Identification of the Best Cut-Off Value of PIVKA-II for the Surveillance of Patients at Risk of Hepatocellular Carcinoma Development.

Patients with cirrhosis are at risk of hepatocellular carcinoma (HCC) development and, according to current guidelines, should undergo surveillance by ultrasound at six month intervals. Due to the known limitations of surveillance strategies based on ultrasonography, the use of tumor biomarkers, although debated, is common practice in many centers. The aim of the study was to identify the best cut-off value for one of such biomarkers, protein induced by vitamin K absence, or antagonist-II (PIVKA-II). We retrospectively enrolled 1187 patients with liver cirrhosis: 205 with a diagnosis of HCC (median age 67 years, 81.0% males) and 982 without tumor (median age 64 years, 56.2% males). During a median follow-up (FU) of 34.6 (11.4−43.7) months, 118 out of 982 (12.0%) patients developed HCC. Serum PIVKA-II was assessed by chemiluminescence immunoassay on the Lumipulse® G600 II platform (Fujirebio, Tokyo, Japan). In the overall cohort (n = 1187), PIVKA-II showed an area under the curve (AUC) of 0.802 for HCC detection. The best cut-off value that maximized sensitivity was 50 mAU/mL (sensitivity = 80%, specificity = 64%). In the 982 patients without HCC at baseline, PIVKA-II > 50 mAU/mL was associated with an increased risk of HCC development during the FU (HR = 1.74, 95% CI 1.21−2.51; p = 0.003)). In conclusion, the evaluation of serum PIVKA-II showed a good performance for HCC detection; a cut-off value > 50 mAU/mL could be suitable for the surveillance of patients who are at risk of developing HCC.

Who Should Not Be Surveilled for HCC Development after Successful Therapy with DAAS in Advanced Chronic Hepatitis C? Results of a Long-Term Prospective Study.

Background and aims: The identification of patients with Hepatitis C Virus (HCV)-positive advanced chronic liver disease (aCLD) successfully treated by Direct Acting Antiviral Agents (DAAs) who really benefit from Hepatocellular Carcinoma (HCC) surveillance programs is still a matter of debate. We performed a long-term prospective cohort study on F3-F4 HCV-positive patients achieving Sustained Virologic Response (SVR) after DAAs treatment in order to identify patients who can safely suspend surveillance. Methods: 1000 patients with HCV-positive aCLD obtaining SVR by DAAs from January 2015 to December 2017 were divided into four groups according to baseline elastographic, ultrasonographic, clinical and biochemical features: (1) Group 1: 324 patients with Liver Stiffness Measurement (LSM) ≥ 9.5 ≤ 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (2) Group 2: 133 patients with LSM ≥ 9.5 ≤ 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5 (3) Group 3: 158 patients with LSM > 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (4) Group 4: 385 patients with LSM > 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5. FIB-4 and APRI scores were calculated at baseline and at SVR achievement. Each patient was surveiled twice-yearly by ultrasound for a median follow-up of 48 months. Results: among Group 1 patients, 1/324 (0.3%) developed HCC (0.09/100 patients/year [PY]), compared to 6/133 (4.5%) Group 2 patients (1.22/100 PY, p = 0.0009), 10/158 (6.3%) Group 3 patients (1.68/100 PY, p = 0.0001), 54/385 (14.0%) Group 4 patients (4.01/100 PY, p < 0.0001). HCC incidence was significantly lower in Group 2 compared to Group 3 (p = 0.004) and in Group 3 compared to Group 4 (p = 0.009). HCC risk fell in patients showing a decrease of FIB-4/APRI scores. Conclusions: the risk of HCC occurrence is negligible in about 90% of HCV-positive patients with baseline LSM ≥ 9.5 ≤ 14.5 kPa plus FIB-4 < 3.25 and APRI < 1.5 achieving SVR. Among this particular subset of patients, FIB-4/APRI scores may represent an accurate and inexpensive tool to distinguish patients not needing long-term HCC surveillance.

Serum glypican-3 for the prediction of survival in patients with hepatocellular carcinoma.

BACKGROUND: Glypican-3 (GPC-3) is a heparan sulfate proteoglycan overexpressed by hepatocellular carcinoma (HCC) cells. Several studies highlighted the diagnostic and prognostic value of GPC-3 expression in liver tissue, while data on the reliability of serum GPC-3 are limited and conflicting. We aimed to evaluate the prognostic value of serum GPC-3 in patients with HCC. METHODS: A total of 449 patients (91 F and 358 M; median age 65 [38-86] years) with a new diagnosis of HCC and available serum samples collected at tumor diagnosis were retrospectively analyzed. All patients had cirrhosis and the main underlying etiology was viral (N.=323, 72%). Barcelona Clinic Liver Cancer (BCLC) staging system was adopted for patients' classification (BCLC 0/A, N.=293, 65% vs. B/C/D, N.=156, 35%) and treatment allocation. Response to therapy was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST). RESULTS: Median overall survival (OS) after HCC diagnosis was 30 months (95% confidence interval [CI]: 27-34). Patients with serum GPC-3>150 pg/mL showed lower overall survival (16; 95%CI: 13-24 months) compared to those with GPC-3≤150 pg/mL (36; 95%CI: 30-56 months) (Log-rank test, P<0.001). At multivariate Cox proportional-hazard regression analysis, presence of ascites (adjusted Hazard Ratio [aHR]=1.84; 95%CI: 1.23-2.74, P=0.003), BCLC stage (aHR=1.65; 95%CI: 1.39-1.97, P<0.001), mRECIST (aHR=0.33; 95%CI: 0.21-0.51, P<0.001) and GPC-3>150 pg/mL (aHR=2.02; 95%CI: 1.47-2.78, P<0.001) resulted significantly associated to overall survival. CONCLUSIONS: Serum GPC-3 resulted an independent prognostic factor for patients with HCC irrespectively from tumor stage and response to therapy.

Cost-effectiveness analysis of personalised versus standard dosimetry for selective internal radiation therapy with TheraSphere in patients with hepatocellular carcinoma.

Aims: To perform a cost-effectiveness analysis (CEA) comparing personalised dosimetry with standard dosimetry in the context of selective internal radiation therapy (SIRT) with TheraSphere for the management of adult patients with locally advanced hepatocellular carcinoma (HCC) from the Italian Healthcare Service perspective. Materials and methods: A partition survival model was developed to project costs and the quality-adjusted life years (QALYs) over a lifetime horizon. Clinical inputs were retrieved from a published randomised controlled trial. Health resource utilisation inputs were extracted from the questionnaires administered to clinicians in three oncology centres in Italy, respectively. Cost parameters were based on Italian official tariffs. Results: Over a lifetime horizon, the model estimated the average QALYs of 1.292 and 0.578, respectively, for patients undergoing personalised and standard dosimetry approaches. The estimated mean costs per patient were €23,487 and €19,877, respectively. The incremental cost-utility ratio (ICUR) of personalised versus standard dosimetry approaches was €5,056/QALY. Conclusions: Personalised dosimetry may be considered a cost-effective option compared to standard dosimetry for patients undergoing SIRT for HCC in Italy. These findings provide evidence for clinicians and payers on the value of personalised dosimetry as a treatment option for patients with HCC.

Liver Cancer-Specific Isoform of Serine Protease Inhibitor Kazal for the Detection of Hepatocellular Carcinoma: Results from a Pilot Study in Patients with Dysmetabolic Liver Disease.

Reliable non-invasive biomarkers for the surveillance of patients at risk of hepatocellular carcinoma (HCC) development represent an unmet medical need. Recently, the liver-cancer-specific isoform of serine protease inhibitor Kazal (LC-SPIK) has been proposed as a valuable biomarker for the detection of HCC in patients with chronic liver disease of viral etiology. In the present study, we assessed the diagnostic accuracy of LC-SPIK, alone or in combination with standard serologic biomarkers (i.e., alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II, PIVKA-II), for the detection of HCC among patients with dysmetabolic liver disease. A total of 120 patients with non-alcoholic fatty liver disease (NAFLD), including 62 patients with a diagnosis of HCC and 58 with cirrhosis but without tumor, were retrospectively analyzed. The serum levels of LC-SPIK were measured by enzyme-linked immunosorbent assay (ImCare Biotech, Doylestown, PA). The serum LC-SPIK values were significantly different between patients with HCC (24.3, 17.6−39.8 ng/mL) and those with cirrhosis but without tumor (11.7, 8.7−18.2 ng/mL) (p < 0.001). By receiver operating characteristic curve analysis, we observed an area under the curve (AUC) of 0.841 for the detection of HCC; the combination with PIVKA-II further increased the accuracy to AUC = 0.926 (cross-validation). The promising results observed in the present pilot study foster additional research to investigate the usefulness of LC-SPIK for the stratification of the risk of HCC development in patients with NAFLD and advanced liver disease.

Effect of COVID-19 Pandemic on Hepatocellular Carcinoma Diagnosis: Results from a Tertiary Care Center in North-West Italy.

The COVID-19 pandemic has forced us to direct most of the available resources towards its management. This has led to the neglect of all other pathologies, including cancer. The aim of this study was to verify whether the difficulty in accessing the health system has led to a reduction in new diagnoses of hepatocellular carcinoma (HCC) and whether this has already been reflected in a more advanced stage of the cancer. A single-center, retrospective study including adult patients with a new diagnosis of HCC was performed. Patients were divided into three groups: the prelockdown phase (May 2019-February 2020), the lockdown phase (March 2020-December 2020), and the postlockdown phase (January 2021-October 2021); 247 patients were included. The number of patients diagnosed with HCC distinctly diminished in the periods March 2020-December 2020 (n = 69; -35%) and January 2021-October 2021 (n = 72; -32%) as compared to the period May 2019-February 2020 (n = 106). Noteworthy was the reduced surveillance in the period January 2021-October 2021 as compared to May 2019-February 2020 (22.9% vs. 36.6%, p = 0.056). No significant changes have yet been observed in tumor characteristics (BCLC staging distribution remained unvaried, p = 0.665). In conclusion, the number of new HCC diagnoses decreased sharply in the first 2 years of the pandemic, with no worsening of the stage. A more advanced stage of the disease could be expected in the next few years in patients who have escaped diagnosis.

Oncostatin M is overexpressed in NASH-related hepatocellular carcinoma and promotes cancer cell invasiveness and angiogenesis.

Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH-related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial-to-mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH-related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro-carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Biomarkers of Oncogenesis, Adipose Tissue Dysfunction and Systemic Inflammation for the Detection of Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease.

Current surveillance strategy for patients with nonalcoholic fatty liver disease (NAFLD) at risk of hepatocellular carcinoma (HCC) development is unsatisfactory. We aimed to investigate the diagnostic accuracy of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), glypican-3 (GPC-3), adiponectin, leptin and interleukin-6 (IL-6), alone or in combination, for the discrimination between NAFLD patients with or without HCC. The biomarkers were investigated in a cohort of 191 NAFLD patients (median age 62, 54-68 years; 121 males and 70 females) with advanced fibrosis/cirrhosis, 72 of whom had a diagnosis of HCC. PIVKA-II showed the best performance for the detection of HCC with an area under the curve (AUC) of 0.853, followed by adiponectin (AUC = 0.770), AFP (AUC = 0.763), GPC-3 (AUC = 0.759) and by IL-6 (AUC = 0.731), while the leptin values were not different between patients with and without HCC. The accuracy of the biomarkers' combination was assessed by a stratified cross-validation approach. The combination of age, gender, PIVKA-II, GPC-3 and adiponectin further improved the diagnostic accuracy (AUC = 0.948); the model correctly identified the 87% of the patients. In conclusion, we developed a model with excellent accuracy for the detection of HCC that may be useful to improve the surveillance of NAFLD patients at risk of tumor development.

Radioembolization vs sorafenib in locally advanced hepatocellular carcinoma with portal vein tumor thrombosis: A propensity score and Bayesian analysis.

OBJECTIVE: In this study we aimed to compare patient outcomes between the use of transarterial radioembolization (TARE) and sorafenib in patients with hepatocellular carcinoma (HCC) and intrahepatic portal vein tumor thrombosis (PVTT). METHODS: A total of 65 patients with HCC and intrahepatic PVTT treated in five Italian hospitals between 2012 and 2018 were included in the analysis. Those with any previous treatment, extension of PVTT to the main portal tract and extrahepatic involvement were excluded. Propensity score matching analysis and Bayesian model averaging analysis were performed. RESULTS: Of the 41 patients treated with TARE and 24 with sorafenib, 11 patients were downstaged to curative-intent surgery (liver transplant in three and hepatectomy in eight), including 10 treated with TARE and one with sorafenib. TARE was more effective than sorafenib in downstaging patients to surgery, achieving a mean survival of 54 months. In the 54 patients without downstaging after treatment, of whom 31 were treated with TARE and 23 with sorafenib, median survival was 20.3 and 9.1 months, respectively (P = 0.001), with different 1-, 2- and 3-year OS rates (64.5%, 42.6% and 37.3% vs 39.1%, 13.0% and 0%). Both propensity score and Bayesian model averaging confirmed an improvement in overall survival in the TARE group compared with sorafenib treatment. CONCLUSIONS: TARE was more effective than sorafenib in downstaging patients with HCC to surgery, providing a significant improvement in survival. Even in patients who were not downstaged to surgery, survival appeared to be superior with TARE over sorafenib.

The Clinical Role of Serum Epidermal Growth Factor Receptor 3 in Hepatitis C Virus-Infected Patients with Early Hepatocellular Carcinoma.

Epidermal growth factor receptor 3 (ERBB3) is a surface tyrosine kinase receptor belonging to the EGFR/ERBB family, involved in tumor development and progression. We evaluated the diagnostic and prognostic value of serum ERBB3 measurement in hepatitis C virus (HCV)-infected patients with early hepatocellular carcinoma (HCC). A total of 164 HCV-infected patients (82 with cirrhosis and 82 with early HCC) were included in the study. HCC was classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Among patients with HCC, 23 (28%) had a diagnosis of very early tumor (BCLC = 0), while 59 (62%) had a diagnosis of early HCC (BCLC = A). Median overall survival (OS) in patients with HCC was 79.2 (95% CI 51.6-124.8) months. While ERBB3 serum values were similar between patients with cirrhosis and those with HCC (p = 0.993), in the latter, serum ERBB3 ≥ 2860 RU resulted significantly and independently associated with OS (Hazard Ratio = 2.24, 95% CI 1.16-4.35, p = 0.017). Consistently, the 1-, 3-, and 5-year OS rates in patients with serum ERBB3 ≥ 2860 RU were 90% (36/40), 53% (19/36), and 28% (8/29) in comparison to patients with serum ERBB3 < 2860 RU, which were 98% (40/41), 80% (32/40), and 74% (26/35) (Log-rank test; p = 0.014). In conclusion, serum ERBB3 values resulted an independent prognostic factor of patients with early HCC and might be useful to tailor more personalized treatment strategies.

Higher Efficiency of Percutaneous Microwave (MWA) Than Radiofrequency Ablation (RFA) in Achieving Complete Response in Cirrhotic Patients with Early Hepatocellular Carcinoma.

BACKGROUND: Contrasting data are available in the literature regarding the superiority of percutaneous microwave ablation (MWA) or radiofrequency ablation (RFA) in very early or early (BCLA 0 or A) hepatocellular carcinoma (HCC). AIMS: The primary outcome was to compare the efficacy of RFA and MWA in achieving complete response in cirrhotic patients with early and very early HCC. The secondary outcomes were to evaluate the overall survival and the recurrence rate. METHODS: A retrospective, observational, single-center study was performed. Inclusion criteria were liver cirrhosis, new diagnosis of a single node of HCC measuring a maximum of 50 mm or up to three nodules with diameter up to 35 mm, treatment with RFA or MWA. Radiological response was evaluated with multiphasic contrast-enhanced Computed Tomography or Magnetic Resonance Imaging at 5-7 weeks after thermal ablation. Complete response was defined when no vital tissue was detected after treatment. RESULTS: Overall, 251 HCC patients were included in this study; 81 patients were treated with MWA and 170 with RFA. The complete response rate was similar in MWA and RFA groups (out of 331 nodules, 87.5% (91/104) were treated with MWA and 84.2% (186/221) were treated with RFA, p = 0.504). Interestingly, a subanalysis demonstrated that for 21-35 mm nodules, the probability to achieve a complete response using MWA was almost 5 times higher than for RFA (OR = 4.88, 95% CI 1.37-17.31, p = 0.014). Moreover, recurrence rate in 21-35 mm nodules was higher with RFA with respect to MWA (31.9% versus 13.5%, p = 0.019). Overall survival was 80.4% (45/56) when treated with MWA and 62.2% (56/90) when treated with RFA (p = 0.027). No significant difference was observed between MWA and RFA treatment in the 15-20 mm nodules group. CONCLUSION: This study showed that MWA is more efficient than RFA in achieving complete response in HCC nodules with 21 to 35 mm diameter.

Serum levels of anti-heat shock protein 27 antibodies in patients with chronic liver disease.

Heat shock protein 27 (HSP27), an intracellular molecular chaperone, is involved in the pathogenesis of cancer by promoting both tumor cell proliferation and resistance to therapy. HSP27 is also present in the circulation and circulating HSP27 (sHSP27) can elicit an autoimmune response with production of antibodies. Levels of sHSP27 are enhanced in patients with hepatocellular carcinoma (HCC); it is, however, unknown whether changes in HSP27 antibody levels occur in patients with HCC and can be exploited as a circulating biomarker of HCC. Our aim was to assess the potential association between newly diagnosed HCC and serum anti-HSP27 antibody levels. In this cross-sectional study, anti-HSP27 antibody levels were measured in serum samples from 71 HCC patients, 80 subjects with chronic liver disease, and 38 control subjects by immunoenzymatic assay. Anti-HSP27 antibody levels did not differ significantly among groups. However, in patients with chronic active hepatitis/cirrhosis, anti-HSP27 levels were significantly higher in subjects with a positive history of alcoholism (p = 0.03). Our data do not support the hypothesis that anti-HSP27 antibody levels may help identify patients with HCC among subjects with chronic liver disease. However, our finding that alcohol-related liver disease is associated with higher anti-HSP27 levels is novel and deserves further investigations.

Alpha-Fetoprotein, Protein Induced by Vitamin K Absence or Antagonist II and Glypican-3 for the Detection and Prediction of Hepatocellular Carcinoma in Patients with Cirrhosis of Viral Etiology.

International guidelines recommend the use of ultrasound as a surveillance tool for hepatocellular carcinoma (HCC) in patients with cirrhosis, while the role of serum biomarkers is still debated. We investigated serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II) and glypican-3 (GPC-3) diagnostic accuracy for HCC detection and prediction in patients with liver cirrhosis of viral etiology under surveillance. A total of 349 patients (200 cirrhosis and 149 HCC) were enrolled. The 200 patients with cirrhosis consisted of 114 patients still HCC-free after 36 months of follow-up and 86 patients that developed HCC after 13.8 (11.0-19.8) months. AFP, PIVKA-II and GPC-3 were measured in serum samples collected at tumor diagnosis in the 149 patients with HCC, and at the beginning of follow-up in the 200 patients with cirrhosis. The higher performance for HCC detection was observed for PIVKA-II (area under the curve (AUC) = 0.790), followed by AFP (AUC = 0.737) and GPC-3 (AUC = 0.637); the combination of AFP + PIVKA-II improved the diagnostic accuracy to AUC = 0.822. Serum PIVKA-II values, but not AFP and GPC-3, were significantly higher in the 86 cirrhotics that developed HCC compared with the 114 cirrhotics still HCC-free after 36 months of follow-up (p = 0.020). PIVKA-II ≥ 55 mAU/mL allowed to identify patients with cirrhosis at higher risk of HCC development (Log-rank test, p < 0.001; adjusted Hazard Ratio = 1.99, p = 0.001). In conclusion, the measurement of PIVKA-II in patients with cirrhosis may be useful to tailor personalized surveillance strategies.

Prognostic Role of Serum Cytokeratin-19 Fragment (CYFRA 21-1) in Patients with Hepatocellular Carcinoma.

Keratin 19 (K19) is a cancer stem cell marker expressed by a subpopulation of hepatocellular carcinoma (HCC), associated with tumor aggressiveness. We evaluated the prognostic value of serum K19 fragment (CYFRA 21-1), in comparison or in combination with alpha-fetoprotein (AFP) and protein induced by vitamin-K absence or antagonist-II (PIVKA-II), in patients with HCC. A total of 160 patients (28F/132M; median age 62, range 44-86 years) with a new diagnosis of HCC and available serum samples collected at tumor diagnosis were analyzed retrospectively. Median overall survival (OS) after HCC diagnosis was 35.1, 95% CI 27.1-70.5 months. Multivariate Cox regression analysis showed that CYFRA 21-1 > 2.7 ng/mL (hazard ratio (HR) = 3.39, p < 0.001), AFP > 20 ng/mL (HR = 2.27, p = 0.007), and PIVKA-II > 200 mAU/mL (HR = 2.17, p = 0.020) were independent predictors of OS. The combination of biomarkers positivity allowed us to stratify patients with HCC into four risk categories associated with a progressively lower survival probability (log-rank test, p < 0.001). CYFRA 21-1 resulted an independent prognostic factor of patients with HCC and its combination with AFP and PIVKA-II might be useful to tailor personalized treatment strategies.

Thermal ablation with fusion imaging guidance of hepatocellular carcinoma without conspicuity on conventional or contrast-enhanced US: surrounding anatomical landmarks matter.

AIM: Evaluating clinical and technical factors affecting thermal ablation of B-Mode/CEUS inconspicuous HCC nodules, relying only on fusion imaging (FI) performed under conscious sedation and using previously acquired CT or MR. MATERIALS AND METHODS: Among 367 HCC nodules treated in the study period, data of 37 B-mode/CEUS undetectable HCC nodules treated with FI-guided ablation were extracted from our prospectively collected institutional database. Analyzed variables included patients' sex, age, cirrhosis etiology, Child-Pugh status, size of the lesion, liver segment, subcapsular or central liver site, type of imaging used for fusion (MR/CT), and the presence of surrounding anatomical landmarks (SAL) < 3 cm from the index lesion. RESULTS: The primary efficacy was 59.4% (22/37 nodules); nine lesions (24.3%) were partially ablated (PA), six lesions (16.7%) were mistargeted (MA). Eight nodules were retreated with a CA obtained in all cases (100% CA, secondary efficacy in 30/37-81.1%). LTP was observed in 2/30 cases (6.7%). Two minor complications were registered (Clavien-Dindo, Grade1, CIRSE Classification Grade 2). SAL were related to a better ablation outcome (37.5% vs 84.6% p = 0.01). No differences were observed between CA group and PA-MA group in terms of lesion size (15.4 mm vs 14.9 mm p = 0.63), liver segment (p = 0.58), subcapsular or central liver site (8/22 36% vs 4/15 26.7% p = 0.84), and imaging (MR vs CT, p = 0.72). CONCLUSION: Even in the presence of potentially critical conditions (completely B-Mode/CEUS inconspicuous nodules, spontaneous breathing, and previously acquired CT or MRI), FI-only guidance is safe and allows having good primary, secondary efficacy and LTP rates. The outcome of the procedure is heavily affected by the presence of SAL.

Stereotactic ablative radiotherapy in the treatment of hepatocellular carcinoma >3 cm.

Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable results to other local therapies. For lesions larger than 3 cm, no definitive standard treatment is present and several options are available. We retrospectively review local control (LC) and survival results of SABR in patients with HCC lesions >3 cm. Between 2012 and 2015, we treated 29 patients (39 lesions) having histological or radiological diagnosis of HCC and at least one lesion sized >3 cm. Patients were prescribed 36-48 Gy in 3-5 fractions (mainly 16 Gy × 3 fractions or 8 Gy × 5 fractions), in 3-5 consecutive days. A total of 15 lesions (52 %) had complete, while 10 (34 %) had partial remission; 3 (11 %) had a stable disease. Mean time for CR achievement was 5.8 months (range 1-17). One- and two-year actuarial LC was 100 %. Moreover, 1- and 2-year progression-free (PFS), cancer-specific and overall survival were 57.9 % [standard error (SE) 0.09; 95 % CI 36.9-74.2] and 41.2 % (SE 0.12; 95 % CI 17.7-63.5), 80.7 % (SE 0.08; 95 % CI 59.6-91.5) and 63.3 % (SE 0.11; 95 % CI 38.4-80.3), 71.7 % (SE 0.08; 95 % CI 51.2-84.7) and 56.2 % (SE 0.10; 95 % CI 33.8-73.6). On multivariate analysis, achieving a CR within the target lesion had a borderline significance with respect to PFS (HR 0.83; SE = 0.014; z -1.15; p = 0.095; 95 % CI 0.71-7.45). Time between HCC diagnosis and SABR delivery (< vs >12 months) was significantly correlated with OS (HR 16.5; SE 21.5; z = 2.14; p = 0.032; 95 % CI 1.27-213.3) as CLIP score (score: 0-1 vs 2) (HR 5.6; SE 4.6; z = 2.10; p = 0.036; 95 % CI 1.11-27.8). A total of 6 major toxic events (G3-G4) were recorded (20 %). In 2 patients (6 %), a radiation-induced liver disease was seen. In conclusion, SABR provided LC and survival rates comparable to other local therapies for patients with HCC lesion sized >3 cm, with acceptable toxicity profile.

Stereotactic ablative radiation therapy prior to liver transplantation in hepatocellular carcinoma.

OBJECTIVE: Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable effectiveness to other local therapies. Only scant information is available concerning the role of SABR prior to liver transplantation (LT) for HCC. We present a consecutive case series investigating the role of SABR as a bridge or downstaging option in HCC patients subsequently submitted to LT. MATERIALS AND METHODS: Between September 2012 and May 2014, 8 patients for a total of 13 lesions underwent SABR prior to LT. Inclusion criteria were a pathological or radiological diagnosis of HCC, lesion size ≤6 cm or lesion number ≤3 with a total diameter ≤6 cm, no extrahepatic metastases, Child-Pugh class A-B, ECOG performance status ≤1. Patients were prescribed 36-48 Gy in 3-5 fractions (8 Gy × 5 fractions or 16 Gy × 3 fractions), in 3-5 consecutive days according to clinical and dosimetric decision making. Radiological response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Pathological response was assessed through the rate of tumor necrosis relative to the total tumor volume. Acute and late toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (CTCAE v 4.0). RESULTS: Among the 13 pathologically evaluated lesions, 8 (61.5 %) lesions had a complete response 2 (15.3 %) had a minimal pathological response and other 2 (15.3 %) showed stable disease. The remaining lesion had a significant pathological response. Maximum detected toxicity included a G2 GGT increase in two patients (at 1 and 3 months respectively). One patient developed a non-classic RILD with a fivefold increase in transaminase enzymes level and a shift in Child-Pugh category from B7 to C10 due to bilirubin increase. Only one modification in the surgical strategy was needed during LT. CONCLUSIONS: SABR proved to be a safe and effective local therapy prior to LT in HCC patients. Prospective controlled clinical trials are needed to evaluate its efficacy compared to other local therapies in this setting.

Unexplained common bile duct dilatation with normal serum liver enzymes: diagnostic yield of endoscopic ultrasound and follow-up of this condition.

BACKGROUND: There is scant literature about common bile duct (CBD) dilatation with normal liver function tests (LFTs). AIMS: The aims of this study were to assess the diagnostic yield of endoscopic ultrasound (EUS) in patients with CBD dilatation, normal LFTs, and prior inconclusive imaging tests, and to assess the natural history of these subjects. METHODS: We retrospectively reviewed our EUS database for patients referred for evaluation of CBD dilatation, normal LFTs, and prior inconclusive imaging. We excluded patients with a prior endoscopic retrograde cholangiopancreatography or a history of biliary obstruction, pancreatitis, or jaundice. Follow-up data were retrieved from medical records or by calling the general practitioners, referring specialists, patients, or their closest relatives. RESULTS: A total of 57 patients were enrolled. The mean CBD diameter was 12.5±3.6 mm. The majority of patients (50.8%) were asymptomatic. Abnormal EUS findings were recorded in 12 (21%) subjects: 6 patients had a periampullary diverticulum, 2 had ampullary adenoma, 2 had signs of chronic pancreatitis, 1 had a cancer of the pancreatic head, and 1 had a 7 mm CBD stone. Neither age, sex, prior cholecystectomy, clinical presentation, CBD diameter, nor a dilated main pancreatic duct were predictors of abnormal EUS findings. None of the patients complained of biliary symptoms or showed abnormal LFTs on long-term follow-up. CONCLUSIONS: CBD dilatation with normal liver chemistry is not always a benign condition. Even when prior imaging tests are negative, EUS may allow to diagnose conditions overlooked by standard diagnostic imaging.

Radiofrequency ablation: technical and clinical long-term outcomes for single hepatocellular carcinoma up to 30 mm.

BACKGROUND AND AIMS: Western guidelines consider radiofrequency ablation (RF) as the standard treatment for 'very early' and 'early' hepatocellular carcinoma (HCC) in nonsurgical cirrhotic patients. RF has also been proposed as the first-line therapy for 'surgical' candidates with a single nodule of 20 mm or less. The aim of this monocentric cohort study was to evaluate the technical and clinical outcomes of RF in the treatment of cirrhotic patients with a single HCC of 30 mm or less. PATIENTS AND METHODS: We included all 209 consecutive patients treated between January 2001 and June 2011. The primary endpoints were the overall survival (OS) rate and safety; the secondary endpoints were primary technique effectiveness, local tumor progression, and the disease-free survival rate. RESULTS: The 5-year OS rate of the entire sample was 44.3% (95% confidence interval: 36.7-55.8); Child-Pugh class B was the worst negative prognostic factor (hazard ratio: 2.06; P=0.008). A subgroup of 70 Child-Pugh class A patients suitable for surgical resection according to current Western operability criteria showed a 5-year OS rate of 60.6%. Treatment-related mortality and morbidity rates were 0 and 3.4%, respectively. Primary technique effectiveness rate was 95.2% after one to three RF sessions. The 5-year cumulative incidence of local tumor progression was 21.5 and 32.5% for nodules ≤20 and 21-30 mm, respectively. The 5-year disease-free survival rate (comprehensive of any kind of tumor progression or death) was 17.8% (95% confidence interval: 11.1-25.8). CONCLUSION: RF is an effective and very safe therapy for HCC up to 30 mm; in 'surgical' cirrhotic patients, the OS rate was similar to those reported in surgical series, although the local recurrence rate was higher.

Serum heat shock protein 27 levels in patients with hepatocellular carcinoma.

Levels of serum heat shock protein 27 (sHsp27) have been studied in numerous cancer types, but their potential relevance in patients with hepatocellular carcinoma (HCC) is undetermined. Our aim was to compare sHsp27 levels in patients with HCC and HCC-free controls. Specifically, we recruited 71 patients with HCC (80 % with early tumour), 80 patients with chronic liver disease (59 with liver cirrhosis and 21 with chronic active hepatitis) and 42 healthy subjects. sHsp27 was measured by immunoenzymatic assay. Results showed that sHsp27 levels were significantly (p < 0.001) higher in patients with HCC than in the other groups, particularly in those with hepatitis C virus (HCV)-related disease. In HCC patients, sHsp27 levels were not associated with prognostic risk factors, such as size/multiplicity of nodules and stage. In logistic regression analysis, performed in patients with liver disease, log-sHsp27 was associated with a significant age-adjusted 2.5-fold increased odds ratio of HCC and with a significant 4.4-fold higher odds ratio of HCC in the subgroup with HCV-related liver disease. In receiver operating characteristic curve analysis, sensitivity and specificity of the best sHsp27 cut-off value (456.5 pg/ml) for differentiating patients with HCC from those with HCC-free chronic liver disease were 70 and 73 %, respectively. In conclusion, sHsp27 levels are enhanced in patients with HCC and may represent a candidate biomarker of HCC.