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Background: Lenvatinib is approved as a first‐line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment‐emergent hypertension (CSTE‐HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE‐HTN on the efficacy and safety of lenvatinib in HCC. Methods: Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE‐HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression‐free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks. Results: A total of 212 patients in the lenvatinib arm developed CSTE‐HTN, and 264 did not. CSTE‐HTN first occurred at 3.7 weeks (median); the worst grade CSTE‐HTN occurred at 4.1 weeks (median). No patients had life‐threatening CSTE‐HTN and/or died due to CSTE‐HTN. Median OS was numerically longer in patients with versus without CSTE‐HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621–1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696–1.089). Median PFS was similar between patients with and without CSTE‐HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680–1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84–1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE‐HTN (34.5%). Conclusions: In this retrospective analysis, CSTE‐HTN was associated with improved OS but not PFS. CSTE‐HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately. Clinically significant treatment‐emergent hypertension (CSTE‐HTN) in patients with hepatocellular carcinoma who are treated with lenvatinib does not negatively impact outcomes when CSTE‐HTN is detected early and managed appropriately with dedicated medication and lenvatinib dose modifications. [ABSTRACT FROM AUTHOR]

Although non-randomized, this study provides high-quality data emphasizing the performance of non-enhanced MRI as a surveillance tool for patients with cirrhosis at high risk of developing HCC. Conversely, the study suffers from some methodological limitations, worth noting before jumping to the conclusion that non-enhanced MRI should be immediately implemented as a surveillance imaging tool for every patient at risk of HCC. In conclusion, non-enhanced MRI cannot be considered a standard modality for HCC surveillance for all patients at risk of HCC, but it has potential, especially as it appears to be almost as sensitive but more applicable than contrast-enhanced liver imaging. 15 M.V. Chan, S.J. McDonald, Y.Y. Ong, K. Mastrocostas, E. Ho, Y.R. Huo, HCC screening: assessment of an abbreviated non-contrast MRI protocol. [Extracted from the article]

Abstract: Background & Aims: Pain management in cirrhosis is a clinical challenge. Most analgesics are metabolized in the liver and cirrhosis may deeply alter their concentration, favouring the appearance of side effects. We aimed to assess the efficacy and safety of oral prolonged‐release association of oxycodone/naloxone tablets (OXN) in the treatment of moderate/severe cancer pain in cirrhotic patients with metastatic hepatocellular carcinoma (HCC). Methods: We enrolled n = 32 HCC patients with moderate/severe cancer pain unresponsive to paracetamol alone or associated with codeine or tramadol. All patients received an initial OXN dose of 5 mg bid to be gradually increased in case of insufficient analgesia. At baseline and follow‐up visits, we evaluated: pain intensity (using the Numerical Rating Scale, NRS), patients’ autonomy in daily activities (Barthel Functioning Index); bowel dysfunction (Bowel Function Index, BFI), signs of hepatic encephalopathy (HE) and other opioid‐induced side effects. Results: No clinically significant adverse effects were reported (median follow‐up 122 days). No significant worsening of the BFI score was noted and no cases of HE were detected. Two patients (6.3%) discontinued treatment before T14 because of mild nausea and dizziness. The remaining n = 30 patients were assessed for efficacy. Treatment led to a significant reduction in the mean of pain scores both at T14 (−37.1 ± 16.3%, P < .001) and at T28 (−55.6 ± 21.5%, P < .001); Barthel scores showed gradual and significant increase from T0 (81.6 ± 13.0) to T14 (86.5 ± 11.4, P = .001) and to T28 (88.3 ± 13.6, P = .009). Conclusions: OXN may be considered a safe and effective option in the fragile population of cirrhotic patients. [ABSTRACT FROM AUTHOR]

Previous meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this benefit translates into improved survival is unknown. We conducted an individual patient data (IPD) meta-analysis to assess the effect of anticoagulation on all-cause mortality in patients with cirrhosis and portal vein thrombosis. In this IPD meta-analysis, we selected studies comparing anticoagulation vs. no treatment in patients with cirrhosis and portal vein thrombosis from PubMed, Embase, and Cochrane databases (until June 2020) (PROSPERO no.: CRD42020140026). IPD were subsequently requested from authors. The primary outcome – the effect of anticoagulation on all-cause mortality – was assessed by a one-step meta-analysis based on a competing-risk model with liver transplantation as the competing event. The model was adjusted for clinically relevant confounders. A multilevel mixed-effects logistic regression model was used to determine the effect of anticoagulation on recanalization. Individual data on 500 patients from five studies were included; 205 (41%) received anticoagulation and 295 did not. Anticoagulation reduced all-cause mortality (adjusted subdistribution hazard ratio 0.59; 95% CI 0.49–0.70), independently of thrombosis severity and recanalization. The effect of anticoagulation on all-cause mortality was consistent with a reduction in liver-related mortality. The recanalization rate was higher in the anticoagulation arm (adjusted odds ratio 3.45; 95% CI 2.22–5.36). The non-portal-hypertension-related bleeding rate was significantly greater in the anticoagulation group. Anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization, but at the expense of increasing non-portal hypertension-related bleeding. CRD42020140026. Anticoagulation is effective in promoting recanalization of portal vein thrombosis in patients with cirrhosis, but whether this benefit translates into improved survival is controversial. Our individual patient data meta-analysis based on a competing-risk model with liver transplantation as the competing event shows that anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization. According to our findings, portal vein thrombosis may identify a group of patients with cirrhosis that benefit from long-term anticoagulation. [Display omitted] • Anticoagulation appears to reduce all-cause mortality in patients with cirrhosis and portal vein thrombosis. • The beneficial effect of anticoagulation on survival is independent of thrombosis severity and recanalization. • Anticoagulation increases the rate of portal vein recanalization at the expense of increased non-portal hypertension-related bleeding. [ABSTRACT FROM AUTHOR]

Background: Patients with single hepatocellular carcinoma (HCC) usually undergo transarterial chemoembolization (TACE) if they are not candidates for curative surgical or ablative therapy. The primary aim of the study was to assess the overall survival and clinical determinants of survival in patients with single HCC who underwent TACE. The secondary aims were tumor response, local and distant recurrence rates, time to recurrence and the impact of TACE on liver function. Methods: The outcomes of 148 consecutive patients with single HCC who underwent TACE from January 2004 to December 2009 were retrospectively analyzed. Results: Complete response (CR) was observed in 95/148 (64%) patients and a partial response (PR) in 39 (26%) patients. The recurrence rate was 27%, 42% and 65% at 6, 12 and 24 months, respectively. The day after TACE, 56 (38%) patients had a Child-Pugh increase ≥1 and 93 (63%) had a MELD increase =1. Median survival was 36.0 months with 1-, 3- and 5-year survival rates of 85%, 50% and 26%, respectively. Bland portal thrombosis was not seen to have any impact at univariate survival analysis; however, a slight impairment of PS (PS-1) in small tumors had some, although minor, impact on prognosis. Factors associated with shorter survival at multivariate analysis were tumor >5 cm, absence of CR, ascites, alpha-fetoprotein (AFP) ≥14.5 ng/mL and a MELD increase ≥1. Conclusions: Transarterial chemoembolization is a valid treatment option in patients with single HCC not suitable for curative treatment. Bland PVT has no major impact on survival and a slight impairment of PS attributable to cirrhosis in patients within the Milan criteria should not preclude the use of TACE. [ABSTRACT FROM AUTHOR]

Keywords: CEUS; Number needed to diagnose; Cost-effectiveness; Metastases; Focal liver lesions; Tumor staging EN CEUS Number needed to diagnose Cost-effectiveness Metastases Focal liver lesions Tumor staging 272 273 2 12/30/20 20210201 NES 210201 See Article, pages 419-427 Contrast-enhanced ultrasound (CEUS) was introduced around 20 years ago and hepatological applications have been the mainstay of its use since then. Since the early works, CEUS has also been shown to detect liver metastases missed by radiologic techniques.[5] However, the fact that CEUS can detect some lesions missed by other radiological techniques does not confirm whether it is worth recommending in all or in specified categories of patients. Therefore, considering this patient population (T3/T4 tumor stage without definite liver metastasis at CT), the number of CEUS exams needed to detect 1 additional metastasis would be 24.5. [Extracted from the article]

We report the case of a 68-year-old man with advanced hepatocellular carcinoma (HCC) with multiple bone metastases (BM) treated with tyrosine kinase inhibitors. Despite an insufficient disease control on BM with a progression free survival (PFS) of 6 months, sorafenib was not discontinued and multiple radiation therapy (RT) sessions with a palliative purpose were performed. Thanks to this aggressive radiotherapy approach in order to control the bone tumor burden, the patient has continued sorafenib for 34.6 months achieving an overall survival (OS) of 41.3 months. This result highlights the importance of a tailored management of patients with advanced HCC and the role of the RT for BM control, even if at lower cumulative radiation dose, for extending patient survival. [ABSTRACT FROM AUTHOR]

Abstract: This review illustrates the state of the art clinical applications and the future perspectives of ultrasound elastographic methods for the evaluation of chronic liver diseases, including the most widely used and validated technique, transient elastography, followed by shear wave elastography and strain imaging elastography. Liver ultrasound elastography allows the non-invasive evaluation of liver stiffness, providing information regarding the stage of fibrosis, comparable to liver biopsy which is still considered the gold standard; in this way, it can help physicians in managing patients, including the decision as to when to start antiviral treatment. The characterization of focal liver lesions and the prognostic role of the elastographic technique in the prediction of complications of cirrhosis are still under investigation. [Copyright &y& Elsevier]

Background & Aims: Both hepatic resection and radiofrequency ablation (RFA) are considered curative treatments for hepatocellular carcinoma (HCC), but their economic impact still remains not determined. Aim of the present study was to analyze the cost-effectiveness (CE) of these two strategies in early stage HCC (Milan criteria). Methods: As first step, a meta-analysis of the pertinent literature of the last decade was performed. Seventeen studies fulfilled the inclusion criteria: 3996 patients underwent resection and 4424 underwent RFA for early HCC. Data obtained from the meta-analysis were used to construct a Markov model. Costs were assessed from the health care provider perspective. A Monte Carlo probabilistic sensitivity analysis was used to estimate outcomes with distribution samples of 1000 patients for each treatment arm. Results: In a 10-year perspective, for very early HCC (single nodule <2cm) in Child–Pugh class A patients, RFA provided similar life-expectancy and quality-adjusted life-expectancy at a lower cost than resection and was the most cost-effective therapeutic strategy. For single HCCs of 3–5cm, resection provided better life-expectancy and was more cost-effective than RFA, at a willingness-to-pay above €4200 per quality-adjusted life-year. In the presence of two or three nodules ⩽3cm, life-expectancy and quality-adjusted life-expectancy were very similar between the two treatments, but cost-effectiveness was again in favour of RFA. Conclusions: For very early HCC and in the presence of two or three nodules ⩽3cm, RFA is more cost-effective than resection; for single larger early stage HCCs, surgical resection remains the best strategy to adopt as a result of better survival rates at an acceptable increase in cost. [Copyright &y& Elsevier]

Background & Aims: Contrast enhanced computed tomography (CT-scan) is a standard of care for the radiological diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. This technique, however, is not validated to exclude intrahepatic cholangiocarcinoma (ICC) which may develop in patients with cirrhosis, as well. Methods: To assess the features of contrast CT-scan in the diagnosis of ICC, we reviewed all CT-scan films obtained in cirrhotic patients with a histologically documented ICC, taking in consideration the pattern and dynamics of the arterial, portal venous and delayed phases of contrast uptake. Results: Thirty-two patients had 40 nodules of ICC (22 male; median age 62years; 13 hepatitis C) that were identified either during surveillance with abdominal ultrasound (21 patients, 66%) or incidentally (11 patients, 34%). ICC was either multifocal or ⩾30mm in 11 of the former and 10 of the latter group (52% vs. 91%, p <0.05). Two nodules (5%) escaped detection by CT-scan, while the remaining 38 showed a heterogeneous contrast enhancement pattern, being the arterial peripheral-rim enhancement present in 19 (50%) cases and a progressive homogeneous contrast uptake in 16 (42%) cases during the three vascular phases, with no relation to tumor size. Importantly, all nodules lacked the radiological hallmark of HCC, the only ICC nodule showing a homogeneous wash-in during the arterial phase followed by a wash-out in the delayed venous phase, however showing a homogeneous wash-in during the portal phase too. Conclusions: ICC in cirrhotic patients displays distinct vascular patterns at CT-scan that allow for differentiation from HCC. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) prognosis strongly depends upon nuclear grade and the presence of microscopic vascular invasion (MVI). The aim of this study was to develop an artificial neural network (ANN) that is able to predict tumour grade and MVI on the basis of non-invasive variables. Methods: Clinical, radiological, and histological data from 250 cirrhotic patients resected (n =200) or transplanted (n =50) for HCC were analyzed. ANN and logistic regression models were built on a training group of 175 randomly chosen patients and tested on the remaining testing group of 75. Receiver operating characteristics curve (ROC) and k-statistics were used to analyze model accuracy in the prediction of the final histological assessment of tumour grade (G1–G2 vs. G3–G4) and MVI (absent vs. present). Results: Pathologic examination showed G3–G4 in 69.6% of cases and MVI in 74.4%. Preoperative serum alpha-fetoprotein (AFP), tumour number, size, and volume were related to tumour grade and MVI (p <0.05) and were used for ANN building, whereas, tumour number did not enter into the logistic models. In the training group, ANN area under ROC curves (AUC) for tumour grade and MVI prediction were 0.94 and 0.92, both higher (p<0.001) than those of logistic models (0.85 for both). In the testing group, ANN correctly identified 93.3% of tumour grades (k =0.81) and 91% of MVI (k =0.73). Logistic models correctly identified 81% of tumour grades (k =0.55) and 85% of MVI (k =0.57). Conclusion: ANN identifies HCC tumour grades and MVI on the basis of preoperative variables more accurately than the conventional linear model and should be used for tailoring clinical management. [Copyright &y& Elsevier]

Abstract: The introduction of second generation microbubble ultrasound (US) contrast agents, such as SonoVue (Bracco, Milan, Italy), has considerably improved the diagnostic yield of US imaging for the evaluation of focal hepatic lesions in recent years because of its ability to very sensitively depict tumoral vascularity. In addition, contrast-enhanced US (CEUS) has the advantage of the absence of ionizing radiation, the widespread availability, even at the bedside, and the possibility to characterize a lesion as soon as detected on conventional B-mode US, commonly used as the first technique for exploration of the liver. The present review focuses on the basic principles of the technique and the various patterns of benign and malignant hepatic lesions at CEUS, contributing to their characterization. Understanding of these enhancement features at CEUS according to the type of tumors enables to make more accurate characterization of focal liver lesions as well as give better advice to oncologists, hepatologists or other clinicians in case of suspected liver tumors. (E-mail: fabio.piscaglia@unibo.it) [Copyright &y& Elsevier]

OBJECTIVES:Noninvasive criteria for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis, recommended by the European Association for the Study of Liver (EASL) in 2001 and by the American Association for the Study of Liver Diseases (AASLD) in 2005, have left a number of small liver neoplastic nodules undefined. We designed this prospective study in 2003 with the aims of assessing the diagnostic contribution of vascular contrast-enhanced techniques and investigating the possible additional contribution of superparamagnetic iron oxide magnetic resonance (SPIO-MR) in this setting.METHODS:Between 2003 and 2005, 75 consecutive small (10–30 mm) liver nodules detected at ultrasonography in 60 patients with cirrhosis were prospectively submitted to contrast-enhanced ultrasound (CEUS), helical-computed tomography (helical-CT), and gadolinium magnetic resonance (gad-MR), each blinded to the other. A total of 68 nodules were also studied with SPIO-MR at the same time as gad-MR.RESULTS:Using the EASL noninvasive criteria, the diagnosis of HCC was established in 44 of 55 (80%) nodules with a final diagnosis of HCC. Gad-MR was the most sensitive technique for detecting the typical vascular pattern. SPIO-MR showed a pattern consistent with HCC in 5 of 10 HCCs, not satisfying the EASL noninvasive criteria, and was negative in 17 of 18 (94.4%) nonmalignant nodules. The review of the present case series according to the AASLD criteria for the noninvasive diagnosis of HCC yielded a sensitivity rate of 81.8%.DISCUSSION:This study shows that both EASL and AASLD noninvasive recall strategies for nodules of 10–30 mm in the cirrhotic liver, based on the vascular pattern of nodules, have a false-negative rate of ∼20%. SPIO-MR may increase the diagnostic potential of noninvasive techniques, contributing to the diagnosis of HCC lacking a typical vascular pattern. [ABSTRACT FROM AUTHOR]

Fibulin-2 has previously been considered as a marker to distinguish rat liver myofibroblasts from hepatic stellate cells. The function of other fibulins in acute or chronic liver damage has not yet been investigated. The aim of this study has been to evaluate the expression of fibulin-1 and -2 in models of rat liver injury and in human liver cirrhosis. Their cellular sources have also been investigated. In normal rat liver, fibulin-1 and -2 were both mainly present in the portal field. Fibulin-1-coding transcripts were detected in total RNA of normal rat liver, whereas fibulin-2 mRNA was only detected by sensitive, real-time quantitative polymerase chain reaction. In acute liver injury, the expression of fibulin-1 was significantly increased (17.23-fold after 48 h), whereas that of fibulin-2 was not modified. The expression of both fibulin-1 and -2 was increased in experimental rat liver cirrhosis (19.16- and 26.47-fold, respectively). At the cellular level, fibulin-1 was detectable in hepatocytes, “activated” hepatic stellate cells, and liver myofibroblasts (2.71-, 122.65-, and 469.48-fold over the expression in normal rat liver), whereas fibulin-2 was restricted to liver myofibroblasts and was regulated by transforming growth factor beta-1 (TGF-β1) in 2-day-old hepatocyte cultures and in liver myofibroblasts. Thus, fibulin-1 and -2 respond differentially to single and repeated damaging noxae, and their expression is differently present in liver cells. Expression of the fibulin-2 gene is regulated by TGF-β1 in liver myofibroblasts. [ABSTRACT FROM AUTHOR]

Objective. To describe three patients with liver lesions mimicking malignant tumours diagnosed finally, using contrast-enhanced ultrasound, as cholangiocellular adenoma (bile duct adenoma). Material and methods. Focal liver lesions found incidentally in three patients. Contrast-enhanced ultrasound was with use of Siemens or Esaote equipment, low MI technique, after an intravenous bolus of 2.4 ml Sonovue (Bracco, Italy). Results. Lesions were 9 mm, 15 mm and 20 mm in diameter and all were enhanced in the arterial phase and hypo-enhanced in the portal venous and late phases, suggesting their malignant nature. In two patients, no primary liver tumour was found, and in the third patient, previously resected for breast cancer, a tissue specimen was considered useful for characterizing tumour receptors for more targeted chemotherapy, the lesion being assumed metastatic in nature. Transcutaneous core biopsies were performed in all three patients. Pathological analysis (including the reference pathology) revealed cholangiocellular adenoma in all of them. Conclusion. Cholangiocellular adenoma is a rare entity and can be a reason for possible false malignant diagnosis using contrast-enhanced ultrasound. Follow-up examinations are recommended. [ABSTRACT FROM AUTHOR]

Surveillance of patients at risk of developing hepatocellular carcinoma (HCC) is based on ultrasound (US) examinations performed at either 6 or 12 month intervals. Early detection of HCC in patients with cirrhosis is a challenging issue, since the different entities that are involved in the multi-step process of hepatocarcinogenesis – such as low-grade and high-grade dysplastic nodule – share common US features. Contrast-enhanced US allows reliable detection of arterial neoangiogenesis associated with a malignant transformation. Several reports have shown that the ability of contrast-enhanced US to diagnose HCC currently approaches that of optimized multidetector computed tomography (CT) or dynamic magnetic resonance (MR) imaging protocols. The use of contrast-enhanced US to characterize nodular lesions in cirrhosis has been recently recommended by the clinical practice guidelines issued by the European Federation of Societies for Ultrasound in Medicine and Biology and the American Association for the Study of Liver Diseases. However, contrast-enhanced US has not resulted in any significant improvement in the ability of US to detect small tumor foci, since a comprehensive assessment of the whole liver parenchyma cannot be accomplished during the short duration of the arterial phase. Hence, CT or MR imaging are still mandatory for proper intrahepatic staging of the disease. [Copyright &y& Elsevier]

In the last decade, new imaging techniques have become available, offering the possibility of investigating contrast perfusion of liver nodules in cirrhosis. It is now accepted that a non-invasive diagnosis of hepatocellular carcinoma (HCC) can be established based on the vascular pattern, obtained with pure blood pool contrast agents. The diagnostic pattern includes: hypervascularity in the arterial phase (15–35 s after contrast injection), consisting in a contrast signal in the nodule greater than in the surrounding parenchyma, followed by contrast wash out, which leads the nodule to show the same, or, more specifically, a lower contrast signal, than the surrounding parenchyma in the portal and late phases (>40 s after injection). Such a pattern can be obtained not only by computed tomography or magnetic resonance imaging, but also by contrast-enhanced ultrasonography, most simply with real-time low mechanical index harmonic imaging ultrasound equipment with second-generation ultrasound contrast agents. The risk of false-positive diagnosis of malignancy isnearly abolished when the functional vascular pattern is not the only feature, but is superimposed on a nodule visible also without contrast. One single contrast imaging technique may suffice to make a diagnosis of HCC if the nodule is >1 cm in diameter and has developed during a surveillance program. Other types of contrast agents, such as those taken up by the reticular-endothelial system cells, may offer additional diagnostic clues, but definitive evidence of their efficacy is still to be produced. In conclusion, contrast-enhanced imaging techniques now offer the possibility of a non-invasive diagnosis of HCC in a large number of cases, reducing the need of invasive investigations, such as ultrasound-guided biopsy or angiography. [ABSTRACT FROM AUTHOR]

Background: Contrast enhanced ultrasound (CEUS) is an imaging technique which appeared on the market around the year 2000 and proposed for the detection of liver metastases in gastrointestinal cancer patients, a setting in which accurate staging plays a significant role in the choice of treatment. Methods: A total of 109 patients with colorectal (n = 92) or gastric cancer prospectively underwent computed tomography (CT) scan and conventional US evaluation followed by real time CEUS. A diagnosis of metastases was made by CT or, for lesions not visibile at CT, the diagnosis was achieved by histopathology or by a malignant behavior during follow-up. Results: Of 109 patients, 65 were found to have metastases at presentation. CEUS improved sensitivity in metastatic livers from 76.9% of patients (US) to 95.4% (p < 0.01), while CT scan reached 90.8% (p = n.s. as CEUS, p < 0.01 as US). CEUS and CT were more sensitive than US also for detection of single lesions (87 with US, 122 with CEUS, 113 with CT). In 15 patients (13.8%), CEUS revealed more metastases than CT, while CT revealed more metastases than CEUS in 9 patients (8.2%) (p = n.s.). Conclusion: CEUS is more sensitive than conventional US in the detection of liver metastases and could be usefully employed in the staging of patients with gastrointestinal cancer. Findings at CEUS and CT appear to be complementary in achieving maximum sensitivity. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present retrospective study was to assess the incidence of adverse events (AE) of a second-generation ultrasound contrast agent in real clinical practice. A total of 28 Italian Centres provided data on the postmarketing use of SonoVue® (Bracco Spa, Milan, Italy) in abdominal examination performed between December 2001 and December 2004. A total of 23 188 investigations were reported. No fatal event occurred. AEs were reported in 29 cases, of which only two were graded as serious; the rest, 27, were nonserious (23 mild, three moderate and one severe). The overall reporting rate of serious AE was 0.0086%. Overall, only four AEs required treatment (two serious, two nonserious including one moderate and one severe AEs). In conclusion, the present large-scale retrospective analysis showed that SonoVue has a good safety profile in abdominal applications, with an AE reporting rate lower than or similar to that reported for radiologic and magnetic resonance contrast agents. (E-mail: Piscagl@med.unibo.it) [Copyright &y& Elsevier]

A case is reported in which a several-fold increase in transaminases and γ-GT was detected in an elderly male patient with fatty liver. The patient was regularly taking a mixture of herbal products, used as a laxative, for a number of years, with no alteration of blood chemistry until 6 months before the present observation. However, the composition of the mixture had been modified by the manufacturer in the past 5 months, with addition of boldo leaf extracts. Transaminases promptly returned to normal after withdrawal of the laxative. It is concluded that boldo leaf extracts might be hepatotoxic, at least in elderly patients with fatty liver. [ABSTRACT FROM AUTHOR]

Hepatic artery pseudo-aneurysm is a rare but severe complication of liver transplantation, which generally requires immediate surgical or angiographic treatment. The diagnosis is usually made by splanchnic percutaneous angiography. We report a case of an intra-hepatic pseudo-aneurysm after surgical correction of a thrombosed hepatic artery and its successful response to conservative management. Duplex Doppler ultrasound, associated with a new B-mode contrast-based sonographic technique, called “perfusional angiosonography”, was used to diagnose the intra-hepatic pseudo-aneurysm. The combination of the two ultrasound techniques was useful in following the course of the pseudo-aneurysm, without further need for angiography. Eventually, this pseudo-aneurysm underwent spontaneous obliteration. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The aim of the present investigation was to study the endogenous circadian clock phase rhythm in cirrhotic patients.METHODS:The study population comprised 13 patients with cirrhosis (seven in Child-Pugh class A and six in classes B/C) and nine healthy controls. Plasma melatonin, tissue plasminogen activator antigen, and plasminogen activator inhibitor 1 antigen were measured at 4-h intervals over a 24-h period. Multiple-components rhythmometry using population mean cosinor methods were employed to analyze the findings.RESULTS:All three variables were characterized in both patients and controls by a statistically significant circadian rhythm, with similar profiles. The peak times of tissue plasminogen activator and plasminogen activator inhibitor 1 antigens were practically identical in controls and cirrhotic patients, irrespective of Child-Pugh class (calculated peak at times 6:52, 6:56, and 7:20 for the inhibitor in controls and Child-Pugh class A and classes B/C patients, respectively; p = ns), whereas the peak of melatonin was delayed in classes B/C patients (at times 2:08, 1:56, and 4:00, respectively; p < 0.05).CONCLUSION:The similar circadian phases of plasminogen activator inhibitor antigen in controls and cirrhotic patients in the present investigation indicates that the output rhythm of the internal timekeeping system is not shifted in this pathological condition. [Copyright &y& Elsevier]

Thoracentesis is one of the most important invasive procedures in the clinical setting. Particularly, thoracentesis can be relevant in the evaluation of a new diagnosed pleural effusion, thus allowing for the collection of pleural fluid so that laboratory tests essential to establish a diagnosis can be performed. Furthermore, thoracentesis is a maneuver that can have therapeutic and palliative purposes. Historically, the procedure was performed based on a physical examination. In recent years, the role of ultrasound has been established as a valuable tool for assistance and guidance in the thoracentesis procedure. The use of ultrasound increases success rates and significantly reduces complications. The aim of this educational review is to provide a detailed and sequential examination of the procedure, focusing on the two main modalities, the ultrasound-assisted and ultrasound-guided form. [ABSTRACT FROM AUTHOR]

The American College of Radiology has released the Liver Imaging Reporting and Data System (LI-RADS) scheme which categorizes focal liver lesions (FLLs) in patients at risk for hepatocellular carcinoma (HCC) according to the degree of risk of nodules to be HCC. It subgroups FLL in LR-1 (definitely benign), LR-2 (probably benign), LR-3 (intermediate probability of malignancy), LR-4 (probably HCC), LR-5 (definitely HCC), and LR-M (probable malignancy not specific for HCC). Computed tomography/magnetic resonance imaging (CT/MRI) and contrast enhanced ultrasound (CEUS) LI-RADS diagnostic algorithm have the goal to standardize the acquisition, interpretation, reporting, and data collection for imaging examinations in patients at risk for HCC. Nevertheless, there remain controversial issues that should be dealt with. The aim of this review is to discuss the pros and cons of the interpretation and reporting part of CT/MRI and CEUS LI-RADS diagnostic algorithm to permit future refinements of the scheme and optimize patient and nodule management. [ABSTRACT FROM AUTHOR]

Background: The application of transthoracic contrast-enhanced ultrasound (CEUS) to the study of peripheral lung lesions is still a topic of debate. The main objective of this review was to evaluate the diagnostic accuracy of CEUS in the diagnosis of malignant subpleural pulmonary consolidations and, therefore, differentiate them from benign ones. Methods: Papers published before December 2023 were detected through a search of PubMed, Cochrane library, and Embase. The pooled specificity and sensitivity, summary receiver operating characteristic (SROC) curve and diagnostic odds ratio (DOR) were used. Results: CEUS is characterized by a pooled sensitivity of 0.95 (95% CI: 0.93–0.97) and a pooled specificity of 0.93 (95% CI: 0.90–0.95) in differentiating benign and malignant subpleural lung diseases; the AUC of SROC was 0.97. Homogeneous CE was characterized by a pooled sensitivity of 0.43 (95% CI: 0.40–0.45) and the pooled specificity of 0.49 (95% CI: 0.46–0.52). Non-homogeneous CE displayed a pooled sensitivity of 0.57 (95% CI: 0.55–0.60) and a pooled specificity of 0.51 (95% CI: 0.48–0.54). The lack of CE displayed a pooled sensitivity of 0.01 (95% CI: 0.00–0.06) and a pooled specificity of 0.76 (95% CI: 0.64–0.85). Marked CE displayed a pooled sensitivity of 0.41 (95% CI: 0.37–0.44) and a pooled specificity of 0.54 (95% CI: 0.50–0.58). Non-marked CE displayed a pooled sensitivity of 0.59 (95% CI: 0.56–0.63) and a pooled specificity of 0.46 (95% CI: 0.42–0.50). The early AT displayed a pooled sensitivity of 0.04 (95% CI: 0.02–0.08) and a pooled specificity of 0.83 (95% CI: 0.77–0.87). The early wash out displayed a pooled sensitivity of 0.61 (95% CI: 0.48–0.72) and a pooled specificity of 0.98 (95% CI: 0.92–1.00). The delayed wash out displayed a pooled sensitivity of 0.15 (95% CI: 0.10–0.20) and a pooled specificity of 0.69 (95% CI: 0.62–0.75). Conclusions: CEUS is characterized by excellent diagnostic accuracy for the diagnosis of the malignancy of subpleural lung lesions. By separately analyzing the CEUS findings, the diagnostic accuracy values are considerably lower and not significant in some cases. The simultaneous evaluation of multiple CEUS features allows us to reach an excellent diagnostic accuracy. Non-homogeneous CE with early wash out are the most indicative features of malignancy of a lung lesion. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent. [ABSTRACT FROM AUTHOR]

Simple Summary: Sarcopenia, conceived as low skeletal muscle mass and function, has been associated with worse outcomes in patients treated with Sorafenib for advanced HCC, with data coming mainly from the Oriental series. Skeletal muscle mass can be easily quantified from abdominal CT scans performed for advanced HCC staging. Sarcopenia and impaired liver function (MELD > 9) are strong predictors of unfavorable outcomes in patients affected by advanced HCC treated with Sorafenib. Their copresence can identify a subset of patients with particularly bad prognoses. Background and aims: Sarcopenia has been associated with poor outcomes in patients with cirrhosis and hepatocellular carcinoma. We investigated the impact of sarcopenia on survival in patients with advanced hepatocellular carcinoma treated with Sorafenib. Methods: A total of 328 patients were retrospectively analyzed. All patients had an abdominal CT scan within 8 weeks prior to the start of treatment. Two cohorts of patients were analyzed: the "Training Group" (215 patients) and the "Validation Group" (113 patients). Sarcopenia was defined by reduced skeletal muscle index, calculated from an L3 section CT image. Results: Sarcopenia was present in 48% of the training group and 50% of the validation group. At multivariate analysis, sarcopenia (HR: 1.47, p = 0.026 in training; HR 1.99, p = 0.033 in validation) and MELD > 9 (HR: 1.37, p = 0.037 in training; HR 1.78, p = 0.035 in validation) emerged as independent prognostic factors in both groups. We assembled a prognostic indicator named "SARCO-MELD" based on the two independent prognostic factors, creating three groups: group 1 (0 prognostic factors), group 2 (1 factor) and group 3 (2 factors), the latter with significantly worse survival and shorter time receiving treatment. [ABSTRACT FROM AUTHOR]

Background: Portal vein thrombosis (PVT) is a rare disease with an estimated incidence of 2 to 4 cases per 100,000 inhabitants. The most common predisposing conditions for PVT are chronic liver diseases (cirrhosis), primary or secondary hepatobiliary malignancy, major infectious or inflammatory abdominal disease, or myeloproliferative disorders. Methods: PVT can be classified on the basis of the anatomical site, the degree of venous occlusion, and the timing and type of presentation. The main differential diagnosis of PVT, both acute and chronic, is malignant portal vein invasion, most frequently by hepatocarcinoma, or constriction (typically by pancreatic cancer or cholangiocarcinoma). Results: The management of PVT is based on anticoagulation and the treatment of predisposing conditions. The aim of anticoagulation in acute thrombosis is to prevent the extension of the clot and enable the recanalization of the vein to avoid the development of complications, such as intestinal infarction and portal hypertension. Conclusions: The treatment with anticoagulant therapy favors the reduction of portal hypertension, and this allows for a decrease in the risk of bleeding, especially in patients with esophageal varices. The anticoagulant treatment is generally recommended for at least three to six months. Prosecution of anticoagulation is advised until recanalization or lifelong if the patient has an underlying permanent pro-coagulant condition that cannot be corrected or if there is thrombosis extending to the mesenteric veins. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality. In the last decade, a breakthrough in the treatment landscape of HCC has been experienced. The unprecedented number of therapeutic options for advanced stages has made the selection of sequence strategies more complex and the need for biomarkers of treatment response or tumor escape more urgent. The understanding of molecular events leading to drug resistance has identified noncoding RNAs as promising therapeutic targets. Preclinical studies testing the combined efficacy of noncoding RNAs and clinically available drugs represent a crucial step to prevent/limit the onset of drug resistance in advanced cases. The incidence of hepatocellular carcinoma (HCC) is increasing, and 40% of patients are diagnosed at advanced stages. Over the past 5 years, the number of clinically available treatments has dramatically increased for HCC, making patient management particularly complex. Immune checkpoint inhibitors (ICIs) have improved the overall survival of patients, showing a durable treatment benefit over time and a different response pattern with respect to tyrosine kinase inhibitors (TKIs). Although there is improved survival in responder cases, a sizeable group of patients are primary progressors or are ineligible for immunotherapy. Indeed, patients with nonviral etiologies, such as nonalcoholic steatohepatitis (NASH), and alterations in specific driver genes might be less responsive to immunotherapy. Therefore, improving the comprehension of mechanisms of drug resistance and identifying biomarkers that are informative of the best treatment approach are required actions to improve patient survival. Abundant evidence indicates that noncoding RNAs (ncRNAs) are pivotal players in cancer. Molecular mechanisms through which ncRNAs exert their effects in cancer progression and drug resistance have been widely investigated. Nevertheless, there are no studies summarizing the synergistic effect between ncRNA-based strategies and TKIs or ICIs in the preclinical setting. This review aims to provide up-to-date information regarding the possible use of ncRNAs as therapeutic targets in association with molecular-targeted agents and immunotherapies and as predictive tools for the selection of optimized treatment options in advanced HCCs. [ABSTRACT FROM AUTHOR]

Background: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients' prognosis. We analyzed and compared these systems (Bolondi, Yamakado, Kinki, Wang, Lee, and Kim criteria) in patients undergoing systemic therapy. Methods: We considered 171 patients with BCLC B HCC treated with sorafenib as first-line systemic therapy in six Italian centers from 2010 to 2021 and retrospectively applied the criteria of six different subclassification systems. Results: Except for the Yamakado criteria, all the subclassification systems showed a statistically significant correlation to overall survival (OS). In the postestimation analysis, the Bolondi criteria (OS of subgroups 22.5, 11.9, and 6.6 mo, respectively; C-index 0.586; AIC 1338; BIC 1344) and the Wang criteria (OS of subgroups 20.6, 11.9, and 7.0, respectively; C-index 0.607; AIC 1337; BIC 1344) presented the best accuracy. Further analyses of these two subclassification systems implemented with the prognostic factor of alpha-fetoprotein (AFP) > 400 ng/mL have shown an increase in accuracy for both systems (C-index 0.599 and 0.624, respectively). Conclusions: Intermediate-stage subclassification systems maintain their predictive value also in the setting of systemic therapy. The Bolondi and Wang criteria showed the highest accuracy. AFP > 400 ng/mL enhances the performance of these systems. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). In this study, we aimed to evaluate the incidence and preoperative predictors of non‐transplantable recurrence in patients with single HCC ≤5 cm treated with frontline LR. Methods: From the Italian Liver Cancer (ITA.LI.CA) database, 512 patients receiving frontline LR for single HCC ≤5 cm were retrieved. Incidence and predictors of recurrence beyond Milan criteria (MC) and up‐to‐seven criteria were compared between patients with HCC <4 and ≥4 cm. Results: During a median follow‐up of 4.2 years, the overall recurrence rate was 55.9%. In the ≥4 cm group, a significantly higher proportion of patients recurred beyond MC at first recurrence (28.9% vs. 14.1%; p < 0.001) and overall (44.4% vs. 25.2%; p < 0.001). Similar results were found considering recurrence beyond up‐to‐seven criteria. Compared to those with larger tumours, patients with HCC <4 cm had a longer recurrence‐free survival and overall survival. HCC size ≥4 cm and high alpha‐fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC (and up‐to‐seven criteria). In the subgroup of patients with available histologic information (n = 354), microvascular invasion and microsatellite lesions were identified as additional independent risk factors for non‐transplantable recurrence. Conclusions: Despite the high recurrence rate, LR for single HCC ≤5 cm offers excellent long‐term survival. Non‐transplantable recurrence is predicted by HCC size and AFP levels, among pre‐operatively available variables. High‐risk patients could be considered for frontline LT or listed for transplantation even before recurrence. [ABSTRACT FROM AUTHOR]

Introduction: The best first-line treatment for patients with advanced hepatocellular carcinoma (HCC) and Child–Pugh (CP) class B remains unknown. The aim of the present study was to perform a real-world analysis on a large sample of patients with unresectable HCC with CP B treated with atezolizumab plus bevacizumab Vs Lenvatinib. Methods: The study population included patients affected by advanced (BCLC-C) or intermediate (BCLC-B) HCC patients not suitable for locoregional therapies from both the Western and Eastern world (Italy, Germany, Republic of Korea and Japan), who received atezolizumab plus bevacizumab or Lenvatinib as first-line treatment. All the study population presented a CP class of B. The primary endpoint of the study was the overall survival (OS) of CP B patients treated with Lenvatinib compared to atezolizumab plus bevacizumab. Survival curves were estimated using the product-limit method of Kaplan–Meier. The role of stratification factors was analyzed with log-rank tests. Finally, an interaction test was performed for the main baseline clinical characteristics. Results: 217 CP B HCC patients were enrolled in the study: 65 (30%) received atezolizumab plus bevacizumab, and 152 (70%) received lenvatinib. The mOS for patients receiving Lenvatinib was 13.8 months (95% CI: 11.6–16.0), compared to 8.2 months (95% CI 6.3–10.2) for patients receiving atezolizumab plus bevacizumab as first-line treatment (atezolizumab plus bevacizumab Vs Lenvatinib: HR 1.9, 95% CI 1.2–3.0, p = 0.0050). No statistically significant differences were highlighted in terms of mPFS. The multivariate analysis confirmed that patients receiving Lenvatinib as first-line treatment have a significantly longer OS compared to patients receiving atezolizumab plus bevacizumab (HR 2.01; 95% CI 1.29–3.25, p = 0.0023). By evaluating the cohort of patients who received atezolizumab plus bevacizumab, we found that Child B patients with ECOG PS 0, or BCLC B stage or ALBI grade 1 were those who had benefited from the treatment thus showing survival outcomes no significantly different compared to those receiving Lenvatinib. Conclusion: The present study suggests for the first time a major benefit from Lenvatinib compared to atezolizumab plus bevacizumab in a large cohort of patients with CP B class HCC. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming is a well-known marker of cancer, and it represents an early event during hepatocellular carcinoma (HCC) development. The recent approval of several molecular targeted agents has revolutionized the management of advanced HCC patients. Nevertheless, the lack of circulating biomarkers still affects patient stratification to tailored treatments. In this context, there is an urgent need for biomarkers to aid treatment choice and for novel and more effective therapeutic combinations to avoid the development of drug-resistant phenotypes. This study aims to prove the involvement of miR-494 in metabolic reprogramming of HCC, to identify novel miRNA-based therapeutic combinations and to evaluate miR-494 potential as a circulating biomarker. Methods: Bioinformatics analysis identified miR-494 metabolic targets. QPCR analysis of glucose 6-phosphatase catalytic subunit (G6pc) was performed in HCC patients and preclinical models. Functional analysis and metabolic assays assessed G6pc targeting and miR-494 involvement in metabolic changes, mitochondrial dysfunction, and ROS production in HCC cells. Live-imaging analysis evaluated the effects of miR-494/G6pc axis in cell growth of HCC cells under stressful conditions. Circulating miR-494 levels were assayed in sorafenib-treated HCC patients and DEN-HCC rats. Results: MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions. High miR-494 serum levels associated with sorafenib resistance in preclinical models and in a preliminary cohort of HCC patients. An enhanced anticancer effect was observed for treatment combinations between antagomiR-494 and sorafenib or 2-deoxy-glucose in HCC cells. Conclusions: MiR-494/G6pc axis is critical for the metabolic rewiring of cancer cells and associates with poor prognosis. MiR-494 deserves attention as a candidate biomarker of likelihood of response to sorafenib to be tested in future validation studies. MiR-494 represents a promising therapeutic target for combination strategies with sorafenib or metabolic interference molecules for the treatment of HCC patients who are ineligible for immunotherapy. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasound (CEUS) is a specialized form of ultrasound (US) performed with an intravenous injection of microbubble contrast agents. It has been successfully used for a variety of applications including characterization of liver tumors. In April 2014, the American College of Radiology (ACR) convened a working group of international experts to develop ACR CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS). An initial version of CEUS LI-RADS was published in August 2016. Although the CEUS LI-RADS concept and principles for liver lesion characterization, using dynamic contrast enhancement features, are similar to those for CT or MRI, there are significant differences between CT/MRI and CEUS LI-RADS. Therefore, CEUS LI-RADS has different diagnostic features and a unique characterization algorithm. The size of a lesion, the type and degree of arterial phase enhancement, the presence of washout, and the timing and degree of washout are the major features used for categorization. This paper describes key differences between CT/MRI and CEUS, and provides a diagnostic algorithm of CEUS LI-RADS with detailed, step-by-step instructions and imaging examples of CEUS LI-RADS categories. [ABSTRACT FROM AUTHOR]

Background: Patients with single hepatocellular carcinoma (HCC) usually undergo transarterial chemoembolization (TACE) if they are not candidates for curative surgical or ablative therapy. The primary aim of the study was to assess the overall survival and clinical determinants of survival in patients with single HCC who underwent TACE. The secondary aims were tumor response, local and distant recurrence rates, time to recurrence and the impact of TACE on liver function.Methods: The outcomes of 148 consecutive patients with single HCC who underwent TACE from January 2004 to December 2009 were retrospectively analyzed.Results: Complete response (CR) was observed in 95/148 (64%) patients and a partial response (PR) in 39 (26%) patients. The recurrence rate was 27%, 42% and 65% at 6, 12 and 24 months, respectively. The day after TACE, 56 (38%) patients had a Child-Pugh increase ≥ 1 and 93 (63%) had a MELD increase ≥ 1. Median survival was 36.0 months with 1-, 3- and 5-year survival rates of 85%, 50% and 26%, respectively. Bland portal thrombosis was not seen to have any impact at univariate survival analysis; however, a slight impairment of PS (PS-1) in small tumors had some, although minor, impact on prognosis. Factors associated with shorter survival at multivariate analysis were tumor >5 cm, absence of CR, ascites, alpha-fetoprotein (AFP) ≥ 14.5 ng/mL and a MELD increase ≥ 1.Conclusions: Transarterial chemoembolization is a valid treatment option in patients with single HCC not suitable for curative treatment. Bland PVT has no major impact on survival and a slight impairment of PS attributable to cirrhosis in patients within the Milan criteria should not preclude the use of TACE. [ABSTRACT FROM AUTHOR]

Biliary anatomic variations are usually asymptomatic, but they may cause problems in diagnostic investigations and interventional and surgical procedures, increasing both their technical difficulty and their postoperative complication rates. The aim of the present study was to evaluate the prevalence of anatomic variations in the intrahepatic biliary ducts (IHBD) in relation to demographical and clinical characteristics in a large study population requiring magnetic resonance cholangiopancreatography (MRCP) for various clinical conditions. The possible association between IHBD and extrahepatic biliary ducts (EHBD) variants was then explored. From January 2017 to May 2019, 1004 patients underwent MRCP. Demographical and clinical data were collected. IHBD and EHBD anatomy were recorded and the EHBD anatomy was classified using both qualitative and quantitative classifications. The presence of a type 3 EHBD variant (an abnormal proximal cystic duct [CD] insertion) in both qualitative and quantitative classifications and an intrapancreatic CD were associated with the presence of IHBD variants at univariate analysis (p = 0.008, p = 0.019, and p = 0.001, respectively). The presence of a posterior or medial insertion of the CD into the EHBD was a strong predictive factor of the presence of IHBD variants both at uni‐ and multivariate analysis (p = 0.002 and p = 0.003 for posterior insertion and p = 0.002 and p = 0.002 for medial insertion, respectively). The presence of gallstones on MRCP resulted in a strong predictor of the presence of an anatomical variant of the IHBD both at uni‐ and multivariate analysis (p = 0.027 and p = 0.046, respectively). In conclusion, the presence of a type 3 variant of the EHBD, an intrapancreatic CD and, especially, a posterior/medial CD insertion into the EHBD represent predictive factors of the concomitant presence of IHBD variants, thus radiologists must be vigilant when encountering these EHBD configurations and always remember to "look up" at the IHBD. Finally, the presence of an IHBD variant is a strong predictive factor of gallstones. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune check point inhibitors (ICPIs) are one of the treatment options for advanced hepatocellular carcinoma (HCC). No biomarker is currently available to upfront select patients to be addressed to one or another drug. We have tested a prospective series of patients with advanced HCC treated with atezolizumab–bevacizumab combination with the aim of identifying biomarkers of response by using a simple cytofluorimetric test on peripheral blood. Due to the relevant role of granulocyte in the immune response, here we have focused on granulocyte immunophenotype by investigating PD1 and PD-L1 expression on their surface by using a simple cytofluorimetric test on peripheral blood. A low baseline PD1+ granulocyte percentage identified patients likely to benefit from atezolizumab–bevacizumab. Our findings warrant to validate this cheap and immediate cytofluorimetric test in larger cohorts, to verify whether the individual accuracy could be informative for the clinical practice. Introduction: Immune check point inhibitors have recently entered the armamentarium of advanced hepatocellular carcinoma (HCC) treatment. Among them, the combination of atezolizumab plus bevacizumab has pushed it a step forward; however, a number of patients still present primary non-responses without any biomarker to predict responses to different options. Here, we aimed to identify a putative baseline biomarker to predict the response to atezolizumab–bevacizumab, by investigating whether baseline PD1+ and PD-L1+ peripheral granulocyte percentages might offer a non-invasive, cheap, and easily feasible assay. Methods: A prospective Italian cohort of 34 patients treated by atezolizumab–bevacizumab was tested to assay the baseline percentage of peripheral granulocytes and their PD1 and PD-L1 expression. The neutrophil to lymphocyte ratio (NLR) was also considered, and all data were compared with the clinical course of patients. Results: A low-baseline PD1+ peripheral granulocyte percentage turned out to predict responder patients (mean ±SD of PD1+ granulocyte percentage in responders versus non-responders: 9.9 ± 9.1 vs. 29.2 ± 17.6; student's t-test, p < 0.01). In line, patients identified by a low PD1+ granulocyte percentage displayed a longer TTP (log-rank test, p < 0.0001). A lower granulocyte percentage on total white blood cells, irrespective of PD1 or PD-L1 expression, is also associated with responses to atezolizumab–bevacizumab (log-rank test, p < 0.05). No predictive value was observed for either the PD-L1+ granulocyte percentage or NLR. Conclusions: A low-baseline PD1+ peripheral granulocyte percentage is associated with responses to atezolizumab–bevacizumab treatment in advanced HCC. These findings encourage evaluating this minimally invasive, cheap, and easy test in further independent cohorts and outlining the relevance of innate immunity in the response to immune-checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: Several retrospective studies tried to assess the prognostic role of different sites of metastases in patients with advanced HCC, but results are often contradictory. These studies also presented results based on population samples with several confounding factors. Although the therapeutic scenario is moving towards immunotherapy, a better knowledge of a different metastatic site response rate to sorafenib is needed, also considering the potential future advent of combination therapies with immune checkpoint and tyrosine-kinase inhibitors. We tried to perform a large-scale multicentric study by enrolling metastatic HCC patients treated with sorafenib as front-line therapy. A low rate of concomitant locoregional treatments during sorafenib in our population study allowed us to focus on the actual response of different sites of metastases to systemic treatment with sorafenib, showing that lymph nodes and lung metastases have worse prognosis. Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate. [ABSTRACT FROM AUTHOR]