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Background & Aims The Pre-TACE-Predict model was devised to assess prognosis of patients treated with trans-arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). However, before entering clinical practice, a model should demonstrate that it performs a useful role. Methods We performed an independent external validation of the Pre-TACE model in a cohort that differs in setting and time period from the one that generated the original model. Data from 826 patients treated with TACE for naïve HCC (2008-2018) were used to assess calibration and discrimination of the Pre-TACE-Predict model. Results The four risk-categories identified by the Pre-TACE-Predict model had gradient monotonicity, with median survivals of 52.0, 36.2, 29.9, and 14.1 months respectively. However, predicted survivals systematically underestimated observed survivals (R2: 0.667). A recalibration was adopted maintaining fixed the prognostic index and modifying the baseline survival function. This resulted in an almost perfect calibration (R2: 0.995) in all the four risk categories. Cox regressions showed that aetiology and macrovascular invasion, included in the Pre-TACE-Predict model, had no prognostic impact in the present study population, and that coefficients for tumour size and multiplicity were overestimated. The c-index was similar to that of the m-HAP-III, but higher than those of HAP, m-HAP-II and the six-and-twelve models. Conclusions The recalibration of Pre-TACE-Predict model improved the estimation of survival probabilities of HCC patients treated with TACE. The highest discriminatory ability of the Pre-TACE-model in comparison to other available models, together with risk stratification and recalibration, makes it the best prognostic tool currently available for these patients.

Background & Aims: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, monofocal hepatocellular carcinoma (HCC) is classified as early (BCLC A) irrespective of its size, even though controversies still exist regarding staging and treatment of large tumours. We aimed at evaluating the appropriate staging and treatment for large (>5cm) monofocal (HCC). Methods: From the Italian Liver Cancer database, we selected 924 patients with small early monofocal HCC (2-5cm; SEM-HCC), 163 patients with larger tumours (>5cm; LEM-HCC) and 1048 intermediate stage patients (BCLC B). Results: LEM-HCC patients had a worse overall survival (OS) than SEM-HCC (31.0 vs 49.0months; P&nbsp

OBJECTIVES:The Barcelona Clinic Liver Cancer (BCLC) intermediate stage (BCLC B) includes a heterogeneous population of patients with hepatocellular carcinoma (HCC). Recently, in order to facilitate treatment decisions, a panel of experts proposed to subclassify BCLC B patients. In this study, we aimed to assess the prognostic capability of the BCLC B stage reclassification in a large cohort of patients with untreated HCC managed by the Italian Liver Cancer Group.METHODS:We assessed the prognosis of 269 untreated HCC patients observed in the period 1987-2012 who were reclassified according to the proposed subclassification of the BCLC B stage from stage B1 to stage B4. We evaluated and compared the survival of the various substages.RESULTS:Median survival progressively decreased from stage B1 (n=65, 24.2%: 25 months) through stages B2 (n=105, 39.0%: 16 months) and B3 (n=22, 8.2%: 9 months), to stage B4 (n=77, 28.6%: 5 months; P

none 48 no Background: In HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma (HCC), the time to HCC recurrence and the effects of sustained viral eradication (SVR) by interferon (IFN)-based or IFN-free regimens on HCC recurrence remain unclear. Aim: To perform an indirect comparison of time to recurrence (TTR) in patients with successfully treated early HCC and active HCV infection with those of patients with SVR by IFN-based and by IFN-free regimens. Methods: We evaluated 443 patients with HCV-related cirrhosis and Barcelona Clinic Liver Cancer Stage A/0 HCC who had a complete radiological response after curative resection or ablation. Active HCV infection was present in 328, selected from the Italian Liver Cancer group cohort; 58 patients had SVR achieved by IFN-free regimens after HCC cure, and 57 patients had SVR achieved by IFN-based regimens after HCC cure. Individual data of patients in the last two groups were extracted from available publications. Results: TTR by Kaplan–Meier curve was significantly lower in patients with active HCV infection compared with those with SVR both by IFN-free (P = 0.02) and by IFN-based (P < 0.001) treatments. TTR was similar in patients with SVR by IFN-free or by IFN-based (P = 0.49) strategies. Conclusion: In HCV-infected, successfully treated patients with early HCC, SVR obtained by IFN-based or IFN-free regimens significantly reduce tumour recurrence without differences related to the anti-viral strategy used. Petta, S.; Cabibbo, G.; Barbara, M.; Attardo, S.; Bucci, L.; Farinati, F.; Giannini, E.G.; Tovoli, F.; Ciccarese, F.; Rapaccini, G.L.; Di Marco, M.; Caturelli, E.; Zoli, M.; Borzio, F.; Sacco, R.; Virdone, R.; Marra, F.; Felder, M.; Morisco, F.; Benvegnù, L.; Gasbarrini, A.; Svegliati-Baroni, G.; Foschi, F.G.; Olivani, A.; Masotto, A.; Nardone, G.; Colecchia, A.; Persico, M.; Boccaccio, V.; Craxì, A.; Bruno, S.; Trevisani, F.; Cammà, C; the Italian Liver Cancer (ITALICA) Group [ ; Maurizio Biselli; Paolo Caraceni; Alessandro Cucchetti; Marco Domenicali; Fabio Piscaglia; Annagiulia Gramenzi; Alessandro Granito; Donatella Magalotti; Carla Serra; Giulia Negrini; Lucia Napoli; Veronica Salvatore; Francesca Benevento;] Petta, S.; Cabibbo, G.; Barbara, M.; Attardo, S.; Bucci, L.; Farinati, F.; Giannini, E.G.; Tovoli, F.; Ciccarese, F.; Rapaccini, G.L.; Di Marco, M.; Caturelli, E.; Zoli, M.; Borzio, F.; Sacco, R.; Virdone, R.; Marra, F.; Felder, M.; Morisco, F.; Benvegnù, L.; Gasbarrini, A.; Svegliati-Baroni, G.; Foschi, F.G.; Olivani, A.; Masotto, A.; Nardone, G.; Colecchia, A.; Persico, M.; Boccaccio, V.; Craxì, A.; Bruno, S.; Trevisani, F.; Cammà, C; the Italian Liver Cancer (ITALICA) Group [ ; Maurizio Biselli; Paolo Caraceni; Alessandro Cucchetti; Marco Domenicali; Fabio Piscaglia; Annagiulia Gramenzi; Alessandro Granito; Donatella Magalotti; Carla Serra; Giulia Negrini; Lucia Napoli; Veronica Salvatore; Francesca Benevento;]

Background and aims Epidemiology of hepatocellular carcinoma is changing worldwide. This study aimed at evaluating the changing scenario of etiology, presentation, management and prognosis of hepatocellular carcinoma in Italy during the last 15 years. Methods Retrospective analysis of the ITA.LI.CA (Italian Liver Cancer) database including 5192 hepatocellular carcinoma patients managed in 24 centers from 2000 to 2014. Patients were divided into three groups according to the date of cancer diagnosis (2000-2004, 2005-2009 and 2010-2014). Results The main results were: 1) progressive patient aging; 2) progressive expansion of non-viral cases and, namely, of “metabolic” hepatocellular carcinomas; 3) increasing proportion of hepatocellular carcinoma diagnosed during a correct (semiannual) surveillance program; 4) favourable cancer stage migration; 4) increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; 5) improved outcomes of ablative and transarterial treatments; 6) improved overall survival (adjusted for the lead time in surveyed patients), particularly after 2009, of both viral and non-viral patients presenting with an early or intermediate stage hepatocellular carcinoma. Conclusions During the last 15 years several etiological and clinical features of hepatocellular carcinoma patients have changed, as their management. The observed improvement of overall survival was due both to the wider use of semiannual surveillance, expanding the proportion of tumors that qualified for curative treatments, and to the improved outcome of locoregional treatments. This article is protected by copyright. All rights reserved.

Background Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. Patients and Methods The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. Results Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). Conclusions The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes.

Background: The role of clinically significant portal hypertension on the prognosis of cirrhotic patients undergoing hepatic resection for hepatocellular carcinoma (HCC) is debated. Aims: In this study, our aim was to assess the role of clinically significant portal hypertension after hepatic resection for HCC in patients with cirrhosis. Methods: We assessed the prognostic role of the presence of clinically significant portal hypertension (oesophageal/gastric varices/portal hypertensive gastropathy or a platelet count 100 vs 86 months, P = 0.742). Conclusions: Presence of clinically significant portal hypertension has no influence on survival of patients with well-compensated cirrhosis undergoing hepatic resection for HCC. © 2013 John Wiley & Sons A/S.

Alpha-fetoprotein is a tumor marker that has been used for surveillance and diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. The prognostic capability of this marker in patients with HCC has not been clearly defined. In this study our aim was to evaluate the prognostic usefulness of serum alpha-fetoprotein in patients with well-compensated cirrhosis, optimal performance status, and small HCC identified during periodic surveillance ultrasound who were treated with curative intent. Among the 3,027 patients included in the Italian Liver Cancer study group database, we selected 205 Child-Pugh class A and Eastern Cooperative Group Performance Status 0 patients with cirrhosis with a single HCC ≤3 cm of diameter diagnosed during surveillance who were treated with curative intent (hepatic resection, liver transplantation, percutaneous ethanol injection, radiofrequency thermal ablation). Patients were subdivided according to alpha-fetoprotein serum levels (i.e., normal ≤20 ng/mL; mildly elevated 21-200 ng/mL; markedly elevated >200 ng/mL). Patient survival, as assessed by the Kaplan-Meier method, was not significantly different among the three alpha-fetoprotein classes (P = 0.493). The same result was obtained in the subgroup of patients with a single HCC ≤2 cm (P = 0.714). An alpha-fetoprotein serum level of 100 ng/mL identified by receiver operating characteristic curve had inadequate accuracy (area under the curve = 0.536, 95% confidence interval = 0.465-0.606) to discriminate between survivors and deceased patients. Conclusion: Alpha-fetoprotein serum levels have no prognostic meaning in well-compensated cirrhosis patients with single, small HCC treated with curative intent. (HEPATOLOGY 2012)

Background An enhanced surveillance schedule has been proposed for cirrhotics with viral etiology, who are considered at extremely high-risk of hepatocellular carcinoma (HCC). Aims We compared the 3- and 6-months surveillance interval, evaluating cancer stage at diagnosis and patient survival. Methods Data of 777 HBV and HCV cirrhotic patients with HCC diagnosed under a 3-months (n = 109, 3MS group) or a 6-months (n = 668, 6MS group) surveillance were retrieved from the Italian Liver Cancer database. Survival in the 3MS group was considered as observed and adjusted for lead-time bias, and survival analysis was repeated after a propensity score matching. Results The 3-months surveillance interval neither reduced the share of patients diagnosed outside the Milano criteria, nor increased their probability to receive curative treatments. The median survival of 6MS patients (55.0 months [45.9–64.0]) was not significantly different from the observed (47.0 months [35.0–58.9]; p = 0.43) and adjusted (44.9 months [33.4–56.4]; p = 0.30) survival of 3MS patients. A propensity score analysis confirmed the absence of a survival advantage for 3MS patients. Conclusions A tightening of surveillance schedule does not increase the diagnosis of early-stage tumors, the feasibility of curative treatments and the survival. Therefore, we should maintain the 6-months interval in the surveillance of viral cirrhotics.

The European Neuroendocrine Tumor Society (ENETS) guidelines advocate a right hemicolectomy (RHC) only in patients with appendiceal neuroendocrine neoplasms (aNENs) at risk for N+(node positive). The risk is defined using site, size, and grading of tumor as well as mesoappendiceal or lymphovascular invasion.A systematic review and meta-analysis was carried out. The data were reported using risk difference (RD) to define the risk of N+. The number needed to treat/harm (NNT/NNH) and the likelihood of being helped or harmed (LHH) were calculated using RD. Two strategies were considered: "to treat all" versus "to treat only patients having aNENs with risk stigmata". The aim was to evaluate the harm/benefit ratio related to the use of the ENETS lymph-nodal metastases (N+) risk factors.Six studies were included involving a total of 261 patients. The RD (-0.30; P 0.001) of N+ was significantly lower in aNENs ≤ 20 mm as compared to those20 mm. One unnecessary RHC every five patients (NNT = 5) could be avoided while 1 patient with N+ every six patients (NNH = 6) remained untreated. The risk was lower than the benefits (LHH = 1.2). The RD NNT, NNH, and LHH values suggested that only a 15 mm cutoff and the presence of lymphovascular invasion could be considered useful.An RHC should be performed in patients with aNENs20 mm. The use of a 15 mm cutoff criterion had a similar outcome to that of a 20 mm cutoff. Lymphovascular invasion should only be considered a minor criterion. Selection based on other parameters should be avoided.

The finding of an indeterminate adrenal mass at radiological investigations is a challenge for physicians. Complex diagnostic work-up, periodic follow-up, or surgical intervention are therefore needed to rule out malignant lesions. Tertiary care hospitals are provided with F-18-fludeoxyglucose (F-18-FDG) positron emission tomography (PET) and F-18-dihydroxyphenylalanine (F-18-DOPA) PET, which aid in the characterization of indeterminate adrenal masses. Nevertheless, the histopathological examination may be required to exclude malignancy or rare etiologies. A 54-year-old woman presented to our clinic 6 months after a cerebral hemorrhage. She was hypertensive and had recently discovered a left adrenal mass of 15 mm during an abdominal ultrasound. Contrast-enhanced CT, following adrenal protocol, revealed a 14-mm adrenal mass without characteristics suggestive of an adrenal adenoma. Tumor markers were negative. Functional tests excluded hormone hypersecretion. An F-18-DOPA PET was negative. An F-18-FDG PET showed mild uptake of both the adrenal glands, with a more circumscribed pattern in the left one (maximum standardized uptake value 5 4). As the clinical diagnosis was still indeterminate, we performed laparoscopic left adrenalectomy. The histopathological examination described a sclerosing angiomatoid nodular transformation (SANT) of the adrenal gland, a benign lesion already described as a rare occurrence only in the spleen. IgG4 levels were reduced. In conclusion, this is a report of a SANT of the adrenal gland, a novel entity that should be taken into consideration in the differential diagnosis of indeterminate adrenal masses at CT scan. Copyright (C) 2019 Endocrine Society

Intravesical instillation of Bacillus Calmette-Guerin (BCG) is used as an adjuvant treatment of bladder cancer. Systemic BCG infection occurs in less than 1% of cases, and pulmonary involvement is even rarer (0.3% - 0.7%), with a favourable prognosis. A 78-year-old male developed miliary tuberculosis (TB) secondary to intravesical BCG treatment and subsequent coronavirus disease 2019 (COVID-19) superinfection that led to patient death. High awareness amongst clinicians is needed to proceed with immediate appropriate therapy in these patients, especially during the COVID-19 pandemic.

Background The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials. Methods This phase II trial tested the efficacy of Nab-paclitaxel (NAB-P)/Gemcitabine (G) versus G alone. Patients were randomized, 1:1 to G 1000 mg/m2 on days 1, 8 and 15 every 28 days versus NAB-P 125 mg/m2 on days 1, 8 and 15 every 28 days plus G 1000 mg/m2 on days 1, 8 and 15 every 28 days. Disease progression rate after three cycles of chemotherapy was the primary end-point. Progression-free survival (PFS), overall survival (OS) and response rate were secondary end-points. Findings A total of124 patients were enrolled. The study showed a reduction of a progressive disease from 45.6% with G to 25.4% with NAB-P/G (P = 0.01) at 3 months. Noteworthy, at 6 months in the G arm, 35.6% of patients present a metastatic spread versus 20.8% in the NAB/G arm. The response rate was 5.3% in the G arm and 27% in the NAB/G arm. Median PFS was 4 months for the G arm and 7 months for the NAB-P/G arm. Median OS was 10.6 in the G arm and 12.7 months in the NAB-P/G arm. One patient died during treatment with G due to a stroke. Interpretation. NAB-P/G reduced the rate of LAPC patients progressing after three cycles of chemotherapy compared with G, especially in terms of distant relapses. It positively affects PFS. To the best of our knowledge, this is the first randomized trial providing evidence that combination chemotherapy is superior to gemcitabine alone in this setting. ClinicalTrials.gov Identifier NCT02043730 .

Background Aneurysms of the pancreaticoduodenal arcades are an uncommon pathology, with a prevalence of 2%, and could be congenital or acquired. Treatment of visceral aneurysms is therefore generally recommended when the aneurysmal sac equals or exceeds 2 cm. Wide-necked (> 4 mm) and main artery branch aneurysms represent a challenge for conventional endovascular coil embolization due to the risk of coil migration. Main body This case describes the technical feasibility of balloon-assisted coil embolization (BACE) in the treatment a wide neck aneurysm of inferior pancreatic duodenal artery due to celiac axis occlusion. Short conclusion In case of celiac trunk occlusion, BACE is a safe procedure associated with optimal technical success rates, in order to treat the aneurysms and to preserve splanchnic vascularization.

Background & Aims Selective Internal Radiation Therapy (SIRT) is emerging as a potential therapy for unresectable intra-hepatic cholangiocarcinoma (iCCA), able to prolong life-expectancy. Aim of the study was to collect available literature, meta-analyze data and results and investigate sources of heterogeneity through a meta-regression approach, before suggesting SIRT as a valuable option. Methods A systematic review of studies published until 1 September 2016 in PubMed and Scopus databases was performed. Patient survival was the primary outcome measure. Meta-analysis was performed using a random-effects model. Meta-regression was applied to investigate relationships existing between clinical and tumour features and the primary outcome. Results Nine observational studies were included in the analysis, involving 224 patients. The 1-, 2-, and 3-year pooled survival estimates were 55.7%, 33.1% and 20.2%. Clinical and tumour characteristics showed medium-to-considerable heterogeneity (I2>50%). Meta-regression analysis showed that determinants of best survivals were the presence of mass-forming iCCA type (median survival = 19.9 months versus 8.1 months for the infiltrative type; p=0.002) that also accounted for most of the heterogeneity between included studies (residual I2=0); SIRT as first line therapy (median survival = 24 months versus 11.5 months for non-naive patients; p=0.048) and the adoption of concomitant chemotherapy (median survival 19.5 months vs. 5.5 months in patients not receiving chemotherapy; P=0.042). Conclusions There is considerable heterogeneity between studies, highlighting that indications for SIRT are extremely varied. To ameliorate SIRT results, naive patients with mass-forming iCCA should be selected as the best candidates, with the possibility of adding concomitant standard chemotherapy. This article is protected by copyright. All rights reserved.

Purpose: Patients with hepatocellular carcinoma (HCC) of intermediate stage (BCLC-B according to the Barcelona Clinic Liver Cancer classification) are a heterogeneous group with different degrees of liver function impairment and tumour burden. The recommended treatment is transarterial chemoembolization (TACE). However, patients in this group may be judged as poor candidates for TACE because the risk-benefit ratio is low. Such patients may receive transarterial radioembolization (TARE) only by entering a clinical trial. Experts have proposed that the stage could be further divided into four substages based on available evidence of treatment benefit. We report here, for the first time, the outcome in patients with BCLC-B2 substage HCC treated with TARE. Methods: A retrospective analysis of the survival of 126 patients with BCLC-B2 substage HCC treated with TARE in three European hospitals was performed. Results: Overall median survival in patients with BCLC-B2 substage was not significantly different in relation to tumour characteristics; 19.35 months (95% CI 8.27–30.42 months) in patients with a single large (>7 cm) HCC, and 18.43 months (95% CI 15.08–21.77 months) in patients with multinodular HCC (p = 0.27). However, there was a higher proportion of long-term survivors at 36 months among those with a single large tumour (29%) than among those with multiple tumours (16.8%). Conclusion: Given the poor efficacy of TACE in treating patients with BCLC-B2 substage HCC, TARE treatment could be a better choice, especially in those with a large tumour.

Background Doxorubicin-loaded drug-eluting beads TACE (DEB-TACE) has been developed to maximize the therapeutic efficacy of conventional trans-catheter arterial chemo-embolization (cTACE) in patients with hepatocellular carcinoma (HCC); however, its cost-effectiveness (CE) still needs to be assessed. Aims To investigate the CE of DEB-TACE versus cTACE. Methods Results from a meta-analysis of the pertinent literature were used to construct a CE Markov simulation model which followed a hypothetical cohort of HCC patients who underwent DEB-TACE or cTACE, covering the entire post-TACE lifespan until death. Costs were assessed from the health-care provider perspective. Results Five randomized controlled trials (RCTs) and 11 observational studies, including 1860 patients (883 DEB-TACE and 977 cTACE), were used for the construction of the model. Considering only survival rates from RCTs (heterogeneity: 0%), DEB-TACE returned 4.0 quality-adjusted life-years (QALYs) and TACE returned 3.3 QALYs (effect size = 1.288). Total costs of cTACE were €10,389 and those of DEB-TACE were €11,418 (effect size = 0.791). DEB-TACE was found more cost-effective than cTACE when a minimum willingness-to-pay of about €2000–3500/QALY was accepted, mainly depending on shorter in-hospital stay and better quality of life. Conclusions Direct incremental costs of DEB-TACE can be acceptable in respect to cTACE, relying on financial resources available from the payer perspective.

Background: Many patients with primary liver cancers are not candidates for surgery, and systemic therapies are seldom effective. Selective internal radiation therapy (SIRT) has been shown to obtain partial and even complete response in unresectable primary tumors. As a “side effect”, SIRT can induce contra-lateral liver hypertrophy. Tumor response to SIRT can be sufficient to allow disengagement from normal vital structures whose involvement is the cause of the initial unresectability. The contra-lateral hypertrophy can thereby increase the future liver remnant (FLR) volume to over the safe threshold so that extended hepatectomy can be performed. Summary: A review of the available literature was performed to assess the tumor response and liver hypertrophy that can be expected after SIRT, in order to delineate whether SIRTcan play a role in conversion therapy for resectability of primary liver malignancies. Key Message: Available data suggest that SIRT in unresectable hepatocellular and cholangiocellular carcinomas can provide a considerable down-sizing of the tumors to possibly allow resection. Hypertrophy of the contra-lateral lobe represents a favorable collateral effect that can help in achieving safer subsequent major hepatectomy. In patients whose FLR volume represents the only surgical concern, portal vein embolization remains the treatment of choice.

Background & aims To develop an individual prognostic calculator for patients with unresectable hepatocellular carcinoma (HCC) undergoing trans-arterial chemo-embolization (TACE). Methods Data from two prospective databases, regarding 361 patients who received TACE as first-line therapy (2000-2012), were reviewed in order to refine available prognostic tools and to develop a continuous individual web-based prognostic calculator. Patients with neoplastic portal vein invasion were excluded from the analysis. The model was built following a bootstrap resampling procedure aimed at identifying prognostic predictors and by carrying out a 10-fold cross-validation for accuracy assessment by means of Harrell's c-statistic. Results Number of tumours, serum albumin, serum total bilirubin, alpha-foetoprotein and maximum tumour size were selected as predictors of mortality following TACE with the bootstrap resampling technique. In the 10-fold cross-validation cohort, the model showed a Harrell's c-statistic of 0.649 (95% CI: 0.610-0.688), significantly higher than that of the Hepatoma Arterial-embolization Prognostic (HAP) score (0.589; 95% CI: 0.552-0.626; P = 0.001) and of the modified HAP-II score (0.611; 95% CI: 0.572-0.650; P = 0.005). Akaike's information criterion for the model was 2520; for the mHAP-II it was 2544 and for the HAP score it was 2554. A web-based calculator was developed for quick consultation at http://www.livercancer.eu/mhap3.html. Conclusions The proposed individual prognostic model can provide an accurate prognostic prediction for each patient with unresectable HCC following treatment with TACE without class stratification. The availability of an online calculator can help physicians in daily clinical practice.

Objective: Primary aldosteronism is associated with higher cardiovascular morbidity as compared with essential hypertension. Vascular complications encompass myocardial infarction and cerebrovascular events. Aortic damage in primary aldosteronism has never been explored, although a few cases of ascending aorta aneurisms have been reported. Design and methods: We consecutively enrolled patients affected by primary aldosteronism (n = 45) and compared them with patients affected by essential hypertension (n = 47), on an outpatient setting. Echocardiographic data of patients with primary aldosteronism were collected during a mean follow-up of 3 years, in subjects who underwent adrenal surgery (n = 12) and those on mineralocorticoid receptor antagonists (n = 33). Results and conclusion: We found that patients with primary aldosteronism had larger ascending aorta diameters than those with essential hypertension before starting any specific treatment. Patients with primary aldosteronism did not show significant changes in the size of ascending aorta during a mean of 3 years of follow-up, irrespective of the type of treatment (medical vs. surgical treatment). A longer follow-up will better clarify if worsening of the aortic damage may be better prevented by surgery rather than by mineralocorticoid receptor antagonists.

Background: Somatostatin analogs are the backbone of neuroendocrine neoplasms treatment. Biliary stone disease is a potentially severe adverse event of somatostatin analogs: an increased incidence has been reported in somatostatin analogs-treated acromegalic patients, but studies on patients with neuroendocrine neoplasms are lacking. Aims: To evaluate biliary stone disease incidence and associated factors in a large series of patients treated with somatostatin analogs for neuroendocrine neoplasms. Methods: A prospectively-collected database of patients with a diagnosis of neuroendocrine neoplasms of any grade and site, treated with somatostatin analogs at our Institution between 1995 and 2017, was retrospectively analyzed. Patients’ demographics and disease characteristics were analyzed to evaluate the incidence and the factors related to biliary stone disease. Results: Three-hundred patients were included; 101 (33.7%) patients underwent cholecystectomy before starting somatostatin analogs. Among 164 patients with gallbladder in situ and no history of stone disease, 60 (36.6%) developed gallstones after a mean of 36.7 months (range 1–239) from treatment start with a mean yearly incidence of 8.73%. Previous cholecystectomy was associated with a lower rate of development of gallstones (p < 0.001) or related complications (p = 0.017). Conclusion: We observed a high incidence of biliary stone disease in patients treated with somatostatin analogs-treated for neuroendocrine neoplams. Previous cholecystectomy was the only factor associated with a lower occurrence of biliary stone disease.

Background Trans-arterial radio-embolization (TARE) is an emerging treatment for the management of hepatocellular carcinoma (HCC). TARE may compete with systemic chemotherapy, sorafenib, in intermediate stage patients with prior chemoembolization failure or advanced patients with tumoral macrovascular invasion with no extra-hepatic spread and good liver function. We performed a budget impact analysis (BIA) evaluating the expected changes in the expenditure for the Italian Healthcare Service within scenarios of increased utilization of TARE in place of sorafenib over the next five years. Methods Starting from patient level data from three oncology centres in Italy, a Markov model was developed to project on a lifetime horizon survivals and costs associated to matched cohorts of intermediate-advanced HCC patients treated with TARE or sorafenib. The initial model has been integrated with epidemiological data to perform a BIA comparing the current scenario with 20 and 80% utilization rates for TARE and sorafenib, respectively, with increasing utilization rates of TARE of 30, 40 and 50% over the next 1, 3 and 5 years. Results Compared to the current scenario, progressively increasing utilization rates of TARE over sorafenib in the next 5 years is expected to save globally about 7 million Euros. Conclusions Radioembolization can be considered a valuable treatment option for patients with intermediate-advanced HCC. These findings enrich the evidence about the economic sustainability of TARE in comparison to standard systemic chemotherapy within the context of a national healthcare service. Electronic supplementary material The online version of this article (10.1186/s12885-018-4636-7) contains supplementary material, which is available to authorized users.

OBJECTIVE. The aim of this study is to determine whether any correlation between CT findings and functional parameters exists to predict subclinical glucocorticoid secretion. MATERIALS AND METHODS. This is a retrospective database study of 55 patients with incidentally discovered adenomas, investigated through CT with an adrenal protocol, assessing diameters and attenuation values on the unenhanced and contrast-enhanced phases. Patients underwent blood cortisol and corticotropin evaluation and overnight dexamethasone suppression test (DST), in accordance with clinical recommendations. Cortisol levels higher than 50 nmol/L after DST identified subclinical cortisol secretion. We identified 28 subjects with lipid-rich nonsecreting adenomas, nine with lipid-rich secreting adenomas, 11 with lipidpoor nonsecreting adenomas, and seven with lipid-poor secreting adenoma. RESULTS. Cortisol levels after DST were significantly and positively related to mass diameters. At univariate analysis, maximum and minimum diameters and attenuation in the delayed phase were significantly related to the presence of secreting or nonsecreting adenoma; at multivariate analysis, only the minimum diameter and the attenuation in the venous phase entered the stepwise logistic regression. Similarly, minimum diameter and attenuation in the venous phase emerged also at the multivariate stepwise regression between radiologic parameters and cortisol levels after DST. The formula of the radiologic score computed by using the coefficients of the multivariate regression was as follows: (0.1914 × minimum diameter) + (0.0308 × enhanced attenuation). The diagnostic accuracy of this discriminatory score in differentiating secreting from nonsecreting adenomas was 84.9%, the sensitivity was 81.3%, and the specificity was 87.2%. Adenomas with scores greater than 7.59 were considered as secreting adenomas, and adenomas with scores less than 7.36 were considered as nonsecreting adenomas. CONCLUSION. This study shows that imaging parameters can predict subclinical cortisol hypersecretion in patients with adrenal adenomas.

Background & Aims: Determining risk for recurrence or survival after curative resection or ablation in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is important for stratifying patients according to expected outcomes in future studies of adjuvant therapy in the era of direct-acting antivirals (DAAs). The aims of this meta-analysis were to estimate the recurrence and survival probabilities of HCV-related early HCC following complete response after potentially curative treatment and to identify predictors of recurrence and survival. Methods: Studies reporting time-dependent outcomes (HCC recurrence or death) after potentially curative treatment of HCV-related early HCC were identified in MEDLINE through May 2016. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using a distribution-free summary survival curve. Primary outcomes were actuarial probabilities of recurrence and survival. Results: Eleven studies met the inclusion criteria. Pooled estimates of actuarial recurrence rates were 7.4% at 6months and 47.0% at 2years. Pooled estimates of actuarial survival rates were 79.8% at 3years and 58.6% at 5years. Heterogeneity among studies was highly significant for all outcomes. By univariate meta-regression analyses, lower serum albumin, randomized controlled trial study design and follow-up were independently associated with higher recurrence risk, whereas tumour size and alpha-foetoprotein levels were associated with higher mortality. Conclusions: This meta-analysis showed that recurrence risk and survival are extremely variable in patients with successfully treated HCV-related HCC, providing a useful benchmark for indirect comparisons of the benefits of DAAs and for a correct design of randomized controlled trials in the adjuvant setting.

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Background:Intrahepatic cholangiocarcinoma (ICC) is a rapidly progressing malignancy; only a minority of the tumours can be resected and the palliative regimens have shown limited success. The aim of this study was to assess overall survival (OS), tumour response and the safety of radioembolization with yttrium-90 (90Y-TARE) in patients with unresectable/recurrent ICC.Methods:Survival was calculated from the date of the 90Y-TARE procedure. Target and overall Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) and European Association for the Study of the Liver (EASL)—measuring delayed-phase contrast enhancement—treatment responses were assessed at 3 months.Results:The overall median survival was 17.9 months (95% CI: 14.3–21.4 months). Significantly longer survival was obtained in naive patients as compared with patients in whom TARE was preceded by other treatments, including surgery (52 vs 16 months, P=0.009). Significantly prolonged OS was recorded for patients with a response based on mRECIST and the EASL criteria while RECIST responses were not found to be associated with survival. Treatment was well-tolerated, and no mortality was reported within 30 days.Conclusions:In unresectable ICC, 90Y-TARE is safe and offers a survival benefit in naive patients, as well as in responders.British Journal of Cancer (2016) advance online publication 23 June 2016; doi:10.1038/bjc.2016.191 www.bjcancer.com.

A 64-year-old man presented to the hospital because of hematemesis; on admission, he had weakness and pale skin, tachycardia and hypotension. Laboratory tests revealed severe anemia (hemoglobin 7.8 g/dL); liver, renal and pancreatic function tests were normal. An upper digestive endoscopy revealed a gastric ulcer of the cardia, treated with metallic clips and adrenalin injection. The patient was treated with fluids and was transfused with three units of red blood cells. In the previous two months, due to the presence of bloating and diarrhea, associated with abdominal distension, a colon-computed tomography (CT) revealed a large retroperitoneal hypodense mass, 53x37 mm in size, without contrast enhancement localized between the body and the tail of the pancreas and the stomach, near the splenic artery and without signs of infiltration. To better define the mass, endoscopic ultrasound and biopsy were performed; however histopathology of multiple biopsies was not diagnostic, because of the presence of necrotic tissue and inflammatory cells. Since hematemesis recurred, the patient underwent a second upper digestive endoscopic examination, but no source of bleeding was found. Then a new contrast enhanced CT was performed that showed a size reduction of the mass, the presence of blood in the stomach and a small pseudoaneurysm of the splenic artery. Because of these findings an angiograpghic study was carried out; angiography confirmed a splenic artery pseudoaneurysm that was successfully embolized with metal microcoils.

Background & Aims: Portosystemic encephalopathy (PSE) is a major complication of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement. Most devices are self-expandable polytetrafluoroethylene-covered stent grafts (PTFE-SGs) that are dilated to their nominal diameter (8 or 10 mm). We investigated whether PTFE-SGs dilated to a smaller caliber (under-dilated TIPS) reduce PSE yet maintain clinical and hemodynamic efficacy. We also studied whether under-dilated TIPS self-expand to nominal diameter over time. Methods: We performed a prospective, non-randomized study of 42 unselected patients with cirrhosis who received under-dilated TIPS (7 and 6 mm) and 53 patients who received PTFE-SGs of 8 mm or more (controls) at referral centers in Italy. After completion of this study, dilation to 6 mm became the standard and 47 patients were included in a validation study. All patients were followed for 6 months; Doppler ultrasonography was performed 2 weeks and 3 months after TIPS placement and every 6 months thereafter. Stability of PTFE-SG diameter was evaluated by computed tomography analysis of 226 patients with cirrhosis whose stent grafts increased to 6, 7, 8, 9, or 10 mm. The primary outcomes were incidence of at least 1 episode of PSE grade 2 or higher during follow up, incidence of recurrent variceal hemorrhage or ascites, incidence of shunt dysfunction requiring TIPS recanalization, and reduction in porto-caval pressure gradient. Results: PSE developed in a significantly lower proportion of patients with under-dilated TIPS (27%) than controls (54%) during the first year after the procedure (P =.015), but the proportions of patients with recurrent variceal hemorrhage or ascites did not differ significantly between groups. No TIPS occlusions were observed. These results were confirmed in the validation cohort. In an analysis of self-expansion of stent grafts, during a mean follow-up period of 252 days after placement, none of the PTFE-SGs self-expanded to the nominal diameter in hemodynamically relevant sites (such as portal and hepatic vein vascular walls). Conclusions: In prospective, non-randomized study of patients with cirrhosis, we found under-dilation of PTFE-SGs during TIPS placement to be feasible, associated with lower rates of PSE, and effective.

CONTEXT: Long-term follow-up studies revealed that patients with subclinical hypercortisolism (SH) due to adrenocortical adenomas have an increased incidence of cardiovascular diseases and mortality. No studies have yet investigated the steroid profile and its implications in patients with SH. OBJECTIVE: The objective of the study was to analyze the steroid profile by liquid chromatography-tandem mass spectrometry in sera from patients with unilateral adrenocortical adenomas. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at an outpatient clinic. PARTICIPANTS: Patients with adrenocortical adenomas (nonsecreting, n = 66; SH, n = 28) and 188 age- and sex-matched controls drawn from the general population participated in the study. MAIN OUTCOME MEASURES: Cortisol, 21-deoxycortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, T, progesterone, 11-deoxycorticosterone, and corticosterone in the basal condition and after a 1-24 ACTH test, and clinical data were measured. RESULTS: Patients with SH showed lower basal and 1-24 ACTH-stimulated levels of dehydroepiandrosterone and androstenedione than those with nonsecreting adenomas and controls. T was also lower in SH females. Receiver-operating characteristic curves showed that androgens had good accuracy in predicting SH (sensitivity and specificity were 71% and 76% for dehydroepiandrosterone and 69% and 61% for androstenedione, respectively). Increased cortisol and reduced dehydroepiandrosterone levels were independently associated with increased waist circumference. Cortisol was also independently associated with increased number of cardiovascular risk factors in SH patients. After 1-24 ACTH stimulation, the SH patients also showed increased production of 21-deoxycortisol and 11-deoxycorticosterone. CONCLUSIONS: Liquid chromatography-tandem mass spectrometry steroid profile performed for the first time in sera from patients with adrenocortical adenomas showed impaired secretion of several steroids in SH patients. This fingerprint can help in better characterizing the functional status of these tumors.

Purpose: We analyzed overall survival (OS) following radioembolization according to macroscopic growth pattern (nodular vs infiltrative) and vascular invasion in intermediate–advanced hepatocellular carcinoma (HCC). Methods: Between September 2005 and November 2013, 104 patients (50.0% portal vein thrombosis [PVT], 29.8% infiltrative morphology) were treated. Results: Median OS differed significantly between patients with segmental and lobar or main PVT (p = 0.031), but was 17 months in both those with patent vessels and segmental PVT. Median OS did not differ for infiltrative and nodular HCC. Median OS was prolonged in patients with a treatment response at 3 months (p = 0.023). Prior TACE was also a significant predictor of improved OS. Conclusion: A further indication for radioembolization might be infiltrative HCC, since OS was similar to nodular types.

A 31-year-old woman with bipolar disorder was hospitalized for suspected neuroleptic malignant syndrome. During her hospital stay, she was affected by acute lower gastrointestinal hemorrhage. After unsuccessful endoscopy, the patient became hemodynamically unstable and underwent angiography that showed bleeding from the right superior rectal artery, embolized by using gelatin sponge (Spongostan, Ferrosan Medical Devices A/S, Søborg, Denmark). The subsequent angiographic study of the right internal iliac artery showed active bleeding from a pseudoaneurysm of the inferior rectal artery that was embolized by using N-butyl-2-cyanoacrylate (Glubran 2, GEM Srl, Viareggio, Italy). The patient had a successful clinical outcome without rectal ischemia.

Purpose: The target lesion response (according to the Choi criteria), safety and survival following selective or superselective transarterial radioembolisation using yttrium-90-resin microspheres (90Y-RE) were evaluated in patients with unresectable, chemotherapy-refractory colorectal cancer liver metastases (mCRC). Materials and methods: A prospective case series evaluated 52 consecutive patients with mCRC who were treated at a single centre following a median of 2 lines of chemotherapy. Results: Nearly half (46.2 %) of the 52 patients had a prior resection of the liver. At baseline, mCRC was limited to the liver (in 56.9 %), liver plus extra-hepatic metastases (23.5 %) or liver plus lung micro-nodules (19.6 %). Disease control rates of target lesions (partial response plus stable disease) at 3 and 6 months post-90Y-RE were 59 and 29 %, respectively. Target lesions were sufficiently downsized in two patients for hepatic resection and in one patient for radiofrequency ablation. Median Kaplan–Meier survival was 11.0 months (95 % confidence interval: 8.0–14.0 months) overall and 12.0 months in liver-only disease (±lung micro-nodules). Determinants of prolonged survival were response at 3 months (P = 0.046), ≤5 liver nodules (P = 0.004), single-liver-lobe involvement (P = 0.037), tumour-to-whole liver ratio 90Y-RE were grade 1 90Y-RE-induced liver disease (n = 1), grade 2 and 3 gastric ulcers (n = 2). Conclusion: These results confirm the effectiveness and safety of selective 90Y-RE in patients with chemotherapy-refractory mCRC, showing 90Y-RE’s potential as a bridging therapy to subsequent resection even in this end-stage population.

Transarterial radioembolization (TARE) is a form of brachytherapy in which intra-arterially injected yttrium-90-loaded microspheres serve as a source for internal radiation purposes. On the average, it produces disease control rates exceeding 80% and it is a consolidated therapy for hepatocellular carcinoma (HCC); however, current data are all based on retrospective series or non-controlled prospective studies since randomized controlled trials comparing it with the other liver-directed therapies for intermediate and locally advanced stage HCC are still underway. The data available show that TARE provides similar or even better survival rates when compared to transarterial chemoembolization (TACE). First-line TARE is best indicated for both intermediate-stage patients (staged according to the barcelona clinic liver cancer staging classification) who have lesions which respond poorly to TACE due to multiple tumors or a large tumor burden, and for locally advanced-stage patients with solitary tumors, and segmental or lobar portal vein tumor thrombosis. In addition, emerging data have suggested the use of TARE in patients who are classified slightly beyond the Milan criteria regarding radical treatment for downstaging purposes. As a second-line treatment, TARE can also be applied in patients progressing to TACE or sorafenib; a large number of phase II/III trials are ongoing with the purpose of evaluating the best association with systemic therapies. Transarterial radioembolization is very well tolerated and has a low rate of complications which are mainly related to unintended non-target tissue irradiation, including the surrounding liver parenchyma. The complications can be additionally reduced by accurate patient selection and a strict pre-treatment evaluation including dosimetry and assessment of the vascular anatomy. Since a correct treatment algorithm for potential TARE candidates is not clear and standardized, this comprehensive review analyzes the best selection criteria for patients who really benefit from TARE and also the new advances of this therapy, which can be a very important weapon against HCC.

Purpose: The major complication occurring with biliary stents is stent occlusion, frequently seen because of tumour in-growth, epithelial hyperplasia, and sludge deposits, resulting in recurrent jaundice and cholangitis. We report a prospective study with the results of first in man percutaneous intraductal radiofrequency (RF) ablation to clear the blocked metal stents in patients with malignant biliary obstruction using a novel bipolar RF catheter. Methods: Nine patients with malignant biliary obstruction and blocked metal stents were included. These patients underwent intraductal biliary RF ablation through the blocked metal stent following external biliary decompression with an internal-external biliary drainage. Results: All nine patients had their stent patency restored successfully without the use of secondary stents. Following this intervention, there was no 30-day mortality, haemorrhage, bile duct perforation, bile leak, or pancreatitis. Of the nine patients, six are alive and three patients are dead with a median follow-up of 122 (range 50-488) days and a median stent patency of 102.5 (range 50-321) days. Six patients had their stent patent at the time of last follow-up or death. Three patients with stent blockage at 321, 290, and 65 days postprocedure underwent percutaneous transhepatic drain insertion and repeat ablation. Conclusions: In this selective group of patients, it appears that this new approach is safe and feasible. Efficacy remains to be proven in future, randomized, prospective studies. © 2013 Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).

Purpose: Previous clinical studies have shown the safety and efficacy of this novel radiofrequency ablation catheter when used for endoscopic palliative procedures. We report a retrospective study with the results of first in man percutaneous intraductal radiofrequency ablation in patients with malignant biliary obstruction. Methods: Thirty-nine patients with inoperable malignant biliary obstruction were included. These patients underwent intraductal biliary radiofrequency ablation of their malignant biliary strictures following external biliary decompression with an internal-external biliary drainage. Following ablation, they had a metal stent inserted. Results: Following this intervention, there were no 30-day mortality, hemorrhage, bile duct perforation, bile leak, or pancreatitis. Of the 39 patients, 28 are alive and 10 patients are dead with a median survival of 89.5 (range 14-260) days and median stent patency of 84.5 (range 14-260) days. One patient was lost to follow-up. All but one patient had their stent patent at the time of last follow-up or death. One patient with stent blockage at 42 days postprocedure underwent percutaneous transhepatic drain insertion and restenting. Among the patients who are alive (n = 28) the median stent patency was 92 (range 14-260) days, whereas the patients who died (n = 10) had a median stent patency of 62.5 (range 38-210) days. Conclusions: In this group of patients, it appears that this new approach is feasible and safe. Efficacy remains to be proven in future, randomized, prospective studies. © 2012 Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).

Background Large regenerative nodules (LRNs) are hyperplastic benign nodules most commonly associated with Budd-Chiari syndrome (BCS), caused by outflow obstruction of the hepatic veins or vena cava. To our knowledge, no cases of LRNs arising in BCS after transjugular intrahepatic portosystemic shunt (TIPS) positioning and detected by Gd-EOB-DTPA MRI have been reported in the literature. Methods A 58-year-old woman with BCS, on the liver transplantation (LT) list, underwent a follow-up enhanced MRI. Two years earlier, a TIPS had been placed. In 2008, recurrent hepaticoencephalopathy resistant to medical treatment fulfilled the LT criteria for BCS treated with TIPS and the patient was therefore added to the LT list. CT performed before TIPS had not detected any hepatic lesions. CT performed six months after TIPS showed its complete patency but documented two indeterminate hypervascular liver lesions. Results MRI performed with Gd-EOB-DTPA revealed additional hypervascular lesions with uptake and retention of the medium in the hepatobiliary phase, thus refecting a benign behavior of hepatocellular composition. These MRI features were related to LRNs as confrmed by histopathologic analysis. Conclusions Gd-EOB-DTPA-enhanced MRI is potentially superior to standard imaging using gadolinium chelates or spiral CT, especially for the differential diagnosis of hypervascular lesions. Gd-EOB-DTPA MRI may become the imaging method of choice for evaluating LT list patients with BCS after TIPS placement.