The Impact of Radiofrequency Ablation on Survival Outcomes and Stent Patency in Patients with Unresectable Cholangiocarcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Endoluminal biliary radiofrequency ablation (RFA) has been proposed as a palliative treatment for patients with malignant biliary obstruction (MBO) in order to improve stent patency and survival. However, the existing data on patients with inoperable extrahepatic cholangiocarcinoma (eCCA) are conflicting. We performed a meta-analysis of randomized trials comparing RFA plus stenting versus stenting alone in patients with inoperable eCCA. We searched for trials published in the PubMed/MEDLINE, Scopus, and Cochrane databases up to November 2023. Data extraction was conducted from published studies, and a quality assessment was carried out in accordance with the guidelines recommended by the Cochrane Collaboration. Hazard ratios (HRs) with 95% CI were estimated from the trials. The primary endpoints of interest were overall survival and stent patency. Out of 275 results, 5 randomized trials and 370 patients were included. While overall survival was not different between the groups (HR 0.62; 95% CI 0.36-1.07; p = 0.09; I2 = 80%;), the subgroup analysis of studies employing plastic stents showed a trend toward better survival in the RFA-treated group (HR 0.42; 95% CI 0.22-0.80; p = 0.009; I2 = 72%). Stent patency was improved in patients receiving RFA (HR 0.64; 95% CI 0.45-0.90; p = 0.01; I2 = 23%). Adverse events were not different between the groups (OR 1.21; 95% CI 0.69-2.12; p = 0.50; I2 = 0%). Despite the promising results, high heterogeneity and potential biases in the included studies suggest the need for further high-quality randomized trials to explore the potential cumulative effects of RFA on CCA treatment outcomes.

Risk Stratification in Primary Biliary Cholangitis.

Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease with a heterogeneous presentation, symptomatology, disease progression, and response to therapy. The current risk stratification assessment, aimed at identifying patients with a higher risk of disease progression, encompasses an in-depth analysis of demographic data, clinical and laboratory findings, antibody profiles, and the evaluation of liver fibrosis using both invasive and noninvasive techniques. Treatment response scores after one year of therapy remain to date a major factor influencing the prognosis of PBC patients. While the initial therapeutic approach with ursodeoxycholic acid (UDCA) is universally applied, new second-line treatment options have recently emerged, with many others under investigation. Consequently, the prevailing one-size-fits-all approach is poised to be supplanted by tailored strategies, ensuring high-risk patients receive the most appropriate treatment regimen from diagnosis. This will require the development of a risk prediction model to assess, at the time of diagnosis, the course, outcome, and response to first and additional treatments of PBC patients. This manuscript provides a comprehensive overview of the current and emerging tools used for risk stratification in PBC and speculates on how these developments might shape the disease landscape in the near future.

The Role of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in Treating Portal Hypertension in Patients with Hepatocellular Carcinoma.

Liver cancer is very frequent, and hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases. Its growing incidence has been greatly affected by the increasing prevalence of metabolic-associated fatty liver disease (MAFLD). The latter is a new epidemic in our era. In fact, HCC is often generated from noncirrhotic liver and its treatment benefits from surgical and nonsurgical approaches, potentially bridged by transjugular intrahepatic portosystemic shunt (TIPS) use. TIPS use is an effective treatment for portal hypertension complications, but its application in patients with HCC and clinically significant portal hypertension (CSPH) remains controversial due to concerns about tumor rupture, dissemination, and increased toxicity. The technical feasibility and safety of TIPS use in HCC patients have been evaluated in several studies. Despite concerns about intraprocedural complications, retrospective studies have shown high success rates and low complication rates in TIPS placement for HCC patients. TIPS use in combination with locoregional treatments, such as transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), has been explored as a treatment option for HCC patients with portal hypertension. These studies have shown improved survival rates in patients undergoing TIPS in combination with locoregional treatments. However, the efficacy and toxicity of TACE in combination with TIPS use require careful evaluation, as changes in venous and arterial flow can affect treatment outcomes and complications. The results from studies evaluating the impact of TIPS on systemic therapy and surgical options are also promising. In conclusion, the TIPS is a sufficiently safe, useful item available for physicians treating complications of portal hypertension. Moreover, a TIPS can be used in combination with locoregional therapy in HCC patients. Systemic chemotherapy can also benefit of the use of TIPS placement. A complex interplay affects TIPS use with surgery. The latter needs further data. The TIPS is a useful and safe add-on treatment, changing the natural course of HCC progression. Its use is regulated by a sophisticated physiologic and pathophysiologic flow of evidence.

Cancer-Associated Fibroblasts in Cholangiocarcinoma: Current Knowledge and Possible Implications for Therapy.

Cholangiocarcinoma (CCA) is an aggressive neoplasia with an increasing incidence and mortality. It is characterized by a strong desmoplastic stroma surrounding cancer cells. Cancer-associated fibroblasts (CAFs) are the main cell type of CCA stroma and they have an important role in modulating cancer microenvironments. CAFs originate from multiple lines of cells and mainly consist of fibroblasts and alpha-smooth muscle actin (α-SMA) positive myofibroblast-like cells. The continuous cross-talking between CCA cells and desmoplastic stroma is permitted by CAF biochemical signals, which modulate a number of pathways. Stromal cell-derived factor-1 expression increases CAF recruitment to the tumor reactive stroma and influences apoptotic pathways. The Bcl-2 family protein enhances susceptibility to CAF apoptosis and PDGFRß induces fibroblast migration and stimulates tumor lymphangiogenesis. Many factors related to CAFs may influence CCA prognosis. For instance, a better prognosis is associated with IL-33 expression and low stromal IL-6 (whose secretion is stimulated by microRNA). In contrast, a worst prognosis is given by the expression of PDGF-D, podoplanin, SDF-1, α-SMA high expression, and periostin. The maturity phenotype has a prognostic relevance too. New therapeutic strategies involving CAFs are currently under study. Promising results are obtained with anti-PlGF therapy, nintedanib (BIBF1120), navitoclax, IPI-926, resveratrol, and controlled hyperthermia.

Gastrointestinal disorders as immune-related adverse events.

Immune checkpoint inhibitors, such as cytotoxic T-lymphocyte antigen 4 inhibitors, programmed cell death 1 inhibitors and programmed cell death-ligand 1 inhibitors, have recently emerged as novel drugs in the anti-cancer therapy. Their use in different types of advanced cancer has shown good results and an increase in survival rates. However, immune-related adverse events (irAEs) are frequent and often require special care. IrAEs may affect all the organs, but they are most commonly seen in skin, lungs, endocrine glands and in the gastrointestinal tract where small bowel, colon, the liver and/or the pancreas can be involved. Despite being usually mild and self-resolving, irAEs may present in severe and life-threatening forms, causing the withdrawal of anti-cancer therapy. IrAEs, therefore, represent a challenging condition to manage that often requires the cooperation between the oncologists and the gastroenterologists in order to identify and treat them adequately.

Temporal and spatial variations of polycyclic aromatic hydrocarbon concentrations around a coke oven plant.

UNLABELLED: From 1995 to 2004, in Genoa, Italy, daily concentrations of twelve polycyclic aromatic hydrocarbons (PAHs) were measured in particulate phase (PM10), around a coke oven plant in operation from the 1950s and closed in 2002. The study permitted to identify the coke oven as the main PAH source in Genoa, causing constant exceeding of benzo(a)pyrene (BaP) air quality target (1.0 ng/m3) in the urban area till 1,900 meters distance downwind the plant. For this reason the plant was closed. Distance and daily hours downwind the coke plant were the main sources of variability of toxic BaP equivalent (BaPeq) concentrations and equations that best fitted these variables were experimentally obtained. During full plant activity, annual average BaPeq concentrations, measured in the three sampling sites aligned downwind to the summer prevalent winds, were: 85 ng/m3 at 40 m (site 2, industrial area), 13.2 ng/m3 at 300 m (site 3, residential area) and 5.6 ng/m3 at 575 m (site 4, residential area). Soon after the coke oven's closure (February 2002) BaPeq concentrations (annual average) measured in residential area, decreased drastically: 0.2 ng/m3 at site 3, 0.4 ng/m3 at site 4. Comparing 1998 and 2003 data, BaPeq concentrations decreased 97.6% in site 3 and 92.8% in site 4. Samples collected at site 3, during the longest downwind conditions, provided a reliable PAH profile of fugitive coke oven emissions. This profile was significantly different from the PAH profile, contemporary found at site 5, near the traffic flow. This study demonstrates that risk assessment based only on distance of residences from a coke plant can be heavily inaccurate and confirmed that seasonal variability of BaPeq concentrations and high variability of fugitive emissions of PAHs during coke oven activities require at least one year of frequent and constant monitoring (10-15 samples each month). IMPLICATIONS: Around a coking plant, polycyclic aromatic hydrocarbons (PAHs), concentrations depend mainly on downwind hours and distance. Equations that best fit these variables were experimentally calculated. Fugitive emissions of an old coke oven did not comply with the threshold BAP air concentration proposed by the World Health Organization (WHO), up to 1,900 m distance. The study identified the PAH profile of fugitive emissions of a coke oven, statistically different from the profile of traffic emissions. During its activity, in the Genoa residential area, 575 m away from the plant, 92.8% of found PAHs was due to coke oven emission only.

Effect of supplementation with vitamin D3 on glucose production pathways in human subjects.

SCOPE: Research reports suggest that vitamin D affects glucose and insulin metabolism; however, the exact mechanisms are unclear. ²H NMR analysis of monoacetone glucose (MAG) after tracer administration provides a non-invasive method of profiling hepatic glucose metabolism. This study examined the effects of supplementation with vitamin D3 on contribution of glycogenolysis to glucose production. METHODS AND RESULTS: Tracer administration and biofluid collections were performed with eight healthy females before and following a 4-wk vitamin D3 administration period. Following an overnight fast subjects ingested deuterated water and acetaminophen. Full void urine samples were collected after 4 h. ²H NMR spectra of urinary monoacetone glucose were acquired to determine the contribution of glycogenolysis to glucose production. The mean contribution of glycogenolysis to glucose production was 60±13%. Supplementation with vitamin D3 had no effect on hepatic glucose production. Regression analysis revealed a significant relationship between carbohydrate intake and the contribution of glycogenolysis (ß=0.914, p=0.004). CONCLUSION: In conclusion, we saw no changes in the percentage contribution of glycogenolysis following supplementation with vitamin D3. The reproducibility of our results and the non-invasive nature of the method highlight the potential for this method in assessing mechanistic modes of action in future nutritional interventions.

A stereoselective synthesis of alpha-deuterium-labelled (S)-alpha-amino acids.

An atom-efficient and stereoselective synthesis has been developed for the preparation of alpha-2H-labelled (S)-alpha-amino acids, starting from a novel chiral diketopiperazine scaffold. Efficient mono-alkylation of the chiral template afforded the (S)-substituted adducts with the nature of the electrophile significantly effecting the stereochemical outcome. Subsequent alkylation was totally selective producing the 1,4-cis adduct as the sole diastereoisomer. The deprotection was carried out using cerium ammonium nitrate followed by acid hydrolysis affording the enantipure alpha-amino acids.

Chiral piperazine-2,5-dione derivatives as effective alpha-glucosidase inhibitors. Part 4.

The potential to inhibit alpha- and beta-glucosidases of a series of chiral piperazine-2,5-dione derivatives was investigated. Three of the seven compounds tested, viz., 1, 5b, and 5c, showed to be non competitive inhibitors of alpha-glucosidase, whereas they exhibited very low inhibitory activity towards beta-glucosidase. The most active compound, 5c (K(I) of alpha-glucosidase=5 microm), had a 100-fold alpha-glucosidase/beta-glucosidase inhibitor selectivity.

(S)-alpha-methyl,alpha-amino acids: a new stereocontrolled synthesis.

A new and convenient stereocontrolled synthesis of the optically pure (S)-alpha-methyl,alpha-amino acids 6(a-d) that exploits the chiral synthon 1,4-N,N-[(S)-1-phenylethyl]-piperazine-2,5-dione (1) is described. The (S)-1-phenylethyl group, bonded to each of the N-atoms of the 2,5-diketopiperazine, acts as a chiral inductor in the first alkylation, while the steric hindrance appears to be the determining factor of stereocontrol in third and forth alkylation.

Personal daily exposures to benzo(a)pyrene of taxi drivers in Genoa, Italy.

Twenty-four hour personal exposures (both occupational and environmental) to benzo(a)pyrene (BaP) of 15 taxi drivers working in Genoa, Italy, were monitored in May-July 1998 (15 samplings), February 1999 (7 samplings) and June 1999 (7 samplings). The mean BaP exposures measured at these different times were 1.4 ng/m3, 1.23 ng/m3 and 1.22 ng/m3, respectively, values were significantly greater than the levels found in controls (0.16+/-0.2 ng/m3). Mean daily personal BaP exposures of taxi drivers were not statistically different from the mean daily airborne BaP concentrations measured by fixed samplers during the same sampling periods.