guided by means of NIRF imaging which means that in these cases NIRF imaging changed the level of anastomosis which was first decided based on visual findings in conventional white light imaging. In 98.7% of the procedures, the use of ICG partly or strongly provided a sense of confidence about the anastomosis. A total of 133 complications occurred, without any statistical significance in the incidence of complications in the anastomoses, whether they were ICG-guided or not. Conclusion The EURO-FIGS registry provides an insight into the current clinical practice across Europe with respect to NIRF imaging of anastomotic perfusion during digestive tract surgery

Chandra Study of the Cepheus B Star Forming Region: Stellar Populations and the Initial Mass Function

Cepheus B (Cep B) molecular cloud and a portion of the nearby Cep OB3b OB association, one of the most active regions of star formation within 1 kpc, has been observed with the ACIS detector on board the Chandra X-ray Observatory. We detect 431 X-ray sources, of which 89% are confidently identified as clustered pre-main sequence stars. Two main results are obtained. First, we provide the best census to date for the stellar population of the region. We identify many members of two rich stellar clusters: the lightly obscured Cep OB3b association, and the deeply embedded cluster in Cep B whose existence was previously traced only by a handful of radio sources and T Tauri stars. Second, we find a discrepancy between the X-ray Luminosity Functions of the Cep OB3b and the Orion Nebula Cluster. This may be due to different Initial Mass Functions of two regions (excess of ~0.3 solar mass stars), or different age distributions. Several other results are obtained. A diffuse X-ray component seen in the field is attributed to the integrated emission of unresolved low mass PMS stars. The X-ray emission from HD 217086 (O7n), the principle ionizing source of the region, follows the standard model involving many small shocks in an unmagnetized radiatively accelerated wind. The X-ray source #294 joins a number of similar superflare PMS stars where long magnetic structures may connect the protoplanetary disk to the stellar surface.Comment: 72 pages, 31 figures, 8 tables. Accepted for publication in Ap

Prediction of In Vivo Laser-Induced Thermal Damage with Hyperspectral Imaging Using Deep Learning.

Thermal ablation is an acceptable alternative treatment for primary liver cancer, of which laser ablation (LA) is one of the least invasive approaches, especially for tumors in high-risk locations. Precise control of the LA effect is required to safely destroy the tumor. Although temperature imaging techniques provide an indirect measurement of the thermal damage, a degree of uncertainty remains about the treatment effect. Optical techniques are currently emerging as tools to directly assess tissue thermal damage. Among them, hyperspectral imaging (HSI) has shown promising results in image-guided surgery and in the thermal ablation field. The highly informative data provided by HSI, associated with deep learning, enable the implementation of non-invasive prediction models to be used intraoperatively. Here we show a novel paradigm "peak temperature prediction model" (PTPM), convolutional neural network (CNN)-based, trained with HSI and infrared imaging to predict LA-induced damage in the liver. The PTPM demonstrated an optimal agreement with tissue damage classification providing a consistent threshold (50.6 ± 1.5 °C) for the damage margins with high accuracy (~0.90). The high correlation with the histology score (r = 0.9085) and the comparison with the measured peak temperature confirmed that PTPM preserves temperature information accordingly with the histopathological assessment

Hyperspectral Imaging in Major Hepatectomies: Preliminary Results from the Ex-Machyna Trial.

Ischemia-reperfusion injury during major hepatic resections is associated with high rates of post-operative complications and liver failure. Real-time intra-operative detection of liver dysfunction could provide great insight into clinical outcomes. In the present study, we demonstrate the intra-operative application of a novel optical technology, hyperspectral imaging (HSI), to predict short-term post-operative outcomes after major hepatectomy. We considered fifteen consecutive patients undergoing major hepatic resection for malignant liver lesions from January 2020 to June 2021. HSI measures included tissue water index (TWI), organ hemoglobin index (OHI), tissue oxygenation (StO2%), and near infrared (NIR). Pre-operative, intra-operative, and post-operative serum and clinical outcomes were collected. NIR values were higher in unhealthy liver tissue (p = 0.003). StO2% negatively correlated with post-operative serum ALT values (r = -0.602), while ΔStO2% positively correlated with ALP (r = 0.594). TWI significantly correlated with post-operative reintervention and OHI with post-operative sepsis and liver failure. In conclusion, the HSI imaging system is accurate and precise in translating from pre-clinical to human studies in this first clinical trial. HSI indices are related to serum and outcome metrics. Further experimental and clinical studies are necessary to determine clinical value of this technology

Partial Hepatic Vein Occlusion and Venous Congestion in Liver Exploration Using a Hyperspectral Camera: A Proposal for Monitoring Intraoperative Liver Perfusion.

INTRODUCTION The changes occurring in the liver in cases of outflow deprivation have rarely been investigated, and no measurements of this phenomenon are available. This investigation explored outflow occlusion in a pig model using a hyperspectral camera. METHODS Six pigs were enrolled. The right hepatic vein was clamped for 30 min. The oxygen saturation (StO2%), deoxygenated hemoglobin level (de-Hb), near-infrared perfusion (NIR), and total hemoglobin index (THI) were investigated at different time points in four perfused lobes using a hyperspectral camera measuring light absorbance between 500 nm and 995 nm. Differences among lobes at different time points were estimated by mixed-effect linear regression. RESULTS StO2% decreased over time in the right lateral lobe (RLL, totally occluded) when compared to the left lateral (LLL, outflow preserved) and the right medial (RML, partially occluded) lobes (p < 0.05). De-Hb significantly increased after clamping in RLL when compared to RML and LLL (p < 0.05). RML was further analyzed considering the right portion (totally occluded) and the left portion of the lobe (with an autonomous draining vein). StO2% decreased and de-Hb increased more smoothly when compared to the totally occluded RLL (p < 0.05). CONCLUSIONS The variations of StO2% and deoxy-Hb could be considered good markers of venous liver congestion

A Novel Technique to Improve Anastomotic Perfusion Prior to Esophageal Surgery: Hybrid Ischemic Preconditioning of the Stomach. Preclinical Efficacy Proof in a Porcine Survival Model

Esophagectomy often presents anastomotic leaks (AL), due to tenuous perfusion of gastric conduit fundus (GCF). Hybrid (endovascular/surgical) ischemic gastric preconditioning (IGP), might improve GCF perfusion. Sixteen pigs undergoing IGP were randomized: (1) Max-IGP (n = 6): embolization of left gastric artery (LGA), right gastric artery (RGA), left gastroepiploic artery (LGEA), and laparoscopic division (LapD) of short gastric arteries (SGA); (2) Min-IGP (n = 5): LGA-embolization, SGA-LapD; (3) Sham (n = 5): angiography, laparoscopy. At day 21 gastric tubulation occurred and GCF perfusion was assessed as: (A) Serosal-tissue-oxygenation (StO2) by hyperspectral-imaging; (B) Serosal time-to-peak (TTP) by fluorescence-imaging; (C) Mucosal functional-capillary-density-area (FCD-A) index by confocal-laser-endomicroscopy. Local capillary lactates (LCL) were sampled. Neovascularization was assessed (histology/immunohistochemistry). Sham presented lower StO2 and FCD-A index (41 ± 10.6%; 0.03 ± 0.03 respectively) than min-IGP (66.2 ± 10.2%, p-value = 0.004; 0.22 ± 0.02, p-value < 0.0001 respectively) and max-IGP (63.8 ± 9.4%, p-value = 0.006; 0.2 ± 0.02, p-value < 0.0001 respectively). Sham had higher LCL (9.6 ± 4.8 mL/mol) than min-IGP (4 ± 3.1, p-value = 0.04) and max-IGP (3.4 ± 1.5, p-value = 0.02). For StO2, FCD-A, LCL, max- and min-IGP did not differ. Sham had higher TTP (24.4 ± 4.9 s) than max-IGP (10 ± 1.5 s, p-value = 0.0008) and min-IGP (14 ± 1.7 s, non-significant). Max- and min-IGP did not differ. Neovascularization was confirmed in both IGP groups. Hybrid IGP improves GCF perfusion, potentially reducing post-esophagectomy AL

X-ray emitting young stars in the Orion Nebula

The Orion Nebula Cluster and the molecular cloud in its vicinity have been observed with the ACIS-I detector on board the Chandra X-ray Observatory with 23 hours exposure. We detect 1075 X-ray sources: 91% are spatially associated with known stellar members of the cluster, and 7% are newly identified deeply embedded cloud members. This provides the largest X-ray study of a pre-main sequence stellar population. We examine here the X-ray properties of Orion young stars as a function of mass. Results include: (a) the discovery of rapid variability in the O9.5 31 M_o star \theta^2A Ori, and several early B stars, inconsistent with the standard model of X-ray production in small wind shocks; (b) support for the hypothesis that intermediate-mass mid-B through A type stars do not themselves produce significant X-ray emission; (c) confirmation that low-mass G- through M-type T Tauri stars exhibit powerful flaring but typically at luminosities considerably below the `saturation' level; (d) confirmation that the presence or absence of a circumstellar disk has no discernable effect on X-ray emission; (e) evidence that T Tauri plasma temperatures are often very high with T >= 100 MK, even when luminosities are modest and flaring is not evident; and (f) detection of the largest sample of pre-main sequence very low mass objects showing high flaring levels and a decline in magnetic activity as they evolve into L- and T-type brown dwarfs.Comment: 82 pages, 16 figures, 6 tables. To appear in the Astrophysical Journal. For a version with high quality images and electronic tables, see ftp://ftp.astro.psu.edu/pub/edf/orion1