Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

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.

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.

The detection of periapical pathoses using digital periapical radiography and cone beam computed tomography in endodontically retreated teeth - part 2: a 1 year post-treatment follow-up.

AIM: Part 2 of this prospective clinical study aimed to compare the 1-year outcome of root canal retreatments, when individual roots and teeth were assessed by periapical radiographs and cone beam computed tomography (CBCT). METHODOLOGY: Subjects participating in this study had been referred for management of an endodontic problem associated with one or more root filled teeth. Root canal retreatment was performed by Specialists or postgraduate students under the direct supervision of Specialist endodontic staff. A total of 98 teeth (84 patients) were reassessed clinically and radiographically 1 year after completion of root canal retreatment. The postoperative periapical radiographs and CBCT scans were compared with their respective pre-treatment (diagnostic) periapical radiographs and CBCT scans. The increase or decrease in size of existing periapical radiolucencies and development of new radiolucencies were assessed by a consensus panel consisting of two calibrated examiners. They also determined an appropriate management plan for each case based on the radiographical findings. Comparison of the outcome diagnosis of individual roots and teeth and case management, when assessed by periapical radiographs and CBCT scans, was performed using chi-squared and McNemar's tests. RESULTS: An overall favourable result of 93% success for teeth (96% roots) was recorded when the assessment was undertaken by periapicals compared with 77% success for teeth (87% roots) when assessed by CBCT. A significant difference in outcome diagnosis of single paired roots (P < 0.0001) and teeth (P = 0.0001) was observed when comparing periapicals to CBCT for the cohort of teeth as a whole. When comparing the future management plan on the basis of radiographic information alone, there was a significant difference between periapicals and CBCT-based management (P = 0.01). CONCLUSION: Diagnosis using CBCT revealed a significantly lower number of favourable outcomes than periapicals in root canal retreatment. This significantly affected the future management of cases attending for a review.

Fever of unknown origin as unique symptom of an indolent mastocytosis.

A 39-years-old man afferred to our hospital for a fever lasting for more than 6 months, without abnormalities at physical examination (in particular no skin alterations); a recent laboratory and instrumental investigation was ineffective and so a fever of unknown origin (FUO) was diagnosed Since he reported an history of infantile mastocytosis (usually auto-resolving) we evaluated his serum-tryptase levels that resulted of 49 ug/L (normal value 20 ug/L), raising the doubt of the presence of an active mastocytosis. The following bone marrow evaluation showed aggregates of CD117 positive cells and a c-Kit point mutation at codon D 816V confirming the diagnosis of indolent mastocytosis.The present case confirm that FUO can be caused by an otherwise asymptomatic indolent mastocytosis, thus suggesting to include the serum-tryptase level measurement in the diagnostic approach to this pathological condition, at least in selected cases.

Changes in centring and shaping ability using three nickel­titanium instrumentation techniques analysed by micro-computed tomography (µCT).

AIM: To compare the centring ability and the shaping ability of ProTaper (PT) files used in reciprocating motion and PT and Twisted Files (TF) used in continuous rotary motion, and to compare the volume changes obtained with the different instrumentation techniques using micro-computed tomography. Methodology Sixty mesial canals of thirty mandibular molars were randomly assigned to three instrumentation techniques: group 1, canals prepared with the PT series (up to F2) (n = 20); group 2, canals prepared with the F2 PT in reciprocating motion (n = 20); group 3 canals prepared with the TF series (size 25) (n = 20). Teeth were scanned pre- and postoperatively using micro-computed tomography to measure volume and shaping changes, and the obtained results were statistically analysed using parametric tests. Results The increase in canal volume obtained with the three instrumentation techniques was not significantly different. Canals were transported mostly towards the mesial aspect in the apical- and mid-third of the roots, and towards the furcal aspect coronally. No difference in the transportation and centring ratio was found between the techniques. There was no significant difference between the times of instrumentation (TF: 62.5 ± 5.4 s; PT: 60.6 ± 3.9 s; and F2 PT file in reciprocating motion: 51.0 ± 3.3 s). Conclusions ProTaper files used in reciprocating motion and PT and TF used in continuous rotary motion were capable of producing centred preparations with no substantial procedural errors.

CD30 serum levels and response to hymenoptera venom immunotherapy.

BACKGROUND: The glycoprotein CD30 is expressed and released by T lymphocytes that secrete type 2 helper cytokines of (T(H)2). These molecules play a role in the pathogenesis of allergic diseases. Venom immunotherapy has proven to be very effective in hymenoptera venom allergy through a shift in cytokine production from T(H)2-type cytokines to T(H)1-type cytokines. OBJECTIVE: To evaluate the relationship between the soluble form of CD30 (sCD30) and venom immunotherapy in patients with hymenoptera venom allergy. MATERIALS AND METHODS: sCD30 levels were assayed by enzyme-linked immunosorbent assay in the sera of 61 healthy controls and 14 patients with hymenoptera venom allergy who had undergone immunotherapy before treatment and 1,3, and 12 months after treatment started. Nine patients were allergic to Apis venom, 4 to Vespula venom, and 1 to Polistes venom. RESULTS: CD30 serum levels (median, interquartile range) were significantly higher in venom-allergic patients before treatment (33.6 U/mL; 14.8-61.6) than in controls (9.7 U/mL, 1.9-21.3) (P < .000). These levels decreased progressively during treatment in all patients except 2 (P < .000). At the third month of therapy, the levels reached statistical significance in comparison with baseline. CONCLUSIONS: This study shows that sCD30 levels are significantly higher in patients with hymenoptera venom allergy and indirectly confirms a preferential T(H)2-type cytokine production in these patients. sCD30 expression decreases during immunotherapy, thus confirming the immunomodulatory role of this treatment in promoting a shift to T(H)1-type cytokines.

Focal nodular hyperplasia after busulfan treatment.

The case of a 48-year-old woman in whom focal nodular hyperplasia of the liver developed after busulfan therapy was administered for essential thrombocytosis is described. Focal nodular hyperplasia is a reactive disorder related to a circulation disorder. The close temporal relation between the haematological disease, busulfan treatment and the appearance of hyperplastic diseases of the liver in our patient supports the possibility that the association of the events might not be casual.

[Celiac disease and spontaneous abortion]. / Malattia celiaca e abortività.

BACKGROUND: Over the last ten years it has become clear that the clinical expression of celiac disease is more heterogeneous than was thought in the past. Although celiac disease is a relatively frequent disease (1/170-200), it is only diagnosed in a small percentage of adult cases compared to the real situation because it is manifested with few symptoms or in an atypical form, or occasionally is completely silent. Gynecological problems have been reported in women with celiac disease, in particular delayed menarche, early menopause, sterility, recurrent abortion and fetal intrauterine growth retardation. The main aim of this study was to investigate the association between celiac disease and abortion, and in particular to evaluate whether patients suffering from recurrent spontaneous abortion might present an atypical or subclinical form of the disease. METHODS: During the period 1997-1998 a series of laboratory tests were carried out at the Department of Obstetrics and Gynecology and at the Institute of Medicine B of Verona University, in a sample of 184 women (149 from the Obstetrics Clinic and 35 from Internal Medicine B ). These tests included circulating anti-gliadin (AGA) and anti-endomysium (EMA) antibodies and total serum immunoglobulins. In positive cases, further diagnostic tests were performed using small bowel biopsy specimens. RESULTS: In our selected sample of cases, 5 women (2.7%) were positive for immunological screening against IgA-EMA and for bowel biopsy (confirmed diagnosis of celiac disease). Four of these women (2.1%) formed part of a group of patients with a positive history of spontaneous abortion and one (0.5%) was from the control group. CONCLUSIONS: An analysis of the cases that emerged from this study and those reported in the literature shows that tests to identify the celiac disease should be extended to the population with a risk of developing this disease. These subjects should include those with a family history or clinical symptoms, in particular women with a history of multiple abortions. In these cases, there are grounds for suspecting an atypical form of celiac disease.

Soluble CD30 serum level in HCV-positive chronic active hepatitis: A surrogate marker of disease activity?

In the present study, high levels of CD30s, a glycoprotein preferentially expressed and released by T lymphocytes producing Th(2)-type cytokines, were seen in the sera of patients with chronic hepatitis C, and a correlation with histological activity of the disease was found. CD30s levels were assayed in the sera of 29 HCV RNA-positive patients with histologically proven chronic active hepatitis and in 30 healthy blood donors. Thirteen of 29 (45%) HCV patients had CD30s serum levels above the normal range (>20 U/ml). Mean CD30s serum levels were significantly higher in HCV patients than in controls (P<0.0005). A positive correlation was found between serum CD30s levels and both the histological activity index (r=0.59, P=0.001) and ALT serum levels (r=0.5; P=0.006). The raised CD30s level found in more severe HCV liver disease indirectly suggests activation and expansion of Th(2)cells. CD30s levels could represent a useful surrogate marker of activity in chronic HCV infections.

Indicators of genetic damage in alcoholics: reversibility after alcohol abstinence.

BACKGROUND/AIMS: Although a primary carcinogenic role of alcohol is not proven, alcohol abuse is associated with an increased risk of cancer of the upper airways, esophagus and liver. METHODOLOGY: Chromosome aberrations and the presence of micronuclei that reflect two types of genetic damage were analyzed in peripheral blood lymphocytes from 11 alcoholic patients who were heavy smokers and in a fair state of general nutrition and 9 subjects who had abstained from alcohol for at least a year. Ten heavy smokers were studied as healthy controls. RESULTS: Chromosome aberrations and micronuclei in alcoholics showed significantly elevated frequencies compared to the control groups, while in alcohol abstainers the values of all two parameters were similar to the values of the control subjects. CONCLUSIONS: These results show that long-term alcohol intake could induce genetic alterations in synergy with tobacco smoke. Interestingly, this damaging action is reversed by abstinence. Our results call for a further effort to find an eventual diagnostic role for these early genetic damage markers.

Alpha-1-thymosin and transcatheter arterial chemoembolization in hepatocellular carcinoma patients: a preliminary experience.

BACKGROUND/AIMS: To evaluate the tolerability and therapeutic potential of the immunostimulating adjuvant alpha-1-thymosin in patients with hepatocellular carcinoma. METHODOLOGY: Twelve patients with hepatocellular carcinoma were treated with alpha-1-thymosin (900 micrograms/m2 subcutaneously twice per week for 6 months) and transcatheter arterial chemoembolization and compared to a historical control group (matched for gender, age, Okuda staging, Child's score, alpha-fetoprotein serum levels and viral infection) treated with transcatheter arterial chemoembolization alone. RESULTS: No severe side effects were recorded in the 2 treatment groups. The combination of alpha-1-thymosin plus transcatheter arterial chemoembolization resulted in a longer survival that reached statistical significance 7 months after the end of treatment (p < 0.05). Patients receiving combined treatment demonstrated a significant increase in peripheral blood mononuclear cells expressing CD3 (p < 0.05) and CD8 (p < 0.025) 3 months after beginning treatment. They also had a significant increase (p < 0.05) in CD16+ and CD56+ cells after 1 month, and a slight reduction in mononuclear cells expressing CD25, a marker for cell activation. No alterations in the response to phytohemagglutinin stimulation were seen during the alpha-1-thymosin treatment. CONCLUSIONS: The absence of toxicity and the favourable effects observed in this open study call for a double blind control study to confirm the efficacy of the combined treatment.

Chemoembolization versus chemotherapy in elderly patients with unresectable hepatocellular carcinoma and contrast uptake as prognostic factor.

BACKGROUND: Age is considered one of the important contraindications to surgery for hepatocellular carcinoma (HCC) in cirrhosis patients. We therefore evaluated the safety and prevalence of side effects in endoarterial therapy (EAT) in subjects aged over 65 years compared with younger treated patients. METHODS: Thirty-eight patients with HCC aged 65 years and over underwent transcatheter arterial chemoembolization (TACE) (n = 28) or intraarterial chemotherapy (IAC) (n = 10). The survival rate was calculated using Kaplan-Meier's method with respect to a control group consisting of younger treated subjects (44 TACE; 21 IAC) comparable for stage of HCC and severity of the underlying cirrhosis. RESULTS: The comparison between the two groups regarding side effects, procedure-related death, and survival did not show any difference considering the whole EAT procedure. TACE in elderly subjects reached a statistically lower outcome with respect to younger patients (p < .025) but remained statistically superior in survival versus both older and younger patients treated with IAC (p < .05, respectively). Stratifying the patients following the degree of Lipiodol uptake of tumor mass in the three groups (Group I, > 75%; Group II, 50-75%; Group III, < 50%), in the young subjects a higher probability of survival was strictly correlated to a degree of uptake over 75%, while in the elderly patients an impregnation over 50% was sufficient to obtain a satisfactory survival curve. CONCLUSIONS: EAT is a reliable and safe therapeutic option for the geriatric patient with HCC, with TACE showing a better efficacy than IAC, requiring a lesser degree of Lipiodol uptake to achieve an improvement of outcome.

A rare case of peritoneal mesothelioma in a male with ascites.

Mesothelial lesions can present significant diagnostic problems. An accurate identification of the lesion is important in deciding what course of action to follow, as well as what the required treatment will be. We report the case of a man with untreatable ascites. Four years after the first symptom appeared, the patient suddenly began to lose weight. The CT scan showed a thickening of the peritoneal profile; a diffuse lesion of the mesothelium was then observed at laparotomy. Histological examination led to a diagnosis of malignant mesothelioma in a well-differentiated mesothelial lesion with diffuse involvement of the serosa of the small intestine and the lesser omentum.