Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients.

BACKGROUND & AIMS: Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians' experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE management changed over time and if these modifications impacted on treatment duration and overall survival (OS). METHODS: We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in 3 tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008-2012; n = 154), and Group B (2013-2017, n = 184). Baseline and follow-up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy. RESULTS: Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs. 568 mg/day, p <0.001) due to more frequent dose modifications. However, treatment duration was longer (5.8 vs. 4.1 months, p = 0.021) with a trend toward a higher cumulative dose in Group B. Notably, the OS was also higher (12.0 vs. 11.0 months, p = 0.003) with a sharp increase in the 2-year survival rate (28.1 vs. 18.4%, p = 0.003) in Group B. Multivariate time-dependent Cox regression analysis confirmed later period of treatment (2013-2017) as an independent predictor of survival (HR 0.728; 95%CI 0.581-0.937; p = 0.013). Unconsidered confounders were unlikely to affect these results at the sensitivity analysis. CONCLUSIONS: Experience in the management of sorafenib-related AEs prolongs treatment duration and survival. This factor should be considered in the design of future randomised clinical trials including a sorafenib treatment arm, as an underestimate of sample size may derive. LAY SUMMARY: Sorafenib has been the standard frontline systemic treatment for hepatocellular carcinoma for over a decade. Its tolerability is limited by different adverse events, which might lead to its permanent discontinuation in a sizeable proportion of patients. After a careful analysis of potential confounders, we demonstrated that the physicians' experience in managing adverse events related to sorafenib has improved over time, with longer treatment periods and less permanent discontinuation for toxicities. More importantly, these improvements also translated into longer patient survival. Our results have relevant repercussions in clinical practice and in the design of future clinical trials.

Inter-operator variability and source of errors in tumour response assessment for hepatocellular carcinoma treated with sorafenib.

OBJECTIVES: To assess the inter-operator concordance and the potential sources of discordance in defining response to sorafenib in hepatocellular carcinoma (HCC). METHODS: All patients who received sorafenib between September 2008 and February 2015 were scrutinised for this retrospective study. Images were evaluated separately by three radiologists with different expertise in liver imaging (operator 1, >10 years; operator 2, 5 years; operator 3, no specific training in liver imaging), according to: response evaluation radiological criteria in solid tumours (RECIST) 1.1, modified RECIST (mRECIST) and response evaluation criteria in cancer of the liver (RECICL). RESULTS: The overall response concordance between the more expert operators was good, irrespective of the criteria (RECIST 1.1, ĸ = 0.840; mRECIST, ĸ = 0.871; RECICL, ĸ = 0.819). Concordance between the less expert operator and the other colleagues was lower. The most evident discordance was in target lesion response assessment, with expert operators disagreeing mostly on lesion selection and less expert operators on lesion measurement. As a clinical correlate, overall survival was more tightly related with "progressive disease" as assessed by the expert compared to the same assessment performed by operator 3. CONCLUSIONS: Decision on whether a patient is a responder or progressor under sorafenib may vary among different operators, especially in case of a non-specifically trained radiologist. Regardless of the adopted criteria, patients should be evaluated by experienced radiologists to minimise variability in this critical instance. KEY POINTS: • Inter-operator variability in the assessment of response to sorafenib is poorly known. • The concordance between operators with expertise in liver imaging was good. • Target lesions selection was the main source of discordance between expert operators. • Concordance with non-specifically trained operator was lower, independently from the response criteria. • The non-specifically trained operator was mainly discordant in measurements of target lesions.

Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma.

BACKGROUND & AIMS: Assessment of long-term outcome is required in hepatitis C virus (HCV)-infected patients with cirrhosis, who have been successfully treated for Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC). However, problems arise due to the lack of models accounting for early changes during follow-up. The aim of this study was to estimate the impact of early events (HCC recurrence or hepatic decompensation within 12months of complete radiological response) on 5-year overall survival (OS) in a large cohort of patients with HCV and cirrhosis, successfully treated HCC. METHODS: A total of 328 consecutive Caucasian patients with HCV-related cirrhosis and BCLC stage 0/A HCC who had complete radiological response after curative resection or thermal ablation were prospectively recruited to this study. Primary endpoint of the study was 5-year OS. Independent baseline and time-dependent predictors of 5-year OS were identified by Cox model. RESULTS: The observed 5-year survival rate was 44%. The observed HCC early recurrence and early hepatic decompensation rate were 21% and 10%, respectively. Early hepatic decompensation (Hazard Ratio [HR] 7.52; 95% confidence intervals (CI): 1.23-13.48) and HCC early recurrence as time-dependent covariates (HR 2.50; 95%CI: 1.23-5.05), presence of esophageal varices at baseline (HR 1.66; 95% CI: 1.02-2.70) and age (HR 1.04; 95% CI: 1.02-1.07) were significantly associated with the 5-year OS. CONCLUSION: Survival in HCV-infected patients with cirrhosis and successfully treated HCC is influenced by early hepatic decompensation. Our study indirectly suggests that direct-acting antiviral agents could improve OS of HCC patients through long-term preservation of liver function, resulting in a lower cirrhosis-related mortality and a greater change of receiving curative treatments. LAY SUMMARY: Survival in hepatitis C virus (HCV) infected patients with cirrhosis and successfully treated hepatocellular carcinoma (HCC), is mainly influenced by early hepatic decompensation. HCV eradication after treatment with new direct-acting antiviral agents could improve overall survival of HCC patients through long-term preservation of liver function.

A Relative Deficiency of Lysosomal Acid Lypase Activity Characterizes Non-Alcoholic Fatty Liver Disease.

Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)-however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled. For each patient, LAL activity was determined on peripheral dried blood spots (DBS) and correlated with clinical and laboratory data. A subgroup analysis among cirrhotic patients was also performed. LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. NAFLD is characterized by a specific deficit in LAL activity, suggesting a pathogenetic role of LAL. We propose that future studies on this topic should rely on tissue specific analyses, as peripheral blood tests are also influenced by confounding factors.

Hepatic Steatosis in Patients with Celiac Disease: The Role of Packaged Gluten-Free Foods.

Background: An increased risk of nonalcoholic fatty liver disease (NAFLD) in patients with celiac disease (CD) adhering to a gluten-free diet (GFD) was recently reported. The nutritional composition of packaged gluten-free foods (PGFF) has been proposed as a possible cause. This hypothesis has not been investigated further, since a systematic structural nutritional interview for all patients would be problematic in clinical practice. Methods: We administered a simple questionnaire based on a Recency, Frequency, and Monetary value (RFM) analysis (a cornerstone of direct marketing segmentation) to consecutive CD patients on a GFD for >6 months and verified its association with NAFLD. Subgroup analyses were performed to understand whether specific patterns of PGFF consumption were significantly associated with NAFLD. Results: Amongst 147 patients (female 82%, median age 42 years), 45 (30.6%) had NAFLD. Total RFM score (adjusted odds ratio = 1.223, 95% CI: 1.059−1.413, p = 0.006), body mass index, and total cholesterol and triglycerides were independently related to NAFLD, and "Bread and bakery" (p = 0.002), "salty convenience" (p = 0.005), and "sweet convenience" (p = 0.049) products were significantly related with NAFLD. Also, questions about the number of purchased PGFF in the last month (monetary value) and different categories of PGFF consumed in the last week (recency) were particularly able to identify NAFLD patients. Conclusions: The specific GFD dietary habits of CD patients were correlated with the degree of risk of NAFLD. Information was obtained through a questionnaire which could be used in clinical practice to favor a patient-tailored approach and in future studies to verify the reproducibility of our results in different geographical areas.

Current guidelines for the management of celiac disease: A systematic review with comparative analysis.

BACKGROUND: Wheat and other gluten-containing grains are widely consumed, providing approximately 50% of the caloric intake in both industrialised and developing countries. The widespread diffusion of gluten-containing diets has rapidly led to a sharp increase in celiac disease prevalence. This condition was thought to be very rare outside Europe and relatively ignored by health professionals and the global media. However, in recent years, the discovery of important diagnostic and pathogenic milestones has led to the emergence of celiac disease (CD) from obscurity to global prominence. These modifications have prompted experts worldwide to identify effective strategies for the diagnosis and follow-up of CD. Different scientific societies, mainly from Europe and America, have proposed guidelines based on CD's most recent evidence. AIM: To identify the most recent scientific guidelines on CD, aiming to find and critically analyse the main differences. METHODS: We performed a database search on PubMed selecting papers published between January 2010 and January 2021 in the English language. PubMed was lastly accessed on 1 March 2021. RESULTS: We distinguished guidelines from 7 different scientific societies whose reputation is worldwide recognized and representative of the clinical practice in different geographical regions. Differences were noted in the possibility of a no-biopsy diagnosis, HLA testing, follow-up protocols, and procedures. CONCLUSION: We found a relatively high concordance between the guidelines for CD. Important modifications have occurred in the last years, especially about the possibility of a no-biopsy diagnosis in children. Other modifications are expected in the next future and will probably involve the extension of the non-invasive diagnosis to the adult population and the follow-up modalities.

Long term effects of gluten-free diet in non-celiac wheat sensitivity.

BACKGROUND & AIMS: Information about the clinical outcome of patients with non-celiac wheat sensitivity (NCWS) treated with gluten-free diet (GFD) derive from studies assessing the symptom response in the first few weeks of treatment. We aimed to evaluate the clinical response to the GFD and the quality of life (QoL) of NCWS patients in the long term. METHODS: Forty-four NCWS (diagnosed according to the Salerno criteria) participated in the study. Participants rated their symptoms according to a 0-10 scale patients and filled in a QoL questionnaire (CDQ) before the beginning of the GFD and during a follow-up evaluation performed after at least one year. To assess the reliability of the questionnaire we also included a control group of 43 matched patients with celiac disease (CD). RESULTS: Upon diagnosis, NCWS patients had a high prevalence of intestinal and extraintestinal symptoms. Also, most symptoms were described as severe and the QoL questionnaire showed high scores. On follow-up, both prevalence and severity of the most common symptoms were significantly reduced. However, persistent intestinal and extraintestinal symptoms of mild severity were found in 65.9 and 72.7% of NCWS patients. In comparison, in the CD group, the prevalence was lower (32.6 and 23.2% respectively) and consistent with previous studies. The analyses of the determinant of QoL showed that, upon diagnosis, NCWS patients had higher scores in the CDQ "gastrointestinal symptoms" (p < 0.001), "emotional aspects" (p < 0.001) and "social problems" (p < 0.001) subclasses compared to CD patients. After the GFD, NCWS and CD patients shared similar scores in all of the subclasses. CONCLUSIONS: A significant proportion of NCWS patients still complains of intestinal and extraintestinal symptoms, even if significantly attenuated by the GFD, even years after the diagnosis. A comprehensive nutritional evaluation of these patients is required to further improve their symptoms and their QoL.

Systemic treatments for hepatocellular carcinoma: challenges and future perspectives.

Sorafenib has been the only approved systemic treatment of hepatocellular carcinoma (HCC) for almost a decade. Recently, two new drugs showed positive results in two Phase III studies. The RESORCE trial identified regorafenib as a valid second-line treatment for patients progressing to sorafenib, the REFLECT trial showed that lenvatinib is noninferior to sorafenib as front-line treatment. Following these trials, the therapeutic scenario will be dominated by anti-VEGFR drugs, with three different molecules showing a proven anticancer activity. Some open problems still remain and different immunotherapy trials are underway, following promising preliminary results. In this review we analyze: the most recent advancements about patients treated with sorafenib; the results of RESORCE and REFLECT trials; and the ongoing Phase III clinical trials. Finally, we discuss how they could address the current problems and possibly reshape the future of the systemic treatments for HCC.

Celiac Disease Diagnosed through Screening Programs in At-Risk Adults Is Not Associated with Worse Adherence to the Gluten-Free Diet and Might Protect from Osteopenia/Osteoporosis.

Screening strategies to detect celiac disease (CD) in at-risk subjects are of paramount importance to prevent the possible long-term complications of this condition. It is therefore of strategic relevance to understand whether patients diagnosed through screening follow a strict gluten-free diet (GFD), as the non-compliance to this diet can make screening efforts pointless. Currently, no studies have verified whether CD patients diagnosed in their adulthood are adhering to the GFD years after the diagnosis. We retrospectively evaluated the medical records of 750 CD patients diagnosed in our center during January 2004⁻December 2013 to verify differences between screening detected and clinically diagnosed patients. The groups shared a similar adherence to the GFD (91.2 versus 89.8%, p = 0.857). Moreover, the rates of non-responsive CD, GFD-induced metabolic alterations, and persistence in controls were also similar. Instead, screening-detected patients had a significantly lower rate of osteopenia/osteoporosis at diagnosis (31.3 versus 46%, p < 0.001). In conclusion, screening strategies for CD in at-risk groups should be encouraged even in the adult population. Patients diagnosed through these strategies had no additional problems compared to those diagnosed for clinical suspicion and might benefit from a protective effect against metabolic bone disease.

Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale.

PURPOSE: In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance. PATIENTS AND METHODS: We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples. RESULTS: In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P = .013). CONCLUSIONS: Our findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.

Comparative analysis of current guidelines for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common malignancies and represents a unique challenge for physicians and patients. Treatment patterns are not uniform between areas despite efforts to promote a common protocol. Even if most hepatologists worldwide adopt the Barcelona Clinic Liver Cancer staging system, Asian and North American physicians are also independently making an effort to expand the indications of each treatment, combining therapies for better outcomes. Also, new therapeutic techniques have emerged and an increasing number of studies are trying to include these paradigm shifts into newer treatment guidelines. Controversial and diverging points in the current international guidelines are emphasized and discussed. Unanswered questions are also analyzed to identify the most needed and promising future perspectives.

Ongoing challenges in the diagnosis of hepatocellular carcinoma.

In 2001, the European Association for the Study of the Liver (EASL) endorsed the possibility of achieving a non-invasive diagnosis of Hepatocellular Carcinoma (HCC) for the first time. Since then, various refinements of the criteria and techniques capable of achieving this diagnosis and the role of plasma and tissue oncomarkers have been reported in the literature and have been accepted to different extents in various geographical areas. Such tools can also potentially imply prognostic significance. The present article critically discusses some of the most relevant and debated challenges which have emerged in this field, including the role of contrast-enhanced ultrasound, and of hepatocyte-specific magnetic resonance contrast agents, the pitfall of transient hepatic attenuation differences, the reliability of biopsy and the status of biomarkers.

Prognostic significance of adverse events in patients with hepatocellular carcinoma treated with sorafenib.

Sorafenib is the standard treatment for patients with hepatocellular carcinoma (HCC) with advanced stage disease. Although its effectiveness has been demonstrated by randomized clinical trials and confirmed by field practice studies, reliable markers predicting therapeutic response have not yet been identified. Like other tyrosine kinase inhibitors, treatment with sorafenib is burdened by the development of adverse effects, the most frequent being cutaneous toxicity, diarrhoea, arterial hypertension and fatigue. In recent years, several studies have analysed the correlation between off-target effects and sorafenib efficacy in patients with HCC. In this review, an overview of the studies assessing the prognostic significance of sorafenib-related adverse events is provided.

Imaging Diagnosis of Hepatocellular Carcinoma: Recent Advances of Contrast-Enhanced Ultrasonography with SonoVue®.

Due to the ability to detect the typical contrast-imaging pattern for hepatocellular carcinoma (HCC), that is hyperenhancement in the arterial phase and hypoenhancement in the late phase on a cirrhotic background, contrast-enhanced ultrasonography (CEUS) was included in the American diagnostic algorithm for HCC in 2005. However, its role has been questioned because of the possibility of misdiagnosis of cholangiocarcinoma. The present review aims to describe the advantages and disadvantages of CEUS applications using Sonovue® for HCC. In particular there is focus on the accuracy of CEUS in detecting the typical HCC pattern, the CEUS patterns of intrahepatic cholangiocarcinoma (ICC), the risk of misdiagnosis with HCC, the diagnostic use of CEUS in cases of locoregional and systemic treatments, and the evaluation of response to antiangiogenic treatment using dedicated software.

Clinical and diagnostic aspects of gluten related disorders.

Gluten is one of the most abundant and widely distributed components of food in many areas. It can be included in wheat, barley, rye, and grains such as oats, barley, spelt, kamut, and triticale. Gluten-containing grains are widely consumed; in particular, wheat is one of the world's primary sources of food, providing up to 50% of the caloric intake in both industrialized and developing countries. Until two decades ago, celiac disease (CD) and other gluten-related disorders were believed to be exceedingly rare outside of Europe and were relatively ignored by health professionals and the global media. In recent years, however, the discovery of important diagnostic and pathogenic milestones led CD from obscurity to global prominence. In addition, interestingly, people feeding themselves with gluten-free products greatly outnumber patients affected by CD, fuelling a global consumption of gluten-free foods with approximately $2.5 billion in United States sales each year. The acknowledgment of other medical conditions related to gluten that has arisen as health problems, providing a wide spectrum of gluten-related disorders. In February 2011, a new nomenclature for gluten-related disorders was created at a consensus conference in London. In this review, we analyse innovations in the field of research that emerged after the creation of the new classification, with particular attention to the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for CD and the most recent research about non-celiac gluten sensitivity.