Development of a risk score to predict portal vein tumor thrombosis in patients with hepatocellular carcinoma.

BACKGROUND: Portal vein tumor thrombosis (PVTT) is a common complication of hepatocellular carcinoma and is one of the most negative prognostic factors. The management of patients with PVTT is challenging. The aim of the study was to develop a score predictive of tumor thrombosis. METHODS: Data from a large cohort of 2243 hepatocellular carcinoma patients (all stages) recorded in the Progetto Epatocarcinoma Campania (January 2013-April 2021) database were analyzed. To construct the score, univariate generalized estimated equation models, the bootstrap approach for internal validation, and a regression coefficient-based scoring system were used. RESULTS: PVTT (any location) was found in 14.4% of cases and was related to shorter survival. Males, younger patients, and symptomatic cases were more prevalent among the PVTT group. At multivariate analysis, size ≥5 cm, massive or infiltrative hepatocellular carcinoma growth, and alpha-fetoprotein ≥400 ng/mL were significantly associated with PVTT. A risk prediction score of PVTT based on eight variables was developed. Using a continuous score, the risk was associated with an odds ratio (OR) of 1.30 (1.27-1.34; P  < 0.001). Considering a dichotomous score >8 versus a score ≤8 the OR for PVTT was 11.33 (8.55-15.00; P  < 0.001). CONCLUSION: The risk score for PVTT might be useful for clinicians to optimize hepatocellular carcinoma management by picking out patients with more aggressive cancers and higher mortality rates. Prospective validation of the score is needed before its application in daily clinical practice.

Rate of non-response to ursodeoxycholic acid in a large real-world cohort of primary biliary cholangitis patients in Italy.

Background and aim: Response to ursodeoxycholic acid (UDCA) is crucial for the prediction of primary biliary cholangitis (PBC) prognosis, and different response criteria were validated and proposed by reference centers for PBC. To date, rates of non-response to UDCA from real-world series are lacking.Methods: Hepatology/Gastroenterology centers belonging to 'Club Epatologi Ospedalieri' (CLEO) and 'Associazione Italiana Gastroenterologi Ospedalieri' (AIGO) were invited to participate in the study, and asked to extract all patients followed for PBC, without any selection or exclusion, and fill in the database provided.Results: Thirty-four centers were enrolled throughout Italy, for a total of 713 patients. None of these centers, except one, had a hepatology outpatient clinic devoted to the care of patients with autoimmune liver diseases. After excluding 79 cases of PBC/autoimmune hepatitis overlaps, 634 patients were analyzed: mean age, 64.4 ± 12.0 years; 91.2% females; F/M 10.3/1. For patients with at least 1 year of UDCA treatment (583), rates of non-response to UDCA were evaluated according to the Paris-I/-II, Toronto and GLOBE criteria, and compared with those in the original cohorts: 27% vs 39% in Paris-I cohort; 39.6% vs 52% in Paris-II; 20.1% vs 43.5% in Toronto; 15.7% vs 30% in GLOBE (age-specific cutoffs). Mean alkaline phosphatase levels on UDCA treatment, and the age-adjusted prevalence of F3/F4 fibrosis, appeared lower in this PBC population than in reference cohorts.Conclusions: A mean ∼15% better response to UDCA is observed in a real-world PBC population, probably due to migration of some of most severe/advanced cases to PBC referral centers.

Adherence to Barcelona Clinic Liver Cancer guidelines in field practice: Results of Progetto Epatocarcinoma Campania.

BACKGROUND AND AIM: The Barcelona Clinic Liver Cancer (BCLC) algorithm is the standard system for clinical management of hepatocellular carcinoma (HCC). Data on adherence to this therapeutic paradigm are scarce. This field practice study aimed to provide a description of HCC cirrhotic patients in Southern Italy, to evaluate the adherence to BCLC guidelines and its impact on patients' survival. METHODS: We analyzed the region-wide Italian database of Progetto Epatocarcinoma Campania, which includes data of HCC cirrhotic patients, prospectively collected from January 2013 to December 2015 in 16 regional centers. RESULTS: Overall, 1008 HCC patients were enrolled: 70.6% patients received therapies recommended by BCLC algorithm, while 29.4% underwent different treatments. Among patients who were treated in adherence to guidelines, a higher rate of diagnosis on surveillance programs, better liver function, lower rate of alpha-fetoprotein > 200 ng/mL, more early-stage and monofocal HCC, lower frequency of nodules > 5 cm, portal vein thrombosis and metastases were observed. The overall survival was evaluated according to HCC stage and no differences between groups and patients managed differently were found. The multivariate analysis showed that non-adherence to treatment guidelines was independently associated to the BCLC stage B, Child-Pugh classes B and C, and the presence of neoplastic thrombosis and metastases. CONCLUSION: Adherence to BCLC algorithm in field practice was high in early and end-stage HCC patients, but it was poor in intermediate and advanced patients.

Polymer models with optimal good-solvent behavior.

We consider three different continuum polymer models, which all depend on a tunable parameter r that determines the strength of the excluded-volume interactions. In the first model, chains are obtained by concatenating hard spherocylinders of height b and diameter rb (we call them thick self-avoiding chains). The other two models are generalizations of the tangent hard-sphere and of the Kremer-Grest models. We show that for a specific value [Formula: see text], all models show optimal behavior: asymptotic long-chain behavior is observed for relatively short chains. For [Formula: see text], instead, the behavior can be parametrized by using the two-parameter model, which also describes the thermal crossover close to the θ point. The bonds of the thick self-avoiding chains cannot cross each other, and therefore the model is suited for the investigation of topological properties and for dynamical studies. Such a model also provides a coarse-grained description of double-stranded DNA, so that we can use our results to discuss under which conditions DNA can be considered as a model good-solvent polymer.

Boceprevir or telaprevir in hepatitis C virus chronic infection: The Italian real life experience.

AIM: To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus (HCV) genotype 1 in the real-world settings. METHODS: This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-TaqMan2.0 (Roche, LLQ 25 IU/mL). RESULTS: All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57 (range 18-78), of whom 18.3% were over 65; mean body mass index 25.6 (range 16-39); genotype 1b (79.4%); diagnosis of cirrhosis (38.2%); and fibrosis F3/4 (71.2%). The following drugs were used: Telaprevir (66.2%) and PEG-IFN-alpha2a (67.6%). Patients were naïve (24.4%), relapsers (30.5%), partial responders (14.8%) and null responders (30.3%). Overall, adverse events (AEs) occurred in 617 patients (73.9%) during the treatment. Anemia was the most frequent AE (52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure (15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age. CONCLUSION: In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, non-responders to peginterferon + ribavirin.

Tuning knot abundance in semiflexible chains with crowders of different sizes: a Monte Carlo study of DNA chains.

We use stochastic simulation techniques to sample the conformational space of linear semiflexible polymers in a crowded medium and study how the knotting properties depend on the crowder size and concentration. The abundance of physical knots in the chains, which for definiteness we model on 10 kb long DNA filaments, is shown to have a non-monotonic, unimodal dependence on the colloid diameter, dc. The maximum incidence of knots occurs when dc is about equal to half of the gyration radius of the isolated chain. The degree of enhancement of knots grows rapidly with the solution density and can be very conspicuous relative to the case of isolated chains with no crowders. For instance, at 30% volume fraction the relative increase is more than fourfold. This dramatic enhancement is shown to originate from the depletion-induced chain compaction over multiple and concurring length scales. The same effect accounts for the variations of the knot length that accompany the changes in knotting probability. The findings suggest that crowded media could be viably used as a passive physical means for controlling and modulating the incidence and length of knots in DNA and other types of semiflexible polymers.

Radiofrequency ablation versus laser ablation for the treatment of small hepatocellular carcinoma in cirrhosis: a randomized trial.

BACKGROUND AND AIM: In patients with cirrhosis and small hepatocellular carcinoma (HCC), thermal ablation is currently recognized as an effective local treatment. Among thermal procedures, radiofrequency ablation (RFA) is the most diffusely used and is the standard against which any new treatment should be compared. In retrospective studies, laser ablation (LA) resulted as safe and effective as RFA. Therefore, we performed a non-inferiority randomized trial comparing RFA with LA in patients with cirrhosis and HCC within Milan criteria. METHODS: Overall, 140 patients with 157 HCC nodules were randomly assigned to receive RFA or LA. The primary end-point was the proportion of complete tumor ablation (CTA). Secondary end-points were time to local progression (TTLP) and overall survival (OS). RESULTS: Per patient CTA rates after RFA and LA were 97.4% (95% CI, 91.0-99.3) and 95.7% (88.1-98.5), respectively (difference = 1.4%, 95% CI from -6.0% to + 9.0%). Per nodule CTA rates for RFA and LA were 97.4% (91.0-99.3) and 96.3% (89.6-98.7), respectively (difference = 1.1%, from -5.7% to + 8.1%). The mean TTLP was comparable between RFA group (42.0 months; 95% CI, 36.83-47.3) and LA group (46.7 months; 95% CI, 41.5-51.9) (P = .591). The mean OS was 42 months in both groups and survival probability at 1 and 3 years was 94% and 89% in RFA group, and 94% and 80% in LA group. CONCLUSION: LA resulted not inferior to RFA in inducing the CTA of HCC nodules and therefore it should be considered as an evaluable alternative for thermal ablation of small HCC in cirrhotic patients.

Phase diagram of mixtures of colloids and polymers in the thermal crossover from good to θ solvent.

We determine the phase diagram of mixtures of spherical colloids and neutral nonadsorbing polymers in the thermal crossover region between the θ point and the good-solvent regime. We use the generalized free-volume theory, which takes into account the polymer-concentration dependence of the depletion thickness and of the polymer compressibility. This approach turns out to be quite accurate as long as q = Rg/Rc ≲ 1 (Rg is the radius of gyration of the polymer and Rc is the colloid radius). We find that, close to the θ point, the phase diagram is not very sensitive to solvent quality, while, close to the good-solvent region, changes of the solvent quality modify significantly the position of the critical point and of the binodals. We also analyze the phase behavior of aqueous solutions of charged colloids and polymers, using the approach proposed by Fortini et al. [J. Phys.: Condens. Matter 17, 7783 (2005)].

Accurate coarse-grained models for mixtures of colloids and linear polymers under good-solvent conditions.

A coarse-graining strategy, previously developed for polymer solutions, is extended here to mixtures of linear polymers and hard-sphere colloids. In this approach, groups of monomers are mapped onto a single pseudoatom (a blob) and the effective blob-blob interactions are obtained by requiring the model to reproduce some large-scale structural properties in the zero-density limit. We show that an accurate parametrization of the polymer-colloid interactions is obtained by simply introducing pair potentials between blobs and colloids. For the coarse-grained (CG) model in which polymers are modelled as four-blob chains (tetramers), the pair potentials are determined by means of the iterative Boltzmann inversion scheme, taking full-monomer (FM) pair correlation functions at zero-density as targets. For a larger number n of blobs, pair potentials are determined by using a simple transferability assumption based on the polymer self-similarity. We validate the model by comparing its predictions with full-monomer results for the interfacial properties of polymer solutions in the presence of a single colloid and for thermodynamic and structural properties in the homogeneous phase at finite polymer and colloid density. The tetramer model is quite accurate for q ≲ 1 (q=Rg/Rc, where Rg is the zero-density polymer radius of gyration and Rc is the colloid radius) and reasonably good also for q = 2. For q = 2, an accurate coarse-grained description is obtained by using the n = 10 blob model. We also compare our results with those obtained by using single-blob models with state-dependent potentials.

Consistent coarse-graining strategy for polymer solutions in the thermal crossover from good to θ solvent.

We extend our previously developed coarse-graining strategy for linear polymers with a tunable number n of effective atoms (blobs) per chain [G. D'Adamo et al., J. Chem. Phys. 137, 024901 (2012)] to polymer systems in thermal crossover between the good-solvent and the θ regimes. We consider the thermal crossover in the region in which tricritical effects can be neglected, i.e., not too close to the θ point, for a wide range of chain volume fractions Φ = c∕c* (c* is the overlap concentration), up to Φ ≈ 30. Scaling crossover functions for global properties of the solution are obtained by Monte Carlo simulations of the Domb-Joyce model with suitably rescaled on-site repulsion. They provide the input data to develop a minimal coarse-grained model with four blobs per chain (tetramer model). As in the good-solvent case, the coarse-grained model potentials are derived at zero density, thus avoiding the inconsistencies related to the use of state-dependent potentials. We find that the coarse-grained model reproduces the properties of the underlying, full-monomer system up to some reduced density Φ which increases when lowering the temperature towards the θ state. Close to the lower-temperature crossover boundary, the tetramer model is accurate at least up to Φ ~/= 10, while near the good-solvent regime reasonably accurate results are obtained up to Φ ~/= 2. The density region in which the coarse-grained model is predictive can be enlarged by developing coarse-grained models with more blobs per chain. We extend the strategy used in the good-solvent case to the crossover regime. This requires a proper treatment of the length rescalings as before, but also a proper temperature redefinition as the number of blobs is increased. The case n = 10 is investigated in detail. We obtain the potentials for such finer-grained model starting from the tetramer ones. Comparison with full-monomer results shows that the density region in which accurate predictions can be obtained is significantly wider than that corresponding to the tetramer case.

A novel needle guide system to perform percutaneous laser ablation of liver tumors using the multifiber technique.

BACKGROUND: Previous studies have shown that laser ablation with the multifiber technique is effective in the treatment of liver tumors. However, the correct positioning of multiple needles may be challenging. PURPOSE: To investigate the use of a novel needle guide system that was developed to perform percutaneous laser ablation of liver tumors with the multifiber technique under ultrasonographic guidance. MATERIAL AND METHODS: Between February 2009 and June 2011, 116 patients (104 hepatocellular carcinomas and 12 metastases) with 127 liver nodules (median diameter, 3.0 cm; range, 1.5-6.0) were treated. Nineteen nodules were in high-risk locations. A needle guide with separate channels to insert two needles in a parallel position and at a prefixed distance was used. RESULTS: Needles were positioned inside the target nodule easily and quickly, and correct spacing (1.5-1.8 cm) between light sources was immediately achieved. Complete tumor ablation was achieved in a single session in 112 (88.2%) lesions. In nodules ≤3.0 cm and >3.0 cm in size, ablation was complete in 93.6% and 79.6% of cases, respectively. Of note, complete ablation was achieved in 91.7% of nodules up to 5.0 cm. CONCLUSION: With the new guidance system, needles could be inserted in parallel fashion, which facilitated positioning the needles in geometrical configurations to maximize the ablative effect. Worthy of note, the complete ablation rate in nodules >3.0 cm using the new guide system was higher than what has been reported in the literature so far.

Predicting the thermodynamics by using state-dependent interactions.

We reconsider the structure-based route to coarse graining in which the coarse-grained model is defined in such a way to reproduce some distribution functions of the original system as accurately as possible. We consider standard expressions for pressure and chemical potential applied to this family of coarse-grained models with density-dependent interactions and show that they only provide approximations to the pressure and chemical potential of the underlying original system. These approximations are then carefully compared in two cases: we consider a generic microscopic system in the low-density regime and polymer solutions under good-solvent conditions. Moreover, we show that the state-dependent potentials depend on the ensemble in which they have been derived. Therefore, care must be used in applying canonical state-dependent potentials to predict phase lines, which is typically performed in other ensembles.

Consistent and transferable coarse-grained model for semidilute polymer solutions in good solvent.

We present a coarse-grained model for linear polymers with a tunable number of effective atoms (blobs) per chain interacting by intra- and intermolecular potentials obtained at zero density. We show how this model is able to accurately reproduce the universal properties of the underlying solution of athermal linear chains at various levels of coarse-graining and in a range of chain densities which can be widened by increasing the spatial resolution of the multiblob representation, i.e., the number of blobs per chain. The present model is unique in its ability to quantitatively predict thermodynamic and large scale structural properties of polymer solutions deep in the semidilute regime with a very limited computational effort, overcoming most of the problems related to the simulations of semidilute polymer solutions in good solvent conditions.

Polymers as compressible soft spheres.

We consider a coarse-grained model in which polymers under good-solvent conditions are represented by soft spheres whose radii, which should be identified with the polymer radii of gyrations, are allowed to fluctuate. The corresponding pair potential depends on the sphere radii. This model is a single-sphere version of the one proposed in Vettorel et al. [Soft Matter 6, 2282 (2010)], and it is sufficiently simple to allow us to determine all potentials accurately from full-monomer simulations of two isolated polymers (zero-density potentials). We find that in the dilute regime (which is the expected validity range of single-sphere coarse-grained models based on zero-density potentials) this model correctly reproduces the density dependence of the radius of gyration. However, for the thermodynamics and the intermolecular structure, the model is largely equivalent to the simpler one in which the sphere radii are fixed to the average value of the radius of gyration and radii-independent potentials are used: for the thermodynamics there is no advantage in considering a fluctuating sphere size.

The use of terlipressin in cirrhotic patients with refractory ascites and normal renal function: a multicentric study.

UNLABELLED: Ascites is a common complication of liver cirrhosis, occurring in more than 50-60% of the patients within 10 years of the diagnosis. In 5-10% of patients, ascites cannot be mobilized, or its early recurrence cannot be prevented by medical treatment. This condition is known as "refractory ascites". The use of terlipressin in cirrhotic patients with refractory ascites and normal renal function has not been evaluated. This prospective study was aimed at evaluating whether terlipressin in addition to standard therapy (diuretics plus albumin) might improve the outcome of refractory ascites in cirrhotic patients without HRS. PATIENTS: 26 cirrhotic patients with refractory ascites were prospectively enrolled in this study. All the patients had tense (grade 3) ascites, and 10/26 showed also massive peripheral edema. Patients received maximum diuretic treatment plus albumin and terlipressin. RESULTS: Complete response was seen in 16/26 patients. The higher response to therapy was seen during the 2nd week of treatment. 6 patients showed a decrease of at least two points in the ascites score. No differences in clinical response to treatment were seen according to the etiology of the disease. CONCLUSIONS: In conclusion, our study shows a synergistic effect of terlipressin vs treatment with albumin plus diuretics in patients with refractory ascites. One could speculate that albumin might enhance the vasoconstrictive response to terlipressin, thus contributing to counterbalance the negative effects of systemic vasodilation, which characterizes the hyperdynamic circulation of cirrhotic patients.

Crystalline free energies of micelles of diblock copolymer solutions.

We report a characterization of the relative stability and structural behavior of various micellar crystals of an athermal model of AB-diblock copolymers in solution. We adopt a previously developed coarse-graining representation of the chains which maps each copolymer on a soft dumbbell. Thanks to this strong reduction of degrees of freedom, we are able to investigate large aggregated systems and for a specific length ratio of the blocks f = M(A)∕(M(A) + M(B)) = 0.6, to locate the order-disorder transition of the system of micelles. Above the transition, mechanical and thermal properties are found to depend on the number of particles per lattice site in the simulation box, and the application of a recent methodology for multiple occupancy crystals [B. M. Mladek et al., Phys. Rev. Lett. 99, 235702 (2007)] is necessary to correctly define the equilibrium state. Within this scheme we have performed free energy calculations at two reduced density ρ∕ρ∗ = 4, 5 and for several cubic structures such as fcc, bcc, and A15. At both densities, the bcc symmetry is found to correspond to the minimum of the unconstrained free energy, that is to the stable symmetry among the few considered, while the A15 structure is almost degenerate, indicating that the present system prefers to crystallize in less packed structures. At ρ∕ρ∗ = 4 close to melting, the Lindemann ratio is fairly high (∼0.29) and the concentration of vacancies is roughly 6%. At ρ∕ρ∗ = 5 the mechanical stability of the stable bcc structure increases and the concentration of vacancies accordingly decreases. The ratio of the corona layer thickness to the core radius is found to be in good agreement with experimental data for poly(styrene-b-isoprene)(22-12) in isoprene selective solvent which is also reported to crystallize in the bcc structure.