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Introduction: Polycythaemia vera patients can present with arterial or venous vascular occlusive events such as thrombosis or cardiovascular disease; disease-related symptoms may significantly impact on the quality of life. The aim of this study was to evaluate the efficacy and safety of erythrocytapheresis compared to phlebotomy in the treatment of polycythaemia patients. Methods: This study reports the findings of a retrospective analysis of 40 polycythaemia vera patients diagnosed according to published guidelines and treated either with erythrocytapheresis or phlebotomy over a four-year period. The goal of treatment was to reduce blood volume and red blood cell count to near normal levels as both of which may attenuate the symptoms and complications associated with polycythaemia. Patients were treated by applying a mathematical model. Results: Using the model, 28 erythrocytapheresis procedures were performed. Blood laboratory values (red blood cell count, haemoglobin count and haematocrit level) were significantly reduced in patients treated with erythrocytapheresis. Moreover, among treated patients, erythrocytapheresis resulted in less work absenteeism and reduced costs due to lost production, with a lower overall procedure cost in comparison to phlebotomy. Conclusion: This model can assist in selecting the proper treatment modality for individual patients. Especially for those with high blood volumes and high achievable haematocrit levels (delta), erythrocytapheresis offers a more efficient method in red blood cell depletion compared to phlebotomy thereby, potentially reducing the number of treatment procedures required for the induction of polycythaemia vera patients as well as the interval between procedures during the maintenance phase.

The CoCrFeNiMnX (X = 5, 20, and 35 at.%) alloys, reinforced with 5 at.% SiC powder, were prepared by mechanical alloying and spark plasma sintering. This preparation method resulted in microstructural refinement of the FCC solid solution grains, while the SiC addition reacted with residual oxygen to form homogeneously distributed ultrafine SiO2 particles. Additionally, the alloys contained Cr7C3 carbides, which were significantly larger than the SiO2 particles and enriched with the alloy's elements, including Mn. Among the tested materials, the reinforced CoCrFeNiMn20 alloy exhibited the highest hardness and compressive yield strength (CYS), achieving 392 ± 9 HV30 or 476 ± 3 HVIT1 and 1024 ± 18 MPa, respectively. This alloy also maintained superior CYS (956 ± 35 MPa) even after 100 h of annealing at 800 °C. The reduction in CYS after annealing was smallest for the CoCrFeNiMn5 alloy (35 MPa) and increased with higher Mn content, highlighting Mn's significant role in diffusion-related processes. At elevated temperatures (600 and 800 °C), the CoCrFeNiMn5 alloy had the highest CYS of 190 ± 33 MPa, while the CoCrFeNiMn35 alloy had the lowest at 80 ± 6 MPa. This trend was also observed in wear rate tests, where the CoCrFeNiMn5 alloy had the lowest specific wear rate coefficient of 3.54 ± 0.09 × 10-4 mm³ N⁻1 m⁻1. This was due to matrix softening and oxide lubrication without significant spalling. Thus, the CoCrFeNiMn5 alloy demonstrated superior mechanical properties and wear resistance under various conditions, making it a promising candidate for applications requiring high strength and durability.

Abstract Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1–3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1–3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0–2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1–2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.

Nearly equiatomic AlCoCrFeNi alloy samples were prepared by induction melting and mechanical alloying (MA) combined with spark plasma sintering (SPS). The cast sample showed a dendritic microstructure composed of spinodally decomposed nanometric constituents of the B2 and BCC phases. The spark plasma sintered sample exhibited an ultrafine-grained microstructure of B2 phase and FCC solid solution and Cr23C6 carbides. The MA + SPS sample was strengthened by compressive stress-strain test up to a yield strength of 2029 ± 5 MPa, resulting significantly higher compared to 1366 ± 32 MPa of the cast sample. In addition to the higher compressive yield strength, the sintered sample exhibited a hardness of more than 130 HV higher compared to the cast alloy. On the other hand, the cast alloy showed high plastic deformation (29%) and significantly high ultimate compressive strength of 3072 ± 122 MPa. Together with these mechanical characteristics, the MA + SPS sample showed good thermal stability while preserving the mechanical properties even after annealing at 800 °C. This was not the case with the cast sample, in which ductility and ultimate strength significantly decreased upon annealing at 800 °C. A substantial yield strength reduction of both MA + SPS and cast samples was recorded when tested at 800 °C. Nevertheless, stress-strain curve trends were observed to be quite different between the two samples, thus suggesting dissimilar deformation mechanisms under high-temperature compression.

Abstract The creep response of the 17-4PH martensitic age-hardening steel in H1150 state was investigated at 427 and 482 °C. Hardness measurements of the heads of the creep samples demonstrated that the material underwent additional age hardening during the high-temperature exposure. Microstructural investigations confirmed that the additional precipitation of carbides and the G-phase occurred at the lowest temperature. A set of constitutive equations previously developed to describe the creep response of particle-strengthened alloys was successfully used to obtain a comprehensive description of the experimental data. The value of the particle strengthening term was obtained from the hardness measurements and corresponded to the Orowan stress. The model accurately described the observed minimum creep rate dependence on the applied stress and explained the occurrence of lower values of the minimum strain rate observed during variable-load experiments.

Abstract The NA48/2 experiment at CERN reports the first observation of the K ± → π 0 π 0 μ ± ν decay based on a sample of 2437 candidates with 15% background contamination collected in 2003–2004. The decay branching ratio in the kinematic region of the squared dilepton mass above 0.03 GeV2/c 4 is measured to be (0.65 ± 0.03) × 10 −6. The extrapolation to the full kinematic space, using a specific model, is found to be (3.45 ± 0.16) × 10 −6, in agreement with chiral perturbation theory predictions.

Background. Lipid–polymer hybrid nanoparticles (LPHNPs) offer a promising method for delivering methylprednisolone (MePD) to treat lung inflammation, addressing aggregation issues seen with polymer-only formulations. Objectives. This study aimed to develop LPHNPs for MePD delivery, assessing their physicochemical properties, drug loading, cytocompatibility, and release profiles, ultimately enabling inhalable microparticle-based powder. Methods. The nanoparticles were formulated using α,β-poly(N-2-hydroxyethyl)-DL-aspartamide-g-Rhodamine B-g-poly(lactic acid) (PHEA-g-RhB-g-PLA) and phospholipids DPPC, DOTAP, and DSPE-PEG2000 in a 45:30:25 weight ratio. Their size, redispersion after freeze-drying, drug loading (DL%), and controlled release were evaluated. Cytocompatibility was assessed on 16-HBE cell lines, measuring anti-inflammatory effects via IL-6 and IL-8 levels. Spray drying was optimized to produce microparticles using mannitol (MAN), leucine (LEU), and N-acetylcysteine (NAC). Results. The nanoparticles had a size of 186 nm and a DL% of 2.9% for MePD. They showed good cytocompatibility, significantly reducing IL-6 and IL-8 levels. Spray drying yielded microparticles with a fine particle fraction (FPF) of 62.3% and a mass median aerodynamic diameter (MMAD) of 3.9 µm. Inclusion of LPHNPs@MePD (0.25% w/v) resulted in FPF and MMAD values of 56.7% and 4.4 µm. In conclusion, this study described the production of novel inhalable powders as carriers for MePD-loaded nanostructures with favorable physicochemical properties, cytocompatibility, and promising aerosol performance, indicating their potential as an effective inhalable therapy for lung inflammation with corticosteroids, especially for treating chronic diseases.

Introduction The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post-hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab is equally effective in viral and non-viral patients. Methods We retrospectively analyzed 885 HCC patients treated with first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% non-viral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multi-variate models to explore potential differences on overall survival (OS), time to progression (TTP), disease control rates based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to second-line treatments and outcomes were also reported and compared between etiologies. Results Overall, no statistically significant differences were found in OS (mOS: viral 15.9 months; non-viral 16.3 months), TTP (mTTP: viral 8.3 months; non-viral 7.2 months), and disease control rates (DCR: viral 78.1%; non-viral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and non-viral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e. NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post-hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and non-viral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.

Giulia Francesca Manfredi,1,2 Ciro Celsa,1,3,4 Chloe John,1 Charlotte Jones,1 Nicole Acuti,1 Bernhard Scheiner,5 Claudia Angela Maria Fulgenzi,1,6 James Korolewicz,1 Matthias Pinter,5 Alessandra Gennari,7 Francesco A Mauri,1 Mario Pirisi,2,8 Rosalba Minisini,2 Federica Vincenzi,2 Michela Burlone,8 Cristina Rigamonti,2,8 Matteo Donadon,9,10 Giuseppe Cabibbo,3 Antonio D’Alessio,1,7 David James Pinato1,7 1Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK; 2Department of Translational Medicine, Università Del Piemonte Orientale, Novara, Italy; 3Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy; 4Department of Surgical, Oncological and Oral Sciences (Di.chir.on.s.), University of Palermo, Palermo, Italy; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 6Department of Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy; 7Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; 8Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy; 9Department of Health Science, Università Del Piemonte Orientale, Novara, Italy; 10Department of Surgery, University Maggiore Hospital della Carità, Novara, ItalyCorrespondence: David James Pinato, Clinical Senior Lecturer and Consultant in Medical Oncology, Imperial College London Hammersmith Campus, Du Cane Road, London, W12 0HS, UK, Tel +44 020 83833720, Email david.pinato@imperial.ac.ukAbstract: Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance.Keywords: immune checkpoint inhibitors, liver cancer, recurrence, tumor microenvironment

Abstract Background The autonomic nervous system is linked to hyperdynamic circulation in cirrhosis and several studies have highlighted the crucial role that systemic inflammation elicits in altering sympathovagal equilibrium with the consequent reduction in heart rate variability (HRV). To investigate the correlation between time‐domain HRV parameters, serum cytokines concentrations and portal hypertension, we studied a cohort of patients with cirrhosis, accounting for etiology and treatments. Methods In this cross‐sectional, observational cohort study, 107 outpatients with non‐alcoholic cirrhosis were assessed consecutively by abdominal ultrasound and by upper gastrointestinal endoscopy to search for esophagogastric varices. 24‐h electrocardiogram Holter monitoring with time‐domain HRV measurement (square root of the mean of successive differences of Normal‐to‐Normal [NN] [RMSSD], standard deviation or the square root of variance [SDNN] and standard deviation of the means of the NN intervals calculated over a 5‐min period [SDANN]) was performed and serum concentrations of osteopontin (OPN), interleukin (IL)‐22, IL‐6, IL‐1Ra and IL‐17 were obtained in all patients. Results IL‐6, OPN, IL‐22 and IL‐1Ra concentrations in cirrhotic patients were associated with disease severity expressed by Child‐Pugh and MELD score, to some portal hypertension's indirect signs and some of its complications. A significant increase in systemic concentrations of OPN in patients with hepatocellular carcinoma was encountered. SDANN and SDNN values were indirectly related to serum levels of IL‐6, OPN, IL‐1Ra and IL‐22. Conclusions This study underlines the interaction between the alteration of the ANS and the activation of inflammatory pathways that characterize cirrhosis taking into account clinical characteristics and treatments.

Porous materials are playing an increasingly relevant role in several fields and industrial sectors with structural and functional applications. Their properties critically depend on the relative density and pore morphology thus it is of great importance monitoring the variations of such structural features. Among the experimental techniques commonly used for investigating the microstructure evolution of porous materials, Mechanical Spectroscopy (MS) provides damping and dynamic modulus of the material during heat treatments. In this work three cases of possible pore structure evolution in different metallic alloys have been examined by MS: (i) growth and coalescence of pores, (ii) closure of pores of nanometric size and (iii) no change of porosity. The results show how dynamic modulus measurements can be successfully employed for a direct monitoring of porosity variations during heating. The technique is quite sensitive and allows to identify the temperature range where pore evolution takes place providing information useful to orientate heat treatments of porous materials.

Background & Aims: Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006–2020) in Italy. Methods: Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006–2010; 2011–2015; 2016–2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Results: Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia,

Background. Lipid–polymer hybrid nanoparticles (LPHNPs) offer a promising method for delivering methylprednisolone (MePD) to treat lung inflammation, addressing aggregation issues seen with polymer-only formulations. Objectives. This study aimed to develop LPHNPs for MePD delivery, assessing their physicochemical properties, drug loading, cytocompatibility, and release profiles, ultimately enabling inhalable microparticle-based powder. Methods. The nanoparticles were formulated using α,β-poly(N-2-hydroxyethyl)-DL-aspartamide-g-Rhodamine B-g-poly(lactic acid) (PHEA-g-RhB-g-PLA) and phospholipids DPPC, DOTAP, and DSPE-PEG2000 in a 45:30:25 weight ratio. Their size, redispersion after freeze-drying, drug loading (DL%), and controlled release were evaluated. Cytocompatibility was assessed on 16-HBE cell lines, measuring anti-inflammatory effects via IL-6 and IL-8 levels. Spray drying was optimized to produce microparticles using mannitol (MAN), leucine (LEU), and N-acetylcysteine (NAC). Results. The nanoparticles had a size of 186 nm and a DL% of 2.9% for MePD. They showed good cytocompatibility, significantly reducing IL-6 and IL-8 levels. Spray drying yielded microparticles with a fine particle fraction (FPF) of 62.3% and a mass median aerodynamic diameter (MMAD) of 3.9 µm. Inclusion of LPHNPs@MePD (0.25% w/v) resulted in FPF and MMAD values of 56.7% and 4.4 µm. In conclusion, this study described the production of novel inhalable powders as carriers for MePD-loaded nanostructures with favorable physicochemical properties, cytocompatibility, and promising aerosol performance, indicating their potential as an effective inhalable therapy for lung inflammation with corticosteroids, especially for treating chronic diseases. [ABSTRACT FROM AUTHOR]

Vinorelbine (VRL), a semi-synthetic vinca alkaloid commonly used in humans with advanced lung cancer, reaches high concentrations in the lung tissue, has proven antineoplastic activity and a low toxicity profile in dogs. Treatment-naïve, client-owned dogs with a cyto/histological diagnosis of advanced pulmonary carcinoma, selected from a laboratory database and previously subjected to imaging, were enrolled in the study. Vinorelbine (15 mg/m2) was administered weekly for 4 weeks and then fortnightly until progressive disease was documented. Staging work-up was repeated by means of diagnostic imaging after the fourth VRL (i.e., 28 days) and monthly thereafter; response to treatment was evaluated according to the RECIST. Toxicity was graded following the VCOGC group. Ten dogs met the inclusion criteria. Partial response was documented in eight dogs. Median time to progression was 88 days (range: 7–112) and median survival time for all dogs was 100 days (range 7–635). The most common side effect was neutropenia. The main limitations of the study were the absence of histological diagnosis in eight cases and the limited number of treated dogs. VRL is well tolerated with an adequate toxicity profile and may be useful in the management of advanced lung tumours if used as a first-line treatment strategy.

A recent revision of the stratigraphic sequence and the finds from the excavations by Anton Mario Radmilli in 1952 and 1954 in the Grotta dei Baffoni Cave near Genga, included also a particular object consisting of a ceramic block with a sub-trapezoidal concave gouge readily identified by Radmilli as a clay mould used for metal melting, which, in fact, contained metallic droplets attached to its surface. It represents an unicum for both its typology and the results of our preliminary archeometric analyses, which sheds some light on the early copper metallurgy in Italy. The terracotta mould was found during the excavation campaign of 1954, in which Radmilli enlarged Trench B already excavated in 1952, in a not-better specified lower anthropic level, from 2.30 to 2.80 m depth (cultural level E), which, according to Radmilli’s stratigraphy, includes horizontal cuts n. XV, XVI, and XVII. Osteological finds from this level were recently radiocarbon-AMS dated to 3,640-3,430 yr cal BCE. Here we present the results we obtained from the analysis of replicas of the clay mould, which allowed us to identify the function of it as a cast for manufacturing small metal ingots. Geochemical SEM-EDS analyses on one metallic droplet detached from the surface of the mould, yielded a maximum composition of 92 wt.% copper (Cu), and 8-12 wt.% zinc (Zn), along with traces of silver (Ag). Thus, the metal appears to be a compound of copper and zinc but not an intentional alloy of the two metals, which can be obtained by smelting sulfide minerals (i.e., Fahlerz) such as tetraedrite-(Zn) or tennantite-(Zn). We interpret this Cu-Zn compound as the result of the work by a metallurgist who utilized the Grotta dei Baffoni Cave as his workshop during a period between the latest Cupper Age (Eneolithic), and the earliest Bronze Age. The interpretation of the results from our metallurgic analyses in the light of what it is known about the early copper metallurgy in Italy, are consistent with this chronological assessment. The experimentation also concerned the bronze dagger to verify a possible relationship with the clay mould, although coming from very different depth.

Introduction:. Autonomic nervous system activity in cirrhotic portal hypertension is linked to hyperdynamic circulation. Heart rate variability (HRV) is a validated noninvasive method to assess the sympathovagal balance. To investigate the correlation between HRV parameters and degree of portal hypertension, we studied a cohort of patients with cirrhosis accounting for etiology and treatments. Patients and Methods:. In this cross-sectional, observational cohort study, 157 outpatients of both sex with nonalcoholic cirrhosis were assessed by upper gastrointestinal endoscopy to search for esophagogastric varices. Twenty-four-hour electrocardiogram Holter monitoring with 3 HRV parameters measurement [SD of the NN intervals, root mean square successive difference of NN intervals, and SD of the averages of NN intervals (SDANN)] according to time-domain analysis were performed in all patients. Sixteen patients with large esophagogastric varices underwent measurements of the HVPG and assessment of HRV parameters at baseline and after 45 days on carvedilol. Results:. The liver dysfunction, expressed by Child-Pugh class or MELD score, was directly related to root mean square successive difference of NN intervals and inversely related to SDANN. Presence of ascites was inversely related to SDANN and to SD of the NN intervals. Treatment with carvedilol had an inverse relation with SDANN. Presence and size of esophagogastric varices had an inverse relation to SDANN and SD of the NN intervals. Upon multivariate analysis the associations between SDANN and Child-Pugh class, size of varices and ascites were confirmed. In the subgroup of 16 patients undergoing HVPG measurement, pressure gradient was unrelated to heart rate and HRV parameters. Conclusions:. Time-domain HRV parameters in patients with cirrhosis, confirm the autonomic nervous system alteration, and their correlation to the degree of portal hypertension suggesting a role of the ANS in hepatic decompensation.

Valentina Burgio,1 Massimo Iavarone,2 Giovanni Giuseppe Di Costanzo,3 Fabio Marra,4 Sara Lonardi,5,6 Emiliano Tamburini,7 Fabio Piscaglia,8 Gianluca Masi,9,10 Ciro Celsa,11 Francesco Giuseppe Foschi,12 Marianna Silletta,13 Daniela Caterina Amoruso,14 Margherita Rimini,15 Mariangela Bruccoleri,2 Raffaella Tortora,3 Claudia Campani,4 Caterina Soldà,6 Massimo Giuseppe Viola,16 Antonella Forgione,8 Fabio Conti,12 Francesca Salani,9,10 Silvia Catanese,9,10 Carmelo Marco Giacchetto,17 Claudia Fulgenzi,13 Carmine Coppola,14 Pietro Lampertico,18 Antonio Pellino,6,19 Gabriele Rancatore,17 Giuseppe Cabibbo,17 Francesca Ratti,20 Federica Pedica,21 Angelo Della Corte,22 Massimo Colombo,18 Francesco De Cobelli,23 Luca Aldrighetti,20 Stefano Cascinu,1,23 Andrea Casadei-Gardini1,23 1Department of Medical Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 2Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; 3Department of Hepatology, Naples, 80131, Italy; 4Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy; 5Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; 6Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; 7Department of Oncology and Palliative Care, Cardinale Hospital, Naples, Italy; 8Division of Internal Medicine, Hepatobiliary and Immunoallergic Disease, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 9Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 10Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 11Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), University of Palermo, Palermo, 90127, Italy; 12Internal Medicine, Infermi Hospital, Faenza (AUSL ROMAGNA), Ravenna, Italy; 13Department of Oncology, Campus Bio Medico, Roma, Italy; 14Hepatology Unit, Internal Medicine, Area Stabiese Hospital, Naples, Italy; 15Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, 4121, Italy; 16Department of General Surgery and Emergency Surgery, Cardinale Hospital, Tricase, Italy; 17Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, 90127, Italy; 18Liver Center, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 19Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; 20Hepatobiliary Surgery Division, Liver Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 21Department of Experimental Oncology, Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 22Department of Radiology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 23School of Medicine, Vita-Salute San Raffaele University, Milan, 20132, ItalyCorrespondence: Andrea Casadei-GardiniDepartment of Medical Oncology, IRCCS San Raffaele Hospital, Via Olgettina n. 60, Milan, ItalyEmail casadeigardini@gmail.comBackground: Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the propensity score matching in a cohort of Italian patients with unresectable HCC who were treated with either sorafenib or lenvatinib.Aims and Methods: To evaluate the effectiveness of sorafenib and lenvatinib as primary treatment of advanced HCC in clinical practice we performed a multicentric analysis of the treatment outcomes of 288 such patients recruited in 11 centers in Italy. A propensity score was used to mitigate confounding due to referral biases in the assessment of mortality and progression-free survival.Results: Over a follow-up period of 11 months the Cox regression model showed 48% reduction of death risk for patients treated with lenvatinib (95% CI: 0.34– 0.81; p = 0.0034), compared with those treated with sorafenib. The median PFS was 9.0 and 4.9 months for lenvatinib and sorafenib arm, respectively. Patients treated with lenvatinib showed a higher percentage of response rate (29.4% vs 2.8%; p < 0.00001) compared with patients treated with sorafenib. Sorafenib was shown to be correlated with more HFSR, diarrhea and fatigue, while lenvatinib with more hypertension and fatigue.Conclusion: Our study highlighted for the first time the efficacy and safety of lenvatinib in an Italian cohort of patients.Keywords: hepatocarcinoma, sorafenib, lenvatinib

Introduction: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. Methods: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. Results: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. Conclusion: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.

This experimental study aims to extend the know-how on biomechanical performances of duplex stainless steel (DSS) for tissue engineering applications to a graded lattice geometry scaffold based on the F53 DSS (UNS S32750 according to ASTM A182) produced by laser powder bed fusion (LPBF). The same dense-out graded geometry based on rhombic dodecahedral elementary unit cells investigated in previous work on 316L stainless steel (SS) was adopted here for the manufacturing of the F53 DSS scaffold (SF53). Microstructural characterization and mechanical and biological tests were carried out on the SF53 scaffold, using the in vitro behavior of the 316L stainless steel scaffold (S316L) as a control. Results show that microstructure developed as a consequence of different volume energy density (VED) values is mainly responsible for the different mechanical behaviors of SF53 and S316L, both fabricated using the same LPBF manufacturing system. Specifically, the ultimate compressive strength (σUC) and elastic moduli (E) of SF53 are three times and seven times higher than S316L, respectively. Moreover, preliminary biological tests evidenced better cell viability in SF53 than in S316L already after seven days of culture, suggesting SF53 with dense-out graded geometry as a viable alternative to 316L SS for bone tissue engineering applications.

Friction Stir Welding (FSW) is a recent joining technique that has received considerable attention. FSW causes significant variations in the material microstructure commonly associated with changes in the mechanical properties. The present study deals with the creep response of pure titanium (CP-Ti grade 2) after FSW. Dog-bone creep samples, obtained by machining, which show the longitudinal axis of each sample being perpendicular to the welding direction, were tested in constant load machines at 550 and 600 °C. The creep response of the FSW samples was analyzed and compared with that of the unwelded material. The shape of the creep curves was conventional, although the FSW samples went to rupture for strains lower than the base metal. The minimum creep rates for FSW samples were, in general, lower than for the unwelded metal tested in equivalent conditions. In addition, when the applied stress was high, deformation concentrated in the parent metal. The creep strain became more and more homogeneous along the gauge length as testing stress decreased. A constitutive model, recently developed for describing the creep response of the base metal, was then used to rationalize the observed reduction in the minimum strain rate in FSW samples.

Metal additive manufacturing (AM) technologies can be classified according to the physical process involving the raw material as fusion-based and solid-state processes. The latter includes sintering-based technologies, which are aligned with conventional fabrication techniques, such as metal injection molding (MIM), and take advantage of the freeform fabrication of the initial green part. In the present work, 17-4PH stainless steel samples were fabricated by material extrusion, or rather bound metal deposition (BMD), a solid-state AM technology. The powder-based raw material was characterized together with samples fabricated using different angular infill strategies. By coupling different characterization technologies, it was possible to identify and classify major properties and defects of the raw material and the fabricated samples. In addition, microstructural modifications were found to be linked with the mesostructural defects typical of the BMD solid-state additive manufacturing technology applied to metals.

Background: Atezolizumab + bevacizumab represent the current standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, direct comparison with other combination treatments including immune checkpoint inhibitors (ICI) + tyrosine kinase inhibitors (TKIs) are lacking. Objectives: This network meta-analysis (NMA) aims to indirectly compare the efficacy and the safety of first-line systemic therapies for unresectable advanced HCC. Method: A literature search of MEDLINE, Embase, and SCOPUS databases was conducted up to October 31, 2022. Phase 3 randomized controlled trials (RCTs) testing TKIs, including sorafenib and lenvatinib, or ICIs reporting overall survival (OS) and progression-free survival (PFS) were included. Individual survival data were extracted from OS and PFS curves to calculate restricted mean survival time. A Bayesian NMA was performed to compare treatments in terms of efficacy (15- and 30-month OS, 6-month PFS) and safety, represented by grade ≥3 (severe) adverse events (SAEs). The incremental safety-effectiveness ratio as measure of net health benefit was calculated as the difference in SAE probability divided by survival difference between the 2 most effective treatments. Results: Nine RCTs enrolling 6,600 patients were included. Atezolizumab plus bevacizumab showed the highest probability (88%) of achieving the 30-month OS landmark. Lenvatinib showed a probability of 86% of achieving best PFS outcomes. ICI monotherapies ranked as most tolerable. Atezolizumab plus bevacizumab showed the best net health benefit for OS, compared to durvalumab plus tremelimumab. When evaluating the net health benefit for PFS, at a willingness-to-risk threshold of 10% of SAEs for life-month gained, atezolizumab plus bevacizumab was favoured in 78% of cases, while at threshold of 30% of SAEs for life-month gained, lenvatinib was favoured in 76% of cases. Conclusions: Atezolizumab plus bevacizumab is the best treatment in terms of net benefit and therefore it should be recommended as standard of care. Compared to atezolizumab plus bevacizumab, lenvatinib monotherapy had the best net benefit for PFS when physicians and patients are available to accept a higher risk of toxicity.

Introduction: Severe haemophilia A is characterized by serious factor VIII deficiency (biological activity

Introduction: In the REFLECT trial, lenvatinib was found to be non-inferior compared to sorafenib in terms of Overall Survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world, and to identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included Western and Eastern populations from 23 centres in five countries. Results: We included 1325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3 and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH related aetiology was independently associated with good prognosis. Median progression free survival was 6.3 months. Multivariate analysis for Progression Free survival revealed that NAFLD/NASH, BCLC, NLR and AST as independent prognostic factors for progression free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited that the appearance of decreased appetite Grade ≥ 2 versus Grade 0-1 as an independent prognostic factor for worse Progression Free Survival. 924 patients on 1325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over two-months from the beginning of second line treatment. From first line therapy the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months) and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC not candidate to locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

Introduction: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4–14.8) and 5.1 (3.3–6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3–4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials.

The austenitic stainless steels utilized in the production of osteosynthesis devices are susceptible to crevice corrosion. Several studies have compared the corrosive behavior of austenitic and duplex stainless steels (DSS), both of which are recognized as viable biomaterials for tissue engineering applications. All of the in vitro and in vivo studies on animals and clinical results reported to date indicate that austeno-ferritic duplex stainless steel can be recommended as a suitable alternative to ASTM F138 steel, since it is resistant to crevice corrosion in the human body and presents superior mechanical properties. The use of DSS for biomedical applications is still under discussion, mainly due to the lack of knowledge of its behavior in terms of device heating or induced movement when exposed to magnetic fields, a potentially harmful effect for the human body. As a breakthrough production technology, additive manufacturing (AM) has demonstrated significant benefits for the fabrication of metal devices with patient-specific geometry. Laser powder bed fusion has particularly been used to manufacture DSS-based components. A fine control of the processing conditions allows for an understanding of DSS microstructural evolution, which is essential for selecting processing parameters and estimating performance, including mechanical properties and corrosion resistance. Furthermore, scientific investigation is necessary for determining the relationships among material, process, and magnetic properties, in order to establish the underlying principles and critical responses. The purpose of this review is to highlight the key performances of DSS for biomedical applications and to point out the relevant role of advanced processing technologies such as additive manufacturing.

Introduction: The prognosis of patients undergoing transarterial chemoembolization (TACE) is extremely variable, and a confounding factor is that TACE is often repeated several times. We retrospectively evaluated the accuracy of different prognostic scores and staging systems in estimating overall survival (OS) in patients with hepatocellular carcinoma (HCC). Methods: An analysis considering prognostic models as time-varying variables was performed, calculating OS from the time of TACE to the time of the subsequent treatment. Total follow-up time for each patient was therefore split into several observation times accounting for each TACE procedure. Values of the likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare different systems. Univariable and multivariable analyses were conducted to identify additional factors predictive of OS. We analyzed 1,610 TACE performed in 1,058 patients recorded in the Italian Liver Cancer database from 2008 through 2016. Results: The median OS of the enrolled patients was 41 months. According to LRT χ2 and AIC values based on the time-varying analysis, mHAP-III achieved the best values (41.72 and 4,625.49, respectively, p < 0.0001), indicating the highest predictive performance compared with all other scores (HAP, mHAP-II, ALBI, and pALBI) and staging systems (MELD, ITALICA, CLIP, MESH, MESIAH, JIS, HKLC, and BCLC). In the multivariable Cox proportional hazards model, mHAP-III maintained an independent effect on OS (hazard ratio 1.31, 95% CI: 1.10–1.55, p < 0.0001). Time-varying age, alcoholic etiology, radiologic response to TACE, and performing ablation or surgery after TACE were additional significant variables resulting from the multivariable model. Conclusion: An innovative time-varying analysis revealed that mHAP-III was the most accurate model in predicting OS in patients with HCC undergoing TACE. Other clinical pre- and post-TACE variables were also found to be relevant for this prediction.

The physiology and behavior of living organisms are featured by time-related variations driven by molecular clockworks that arose during evolution stochastically and heterogeneously. Over the years, several high-throughput experiments were performed to evaluate time-dependent gene expression in different cell types across several species and experimental conditions. Here, these were retrieved, manually curated, and analyzed by two software packages, BioCycle and MetaCycle, to infer circadian or ultradian transcripts across different species. These transcripts were stored in RhythmicDB and made publically available.