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The first and further decompensation mark the natural history and the risk of mortality in patients with cirrhosis. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on both liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD). Consecutive patients with clinical (LSM>10 kPa) or biopsy-proven (F3-F4 fibrosis) diagnosis of cACLD due to MASLD were included. First and further decompensation were defined according to Baveno VII criteria. The acute (AD) and non-acute (NAD)[MOU1] [VW(2] presentation of the decompensation was also evaluated. Competing risk analysis and cumulative incidence functions (CIF) [MOU3] were assessed by Fine and Gray. Cause-specific Cox models with baseline and time-dependent variables were applied. Multistate model was built to better assess the clinical course of cACLD due to MASLD. The cumulative incidence of the first decompensation was 3.5% at 5 years, increasing 20-times the risk of LR-D at cause-specific Cox analysis; the cumulative incidence of further decompensation was 44% at 5 years among patients with first decompensation, additionally increasing 1.6-times the risk of LR-D. Ascites, followed by variceal bleeding, were the most common events in both first and further decompensation. The impact of AD and NAD as both first or further event on LR-D was similar[MOU4]. Hepatocellular carcinoma (HCC) further independently increased the risk of LR-D of 3.2-times and 1.6-times, respectively, in the whole cohort of cACLD due to MASLD and in those who experienced first decompensation. The first and further decompensations (AD and NAD) represent tipping points in the clinical course of patients with cACLD due to MASLD, increasing 20-times and additionally 1.6-times the risk of LR-D. HCC is an independent predictor of LR-D in patients with cACLD due to MASLD, resulting in an additional risk of LR-D when associated with both first and further decompensation. [ABSTRACT FROM AUTHOR]

Clinically significant portal hypertension (CSPH) in patients with advanced chronic liver disease (ACLD) is high-risk condition for liver-related events (LRE). According with BAVENO VII, non-invasive tests (NIT) should be preferred to rule in or out for CSPH to avoid endoscopy. The novel score HVPG-3Parameters gave a prediction of HVPG showing good accuracy in CSPH prediction. Aim is to evaluate the ability of HVPG-3P in PH and LRE prediction. A retrospective study was conducted in two different Italian centers: University of Naples and University of Marche. In 10 years, consecutive compensated-ACLD patients who underwent upper-GI endoscopy for PH assessment were enrolled. NIT (FIB-4,ANTICIPATE,PLT/spleen-diameter ratio and HVPG-3P) were calculated. During the follow-up any LRE were recorded. Two-hundred and ninety-one ACLD subjects (with no differences between centers) were recruited (62.1% males, mean age 60 years). Mean LSM was 23.6±11.7kPa; HVPG-3P was 13.3±2.0mmHg, ANTICIPATE was 1.0±1.6, FIB-4 was 5.0±3.2, platelets/spleen-diameter ratio was 906.5±568.2. One-hundred and forty-two (48,9%) subjects showed PH endoscopic signs. They had higher LSM (26.6±12.4vs20.8±10.3kPa, p=0.00002), HVPG-3P (14.2±1.6vs12.4±2.0mmHg, p<0.001), ANTICIPATE (1.66±1.4vs0.31±1.5, p<0.001), FIB-4 (5.87±3.28vs4.13±2.84, p=0.001) and lower platelets/spleen-diameter ratio (652.4±323.6vs1148.6±641.8, p<0.0001) compared to subjects without PH endoscopic signs. During a median follow-up of 41.5months (IQR 17.8-74.0) LRE occurred in a median of 18.9months (IQR 7.5-37) in 126/291 (43.2%). Patients who experienced LRE showed higher LSM (26.0±12.3 vs21.9±11.0kPa, p=0.003), HVPG-3P (14.1±1.7vs12.6±2.0mmHg, p<0.0001), ANTICIPATE (1.54±1.57vs0.55±1.56, p<0.0001), FIB-4 (6.02±3.36vs4.19±2.79, p<0.0001) and lower platelets/spleen-diameter ratio (694.9±385.7vs1068.0±630.0, p<0.0001). The HVPG-3P seems to have a good performance in PH and LRE prediction (considering the results from Random Forest model: MDA 4.52 and 6.55, higher than the majority of variables). HVPG-3P is a simple tool for non-invasive prediction of PH and could be used to stratify the risk of LRE in patients with ACLD. However, this score needs to be validated in larger cohorts. [ABSTRACT FROM AUTHOR]

• Carbon ion radiotherapy to sacral chordoma is sensitive to bowel density variations. • Density overwrite on planning CT models realistic intestinal filling conditions. • Dosimetric perturbation caused by density variations is evaluated prior treatment. Carbon ion radiotherapy (CIRT) is sensitive to anatomical density variations. We examined the dosimetric effect of variable intestinal filling condition during CIRT to ten sacral chordoma patients. For each patient, eight virtual computed tomography scans (vCTs) were generated by varying the density distribution within the rectum and the sigmoid in the planning computed tomography (pCT) with a density override approach mimicking a heterogeneous combination of gas and feces. Totally full and empty intestinal preparations were modelled. In addition, five different intestinal filling conditions were modelled by a mixed density pattern derived from two combined and weighted Gaussian distributions simulating gas and feces respectively. Finally, a patient-specific mixing proportion was estimated by evaluating the daily amount of gas detected in the cone beam computed tomography (CBCT). Dose distribution was recalculated on each vCT and dose volume histograms (DVHs) were examined. No target coverage degradation was observed at different vCTs. Rectum and sigma dose degradation ranged respectively between: [−6.7; 21.6]GyE and [−0.7; 15.4]GyE for D 50% ; [−377.4; 1197.9] and [−95.2; 1027.5] for AUC; [−1.2; 10.7]GyE and [−2.6; 21.5]GyE for D 1%. Variation of intestinal density can greatly influence the penetration depth of charged particle and might compromise dose distribution. In particular cases, with large clinical target volume in very close proximity to rectum and sigmoid colon, it is appropriate to evaluate the amount of gas present in the daily CBCT images even if it is totally included in the reference planning structures. [ABSTRACT FROM AUTHOR]

The efficacy of systemic therapy for unresectable advanced hepatocellular carcinoma (aHCC) has not been proven in patients with Child-Pugh (C-P) B cirrhosis. Nevertheless, in real-world these patients are treated with tyrosine-kinase inhibitors (TKIs) since their toxicity is similar to that observed in C-P A patients and, off-label, with Metronomic Capecitabine (MC) in patients not amenable to TKIs. This study aimed to compare Sorafenib and MC's outcomes versus best supportive care (BSC) in C-P B-HCC patients. Between 2008 and 2020, among 774 consecutive C-P B patients with aHCC not amenable/responding to locoregional treatments extracted from the ITA.LI.CA database, 410 underwent Sorafenib, 62 MC, and 302 BSC. The propensity score matching method was used to correct the baseline unbalanced prognostic factors, with a 1:1 allocation of Sorafenib vs BSC, MC vs BSC, and Sorafenib vs MC patients, and Kaplan-Meier method and Log-rank test were used to define overall survival (OS) and differences. in the unmatched population median OS (95% CI) was 9.9 (8.3-11.4) months in Sorafenib, 8.0 (0.4-15.7) months in MC, and 3.9 (3.1-4.8) months in BSC-treated patients (p<0.001 for Sorafenib vs BSC and for MC vs BSC; p=0.812 for Sorafenib vs MC). In Sorafenib vs BSC-matched patients (135 couples) median OS was 7.3 (4.8-9.7) vs 3.9 (2.6-5.2) months (p<0.001). Independent predictors of survival were ECOG-Performance Status >1 [HR: 1.61 (1.22-2.13)], tumour size [HR: 1.04 (1.01-1.07)] macrovascular invasion [HR: 1.48 (1.12-1.96)], AFP >400 ng/mL [HR: 1.52 (1.14-2.04)], treatment-naïve [HR: 1.54 (1.15-2.07)] and Sorafenib [HR: 0.51 (0.38-0.68)]. In MC vs BSC matched patients (40 couples) median OS was 9.0 (0.2-17.8) vs 3.0 (2.2-3.8) months (p<0.001). In Sorafenib vs MC-matched patients (55 couples) the median OS did not differ (p=0.283). C-P B patients with aHCC undergoing BSC have poor survival. Both Sorafenib and MC treatment improve their prognosis. [ABSTRACT FROM AUTHOR]

• Non-dedicated line OPT requires challenging and time-demanding set-up preparation. • A simulator for patient-specific setup virtualization and optimization is proposed. • New approach validation is based on geometric data of 30 patients treated in CNAO. • Treatment requirements, both clinical and geometric are met. • Clinical impact in terms of time-demand and patient safety. An Eye Tracking System (ETS) is used at CNAO for providing a stable and reproducible ocular proton therapy (OPT) set-up, featuring a fixation light (FL) and monitoring stereo-cameras embedded in a rigid case. The aim of this work is to propose an ETS set-up simulation algorithm, that automatically provides the FL positioning in space, according to patient-specific gaze direction and avoiding interferences with patient, beam and collimator. Two configurations are provided: one in the CT room for acquiring images required for treatment planning with the patient lying on a couch, and one related to the treatment room with the patient sitting in front of the beam. Algorithm validation was performed reproducing ETS simulation (CT) and treatment (room) set-up for 30 patients previously treated at CNAO. The positioning accuracy of the device was quantified through a set of 14 control points applied to the ETS case and localizable both in the CT volume and in room X-ray images. Differences between the position of ETS reference points estimated by the algorithm and those measured by imaging systems are reported. The corresponding gaze direction deviation is on average 0.2° polar and 0.3° azimuth for positioning in CT room and 0.1° polar and 0.4° azimuth in the treatment room. The simulation algorithm was embedded in a clinically usable software application, which we assessed as capable of ensuring ETS positioning with an average accuracy of 2 mm in CT room and 1.5 mm in treatment room, corresponding to gaze direction deviations consistently lower than 1°. [ABSTRACT FROM AUTHOR]

• A new spatial normalization framework for brain dose distributions is proposed. • The proposed framework is based on the combined use of MR and planning CT images. • A formal criterion for non-acceptable normalization is provided. • The devised framework is robust and paves the way for future brain toxicity studies. To devise a novel Spatial Normalization framework for Voxel-based analysis (VBA) in brain radiotherapy. VBAs rely on accurate spatial normalization of different patients' planning CTs on a common coordinate system (CCS). The cerebral anatomy, well characterized by MRI, shows instead poor contrast in CT, resulting in potential inaccuracies in VBAs based on CT alone. We analyzed 50 meningioma patients treated with proton-therapy, undergoing planning CT and T1-weighted (T1w) MRI. The spatial normalization pipeline based on MR and CT images consisted in: intra-patient registration of CT to T1w, inter-patient registration of T1w to MNI space chosen as CCS, doses propagation to MNI. The registration quality was compared with that obtained by Statistical Parametric Mapping software (SPM), used as benchmark. To evaluate the accuracy of dose normalization, the dose organ overlap (DOO) score was computed on gray matter, white matter and cerebrospinal fluid before and after normalization. In addition, the trends in the DOOs distribution were investigated by means of cluster analysis. The registration quality was higher for the proposed method compared to SPM (p < 0.001). The DOO scores showed a significant improvement after normalization (p < 0.001). The cluster analysis highlighted 2 clusters, with one of them including the majority of data and exhibiting acceptable DOOs. Our study presents a robust tool for spatial normalization, specifically tailored for brain dose VBAs. Furthermore, the cluster analysis provides a formal criterion for patient exclusion in case of non-acceptable normalization results. The implemented framework lays the groundwork for future reliable VBAs in brain irradiation studies. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). Salvage liver transplantation (LT) may be an option provided that a transplantable recurrence has occurred. We aimed to assess incidence and preoperative predictors of recurrence beyond Milan criteria (MC) in patients with small (≤ 5 cm) single HCC treated with first-line LR. Data of 512 patients with single HCC ≤5 cm treated with frontline LR were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Incidence and predictors of recurrence beyond MC was compared across two groups according to tumor diameter (HCC ≤3 cm vs. >3 cm). During a median follow-up of 4.2 years, the overall recurrence rate was 55.9%. Only 18.0% of patients had a first recurrence beyond MC (14.0% in the ≤3 cm group and 23.9% in the >3 group; p=0.005), while the overall recurrence rate beyond MC was 30.3% (25.1% and 38.0% patients in the ≤3 cm and >3 cm groups, respectively; p=0.002) (Figure). Compared to those with larger tumors, patients with HCC ≤3 cm had a longer recurrence-free survival (4.0 [95% CI 3.3-4.7] vs. 2.5 [95% CI 2.0-3.0] years; p=0.002) and overall survival (9.9 [95% CI 6.5-13.4] vs. 7.8 [95% CI 5.7-9.9] years; p=0.008). HCC size and alpha-fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC. A subanalysis in patients with "ab initio" potentially transplantable HCC confirmed these results. Despite the high recurrence rate, LR for single HCC ≤ 5 cm offers excellent long-term survival. Recurrence beyond MC is predicted by HCC size and AFP levels. Referral for salvage LT should be immediate at the first HCC recurrence, but high-risk patients (HCC >3 cm and high AFP) could be considered for frontline LT or listed for transplantation even before recurrence. [ABSTRACT FROM AUTHOR]

Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcoholic aetiology associates with a worse prognosis compared to hepatitis B and C infections, due to a lower percentage of HCCs diagnosed under regular surveillance and a higher comorbidity burden in alcoholic patients. This study aimed at describing the evolving clinical scenario of alcohol-related HCC over a 15-year period (2006-2020) in Italy. Data of the Italian Liver Cancer (ITA.LI.CA) registry were used: 1391 alcoholic patients were allocated to 3 groups based on the year of cancer diagnosis (2006-2010; 2011-2015; 2016-2020) and patient characteristics, HCC treatment and overall survival were compared among groups. Survival predictors were also investigated. Around 80% of alcoholic patients were classified as metabolic dysfunction-associated fatty liver disease (MAFLD) cases. Throughout the quinquennia, <50% of HCCs were detected by surveillance programs. The tumour burden at diagnosis slightly decreased but not enough to change the distribution of ITA.LI.CA cancer stages. The use of intra-arterial and targeting systemic therapies increased across quinquennia. A modest improvement of survival was observed in the last quinquennia, particularly after 24 months of patient observation. Cancer stage, HCC treatment and presence of oesophageal varices were independent predictors of survival. In the last 15 years, minor improvements have been obtained in the outcome of alcohol-related HCC, mainly because of a persistent underuse of surveillance programs and the consequent steadily low amenability to curative treatments. Oesophageal varices are an independent grim prognosticator and therefore this variable should be included in prognostic systems. MAFLD is a widespread condition in alcohol abusers, but its presence did not achieve a pivotal prognostic role once HCC has developed. [ABSTRACT FROM AUTHOR]

Discontinuation of hepatitis B (HBV) immune globulin (HBIG) after liver transplantation (LT) for HBV-related cirrhosis with and without hepatocellular carcinoma (HCC) represents a challenging option. The adherence to this option in real-life practice is unknown. In a contemporary cohort of patients transplanted for HBV, with and without HCC, we aimed to; 1) assess the rate of HBV recurrence (HBV-R); 2) evaluate risk factors for HBV-R; 3) evaluate the association between HBV-R and HCC recurrence (HCC-R) and patient survival. This is a multicentric, retrospective study designed by the "Permanent Transplant Commission" of the Italian Association for the Study of the Liver. All recipients who underwent LT for HBV cirrhosis were included. Exclusion criteria were: LT prior to January 1, 2010; age <18 years old; combined transplantation; HIV coinfection; duration of follow-up after LT <12 months. HBV-R was defined by positivity of HBV-DNA and/or HBsAg. Uni and multivariate linear regression analysis were used to identify predictors of HBV/HCC-R. 1115 patients were included. Indications for LT were HCC (51%), decompensated cirrhosis (41.2%), acute on chronic liver failure (ACLF) (3.4%), and acute liver failure (ALF) (4.2%). Life-long HBIG + nuclos(t)ide analogues (NA) was the most common used prophylaxis (94.4%). Overall rate of HBV-R was 2.2% (median time after LT: 7 months). Patients under life-long HBIG + NA had lower rates of HBV-R than those in whom HBIG were withdrawn and those who received NA alone (1.4% vs. 10.7% vs. 13.6%; respectively, p<0.001). HBV-R was associated with a lower survival after LT (p=0.008). In patients transplanted for HCC (n=535), the rate of HBV-R was 2.8% and of HCC-R was 10.3% (median time from LT: 17 months). Rate of HBV-R was higher in patients with vs. without HCC-R (14.6% vs. 1.2%; p<0.001). Multivariate analysis showed that HBV-R was the only parameter independently associated with HCC-R (HR: 20; CI95% 5-86; p<0.001). HCC-R was associated with a significantly reduced survival after LT (5-year survival 36% vs. 94%; p<0.001). Life-long HBIG + NA is the most commonly used scheme for HBV-R prophylaxis after LT in Italy, leading to a low risk of HBV-recurrence. In LT recipients, HBV recurrence is associated with an increased risk of death. In patients transplanted for HCC, HBV-R is independently associated with HCC recurrence. Therefore, discontinuation of HBIG in these patients should be considered only in the setting of clinical trials [ABSTRACT FROM AUTHOR]

Even though hepatocellular carcinoma (HCC) is mainly characterized by a locoregional progression, the prognosis of some patients is burdened by the development of metastases. We aimed to identify risk factors of extrahepatic progression (EHP) in HCC patients undergoing transarterial chemoembolization (TACE). From the ITA.LI.CA database, 890 patients treated with first-line TACE were retrieved. Incidence and predictors of EHP were compared between patients with tumor burden score (TBS) ≤4.2 and >4.2 (cut-off determined by ROC curve analysis). Validation (n=442) and derivation (n=448) cohorts were used to create a predictive model for EHP after TACE (EHPaT score). During a median follow-up of 28.6 months (IQR, 14.0-50.0), 76.2% of patients showed progression after treatment. In the TBS >4.2 group, a significantly higher proportion of patients demonstrated extrahepatic spread at first progression (11.2% vs. 4.3%; p<0.001) and overall during follow-up (35.4% vs. 19.3%; p<0.001). The most common sites of metastases were lymph nodes and lung. Patients with TBS ≤4.2 had a significantly longer progression free survival (11.6 vs. 9.0 months; p<0.001) and overall survival (54.1 vs. 31.1 months; p<0.001). Independent predictors of EHP were TBS, radiological response and alpha-fetoprotein (AFP) levels. The Cox Score for the prediction of EHP (incorporating TBS, AFP, radiological response and etiology) yielded an AUROC of 0.743 (95% CI 0.656-0.830) at first progression and an AUROC of 0.701 (95% CI 0.645-0.757) overall during the follow-up in the derivation cohort. Similar results were obtained in the validation cohort. Although HCC is characterized by predominantly locoregional progression, identifying risk factors for metastases development is relevant for prognostic prediction and treatment allocation. Tumor burden, together with radiological response and AFP, has to be considered in the prediction of EHP after TACE. The EHPaT score revealed to be a useful tool in predicting of metastases development. [ABSTRACT FROM AUTHOR]

Hadrontherapy is a method for treating cancer with very targeted dose distributions and enhanced radiobiological effects. To fully exploit these advantages, in vivo range monitoring systems are required. These devices measure, preferably during the treatment, the secondary radiation generated by the beam-tissue interactions. However, since correlation of the secondary radiation distribution with the dose is not straightforward, Monte Carlo (MC) simulations are very important for treatment quality assessment. The INSIDE project constructed an in-beam PET scanner to detect signals generated by the positron-emitting isotopes resulting from projectile-target fragmentation. In addition, a FLUKA-based simulation tool was developed to predict the corresponding reference PET images using a detailed scanner model. The INSIDE in-beam PET was used to monitor two consecutive proton treatment sessions on a patient at the Italian Center for Oncological Hadrontherapy (CNAO). The reconstructed PET images were updated every 10 s providing a near real-time quality assessment. By half-way through the treatment, the statistics of the measured PET images were already significant enough to be compared with the simulations with average differences in the activity range less than 2.5 mm along the beam direction. Without taking into account any preferential direction, differences within 1 mm were found. In this paper, the INSIDE MC simulation tool is described and the results of the first in vivo agreement evaluation are reported. These results have justified a clinical trial, in which the MC simulation tool will be used on a daily basis to study the compliance tolerances between the measured and simulated PET images. [ABSTRACT FROM AUTHOR]