Erica Villa - Academia.edu (original) (raw)

Papers by Erica Villa

Research paper thumbnail of Angiogenesis: the Yin and Yang in intrahepatic cholangiocarcinoma

Hepatoma Research, 2023

The tumor microenvironment (TME) constitutes a complex structure comprising different cell types ... more The tumor microenvironment (TME) constitutes a complex structure comprising different cell types and soluble factors that surround the tumor and promote its progression. Primarily for its pivotal role in malignant growth, TME has become a potential therapeutic objective for developing new targeted therapy and a marker for assessing therapeutic response. In intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver malignancy, TME has also gained a central role in understanding the mechanisms underlying tumor progression. In this review, we focused on the role of angiogenic factors and their pathway in iCCA and analyzed possible therapeutic and prognostic implications.

Research paper thumbnail of Obese zebrafish: A small fish for a major human health condition

Animal Models and Experimental Medicine

Obesity is becoming a silent worldwide epidemic, with a steady increase in both adults and childr... more Obesity is becoming a silent worldwide epidemic, with a steady increase in both adults and children. To date, even though several drugs have been licensed for longterm obesity treatment, none of them are yet used in routine clinical practice. So far the only successful intervention has been behavioral therapy. A suitable and economic experimental model mimicking the human condition would therefore be extremely useful to evaluate preventive measures and novel treatments. Zebrafish are emerging as an important model system to study obesity and related metabolic disease. Remarkable similarities have been reported in lipid metabolism and the adipogenic pathway between zebrafish and mammals. Moreover, the zebrafish possesses a number of features-the relative inexpensiveness of animal husbandry, its optical transparency and the ability to produce a large number of offspring at low cost-that make it ideal for large-scale screening and for testing drugs and intervention. In this review, we summarize recent progress in using zebrafish as a model system to study obesity and obesity-related metabolic disorders. We describe several zebrafish models (in both larvae and adult animals) that develop obesity and nonalcoholic fatty liver disease (NAFLD) using different approaches, including gene manipulation, diet manipulation and modification of microbiota composition. For these models, we have outlined the specific aspects related to obesity and its development and we have summarized their advantages and limitations.

Research paper thumbnail of Missed treatment in an Italian HBV infected patients cohort: HBV RER

Digestive and Liver Disease, 2016

Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical p... more Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical practice and the characteristics of the patients who do not receive antiviral therapy. HBV-RER is an observational multicenter network that collected data of patients with HBV infection during a 3 years observational period (2009-2012). Among 2527 HBsAg positive patients, 1099 were never treated (NT); only 280 were included in the analysis due to different exclusion causes A minority was HBeAg-positive. The median age was 42. At liver biopsy most patients had Metavir score of F0-F1. Univariate analysis between 280 NT patients and the 290 naïve to treatment showed that NT patients were mostly female (P=0.002), not Italian (P=0.044), younger (P<0.001). Metavir score was lower in NT (P0.002), such as the Fib4 score (P<0.001). HBV DNA level was significantly higher in NT. At multivariate analysis, independent variables associated with no-treatment were younger age, female gender, Metavir score F0-F1, Fib4 lower than 1.6 and lower blood level of HBV-DNA. There is a large number of patients eligible to treatment who do not receive it. A younger age and a less severe disease seem to be associated to deferral of treatment.

Research paper thumbnail of Letter: TNFα inhibitors and prevalence of fatty liver disease in chronic inflammatory diseases

Alimentary pharmacology & therapeutics, 2015

Research paper thumbnail of Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy. A randomized controlled trial

Research paper thumbnail of Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma

Cancer research, 1995

The development of hepatocellular carcinoma (HCC) in addition to cirrhosis affects males in a sig... more The development of hepatocellular carcinoma (HCC) in addition to cirrhosis affects males in a significantly higher proportion than females. Liver estrogen receptors increase when HCC develops in males; however, these tumors usually respond poorly to antiestrogens. We have, therefore, hypothesized that, similar to breast cancer, estrogen receptors in males with HCC may be mutated. Variant estrogen receptor transcripts (lacking exon 5 of the hormone binding domain) were investigated by reverse transcription-PCR in 14 patients (7 males and 7 females) with HCC. While females mostly displayed the wild-type transcript (both in peritumoral and in tumor liver tissue), males showed both transcripts in the cirrhotic tissue and almost only the variant in the tumor. As the variant ER transcripts when translated could give rise to truncated receptors still able to constitutively activate transcription, they may be key factors in favoring deregulated proliferation in the male liver.

Research paper thumbnail of Coagulopathy in Liver Diseases: Complication or Therapy?

Digestive Diseases, 2014

Coagulopathy in cirrhosis is a composite condition where liver synthetic deficit rebalances coagu... more Coagulopathy in cirrhosis is a composite condition where liver synthetic deficit rebalances coagulation to a parallel reduction of both pro- and anticoagulant factors. Cirrhosis is therefore no longer considered a hypocoagulable state but rather a more unstable hemostatic balance with a lower threshold for tipping toward thrombosis or bleeding. Tendency to bleeding in cirrhosis is due to the reduction in the synthesis of procoagulants and a low platelet count as well as hyperfibrinolysis. Variceal hemorrhage is a frequent bleeding complication in decompensated cirrhosis. However, the possible contribution of coagulopathy as a precipitant or an aggravating factor is poorly documented and further data are required to clarify its real contributing role. Moreover, apart from the gastrointestinal tract, the occurrence of spontaneous and procedure-related bleeding elsewhere in the body, whilst not uncommon, is less than would be expected. By contrast, a large-scale population-based study has shown the propensity towards venous thrombosis in patients with liver diseases. Portal vein thrombosis (PVT) is a critical but frequent event occurring in up to 40% of patients with liver cirrhosis. PVT causes deterioration of the clinical course, the complications of portal hypertension and an increase in post-transplant mortality. The pathogenesis of PVT includes both local alterations, like blood flow reduction and endothelial activation, and systemic derangement. Systemic prohemostatic alterations include high von Willebrand factor, low ADAMTS-13, low levels of anticoagulants (antithrombin, proteins C and S) and increases in procoagulants like factor VIII. Low-molecular-weight heparin such as enoxaparin has proven to be safe and effective in both the treatment and prevention of PVT. In addition, patients in prophylaxis with enoxaparin showed a lower rate of decompensation and a better survival without bleeding complications. In such patients, circulating bacterial DNA, endotoxemia and markers of inflammation were attenuated compared to controls. These results therefore suggest a possible connection between enoxaparin, decrease of endotoxemia and reduction of portal hypertension. The approach to the coagulopathy in patients with liver diseases is changing: while the main goal for clinicians so far has been to reduce the risk of bleeding, the results of these new studies highlight the importance of preventing or treating thrombophilic disorders like PVT to avoid microcirculatory damage and eventually liver decompensation.

Research paper thumbnail of The role played by gender in viral hepatitis

Scandinavian Journal of Clinical & Laboratory Investigation, 2014

Although not a classical target for estrogens, the liver is a target for their action and is sens... more Although not a classical target for estrogens, the liver is a target for their action and is sensitive to their deprivation. The occurrence of menopause is accompanied by a chain of events depending on the progressive estrogen deprivation that eventually leads to a shift from a low inflammatory to a high inflammatory state. This has a series of well-known consequences in many different organs and tissues (bone, heart, brain, body fat etc.) among which the liver is particularly interesting. The consequences are extremely evident in HCV-positive women in whom HCV infection and menopause cooperate to induce higher necro-inflammatory features, increased hepatic steatosis and eventually faster progression of fibrosis. In addition, menopause is the strongest negative factor for sustained viral response (SVR) in HCV-positive females, especially HCV genotype 1 (in whom menopause was the only independent factor for failure of antiviral therapy). This suggests that HCV-positive women should be treated early during fertile age to obtain maximal response to antiviral therapy.

Research paper thumbnail of Sex, liver desease, and response to antiviral therapy

Hot Topics in Viral Hepatitis, 2013

Research paper thumbnail of Orthogonal polarization spectral imaging: a new tool in morphologic surveillance in intestinal transplant recipients

Transplantation Proceedings, 2002

Research paper thumbnail of Phytoestrogens and liver disease

Molecular and Cellular Endocrinology, 2002

Phytoestrogens are plant substances that are similar to 17-beta-estradiol and produce estrogenic ... more Phytoestrogens are plant substances that are similar to 17-beta-estradiol and produce estrogenic effects. A protective role in the development of breast and prostate cancer has been hypothesized. Estrogen receptors and their variant forms play a significant role in the pathogenesis of hepatocellular carcinoma (HCC); therefore weak estrogenic substances in the diet may play a role in its development. To investigate the role of phytoestrogens in HCC an investigation of dietary intake of these substances has been performed. Cases, patients at first diagnosis of cirrhosis or HCC were chosen. Questionnaire was built up using indications from previously published papers, extending the registration of details of the diet to reconstruct intake of nutrients for the last year. Interviews were always performed by the same dietician. Quantities determined with the help of photos of servings. Data were analyzed with Winfood database completed with data regarding content in phytoestrogens of food, beverages and seasonings. So far 92 cirrhotic patients and 32 HCCs have been interviewed. No significant difference was registered among the two groups regarding total caloric intake or single nutrients (lipids, carbohydrates, proteins). A significant lower intake of genistein was evidenced in patients at first diagnosis of HCC in comparison with cirrhotics; no significant difference was found in daidzein intake. Lignans intake was strictly related with wine intake; intake was significantly lower in cases only when wine was taken into account otherwise it was similar. Results can be summarized as follows: (1) there are no clear-cut differences (both qualitative or quantitative) between cirrhotics and HCC patients in the overall daily caloric intake while; (2) definite differences exist in the intake of some of the phytoestrogens (genistein, SEC, MAT); (3) differences between cases and controls in SEC and MAT are mainly attributable to lower alcohol intake in cases while; (4) significantly lower genistein intake in HCC only seems due to personal preferences of patients. In conclusion, these differences that we have evidenced in the diet in regard to estrogen-like substances may be relevant in modulating the risk of developing HCC in cirrhotic patients.

Research paper thumbnail of Hepatitis B virus infection of peripheral blood mononuclear cells is common in acute and chronic hepatitis

Journal of Medical Virology, 1990

Research paper thumbnail of Hepatitis C virus infection, HBsAg carrier state and hepatocellular carcinoma

Journal of Hepatology, 1992

In 1990, a case-control study was conducted in Italy to investigate the possible association betw... more In 1990, a case-control study was conducted in Italy to investigate the possible association between HCV infection and hepatocellular carcinoma (HCC). Serum samples from 65 subjects with newly diagnosed hepatocellular carcinoma and 99 hospital control subjects were tested for the presence of anti-HCV by second-generation ELISA test; positive sera were assayed by RIBA anti-HCV second-generation test. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). The presence of HCV and/or HBsAg serologic markers was significantly associated with hepatocellular carcinoma risk: the relative risk (RR) of HCC was 21.3 (95% CI = 8.8-51.5) for anti-HCV positivity in the absence of HBsAg; the relative risk of HCC was 13.3 (95% CI = 5.5-32.2) for the presence of HBsAg in the absence of anti-HCV. A higher risk (77.0) was observed when both markers were present. These findings indicate that HCV and HBsAg are independent risk factors for HCC. The results of multivariate analysis showed that the adjusted RR linking anti-HCV and HCC was 26.9 (95% CI = 9.9-72.5), the adjusted RR linking HBsAg and HCC was 11.4 (95% CI = 3.1-41.4), whereas no association (RR 1.5; 95% CI = 0.6-3.6) was found to link HCC with anti-HBc and/or anti-HBs positivity. Through the computation of population attributable risk we estimate that 25% of HCC cases occurring in Italy could be attributed to anti-HCV positivity alone and 20% to HBsAg carrier state alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Statements from the Taormina expert meeting on occult hepatitis B virus infection

Journal of Hepatology, 2008

Research paper thumbnail of No inflammation? No cancer! Clear HBV early and live happily

Journal of Hepatology, 2010

Some individuals who are chronically infected with hep

Research paper thumbnail of Detection of hepatitis B virus transcripts in patients with chronic liver disease

Journal of Hepatology, 1990

Hepatitis B virus (HBV) transcription was studied by Notthem blot aoalyxis o" total cellular RNA ... more Hepatitis B virus (HBV) transcription was studied by Notthem blot aoalyxis o" total cellular RNA pwitied from liver biopsies in 70 patients with chronic liver disease (24 HBsAg positive. 15 autiHE% andlor a"tiHRc positive, 31 HBV aeg-at&). No transcripts were found in the HBV negative and in the autiHBr and/or antiHBc positive patients. I" the others. three major RNA species were identified: i. a 3.5 kb transcript correspooding to the RNA pregenomc; ii. 2.4-2.1 kbtmoscript corresponding to the s ar.d preS1 gene RNA; iii. lower mokdar weight species. All three forms were pnscnt simulraneously only in patients with sctive viral replication, with a strict relation between the presz%ce of the 3.5 Lb RNA ia the liver and serum HBV-DNA. II. conclusion, Northern blot analysis ca" easily be performed to study viral replication and it can contribute to a better understanding of the molecular processes uoderiying HBV infcetion and leading to liver disease in ma". With the advent of rewmbiiant DNA technology, much has bee" learned about the physical state of hepatitis B virus (HBV) genome in human liver disease (Refs. 1-5; for a review, see R&s. 6-7). Less is known about HBV transcription and gene expression in infected liver. Previous rtudies, perfomxd in chimpanzee HBV infect& liver (8.9) as well as iu in vitro tissue culture systems (10,ll) have revealed that two major RNA species are present: a 3.5 kb mRNA species, linked to HB core antigen expression and geuome replication, and a 2.1-2.4 kb mRNA, linked to HBsAg expression.

Research paper thumbnail of Field-practice study of sorafenib therapy for hepatocellular carcinoma: A prospective multicenter study in Italy

Hepatology, 2011

1 on behalf of the SOFIA (SOraFenib Italian Assessment) study group A multicenter randomized cont... more 1 on behalf of the SOFIA (SOraFenib Italian Assessment) study group A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. Conclusion: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy.

Research paper thumbnail of Prognostic features and survival of hepatocellular carcinoma in Italy

European Journal of Cancer, 2001

The aim of this study was to evaluate the prognostic factors at presentation and survival in Ital... more The aim of this study was to evaluate the prognostic factors at presentation and survival in Italian patients with hepatocellular carcinoma (HCC). Clinical and demographic data of 176 patients consecutively observed from 1993 to 1997 were evaluated by univariate and multivariate analyses. Overall median survival was 18 months. At univariate analysis, low albumin, high bilirubin, high alkaline phosphatase, high alpha-fetoprotein (AFP); high platelet count, hepatitis B surface antigen (HBsAg)-positivity, the presence of ascites, of encephalopathy, of portal vein thrombosis (PVT), male sex, no treatment, poor dierentiation, untreatable tumours and incidental diagnosis were each associated with shorter survival. HBsAg-positive subjects more often presented with untreatable lesions or diuse tumours (P=0.001 and P=0.007, respectively) and had signi®cantly worse survival (P=0.0057). By multiple regression analysis, low albumin, high bilirubin, abnormal AFP, presence of PVT and of untreatable lesions were independent risk factors for worse survival. Thus, the most important factors in¯uencing survival are the degree of functional impairment of the liver, the presence of hepatitis B viral (HBV) infection, the type of diagnosis and the aggressiveness of the tumour.

Research paper thumbnail of Evaluation by color doppler ultrasound of hemodynamic changes in living-related liver transplant

Digestive and Liver Disease, 2001

Policliciw di Modem Organ shortage hss prompted the set up ofnm transplant techniques like living... more Policliciw di Modem Organ shortage hss prompted the set up ofnm transplant techniques like living-related liver transplant (LRLT). The hemcdycamic changes in liver tramplant (LT) have been reported in pediatric living-related LT but not in adult LRLT. llre pcrpcse of this study wss tc CvaluatE the hemcdymanic chtmgm in portal flow (mean velocity: Vm and portal blood flow volume: PBFV), in resistawe index (RI) of hepatic artery (HA) and in the hepstic veins flow sI?er LRLT. Three living-r&ted liver tmcsplscts were pmfmmed &cm April 2001 to June 2001 at Policlicicc di Modem in 3 adult patients. In all 3 patients, right lobe transplant wss perfcm~ed. All donors and &pie& tmdetwecl s detailed prc-opcmtive imsging study of the vaaculsr anatomy icclcdbtg ic&paative Color Doppler Ultmscccd (CDUS)(Eslote AU5 with 3.5 to 7.5 MHZ tmcsd,,ce@.Tc evslcste changes in portal vocccs flew velocity ss Vm we rewrded the angle cmss scd cmss se&iccsl .wes at the same site for cmrecticn of Vm and csloulsticn of PBFV. The vclccitv wss ccrrected bv the angle (30 to 64) bzhvm the Icog axis of the pcrtnl vein md the dopplcr l&n. No swgicsi compticaticns cxctmd dtming .utd aft= LT in the dcrtcm cr in the rsipisnta. After LT there were pmgnxsivc chatgas in portal& &VI @ctb Vm and PBFV). During ihe 6rst week the pmial vein velocity slowly inarpscd (24 br after LT: 31s c&xc; 1 week &er 37i5 c&se@ tc resch a steady state 8Rer one month (34+3 cmhm). PEN had * similar b&.&x. Hypakicetic ctisticn with M in-in systmic ad pcttal flow persisted during and a&r liver ttacspLrmtion At& the first month, rczipicct's psrsmetetn gmdcslly becsmc similar to those of the dcncr. We evslcated alsctheRIofHA:wcbauawcrere.wtded cithadurinnthefirst24hc~~e~w~~~e first month s&r LRLT. No-cbattgm were ever registered ii hepatic vcbts flciv or its pattern. In eonclwicr, I) s hypaldnctic state with insrcpaed &cchcic tlcw wss observed in all CP(CI &a tranaplantationassby~~~PBN1;is useful, during and sftu tmcsplact&m, tc check wttcus and arterial blood flow and tc disgccsc early vascclsr complications in crder to avoid gmt? failure.

Research paper thumbnail of Variant ER alpha plus beta estrogen receptors in hepatocellular carcinoma: A marker of biological aggressiveness

Digestive and Liver Disease, 2001

Policlinico di Mcdena Human bepatocellular carcinoma (HCC) expresses estrogen receptor (BR) a wld... more Policlinico di Mcdena Human bepatocellular carcinoma (HCC) expresses estrogen receptor (BR) a wld type (wtBR) and/or an cxon 5 deleted variant form (vER) tmnscripts. vBR+ HCC are significantly more ageive than wtBR+ HCC. Tbe survival rate at 1 year is significantly lower in vER+ HCC than in v&R+ HCC (Hepatology, 2wO,32; 233.238). No information is instead available on the relevance and mle in HCC ofBRb (whose presence in bepatocytes is still debated). Aim of the study was to determine the relationship between ER type and cell proliferation, invasiveness and apoptosis in HCC. Liver biopsies of patients with HCC and cirrhosis were obtained for the determination of ER by RT-PCR. Twenty HCC expressing wtER and 20 expressing vER were used in this study. A core of liver biopsy was embedded in paraffin for light microscopy and for immunohistochcmistry. Apoptosis was measured by the detection of DNA fragmentation while Ki67, detected using the antibody MIP-I, was used as index of cell proliferation. The levels of metallopmteinase 9 (MMP9), as an index of invasiveness ofcancer, were also evaluated by immunobistocbemistry. No difference in the percentage of apoptatic cells was found between HCC wtBR+ or vBR+. Ki67 positive cells were 8% in the HCC expressing WtER and 17% in those positive for vER (p=O).Wl). MMP9 levels were lower in HCC wlER+ than HCC vER+. While 20% of the HCC exprwsed EP.a, ERb were present only in 12% of the camem @0.02). The localization of ERa WBS both nuclear and cytoplasmatic while ERb wete present almost exclusively in the cytoplasm of the bepatocytes. The HCC that showed bigbest levels of proliferation were those expmsabtg elevated levels of ERa (both nuclear and cytoplwmic) and higher levels of ERb in immunobistochemistry but were cbamcterizcd a# predominantly vBR by RT/PCR. In conclusion, these data show that the presence of vBR identifies HCC with w extremely elevated proliferation rate and local invasiveness. Apoptosis was almost absent in HCC, independently form BR status. The presence of vBR correlated with the contempormy presence of cyioplasmic ERa and ERb and was asscciated with highest pmliferation levels. These cbamctistics may constitute the molecular basis for to the more aggressive behavior of HCC expressing vER and conhibute to their poorer prognosis as compared to those expressing wtER.

Research paper thumbnail of Angiogenesis: the Yin and Yang in intrahepatic cholangiocarcinoma

Hepatoma Research, 2023

The tumor microenvironment (TME) constitutes a complex structure comprising different cell types ... more The tumor microenvironment (TME) constitutes a complex structure comprising different cell types and soluble factors that surround the tumor and promote its progression. Primarily for its pivotal role in malignant growth, TME has become a potential therapeutic objective for developing new targeted therapy and a marker for assessing therapeutic response. In intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver malignancy, TME has also gained a central role in understanding the mechanisms underlying tumor progression. In this review, we focused on the role of angiogenic factors and their pathway in iCCA and analyzed possible therapeutic and prognostic implications.

Research paper thumbnail of Obese zebrafish: A small fish for a major human health condition

Animal Models and Experimental Medicine

Obesity is becoming a silent worldwide epidemic, with a steady increase in both adults and childr... more Obesity is becoming a silent worldwide epidemic, with a steady increase in both adults and children. To date, even though several drugs have been licensed for longterm obesity treatment, none of them are yet used in routine clinical practice. So far the only successful intervention has been behavioral therapy. A suitable and economic experimental model mimicking the human condition would therefore be extremely useful to evaluate preventive measures and novel treatments. Zebrafish are emerging as an important model system to study obesity and related metabolic disease. Remarkable similarities have been reported in lipid metabolism and the adipogenic pathway between zebrafish and mammals. Moreover, the zebrafish possesses a number of features-the relative inexpensiveness of animal husbandry, its optical transparency and the ability to produce a large number of offspring at low cost-that make it ideal for large-scale screening and for testing drugs and intervention. In this review, we summarize recent progress in using zebrafish as a model system to study obesity and obesity-related metabolic disorders. We describe several zebrafish models (in both larvae and adult animals) that develop obesity and nonalcoholic fatty liver disease (NAFLD) using different approaches, including gene manipulation, diet manipulation and modification of microbiota composition. For these models, we have outlined the specific aspects related to obesity and its development and we have summarized their advantages and limitations.

Research paper thumbnail of Missed treatment in an Italian HBV infected patients cohort: HBV RER

Digestive and Liver Disease, 2016

Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical p... more Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical practice and the characteristics of the patients who do not receive antiviral therapy. HBV-RER is an observational multicenter network that collected data of patients with HBV infection during a 3 years observational period (2009-2012). Among 2527 HBsAg positive patients, 1099 were never treated (NT); only 280 were included in the analysis due to different exclusion causes A minority was HBeAg-positive. The median age was 42. At liver biopsy most patients had Metavir score of F0-F1. Univariate analysis between 280 NT patients and the 290 naïve to treatment showed that NT patients were mostly female (P=0.002), not Italian (P=0.044), younger (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Metavir score was lower in NT (P0.002), such as the Fib4 score (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). HBV DNA level was significantly higher in NT. At multivariate analysis, independent variables associated with no-treatment were younger age, female gender, Metavir score F0-F1, Fib4 lower than 1.6 and lower blood level of HBV-DNA. There is a large number of patients eligible to treatment who do not receive it. A younger age and a less severe disease seem to be associated to deferral of treatment.

Research paper thumbnail of Letter: TNFα inhibitors and prevalence of fatty liver disease in chronic inflammatory diseases

Alimentary pharmacology & therapeutics, 2015

Research paper thumbnail of Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy. A randomized controlled trial

Research paper thumbnail of Variant estrogen receptor messenger RNA species detected in human primary hepatocellular carcinoma

Cancer research, 1995

The development of hepatocellular carcinoma (HCC) in addition to cirrhosis affects males in a sig... more The development of hepatocellular carcinoma (HCC) in addition to cirrhosis affects males in a significantly higher proportion than females. Liver estrogen receptors increase when HCC develops in males; however, these tumors usually respond poorly to antiestrogens. We have, therefore, hypothesized that, similar to breast cancer, estrogen receptors in males with HCC may be mutated. Variant estrogen receptor transcripts (lacking exon 5 of the hormone binding domain) were investigated by reverse transcription-PCR in 14 patients (7 males and 7 females) with HCC. While females mostly displayed the wild-type transcript (both in peritumoral and in tumor liver tissue), males showed both transcripts in the cirrhotic tissue and almost only the variant in the tumor. As the variant ER transcripts when translated could give rise to truncated receptors still able to constitutively activate transcription, they may be key factors in favoring deregulated proliferation in the male liver.

Research paper thumbnail of Coagulopathy in Liver Diseases: Complication or Therapy?

Digestive Diseases, 2014

Coagulopathy in cirrhosis is a composite condition where liver synthetic deficit rebalances coagu... more Coagulopathy in cirrhosis is a composite condition where liver synthetic deficit rebalances coagulation to a parallel reduction of both pro- and anticoagulant factors. Cirrhosis is therefore no longer considered a hypocoagulable state but rather a more unstable hemostatic balance with a lower threshold for tipping toward thrombosis or bleeding. Tendency to bleeding in cirrhosis is due to the reduction in the synthesis of procoagulants and a low platelet count as well as hyperfibrinolysis. Variceal hemorrhage is a frequent bleeding complication in decompensated cirrhosis. However, the possible contribution of coagulopathy as a precipitant or an aggravating factor is poorly documented and further data are required to clarify its real contributing role. Moreover, apart from the gastrointestinal tract, the occurrence of spontaneous and procedure-related bleeding elsewhere in the body, whilst not uncommon, is less than would be expected. By contrast, a large-scale population-based study has shown the propensity towards venous thrombosis in patients with liver diseases. Portal vein thrombosis (PVT) is a critical but frequent event occurring in up to 40% of patients with liver cirrhosis. PVT causes deterioration of the clinical course, the complications of portal hypertension and an increase in post-transplant mortality. The pathogenesis of PVT includes both local alterations, like blood flow reduction and endothelial activation, and systemic derangement. Systemic prohemostatic alterations include high von Willebrand factor, low ADAMTS-13, low levels of anticoagulants (antithrombin, proteins C and S) and increases in procoagulants like factor VIII. Low-molecular-weight heparin such as enoxaparin has proven to be safe and effective in both the treatment and prevention of PVT. In addition, patients in prophylaxis with enoxaparin showed a lower rate of decompensation and a better survival without bleeding complications. In such patients, circulating bacterial DNA, endotoxemia and markers of inflammation were attenuated compared to controls. These results therefore suggest a possible connection between enoxaparin, decrease of endotoxemia and reduction of portal hypertension. The approach to the coagulopathy in patients with liver diseases is changing: while the main goal for clinicians so far has been to reduce the risk of bleeding, the results of these new studies highlight the importance of preventing or treating thrombophilic disorders like PVT to avoid microcirculatory damage and eventually liver decompensation.

Research paper thumbnail of The role played by gender in viral hepatitis

Scandinavian Journal of Clinical & Laboratory Investigation, 2014

Although not a classical target for estrogens, the liver is a target for their action and is sens... more Although not a classical target for estrogens, the liver is a target for their action and is sensitive to their deprivation. The occurrence of menopause is accompanied by a chain of events depending on the progressive estrogen deprivation that eventually leads to a shift from a low inflammatory to a high inflammatory state. This has a series of well-known consequences in many different organs and tissues (bone, heart, brain, body fat etc.) among which the liver is particularly interesting. The consequences are extremely evident in HCV-positive women in whom HCV infection and menopause cooperate to induce higher necro-inflammatory features, increased hepatic steatosis and eventually faster progression of fibrosis. In addition, menopause is the strongest negative factor for sustained viral response (SVR) in HCV-positive females, especially HCV genotype 1 (in whom menopause was the only independent factor for failure of antiviral therapy). This suggests that HCV-positive women should be treated early during fertile age to obtain maximal response to antiviral therapy.

Research paper thumbnail of Sex, liver desease, and response to antiviral therapy

Hot Topics in Viral Hepatitis, 2013

Research paper thumbnail of Orthogonal polarization spectral imaging: a new tool in morphologic surveillance in intestinal transplant recipients

Transplantation Proceedings, 2002

Research paper thumbnail of Phytoestrogens and liver disease

Molecular and Cellular Endocrinology, 2002

Phytoestrogens are plant substances that are similar to 17-beta-estradiol and produce estrogenic ... more Phytoestrogens are plant substances that are similar to 17-beta-estradiol and produce estrogenic effects. A protective role in the development of breast and prostate cancer has been hypothesized. Estrogen receptors and their variant forms play a significant role in the pathogenesis of hepatocellular carcinoma (HCC); therefore weak estrogenic substances in the diet may play a role in its development. To investigate the role of phytoestrogens in HCC an investigation of dietary intake of these substances has been performed. Cases, patients at first diagnosis of cirrhosis or HCC were chosen. Questionnaire was built up using indications from previously published papers, extending the registration of details of the diet to reconstruct intake of nutrients for the last year. Interviews were always performed by the same dietician. Quantities determined with the help of photos of servings. Data were analyzed with Winfood database completed with data regarding content in phytoestrogens of food, beverages and seasonings. So far 92 cirrhotic patients and 32 HCCs have been interviewed. No significant difference was registered among the two groups regarding total caloric intake or single nutrients (lipids, carbohydrates, proteins). A significant lower intake of genistein was evidenced in patients at first diagnosis of HCC in comparison with cirrhotics; no significant difference was found in daidzein intake. Lignans intake was strictly related with wine intake; intake was significantly lower in cases only when wine was taken into account otherwise it was similar. Results can be summarized as follows: (1) there are no clear-cut differences (both qualitative or quantitative) between cirrhotics and HCC patients in the overall daily caloric intake while; (2) definite differences exist in the intake of some of the phytoestrogens (genistein, SEC, MAT); (3) differences between cases and controls in SEC and MAT are mainly attributable to lower alcohol intake in cases while; (4) significantly lower genistein intake in HCC only seems due to personal preferences of patients. In conclusion, these differences that we have evidenced in the diet in regard to estrogen-like substances may be relevant in modulating the risk of developing HCC in cirrhotic patients.

Research paper thumbnail of Hepatitis B virus infection of peripheral blood mononuclear cells is common in acute and chronic hepatitis

Journal of Medical Virology, 1990

Research paper thumbnail of Hepatitis C virus infection, HBsAg carrier state and hepatocellular carcinoma

Journal of Hepatology, 1992

In 1990, a case-control study was conducted in Italy to investigate the possible association betw... more In 1990, a case-control study was conducted in Italy to investigate the possible association between HCV infection and hepatocellular carcinoma (HCC). Serum samples from 65 subjects with newly diagnosed hepatocellular carcinoma and 99 hospital control subjects were tested for the presence of anti-HCV by second-generation ELISA test; positive sera were assayed by RIBA anti-HCV second-generation test. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). The presence of HCV and/or HBsAg serologic markers was significantly associated with hepatocellular carcinoma risk: the relative risk (RR) of HCC was 21.3 (95% CI = 8.8-51.5) for anti-HCV positivity in the absence of HBsAg; the relative risk of HCC was 13.3 (95% CI = 5.5-32.2) for the presence of HBsAg in the absence of anti-HCV. A higher risk (77.0) was observed when both markers were present. These findings indicate that HCV and HBsAg are independent risk factors for HCC. The results of multivariate analysis showed that the adjusted RR linking anti-HCV and HCC was 26.9 (95% CI = 9.9-72.5), the adjusted RR linking HBsAg and HCC was 11.4 (95% CI = 3.1-41.4), whereas no association (RR 1.5; 95% CI = 0.6-3.6) was found to link HCC with anti-HBc and/or anti-HBs positivity. Through the computation of population attributable risk we estimate that 25% of HCC cases occurring in Italy could be attributed to anti-HCV positivity alone and 20% to HBsAg carrier state alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Statements from the Taormina expert meeting on occult hepatitis B virus infection

Journal of Hepatology, 2008

Research paper thumbnail of No inflammation? No cancer! Clear HBV early and live happily

Journal of Hepatology, 2010

Some individuals who are chronically infected with hep

Research paper thumbnail of Detection of hepatitis B virus transcripts in patients with chronic liver disease

Journal of Hepatology, 1990

Hepatitis B virus (HBV) transcription was studied by Notthem blot aoalyxis o" total cellular RNA ... more Hepatitis B virus (HBV) transcription was studied by Notthem blot aoalyxis o" total cellular RNA pwitied from liver biopsies in 70 patients with chronic liver disease (24 HBsAg positive. 15 autiHE% andlor a"tiHRc positive, 31 HBV aeg-at&). No transcripts were found in the HBV negative and in the autiHBr and/or antiHBc positive patients. I" the others. three major RNA species were identified: i. a 3.5 kb transcript correspooding to the RNA pregenomc; ii. 2.4-2.1 kbtmoscript corresponding to the s ar.d preS1 gene RNA; iii. lower mokdar weight species. All three forms were pnscnt simulraneously only in patients with sctive viral replication, with a strict relation between the presz%ce of the 3.5 Lb RNA ia the liver and serum HBV-DNA. II. conclusion, Northern blot analysis ca" easily be performed to study viral replication and it can contribute to a better understanding of the molecular processes uoderiying HBV infcetion and leading to liver disease in ma". With the advent of rewmbiiant DNA technology, much has bee" learned about the physical state of hepatitis B virus (HBV) genome in human liver disease (Refs. 1-5; for a review, see R&s. 6-7). Less is known about HBV transcription and gene expression in infected liver. Previous rtudies, perfomxd in chimpanzee HBV infect& liver (8.9) as well as iu in vitro tissue culture systems (10,ll) have revealed that two major RNA species are present: a 3.5 kb mRNA species, linked to HB core antigen expression and geuome replication, and a 2.1-2.4 kb mRNA, linked to HBsAg expression.

Research paper thumbnail of Field-practice study of sorafenib therapy for hepatocellular carcinoma: A prospective multicenter study in Italy

Hepatology, 2011

1 on behalf of the SOFIA (SOraFenib Italian Assessment) study group A multicenter randomized cont... more 1 on behalf of the SOFIA (SOraFenib Italian Assessment) study group A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. Conclusion: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy.

Research paper thumbnail of Prognostic features and survival of hepatocellular carcinoma in Italy

European Journal of Cancer, 2001

The aim of this study was to evaluate the prognostic factors at presentation and survival in Ital... more The aim of this study was to evaluate the prognostic factors at presentation and survival in Italian patients with hepatocellular carcinoma (HCC). Clinical and demographic data of 176 patients consecutively observed from 1993 to 1997 were evaluated by univariate and multivariate analyses. Overall median survival was 18 months. At univariate analysis, low albumin, high bilirubin, high alkaline phosphatase, high alpha-fetoprotein (AFP); high platelet count, hepatitis B surface antigen (HBsAg)-positivity, the presence of ascites, of encephalopathy, of portal vein thrombosis (PVT), male sex, no treatment, poor dierentiation, untreatable tumours and incidental diagnosis were each associated with shorter survival. HBsAg-positive subjects more often presented with untreatable lesions or diuse tumours (P=0.001 and P=0.007, respectively) and had signi®cantly worse survival (P=0.0057). By multiple regression analysis, low albumin, high bilirubin, abnormal AFP, presence of PVT and of untreatable lesions were independent risk factors for worse survival. Thus, the most important factors in¯uencing survival are the degree of functional impairment of the liver, the presence of hepatitis B viral (HBV) infection, the type of diagnosis and the aggressiveness of the tumour.

Research paper thumbnail of Evaluation by color doppler ultrasound of hemodynamic changes in living-related liver transplant

Digestive and Liver Disease, 2001

Policliciw di Modem Organ shortage hss prompted the set up ofnm transplant techniques like living... more Policliciw di Modem Organ shortage hss prompted the set up ofnm transplant techniques like living-related liver transplant (LRLT). The hemcdycamic changes in liver tramplant (LT) have been reported in pediatric living-related LT but not in adult LRLT. llre pcrpcse of this study wss tc CvaluatE the hemcdymanic chtmgm in portal flow (mean velocity: Vm and portal blood flow volume: PBFV), in resistawe index (RI) of hepatic artery (HA) and in the hepstic veins flow sI?er LRLT. Three living-r&ted liver tmcsplscts were pmfmmed &cm April 2001 to June 2001 at Policlicicc di Modem in 3 adult patients. In all 3 patients, right lobe transplant wss perfcm~ed. All donors and &pie& tmdetwecl s detailed prc-opcmtive imsging study of the vaaculsr anatomy icclcdbtg ic&paative Color Doppler Ultmscccd (CDUS)(Eslote AU5 with 3.5 to 7.5 MHZ tmcsd,,ce@.Tc evslcste changes in portal vocccs flew velocity ss Vm we rewrded the angle cmss scd cmss se&iccsl .wes at the same site for cmrecticn of Vm and csloulsticn of PBFV. The vclccitv wss ccrrected bv the angle (30 to 64) bzhvm the Icog axis of the pcrtnl vein md the dopplcr l&n. No swgicsi compticaticns cxctmd dtming .utd aft= LT in the dcrtcm cr in the rsipisnta. After LT there were pmgnxsivc chatgas in portal& &VI @ctb Vm and PBFV). During ihe 6rst week the pmial vein velocity slowly inarpscd (24 br after LT: 31s c&xc; 1 week &er 37i5 c&se@ tc resch a steady state 8Rer one month (34+3 cmhm). PEN had * similar b&.&x. Hypakicetic ctisticn with M in-in systmic ad pcttal flow persisted during and a&r liver ttacspLrmtion At& the first month, rczipicct's psrsmetetn gmdcslly becsmc similar to those of the dcncr. We evslcated alsctheRIofHA:wcbauawcrere.wtded cithadurinnthefirst24hc~~e~w~~~e first month s&r LRLT. No-cbattgm were ever registered ii hepatic vcbts flciv or its pattern. In eonclwicr, I) s hypaldnctic state with insrcpaed &cchcic tlcw wss observed in all CP(CI &a tranaplantationassby~~~PBN1;is useful, during and sftu tmcsplact&m, tc check wttcus and arterial blood flow and tc disgccsc early vascclsr complications in crder to avoid gmt? failure.

Research paper thumbnail of Variant ER alpha plus beta estrogen receptors in hepatocellular carcinoma: A marker of biological aggressiveness

Digestive and Liver Disease, 2001

Policlinico di Mcdena Human bepatocellular carcinoma (HCC) expresses estrogen receptor (BR) a wld... more Policlinico di Mcdena Human bepatocellular carcinoma (HCC) expresses estrogen receptor (BR) a wld type (wtBR) and/or an cxon 5 deleted variant form (vER) tmnscripts. vBR+ HCC are significantly more ageive than wtBR+ HCC. Tbe survival rate at 1 year is significantly lower in vER+ HCC than in v&R+ HCC (Hepatology, 2wO,32; 233.238). No information is instead available on the relevance and mle in HCC ofBRb (whose presence in bepatocytes is still debated). Aim of the study was to determine the relationship between ER type and cell proliferation, invasiveness and apoptosis in HCC. Liver biopsies of patients with HCC and cirrhosis were obtained for the determination of ER by RT-PCR. Twenty HCC expressing wtER and 20 expressing vER were used in this study. A core of liver biopsy was embedded in paraffin for light microscopy and for immunohistochcmistry. Apoptosis was measured by the detection of DNA fragmentation while Ki67, detected using the antibody MIP-I, was used as index of cell proliferation. The levels of metallopmteinase 9 (MMP9), as an index of invasiveness ofcancer, were also evaluated by immunobistocbemistry. No difference in the percentage of apoptatic cells was found between HCC wtBR+ or vBR+. Ki67 positive cells were 8% in the HCC expressing WtER and 17% in those positive for vER (p=O).Wl). MMP9 levels were lower in HCC wlER+ than HCC vER+. While 20% of the HCC exprwsed EP.a, ERb were present only in 12% of the camem @0.02). The localization of ERa WBS both nuclear and cytoplasmatic while ERb wete present almost exclusively in the cytoplasm of the bepatocytes. The HCC that showed bigbest levels of proliferation were those expmsabtg elevated levels of ERa (both nuclear and cytoplwmic) and higher levels of ERb in immunobistochemistry but were cbamcterizcd a# predominantly vBR by RT/PCR. In conclusion, these data show that the presence of vBR identifies HCC with w extremely elevated proliferation rate and local invasiveness. Apoptosis was almost absent in HCC, independently form BR status. The presence of vBR correlated with the contempormy presence of cyioplasmic ERa and ERb and was asscciated with highest pmliferation levels. These cbamctistics may constitute the molecular basis for to the more aggressive behavior of HCC expressing vER and conhibute to their poorer prognosis as compared to those expressing wtER.