Project for interventional Oncology LArge-database in liveR Hepatocellular carcinoma - Preliminary CT-based radiomic analysis (POLAR Liver 1.1).

OBJECTIVE: The objective of this study is to find a contrast-enhanced CT-radiomic signature to predict clinical incomplete response in patients affected by hepatocellular carcinoma who underwent locoregional treatments. PATIENTS AND METHODS: 190 patients affected by hepatocellular carcinoma treated using focal therapies (radiofrequency or microwave ablation) from September 2018 to October 2020 were retrospectively enrolled. Treatment response was evaluated on a per-target-nodule basis on the 6-months follow-up contrast-enhanced CT or MR imaging using the mRECIST criteria. Radiomics analysis was performed using an in-house developed open-source R library. Wilcoxon-Mann-Whitney test was applied for univariate analysis; features with a p-value lower than 0.05 were selected. Pearson correlation was applied to discard highly correlated features (cut-off=0.9). The remaining features were included in a logistic regression model and receiver operating characteristic curves; sensitivity, specificity, positive and negative predictive value were also computed. The model was validated performing 2000 bootstrap resampling. RESULTS: 56 treated lesions from 42 patients were selected. Treatment responses were: complete response for 26 lesions (46.4%), 18 partial responses (32.1%), 10 stable diseases (17.9%), 2 progression diseases (3.6%). Area-Under-Curve value was 0.667 (95% CI: 0.527-0.806); accuracy, sensitivity, specificity, positive and negative predictive values were respectively 0.66, 0.85, 0.50, 0.59 and 0.79. CONCLUSIONS: This contrast-enhanced CT-based model can be helpful to early identify poor responder's hepatocellular carcinoma patients and personalize treatments.

Acute pancreatitis and parathyroid carcinoma: a case report and literature review.

OBJECTIVE: Parathyroid carcinoma is a rare etiology of primary hyperparathyroidism (PHPT) and subsequent hypercalcemia. Among clinical manifestations of hypercalcemia, acute pancreatitis is very uncommon. Nevertheless, acute pancreatitis may be an initial clinical manifestation of parathyroid cancer. PATIENTS AND METHODS: We present a case report and literature review on hypercalcemia-induced acute pancreatitis secondary to parathyroid carcinoma. RESULTS: A 56 years-old man, who had previously received a diagnosis of pancreatic cancer with peritoneal and bone metastasis, complained of persistent postprandial epigastric pain, weight loss (12 kg) and hypercalcemia. He underwent endoscopic ultrasound, which did not identify any solid masses, but a pseudocyst of the pancreas body consistent with a local complication of acute pancreatitis. Plasma levels of parathyroid hormone were markedly increased, and neck ultrasound and scintigraphy confirmed the diagnosis of PHPT. Parathyroidectomy was performed and histological examination revealed parathyroid carcinoma. Searching on PubMed for the keywords "parathyroid carcinoma" AND "acute pancreatitis", from 1969 to March 2021 we found only 12 case reports of acute pancreatitis due to parathyroid cancer. The causal relationship between PHPT and acute pancreatitis has been widely discussed in literature but is still a controversial issue. CONCLUSIONS: Acute pancreatitis induced by primary hyperparathyroidism due to parathyroid carcinoma is an extremely rare condition. However, when hypercalcemia is found, serum PTH levels should always be determined in order to rule out PHPT and hypercalcemia-induced acute pancreatitis should be suspected in presence of hypercalcemia and abdominal symptoms.

The diagnostic performance of PIVKA-II in metabolic and viral hepatocellular carcinoma: a pilot study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a primary liver tumor derived from metabolic or viral chronic hepatitis, with few treatment options in advanced cases. New biomarkers that allow improving diagnosis and staging are widely desired. Here, we aim to evaluate the performance of Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) in combination with α-fetoprotein (AFP), in the diagnosis of HCC in patients with metabolic or viral hepatitis. PATIENTS AND METHODS: We enrolled 60 HCC patients (20 metabolic and 40 viral) and 20 healthy subjects (HS) as negative controls. PIVKA-II, AFP, Matrix metalloproteinase-9 (MMP-9) and Fibroblast growth factor (FGF) serum levels were assessed by immunoassays. RESULTS: AFP and PIVKA-II levels were obviously higher in patients than in HS. AFP displayed a better diagnostic performance than PIVKA-II for viral HCC while PIVKA-II was better for metabolic HCC. The combination of the two biomarkers did not improve the discriminating ability. CONCLUSIONS: PIVKA-II may be considered an independent predictor of macrovascular invasion from HCC cells and it can be used to better stratify HCC patients and should be evaluated in prospective studies for early detection of advanced HCC in metabolic subjects.

Biomarkers in HCV-related mixed cryoglobulinemia patients withnon-Hodgkin lymphoma.

OBJECTIVE: Chronic Hepatitis C virus (HCV) infection can cause severe extrahepatic manifestations, such as mixed cryoglobulins (MC), up to the development of B cell nonHodgkin's lymphoma (B-NHL). Mechanisms transforming of HCV infection into lymphoproliferative and/or autoimmune disorders are still poorly understood. In course of HCV infection, the sustained virus-driven antigenic stimulation may probably induce a B-cell clonal expansion. Measurements of serum free light chains (FLCs) levels, considered as a direct marker of B cell activity, are analyzed with increasing interest in clinical practice, for diagnosis, monitoring and follow-up of plasma cell dyscrasia. Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed and actively shed by most myeloma cells. Membrane CD138 represents the major receptor protein for HCV attachment to the hepatocyte surface and high levels of circulating sCD138 levels are detected in patients at early stage of B-cell chronic lymphocytic leukemia. This study is aimed to evaluate sCD138 and FLC levels as diagnostic biomarkers of HCV-related MC with B-NHL. PATIENTS AND METHODS: We enrolled 35 HCV-MC-NHL patients, characterized for the specific type of cryoglobulins, and 25 healthy blood donors (HBD) as negative control. Serum sCD138 levels were determined using ELISA kits specific for human sCD138. Serum FLCs were assessed by means of the turbidimetric assay. RESULTS: We found that serum levels of sCD138, as well as FLCs, were significantly higher in patients than in HBD (p<0.001). CONCLUSIONS: In agreement with the definition of HCV-driven lymphoproliferative disorders as the consequence of a multifactorial and multistep pathogenetic process, we suggest that sCD138 and FLCs could be considered putative independent markers of worsening progression of the disease.

SARS-CoV2 RNA detection in a pancreatic pseudocyst sample.

The involvement of gastrointestinal system in SARS-CoV2 related disease, COVID-19, is increasingly recognized. COVID-19 associated pancreatic injury has been suggested, but its correlation with pancreatic disease is still unclear. In this case report, we describe the detection of SARS-CoV2 RNA in a pancreatic pseudocyst fluid sample collected from a patient with SARS-CoV2 associated pneumonia and a pancreatic pseudocyst developed as a complication of an acute edematous pancreatitis. The detection of SARS-CoV2 within the pancreatic collection arise the question of whether this virus has a tropism for pancreatic tissue and whether it plays a role in pancreatic diseases occurrence.

Serum immunoglobulin free light chain levels in systemic autoimmune rheumatic diseases.

Several reports have highlighted the abnormal increments of serum immunoglobulin free light chains (FLCs) in the course of systemic autoimmune rheumatic diseases (SARD), but a comparative analysis among different conditions is still lacking. A strong association between elevated FLC and hepatitis C virus (HCV)-related mixed cryoglobulinaemia (HCVMC) has been well established. Here, we aimed to analyse serum FLC levels in patients with four different SARD in comparison with HCVMC. Using a turbidimetric assay, free κ and λ chains were quantified in sera from 198 SARD patients (37 rheumatoid arthritis, RA; 47 systemic lupus erythematosus, SLE; 52 anti-phospholipid syndrome, APS; 62 primary Sjogren's syndrome, pSS), 62 HCVMC and 50 healthy blood donors (HD). All patient groups showed increased κ levels when compared to HD: 33·5 ± 2·6 mg/l in HCVMC, 26·7 ± 2·3 mg/l in RA, 29·7 ± 1·9 mg/l in SLE, 23·8 ± 1·1 mg/l in APS, 24·2 ± 1·1 mg/l in pSS; 10·1 ± 0·6 mg/l in HD. Free λ levels displayed a significant increase only for HCVMC (20·4 ± 1·4 mg/l) and SLE (18·4 ± 1·0 mg/l) compared to HD (13·6 ± 0·9 mg/l). The increase of κ compared to λ takes into account a κ /λ ratio of 1·6 for all groups. Our results substantially analyse and strengthen the association between FLC and SARD focusing the questions regarding their role in the pathogenesis and diagnosis of human diseases. Unfortunately, the biochemical differences distinguishing normal from pathological FLC have not been identified. Production of different isotypes is probably connected to still-unknown pathways.

Critical analysis of major and ancillary features of LI-RADS v2018 in the differentiation of small (≤ 2 cm) hepatocellular carcinoma from dysplastic nodules with gadobenate dimeglumine-enhanced magnetic resonance imaging.

OBJECTIVE: To evaluate the performance of major features, ancillary features, and categories of Liver Imaging Reporting and Data System (LI-RADS) version 2018 at magnetic resonance (MR) imaging in the differentiation of small hepatocellular carcinoma (HCC) from dysplastic nodules (DNs). PATIENTS AND METHODS: This retrospective study included cirrhotic patients with pathologically proven untreated HCCs and DNs (≤ 2 cm) and liver MR imaging performed with gadobenate dimeglumine contrast agent within 3 months before pathological analysis, between 2015 and 2018. 37 patients with 43 observations (17 HCCs and 26 DNs) met the inclusion criteria. Two radiologists assessed major and ancillary imaging features for each liver observation and assigned a LI-RADS v2018 category in consensus. Estimates of diagnostic performance of major features, ancillary features, and LI-RADS categories were assessed based on their sensitivity, specificity, positive (PPV), and negative predictive values (NPV). RESULTS: Major features (nonrim arterial phase hyperenhancement, nonperipheral "washout", and enhancing "capsule") had a sensitivity of 94.1%, 88.2%, and 41.2%, and a specificity of 57.7%, 42.3%, and 88.5% for HCC, respectively. Ancillary features (hepatobiliary phase hypointensity, mild-moderate T2 hyperintensity, restricted diffusion, and fat in the lesion more than adjacent liver) had a sensitivity of 94.1%, 64.7%, 58.8%, and 11.8%, and a specificity of 26.9%, 61.5%, 65.4%, and 76.9% for HCC, respectively. The LR-5 category (determined by using major features only vs. the combination of major and ancillary features) had a sensitivity of 88.2% at both evaluations and a specificity of 76.9% and 80.8% for HCC, respectively. The combination of LR-4, LR-5 categories (determined by using major features only vs. the combination of major and ancillary features) had a sensitivity of 94.1% at both interpretations and a specificity of 65.4% and 26.9% for HCC, respectively. The use of ancillary features modified LI-RADS category in 25.6% of observations (11/43), predominantly upgraded from LR-3 to LR4 (10/11), increasing the proportion of low-grade DNs and high-grade DNs categorized as LR-4 (from 15.4% to 61.5% and from 7.7% to 46.1%, respectively). CONCLUSIONS: The added value of ancillary features in combination with major features is limited for the non-invasive diagnosis of small HCC; however, their use modifies the final category in a substantial proportion of observations from LR-3 to LR-4, thus allowing possible changes in the management of patients at risk for HCC.

Lack of association between Vitamin D status and free light chains profile with different chronic HCV-related liver and extrahepatic disorders.

OBJECTIVE: A still uncertain association between vitamin D levels and HCV chronic liver diseases has been reported. Increased levels of serum-free light chains (FLCs) and an altered k/λ FLC ratio correlate with Mixed Cryoglobulinemia (MC) vasculitis and/or B-cell non-Hodgkin's lymphoma in HCV-positive patients. We aimed to investigate the possible role of vitamin D, vitamin D Binding Protein (DBP), and FLCs levels as a tool for discriminating different stages of HCV- related MC and chronic liver diseases. PATIENTS AND METHODS: Sixty-five untreated patients were retrospectively enrolled and 21 healthy blood donors (HBD) were used as controls. Vitamin D, DBP, FLCs, and cryoglobulins levels were measured. Based on cryoglobulins, patients were divided in three subgroups (without cryoglobulins, type II, and type III). RESULTS: We didn't find any significant differences in vitamin D and DBP levels between HCV patients' main groups and HBD. Serum FLCs levels were significantly higher in HCV patients than in HBD. FLCs ratio among patients' subgroups did not reveal differences. CONCLUSIONS: Our results confirm the presence of an increased serum level of FLCs in HCV patients and suggest that nor vitamin D and DBP or FLC levels can be considered reliable biomarkers for discriminating different stages of HCV-associated chronic liver diseases and/or HCV-associated extrahepatic manifestation. We confirm that serological FLCs levels are significantly higher in patients than in HBD as a signature of B cell activation in course of HCV infection.

A novel biomarker score for the screening and management of patients with plasma cell proliferative disorders.

OBJECTIVE: Monoclonal plasma cell proliferative disorders comprise a wide spectrum of diseases associated to clonal B-cell expansion. Serum protein electrophoretic profile (SPEP) and circulating free light chains (FLCs) levels are the mainstay of diseases management. Recently, soluble (s) Syndecan-1 (SDC1, CD138) produced by myeloma plasma cells has been suggested in the monitoring and follow-up of patients with myeloma. The aim of our study is to evaluate sCD138 in addition with FLCs and SPEP for the screening of patients with different evolutive disease pathways. PATIENTS AND METHODS: Sera from 73 patients with monoclonal gammopathy of undetermined significance (MGUS), 120 smoldering and 42 multiple myeloma (SMM and MM, respectively), 70 HCV-related mixed cryoglobulinemia (MC), 35 B-cell non-Hodgkin's lymphoma (B-NHL) and sera from 50 healthy donors (HD), were tested for sCD138, FLCs (assessed by means of ELISA and turbidimetric assay, respectively) and electrophoresis pattern (performed on Capillarys system) for the generation of a novel biomarker score (BS). RESULTS: Our results were grouped according to the two main lines of disease progression (vs. MM or B-NHL): in one group we found BS mean values of 0.2, 3.4, 5.3, 7.1 for HD, MGUS, SMM and MM, respectively; in the other group of 0.2, 4.4, 6.7 for HD, MC and B-NHL. CONCLUSIONS: We showed that BS mean values follow the ingravescence disease status towards the two main lines of progression to cancerous conditions; it could represent an additional useful tool in the management of screening and/or follow-up.

IgG cryoglobulinemia.

OBJECTIVE: Mixed Cryoglobulinemia is the most well-known Hepatitis C Virus (HCV)-associated extrahepatic manifestation. MC is both an autoimmune and B-lymphoproliferative disorder. Cryoglobulins (CGs) are classified into three groups according to immunoglobulin (Ig) composition: type I is composed of one isotype or Ig class. Type II and type III mixed CGs are immune complexes composed of polyclonal IgGs acting as autoantigens and mono, polyclonal or oligoclonal IgM with rheumatoid factor activity. IgG1 and IgG3 are the predominant subclasses involved. This study shows the simultaneous presence of IgG-RF and IgG3, supporting the hypothesis of an involvement of this subclass in the initiation of early stages of CGs. PATIENTS AND METHODS: We describe a case series of six HCV-positive patients, all of whom had peripheral neuropathy and transient ischemic attacks, presenting cryoprecipitates formed by IgG3 and IgG1. Cryoprecipitate IgG subclass research was carried out by immunofixation electrophoresis by using antisera against IgG1, IgG2, IgG3, and IgG4. RESULTS: Our six patients presented with an immunochemical pattern characterized by the mere presence of IgG1 and IgG3 subclasses with probable RF activity and one of these six patients exhibited monoclonal IgG3 in his cerebrospinal fluid. CONCLUSIONS: We can hypothesize that the IgG passage through the blood-brain barrier could have contributed to the cause of TIAs, through a mechanism involving the precipitation of circulating immune complexes formed by the two subclasses in the intrathecal vessels.

Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon.

BACKGROUND: In HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma (HCC), the time to HCC recurrence and the effects of sustained viral eradication (SVR) by interferon (IFN)-based or IFN-free regimens on HCC recurrence remain unclear. AIM: To perform an indirect comparison of time to recurrence (TTR) in patients with successfully treated early HCC and active HCV infection with those of patients with SVR by IFN-based and by IFN-free regimens. METHODS: We evaluated 443 patients with HCV-related cirrhosis and Barcelona Clinic Liver Cancer Stage A/0 HCC who had a complete radiological response after curative resection or ablation. Active HCV infection was present in 328, selected from the Italian Liver Cancer group cohort; 58 patients had SVR achieved by IFN-free regimens after HCC cure, and 57 patients had SVR achieved by IFN-based regimens after HCC cure. Individual data of patients in the last two groups were extracted from available publications. RESULTS: TTR by Kaplan-Meier curve was significantly lower in patients with active HCV infection compared with those with SVR both by IFN-free (P = 0.02) and by IFN-based (P < 0.001) treatments. TTR was similar in patients with SVR by IFN-free or by IFN-based (P = 0.49) strategies. CONCLUSION: In HCV-infected, successfully treated patients with early HCC, SVR obtained by IFN-based or IFN-free regimens significantly reduce tumour recurrence without differences related to the anti-viral strategy used.

An update on clinical applications of hepatospecific contrast media in magnetic resonance imaging of liver parenchyma.

Hepatobiliary-specific contrast agents are now widely used in magnetic resonance imaging (MRI) of liver parenchyma. As extracellular fluid agents, they provide informations regarding lesion vascularity and their use in the hepatobiliary or delayed phase (DPI), and give additional data regarding hepatocyte presence and function. The aim of this article is to review the recent literature about MRI using hepatobiliary-specific contrast agents and to discuss benefits and limits of their clinical applications. Since November 2008, hepatobiliary contrast agents were routinely employed in our Institution for the characterization of equivocal liver lesions detected by other imaging modalities, and for the evaluation of hepatic nodules in liver cirrhosis. The informations provided are particularly relevant for the detection of metastases, for the differentiation between focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), and for the detection and differentiation between dysplastic nodules (DNs) and hepatocellular carcinoma (HCC) in the cirrhotic liver. The role in the cirrhosis grading and the quantification of liver function is still controversial. Finally, their biliary excretion allows evaluation of anatomy and function of the biliary tree. According to our and reported data, hepatobiliary contrast agents are able to improve liver lesions detection and characterization; their introduction in clinical practice has improved MRI diagnostic efficacy/accuracy, allowing to decrease the number of invasive diagnostic procedures.

Years of life that could be saved from prevention of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour ≥ 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost.

Comparison between alcohol- and hepatitis C virus-related hepatocellular carcinoma: clinical presentation, treatment and outcome.

BACKGROUND: Hepatitis C virus (HCV) and alcohol abuse are the main risk factors for hepatocellular carcinoma (HCC) in Western countries. AIM: To investigate the role of alcoholic aetiology on clinical presentation, treatment and outcome of HCC as well as on each Barcelona Clinic Liver Cancer (BCLC) stage, as compared to HCV-related HCCs. METHODS: A total of 1642 HCV and 573 alcoholic patients from the Italian Liver Cancer (ITA.LI.CA) database, diagnosed with HCC between January 2000 and December 2012 were compared for age, gender, type of diagnosis, tumour burden, portal vein thrombosis (PVT), oesophageal varices, liver function tests, alpha-fetoprotein, BCLC, treatment and survival. Aetiology was tested as predictor of survival in multivariate Cox regression models and according to HCC stages. RESULTS: Cirrhosis was present in 96% of cases in both groups. Alcoholic patients were younger, more likely male, with HCC diagnosed outside surveillance, in intermediate/terminal BCLC stage and had worse liver function. After adjustment for the lead-time, median (95% CI) overall survival (OS) was 27.4 months (21.5-33.2) in alcoholic and 33.6 months (30.7-36.5) in HCV patients (P = 0.021). The prognostic role of aetiology disappeared when survival was assessed in each BCLC stage and in the Cox regression multivariate models. CONCLUSIONS: Alcoholic aetiology affects survival of HCC patients through its negative effects on secondary prevention and cancer presentation but not through a greater cancer aggressiveness or worse treatment result. In fact, survival adjusted for confounding factors was similar in alcoholic and HCV patients.

Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.

BACKGROUND: Psoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment. AIM: To estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates. METHODS: A retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time-dependent predictors were updated at each available time point. RESULTS: Four hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03). CONCLUSIONS: Paradoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis.

A randomized double-blind placebo-controlled clinical trial on efficacy and safety of association of simethicone and Bacillus coagulans (Colinox®) in patients with irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder that affects 15-20% of the Western population. BACKGROUND: There are currently few therapeutic options available for the treatment of IBS. The aim of this study is to evaluate the efficacy and the safety of a medical device containing a combination of Simethicone and Bacillus coagulans in the treatment of IBS. PATIENTS AND METHODS: This is a monocentric double-blind, placebo-controlled parallel group clinical trial. Adult subjects suffering from IBS as defined by Rome III criteria were enrolled. Bloating, discomfort, abdominal pain were assessed as primary end point. Subjects received the active treatment or placebo 3 time a day after each meal for 4 weeks of study period. Subjects were submitted to visit at Day 0 (T1), at Days 14 (T2) and 29 (T3). RESULTS: Fifty-two patients were included into the study. Intragroup analysis showed a significant reduction of the bloating, discomfort and pain in Colinox® group (CG) compared to placebo group (PG). Between group analysis confirmed, at T1-T3, significant differences between CG and PG in bloating and discomfort. DISCUSSION: Simethicone is an inert antifoaming able to reduce bloating, abdominal discomfort. Literature offers increasing evidence linking alterations in the gastrointestinal microbiota and IBS and it is well known that probiotics are important to restore the native gut microbiota. The Colinox medical device is specifically targeted against most intrusive symptom of IBS (bloating) and it is also able to counteract the most accredited ethiopathogenetic factor in IBS (alterations of intestinal microbiota). CONCLUSIONS: This is the first randomized double-blind placebo-controlled clinical trial demonstrating the efficacy and safety of a combination of simethicone and Bacillus coagulans in treatment of IBS.

Single-step multimodal locoregional treatment for unresectable hepatocellular carcinoma: balloon-occluded percutaneous radiofrequency thermal ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE).

PURPOSE: This study was undertaken to evaluate the feasibility, safety and efficacy of a new combined single-step therapy in patients with unresectable multinodular unilobar hepatocellular carcinoma (HCC), with at least one lesion >3 cm, with balloon-occluded radiofrequency ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE) of the main lesion and TACE of the other lesions. The second purpose of our study was to compare the initial effects in terms of tumour necrosis of this new combined therapy with those obtained in a matched population treated with TACE alone in a singlestep treatment in our centre in the previous year. METHODS AND MATERIALS: This pilot study was approved by the institutional review board, and informed consent was obtained from all patients. Ten consecutive patients with multinodular (two to six nodules) unilobar unresectable HCC and with a main target lesion >3 cm (range, 3.5-6 cm) not suitable for curative therapy were enrolled in our single-centre multidisciplinary pilot study. The schedule consisted of percutaneous RFA (single 3-cm monopolar needle insertion) of the target lesion during occlusion of the hepatic artery supplying the tumour, followed by selective TACE, plus lobar TACE for other lesions (450-mg carboplatin and lipiodol plus temporary embolisation with SPONGOSTAN). Adverse events and intra- and periprocedural complications were clinically assessed. Early local efficacy was evaluated on 1-month follow-up multiphasic computed tomography (CT) on the basis of the Modified Response Evaluation Criteria in Solid Tumors (m-RECIST). A separate evaluation of target lesions in terms of enhancement, necrotic diameter and presence and distribution of lipiodol uptake was also performed. RESULTS: No major complications occurred. Overall technical success, defined as complete devascularisation of all nodules during the arterial phase, was achieved in seven of 10 patients, with three cases of partial response (persistence of small hypervascular nodules). When considering only target lesions, technical success was obtained in all patients, with a nonenhancing area corresponding in shape to the previously identified HCC (necrotic diameter, 3.5-5 cm) and with circumferential peripheral lipiodol uptake (safety margin) of at least 0.5 cm (0.5-1.3cm). CONCLUSIONS: TACE and BO-RFA, plus TACE in a singlestep approach seems to be a safe and effective combined therapy for treating advanced, unresectable HCC lesions, allowing a high rate of complete local response to be achieved in large lesions also.

Potential use of liver function breath tests in the clinical practice.

BACKGROUND: Assessment of hepatic functional reserve in acute and chronic liver disease is a discriminating factor for prognostic and therapeutic reasons. For this reason dynamic liver function tests have been developed. AIM: To review the breath method with stable carbon isotopes in hepatological setting. MATERIALS AND METHODS: We conducted a literature review to analyze the experimental evidence about the diagnostic potential of breath tests of liver function. RESULTS: Liver breath tests are able to discriminate between healthy subjects and patients with liver cirrhosis. The use for the assessment of liver fibrosis seems to be still burdened with less capability to discriminate between intermediate stages. CONCLUSIONS: Liver breath test are a promising tool for the evaluation of hepatic functional reserve but the use of such methods in clinical practice is limited to specialized or research centers. Most extensive studies are necessary to facilitate the spread of these methods in clinical practice.

Differentiating hepatocellular carcinoma from dysplastic nodules at gadobenate dimeglumine-enhanced hepatobiliary-phase magnetic resonance imaging.

PURPOSE: We evaluated whether the addition of delayed phase imaging (DPI) gadobenate dimeglumine-enhanced MRI to dynamic postcontrast imaging improves the characterization of small hepatocellular carcinoma (HCC) and the differentiation between HCC, high grade dysplastic nodules (HGDN), and low grade dysplastic nodules (LGDN). METHODS: Twenty-five cirrhotic patients with 30 nodules (16 HCC, 8 HGDNs, and 6 LGDNs; maximum size of 3 cm) were included in this retrospective study. The diagnostic reference standard was histology. All the patients underwent MRI both prior to and following intravenous administration of gadobenate dimeglumine. The lesions were classified as hypointense, isointense, hyperintense on DPI for qualitative assessment. In the quantitative analysis the relative tumor-liver contrast to noise ratio (CNR) of the lesions on DPI was calculated. RESULTS: All HCCs were hypointense on DPI while only 8 (57.1%) of 14 DNs were hypointense and only 1 of 6 (16.6%) LGDNs was hypointense. There was a statistically significant difference in the hypointensity on DPI between HCCs and DNs (p = 0.003) in the qualitative analysis but not in the CNR values while there was a strong statistically significant difference in the hypointensity on DPI in the qualitative (p = 0.00001) and quantitative analysis (p < 0.05) between LGDNs and the group obtained by unifying HGDNs and HCCs. CONCLUSION: DPI is helpful in differentiating HCCs and HGDNs from LGDNs. Demonstration of hypointensity on DPI should raise the suspicion of HGDN or hypovascular HCC in the case of nodules with atypical dynamic pattern.

Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-α agents: effects of combined therapy with immunosuppressants.

BACKGROUND AND AIMS: Our first objective was to evaluate the immune response to the adjuvanted 2009 A/H1N1 pandemic (pH1N1) vaccine in inflammatory bowel disease (IBD) patients treated with anti-TNF-α alone or combined with immunosuppressants (IS). Second and third aims were the safety of pH1N1 vaccine and the effects on IBD clinical activity. METHODS: 36 patients with Crohn's disease (CD) and 26 with ulcerative colitis (UC) and thirty-one healthy control (HC) subjects were enrolled. 47 patients were on anti TNF-α maintenance monotherapy and 15 on anti TNF-α combined with IS. Sera were collected at baseline (T0) and 4 weeks after the vaccination (T1) for antibody determination by hemagglutination inhibition (HAI). Disease activity was monitored at T0 and T1. RESULTS: Seroprotective titers (≥1:40) in patients were comparable to HC. Seroconvertion rate (≥4 fold increase in HAI titer) was lower than HC in IBD patients (p=0.009), either on anti TNF-α monotherapy (p=0.034) or combined with IS (p=0.011). Geometric mean titer (GMT) of antibodies at T1 was significantly lower in patients on combined therapy versus those on monotherapy (p=0.0017) and versus HC (p=0.011). The factor increase of GMT at T1 versus T0 was significantly lower in IBD patients versus HC (p=0.042), and in those on combined immunosuppression, both versus monotherapy (p=0.0048) and HC (p=0.0015). None of the patients experienced a disease flare. CONCLUSION: Our study has shown a suboptimal response to pH1N1 vaccine in IBD patients on therapy with anti TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.