Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

AGILE 3+ Score for the Diagnosis of Advanced Fibrosis and for Predicting Liver-related Events in NAFLD.

BACKGROUND & AIMS: We aimed to assess the diagnostic accuracy of AGILE 3+, a recently developed score based on the combination of aspartate aminotransferase/alanine aminotransferase ratio, platelet count, diabetes status, sex, age, and liver stiffness measurement (LSM) by transient elastography, when compared with Fibrosis-4 (FIB-4) and LSM, for the diagnosis of advanced fibrosis and for the prediction of liver-related events (LREs) occurrence in patients with NAFLD. METHODS: A total of 614 consecutive patients with biopsy-proven NAFLD or clinical diagnosis of NAFLD-related compensated cirrhosis were enrolled. LREs were recorded during follow-up. FIB-4, LSM by transient elastography (FibroScan device), and AGILE 3+ were measured. The diagnostic performance of noninvasive criteria for advanced fibrosis and for the prediction of LREs was assessed using the area under the receiver operating characteristic curve (AUROC) and decision curve analysis. RESULTS: In patients with biopsy-proven NAFLD (n = 520), LSM and AGILE 3+ had higher AUROC than FIB-4 (0.88 for LSM and AGILE 3+ vs 0.78 for FIB-4; P < .001) for advanced fibrosis, and AGILE 3+ exhibited a smaller indeterminate area in the test (25.2% for FIB-4 vs 13.1% for LSM vs 8.3% for AGILE 3+). Within the entire cohort of patients, AGILE 3+ had significantly higher AUROC for predicting LREs with respect to LSM (AUROC 36 months 0.95 vs 0.93; P =.008; 60 months 0.95 vs 0.92; P = .006; 96 months 0.97 vs 0.95; P = .001). Decision curve analysis showed that all scores had modest net benefit for ruling-out advanced fibrosis at the risk threshold of 5% to 10% where advanced fibrosis was absent. At the risk threshold of 5% of false negatives or false positives in LRE at 36, 60, 96, and 120 months, AGILE 3+ outperformed both FIB-4 and LSM for ruling out LRE. CONCLUSIONS: Depending on resource availability, clinical setting, and the risk scenarios, AGILE 3+ is an accurate and valid alternative to FIB-4 and LSM for the noninvasive assessment of disease severity and prognosis in patients with NAFLD.

The Evolving Scenario in the Assessment of Radiological Response for Hepatocellular Carcinoma in the Era of Immunotherapy: Strengths and Weaknesses of Surrogate Endpoints.

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.

LI-RADS ancillary features favoring benignity: is there a role in LR-5 observations?

OBJECTIVES: The Liver Imaging Reporting and Data System algorithm allows category downgrade in the presence of ancillary features (AFs) favoring benignity, even in observations categorized as LR-5. This study aims to assess the role of AFs favoring benignity in LR-5 observations and their impact on category downgrade. METHODS: This study included high-risk patients with at least one LR-5 observation imaged with gadoxetate disodium MRI. Three readers with different experience levels independently evaluated the presence of AFs favoring malignancy (not hepatocellular carcinoma (HCC) in particular and HCC in particular) and AFs favoring benignity. Category downgrade was considered possible in the presence of ≥ 1 AF favoring benignity and no AF favoring malignancy. Correlation between observations size and number of AFs was assessed using Spearman's rank correlation coefficient. Cohen's kappa (k) test was used to assess inter-reader agreement. RESULTS: The final study cohort included 162 LR-5 (mean size: 23 ± 16 mm) in 119 patients. AFs favoring benignity were reported in 9 (5.6%), 20 (12.3%), and 10 (6.2%) LR-5 observations by reader 1, reader 2, and reader 3, respectively. Hepatobiliary phase isointensity was observed in 6 (3.7%), 2 (1.2%), and 7 (4.3%) observations, respectively. Category downgrade was considered possible in only one (0.6%) observation by reader 1 and reader 3. There was a significant correlation between observation size and number of AFs favoring malignancy (p < 0.001), not HCC in particular (p ≤ 0.010), and favoring HCC in particular (p < 0.001). Inter-reader agreement of AFs favoring benignity was poor to moderate (k range: - 0.01, 0.43). CONCLUSIONS: AFs favoring benignity are not uncommon in LR-5 observations, but category downgrade is exceptional. KEY POINTS: • Ancillary features favoring benignity are encountered in 5.6-12.3% of observations categorized as LR-5. • Category downgrade of LR-5 observations is very rare (0.6% of observations) in the presence of AFs favoring benignity due to the high prevalence (98-99%) of ancillary features favoring malignancy in LR-5 observations. • The inter-reader agreement of ancillary features favoring benignity is poor to moderate (k range: - 0.01, 0.43) in readers with different levels of experience.

Superficial Heating Evaluation by Thermographic Imaging before and after Tecar Therapy in Six Dogs Submitted to a Rehabilitation Protocol: A Pilot Study.

Thermography is a non-invasive diagnostic method commonly used to monitor changes of the body surface temperature potentially induced by different conditions such as fever, inflammation, trauma, or changes of tissue perfusion. Capacitive-resistive diathermy therapy (such as energy transfer capacitive and resistive-Tecar) is commonly used in rehabilitation due to its diathemic effect secondary to blood circulation increase that could accelerate the healing process. The aim of this study was to monitor by thermal camera the diathermic effects induced by Tecar on the surface of the region of application. The investigation was conducted on six dogs referred for Tecar therapy to treat muscle contractures (three dogs) or osteoarthritis (three dogs). Eleven anatomical treated regions were recorded. Thermographic images and relative measurements were obtained by each region immediately before (T0), at conclusion (T1), and sixty seconds after the Tecar application (T2). Data were recorded and statistically analyzed. A comparison of temperature differences (maximum, minimum and mean values) between T0 and T1, T0 and T2, and T1 and T2 was performed by ANOVA test with Bonferroni post hoc (p ≤ 0.05). Statistically significant differences were detected for mean temperature between T0 (32.42 ± 1.57 °C) and T1 (33.36 ± 1.17 °C) (p = 0.040) and between T1 and T2 (32.83 ± 1.31 °C) (p = 0.031). Furthermore, there was no significant difference between the mean temperature at T0 and T2, demonstrating that superficial diathermic effect exhausted within 60 s.

Perilesional photobiomodulation therapy and physical rehabilitation in post-operative recovery of dogs surgically treated for thoracolumbar disk extrusion.

BACKGROUND: Recent studies have reported contrasting results of the effects of laser therapy on post-operative intervertebral disk herniation, with a lack of evidence-based advantages of this modality within a rehabilitation protocol. The aim of this study was to report the clinical effects of photobiomodulation therapy within a post-operative rehabilitation protocol in dogs submitted to surgery for thoracolumbar disk extrusion. Twenty-four dogs were included in the study (12 dogs treated with laser therapy and rehabilitation protocol and 12 dogs treated with same rehabilitation protocol but without laser therapy). RESULTS: All dogs treated with laser therapy showed improved neurological status (Modified Frankel Score more than 3 within 30 days of physiotherapy starting) if deep nociception on admission was maintained (P = 0.04). However, Kaplan-Meier analysis did not show any statistical difference in time to regain ambulatory ability, although there was a tendency for a shorter mean time of 14.2 ± 8.55 days in the laser group versus 24 ± 18.49 days in the no laser group. CONCLUSIONS: The use of laser therapy in the post-operative rehabilitation of dogs affected by intervertebral disc extrusion and submitted to surgery for spinal decompression could help improve their neurological status.

Curative therapies for hepatocellular carcinoma: an update and perspectives.

Curative treatments, including liver transplantation, surgical resection and percutaneous treatments, are the recommended therapies in BCLC-0 (Barcelona Clinic of Liver Cancer) or BCLC-A hepatocellular carcinoma (HCC). This review provides an overview of some issues of clinical importance concerning curative treatments in HCC.

Ultrasound-guided ablation for hepatocellular carcinoma: time for a reappraisal?

Ultrasound-guided techniques play a key role in the clinical management of hepatocellular carcinoma. Among these, percutaneous ethanol injection (PEI) was the first technique to be proposed for the treatment of nodular-type hepatocellular carcinoma: the role of PEI was first discussed during the European Association for the Study of the Liver conference held in Barcelona in 2000, 15 years ago. Since then, other techniques have been introduced and radiofrequency ablation now represents the most widely used percutaneous technique. PEI and radiofrequency ablation are widely used in clinical practice. However, only scant progresses in the application of these techniques have been performed over the past 15 years, and percutaneous approaches are often only marginally discussed and studied. Here, we discuss the most relevant clinical issues regarding PEI and radiofrequency ablation that have emerged in the past years.

Transarterial chemoembolization and sorafenib in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients.

Natural history of untreatable hepatocellular carcinoma: A retrospective cohort study.

AIM: To investigate the clinical course of untreatable hepatocellular carcinoma (HCC) identified at any stage and to identify factors associated with mortality. METHODS: From January 1999 to December 2010, 320 out of 825 consecutive patients with a diagnosis of HCC and not appropriate for curative or palliative treatments were followed and managed with supportive therapy. Cirrhosis was diagnosed by histological or clinical features and liver function was evaluated according to Child-Pugh score. The diagnosis of HCC was performed by Ultra-Sound guided biopsy or by multiphasic contrast-enhanced computed tomography or gadolinium-enhanced magnetic resonance imaging. Data were collected for each patient including all clinical, laboratory and imaging variables necessary for the outcome prediction staging systems considered. HCC staging was performed according Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program scores. Follow-up time was defined as the number of months from the diagnosis of HCC to death. Prognostic baseline variables were analyzed by multivariate Cox analysis to identify the independent predictors of survival. RESULTS: Seventy-five per cent of patients had hepatitis C. Ascites was present in 169 patients (53%), while hepatic encephalopathy was present in 49 patients (15%). The Child-Pugh score was class A in 105 patients (33%), class B in 142 patients (44%), and class C in 73 patients (23%). One hundred patients (31%) had macroscopic vascular invasion and/or extra-hepatic spread of the tumor. A single lesion > 10 cm was observed in 34 patients (11%), while multinodular HCC was present in 189 patients (59%). Thirty nine patients (12%) were BCLC early (A) stage, 55 (17%) were BCLC intermediate (B) stage, 124 (39%) were BCLC advanced (C) stage, and 102 (32%) were end-stage BCLC (D). At the time of this analysis (July 2011), 28 (9%) patients were still alive. Six (2%) patients who were lost during follow-up were censored at the last visit. The overall median survival was 6.8 mo, and the 1-year survival was 32%. The 1-year survival according to BCLC classes was 100%, 79%, 12% and 0%, for BCLC A, B, C and D, respectively. There was a significant difference in survival between each BCLC class. The median survival of patients of BCLC stages A, B, C and D was 33, 17.4, 6.9, and 1.8 mo, respectively (P < 0.05 for comparison between stages). The median survival of Child-Pugh A, B and C classes were 9.8 mo (range 6.4-13), 6.1 (range 4.9-7.3), and 3.7 (range 1.5-6), respectively (P < 0.05 for comparison between stages). By univariate analysis, the variables significantly associated to an increased liklihood of mortality were Eastern Cooperative Oncology Group performance status (PS), presence of ascites, low level of albumin, elevated level of bilirubin, international normalized ratio (INR) and Log-[(α fetoprotein (AFP)]. At multivariate analysis, mortality was independently predicted by bad PS (P < 0.0001), high INR values (P = 0.0001) and elevated Log-(AFP) levels (P = 0.009). CONCLUSION: This study confirms the heterogeneous behavior of untreated HCC. BCLC staging remains an important prognostic guide and may be important in decision-making for palliative treatment.

Causes of and prevention strategies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated with a high rate of mortality and its prevalence in the United States and in Western Europe is increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the incidence of non-alcoholic steatohepatitis-related HCC may also be expected to increase, and a potential role of behavior treatment and/or insulin-sensitizing drugs can be envisaged. Vaccination against HBV is the most efficient primary prevention measure currently available to reduce the HCC incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature suggests a slight preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders.

Minor hepatic resection for hepatocellular carcinoma in cirrhotic patients: Kelly clamp crushing resection versus heat coagulative necrosis with bipolar radiofrequency device.

Hemorrhage and postoperative liver insufficiency are frequent and serious complications of hepatic resection in cirrhotic patients. The aim of this study was to assess retrospectively whether the surgical techniques using Kelly clamp crushing resection or heat coagulative necrosis with a bipolar radiofrequency device can reduce the incidence of the above complications and an eventual recurrence of neoplasia on the liver slice. We retrospectively reviewed the results of 35 patients who had undergone resection for monofocal hepatocellular carcinoma at our center. Thirteen patients (Group A) had undergone liver resection with Kelly clamp crushing resection, 22 patients (Group B) had had liver resection assisted with a bipolar radiofrequency device. Radiofrequency-assisted liver resection was associated with diminished blood loss (P < 0.0001), a lower blood transfusion rate (P < 0.005), reduced operative time (P < 0.0001), and better postoperative serum albumin levels (P < 0.03). This nonrandomized retrospective study suggests that radiofrequency-assisted liver resection is associated with better results than the Kelly clamp crushing resection technique in cirrhotic patients with focal hepatocellular carcinoma and preserved liver function. These results should now be assessed prospectively in a randomized clinical trial.

Update on new approaches in the management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major health problem. It is currently the third cause of cancer-related death, it is highly prevalent in the Asia-Pacific region and Africa, and is increasing in Western countries. The natural history of HCC is very heterogeneous and prediction of survival in individual patients is not satisfactory because of the wide spectrum of the disease. During the past decade, major advances have been achieved in prevention, through better surveillance of patients at risk, and in therapy through better surgical and ablative therapies and multimodal treatment approaches. Moreover, the increasing knowledge of molecular hepatocarcinogenesis provides the opportunity for targeted therapies. In this setting, the impact of sorafenib on advanced-stage HCC is a landmark finding in the treatment of liver cancer. The role of sorafenib administration as adjuvant therapy after curative treatment is being evaluated in clinical studies. Future research should lead to a molecular classification of the disease and a more personalized treatment approach.

Multimodal approaches to the treatment of hepatocellular carcinoma.

The prevalence of hepatocellular carcinoma in Europe and the US is increasing and is currently the leading cause of death in patients with cirrhosis. Surveillance programs for patients with cirrhosis aim to detect tumors at an early stage, when the greatest therapeutic benefits can be achieved. Curative treatments for early-stage tumors include liver transplantation, resection and percutaneous ablation. Transarterial chemoembolization (TACE) and sorafenib can improve survival for patients with intermediate and advanced tumors, respectively. In clinical practice, combination therapies are often used, despite limited evidence to support this approach from randomized controlled trials. Combination therapy with radiofrequency ablation (RFA) plus percutaneous ethanol injection can, however, improve survival for selected patients compared with RFA alone. Combined treatment with TACE and RFA also improves patients' survival compared with TACE or RFA monotherapy. TACE performed before or after surgical resection, however, is not beneficial. Prevention of tumor progression in patients awaiting liver transplantation requires nonsurgical treatments; however, the real advantages of the available treatment modalities are yet to be defined. The role of sorafenib administration in combination with TACE after the use of potentially curative treatments, for the treatment of intermediate hepatocellular carcinoma, or in selective settings after liver transplantation, requires further study.