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Filippo SCHEPIS
Professore Associato
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa
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Pubblicazioni
2023
- Assessment of portal hypertension severity using machine learning models in patients with compensated cirrhosis
[Articolo su rivista]
Reinis, J.; Petrenko, O.; Simbrunner, B.; Hofer, B. S.; Schepis, F.; Scoppettuolo, M.; Saltini, D.; Indulti, F.; Guasconi, T.; Albillos, A.; Tellez, L.; Villanueva, C.; Brujats, A.; Garcia-Pagan, J. C.; Perez-Campuzano, V.; Hernandez-Gea, V.; Rautou, P. -E.; Moga, L.; Vanwolleghem, T.; Kwanten, W. J.; Francque, S.; Trebicka, J.; Gu, W.; Ferstl, P. G.; Gluud, L. L.; Bendtsen, F.; Moller, S.; Kubicek, S.; Mandorfer, M.; Reiberger, T.
abstract
Background & Aims: In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. Methods: A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. Results: Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). Conclusions: Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. Impact and implications: We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.
2023
- Endovascular Assessment of Liver Hemodynamics in Patients with Cirrhosis Complicated by Portal Hypertension
[Articolo su rivista]
Ferral, H.; Schepis, F.; Gaba, R. C.; Garcia-Tsao, G.; Zanetto, A.; Perez-Campuzano, V.; Haskal, Z. J.; Garcia-Pagan, J. C.
abstract
The hepatic venous pressure gradient (HVPG) is currently considered the gold standard to assess portal hypertension (PH) in patients with cirrhosis. A meticulous technique is important to achieve accurate and reproducible results, and values obtained during measurement are applied in risk stratification of patients with PH, allocating treatment options, monitoring follow-up, and deciding management options in surgical patients. The use of portosystemic pressure gradients in patients undergoing placement of transjugular intrahepatic portosystemic shunts has been studied extensively and has great influence on decisions on shunt diameter. The purpose of this study was to describe the recommended technique to measure HVPG and portosystemic pressure gradient and to review the existing literature describing the importance of these hemodynamic measurements in clinical practice.
2023
- Feasibility, safety, and outcome of second-line nivolumab/bevacizumab in liver transplant patients with recurrent hepatocellular carcinoma
[Articolo su rivista]
Di Marco, Lorenza; Pivetti, Alessandra; Foschi, Francesco Giuseppe; D'Amico, Roberto; Schepis, Filippo; Caporali, Cristian; Casari, Federico; Lasagni, Simone; Critelli, Rosina Maria; Milosa, Fabiola; Romanzi, Adriana; Marcelli, Gemma; De Maria, Nicola; Romagnoli, Dante; Catellani, Barbara; Scianò, Filippo; Magistri, Paolo; Colecchia, Antonio; Sighinolfi, Pamela; Di Benedetto, Fabrizio; Martinez-Chantar, Maria-Luz; Villa, Erica
abstract
2023
- GALAD outperforms aMAP and ALBI for predicting HCC in patients with compensated advanced chronic liver disease: A 12-year prospective study
[Articolo su rivista]
Villa, Erica; Donghia, Rossella; Baldaccini, Valentina; Tedesco, Calogero C; Shahini, Endrit; Cozzolongo, Raffaele; Ascari, Sara; Pesole, Pasqua Letizia; Coletta, Sergio; Critelli, Rosina Maria; Lasagni, Simone; Schepis, Filippo; Semellini, Filippo; Giannelli, Gianluigi
abstract
Background and aims: Surveillance programs are strongly recommended in patients with liver cirrhosis for early detection of HCC development. Six-monthly ultrasound sonography is the most reliable and commonly used technique, especially when associated with serum determination of α-fetoprotein, but different score systems have been proposed to overcome the unsatisfactory diagnostic accuracy of α-fetoprotein. The aim of this 12-year prospective study is to compare the gender, age, AFP-L3, AFP, des-gamma-carboxy prothrombin (GALAD) versus age, gender, bilirubin, albumin, and platelets and albumin-bilirubin scores in predicting HCC onset. Approach and results: A cohort of 545 consecutive patients with compensated advanced chronic liver disease without suspected focal lesions was followed up every 6 months by liver imaging and α-fetoprotein to detect HCC occurrence. Harrell's C-index for censored data was employed to evaluate the performance of any parameters or scores helping to predict HCC development. ROC curve analysis showed that the GALAD score was more accurate in evaluating HCC development than albumin-bilirubin and age, gender, bilirubin, albumin, and platelets. The AUC ranged from 0.7268 to 0.6851 at 5 and 10 years, both in the total cohort and in the sub-cohorts (viral hepatitis, NASH, and alcohol). The HCC Risk model was constructed using univariate and multivariate Cox proportional hazard regression analysis, showing a strong association of GALAD with HR > 1, p < 0.05, in the total and sub-cohorts, and a better risk prediction in the alcohol cohort, both alone and standardized with other blood parameters. Conclusions: GALAD is the most reliable and accurate score system to detect HCC risk of development in patients with compensated advanced chronic liver disease.
2023
- Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study
[Articolo su rivista]
Riggio, O.; Celsa, C.; Calvaruso, V.; Merli, M.; Caraceni, P.; Montagnese, S.; Mora, V.; Milana, M.; Saracco, G. M.; Raimondo, G.; Benedetti, A.; Burra, P.; Sacco, R.; Persico, M.; Schepis, F.; Villa, E.; Colecchia, A.; Fagiuoli, S.; Pirisi, M.; Barone, M.; Azzaroli, F.; Soardo, G.; Russello, M.; Morisco, F.; Labanca, S.; Fracanzani, A. L.; Pietrangelo, A.; Di Maria, G.; Nardelli, S.; Ridola, L.; Gasbarrini, A.; Camma, C.
abstract
Introduction: Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE. Methods: We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT). Results: During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission. Conclusion: In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.
2023
- Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Long-term Outcome
[Articolo su rivista]
Magaz, Marta; Giudicelli-Lett, Heloïse; Nicoară-Farcău, Oana; Rajoriya, Neil; Goel, Ashish; Raymenants, Karlien; Hillaire, Sophie; Crespo, Gonzalo; Téllez, Luis; Elkrief, Laure; Fondevila, Constantino; Orts, Lara; Nery, Filipe; Shukla, Akash; Larrue, Hélène; Fundora, Yiliam; Degroote, Helena; Aguilera, Victoria; Llop, Elba; Turco, Laura; Indulti, Federica; Gioia, Stefania; Tosetti, Giulia; Bitto, Niccolò; Becchetti, Chiara; Alvarado, Edilmar; Roig, Cristina; Diaz, Raquel; Praktiknjo, Michael; Konicek, Anna-Lena; Soy, Guillem; Olivas, Pol; Fortea, José Ignacio; Masnou, Helena; Puente, Ángela; Ardèvol, Alba; Álvarez-Navascués, Carmen; Romero, Marta; Scheiner, Bernhard; Semmler, Georg; Mandorfer, Mattias; Damião, Filipe; Baiges, Anna; Turon, Fanny; Simón-Talero, Macarena; González-Alayón, Carlos; Díaz, Alba; García-Criado, Ángeles; de Gottardi, Andrea; Reverter, Enric; Blasi, Annabel; Genescà, Joan; Roux, Olivier; Francoz, Claire; Noronha Ferreira, Carlos; Reiberger, Thomas; Rodríguez, Manuel; Morillas, Rosa María; Crespo, Javier; Trebicka, Jonel; Bañares, Rafael; Villanueva, Càndid; Berzigotti, Annalisa; Primignani, Massimo; La Mura, Vincenzo; Riggio, Oliviero; Schepis, Filippo; Procopet, Bogdan; Verhelst, Xavier; Calleja, José Luis; Bureau, Christophe; Albillos, Agustín; Nevens, Frederik; Hernández-Gea, Virginia; Tripathi, Dhiraj; Rautou, Pierre-Emmanuel; Durand, François; García-Pagán, Juan Carlos
abstract
Background: Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. Methods: Retrospective multicentre study of 79 patients who received LT for PSVD. Results: Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. Conclusions: LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.
2023
- Mortality after transjugular intrahepatic portosystemic shunt in older adult patients with cirrhosis: A validated prediction model
[Articolo su rivista]
Vizzutti, F.; Celsa, C.; Calvaruso, V.; Enea, M.; Battaglia, S.; Turco, L.; Senzolo, M.; Nardelli, S.; Miraglia, R.; Roccarina, D.; Campani, C.; Saltini, D.; Caporali, C.; Indulti, F.; Gitto, S.; Zanetto, A.; Di Maria, G.; Bianchini, M.; Pecchini, M.; Aspite, S.; Di Bonaventura, C.; Citone, M.; Guasconi, T.; Di Benedetto, F.; Arena, U.; Fanelli, F.; Maruzzelli, L.; Riggio, O.; Burra, P.; Colecchia, A.; Villa, E.; Marra, F.; Camma, C.; Schepis, F.
abstract
Background and Aims: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults. Approach and Results: We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis. Conclusions: After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted.
2023
- Oesophageal varices predict complications in compensated advanced non-alcoholic fatty liver disease
[Articolo su rivista]
Pennisi, G.; Enea, M.; Vigano, M.; Schepis, F.; de Ledinghen, V.; Berzigotti, A.; Wai-Sun Wong, V.; Fracanzani, A. L.; Sebastiani, G.; Lara-Romero, C.; Bugianesi, E.; Svegliati-Baroni, G.; Marra, F.; Aghemo, A.; Valenti, L.; Calvaruso, V.; Colecchia, A.; Di Maria, G.; La Mantia, C.; Lin, H.; Mendoza, Y. P.; Pugliese, N.; Ravaioli, F.; Romero-Gomez, M.; Saltini, D.; Craxi, A.; Di Marco, V.; Camma, C.; Petta, S.
abstract
Background & Aims: We aimed to evaluate the impact of oesophageal varices (OV) and their evolution on the risk of complications of compensated advanced chronic liver disease (cACLD) caused by non-alcoholic fatty liver disease (NAFLD). We also assessed the accuracy of non-invasive scores for predicting the development of complications and for identifying patients at low risk of high-risk OV. Methods: We performed a retrospective assessment of 629 patients with NAFLD-related cACLD who had baseline and follow-up oesophagogastroduodenoscopy and clinical follow-up to record decompensation, portal vein thrombosis (PVT), and hepatocellular carcinoma. Results: Small and large OV were observed at baseline in 30 and 15.9% of patients, respectively. The 4-year incidence of OV from absence at baseline, and that of progression from small to large OV were 16.3 and 22.4%, respectively. Diabetes and a ≥5% increase in BMI were associated with OV progression. Multivariate Cox regression revealed that small (hazard ratio [HR] 2.24, 95% CI 1.47–3.41) and large (HR 3.86, 95% CI 2.34–6.39) OV were independently associated with decompensation. When considering OV status and trajectories, small (HR 2.65, 95% CI 1.39–5.05) and large (HR 4.90, 95% CI 2.49–9.63) OV at baseline and/or follow-up were independently associated with decompensation compared with the absence of OV at baseline and/or follow-up. The presence of either small (HR 2.8, 95% CI 1.16–6.74) or large (HR 5.29, 95% CI 1.96–14.2) OV was also independently associated with incident PVT. Conclusion: In NAFLD-related cACLD, the presence, severity, and evolution of OV stratify the risk of developing decompensation and PVT. Impact and implications: Portal hypertension is the main driver of liver decompensation in chronic liver diseases, and its non-invasive markers can help risk prediction. The presence, severity, and progression of oesophageal varices stratify the risk of complications of non-alcoholic fatty liver disease. Easily obtainable laboratory values and liver stiffness measurement can identify patients at low risk for whom endoscopy may be withheld, and can also stratify the risk of liver-related complications.
2023
- Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients
[Articolo su rivista]
Benmassaoud, Amine; Macias, Juan; Delamarre, Adèle; Corma-Gomez, Anaïs; Guaraldi, Giovanni; Milic, Jovana; Rockstroh, Jürgen K; Van Bremen, Kathrin; Tsochatzis, Emmanuel; Mulay, Akhilesh; Price, Jennifer; Garvey, Lucy J; Lemoine, Maud; Kablawi, Dana; Lebouche, Bertrand; Klein, Marina B; Ballesteros, Luz R; Boesecke, Christopher; Schepis, Filippo; Bhagani, Sanjay; Cooke, Graham; Berzigotti, Annalisa; Hirose, Kyoko; Pineda, Juan A; Ramanakumar, Agnihotram V; De-Ledinghen, Victor; Saeed, Sahar; Sebastiani, Giada
abstract
Background and aims: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. Methods: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). Results: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. Conclusions: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone.
2023
- Reply
[Articolo su rivista]
Vizzutti, Francesco; Celsa, Ciro; Battaglia, Salvatore; Miraglia, Roberto; Enea, Marco; Marra, Fabio; Caporali, Cristian; Cammà, Calogero; Schepis, Filippo
abstract
2023
- Reply
[Articolo su rivista]
Vizzutti, F.; Celsa, C.; Battaglia, S.; Miraglia, R.; Enea, M.; Marra, F.; Colecchia, A.; Camma, C.; Schepis, F.
abstract
2023
- Targeted decrease of portal hepatic pressure gradient improves ascites control after TIPS
[Articolo su rivista]
Queck, A.; Schwierz, L.; Gu, W.; Ferstl, P. G.; Jansen, C.; Uschner, F. E.; Praktiknjo, M.; Chang, J.; Brol, M. J.; Schepis, F.; Merli, M.; Strassburg, C. P.; Lehmann, J.; Meyer, C.; Trebicka, J.
abstract
Background: Ascites is a definitive sign of decompensated liver cirrhosis driven by portal hypertension. Although transjugular intrahepatic portosystemic shunt insertion (TIPS) is indicated for therapy of recurrent and refractory ascites, there is no evidence-based recommendation for a specific target of portal hepatic pressure gradient (PPG) decrease. Methods: In this single-center, retrospective trial, we investigated the decrease of PPG in 341 patients undergoing TIPS insertion for therapy of refractory or recurrent ascites until 2015. During each procedure, portal and inferior vena cava pressures were invasively measured and correlated with patients' outcome and ascites progression over time, according to the prespecified Noninvasive Evaluation Program for TIPS and Follow-Up Network protocol (NCT03628807). Results: Patients without ascites at 6 weeks after TIPS had significantly greater PPG reduction immediately after TIPS, compared to the patients with refractory ascites (median reduction 65% vs. 55% of pre-TIPS PPG; p = 0.001). Survival was significantly better if ascites was controlled, compared to patients with need for paracentesis 6 weeks after TIPS (median survival: 185 vs. 41 weeks; HR 2.0 [1.3–2.9]; p < 0.001). Therefore, higher PPG reduction by TIPS (p = 0.005) and lower PPG after TIPS (p = 0.02) correlated with resolution of severe ascites 6 weeks after TIPS. Multivariable analyses demonstrated that higher Child-Pugh score before TIPS (OR 1.3 [1.0–1.7]; p = 0.03) and lower serum sodium levels (OR 0.9 [0.9–1.0]; p = 0.004) were independently associated with ascites persistence 6 weeks after TIPS, whereas PPG reduction (OR 0.98 [0.97–1.00]; p = 0.02) was associated with resolution of ascites 6 weeks after TIPS. Conclusion: Extent of PPG reduction and/or lowering of target PPG immediately after TIPS placement is associated with improved ascites control in the short term and with survival in the long term. A structured follow-up visit for patients should assess persistence of ascites at 6 weeks after TIPS.
2023
- The role of transjugular intrahepatic portosystemic shunt in patients with cirrhosis and ascites: Recent evolution and open questions
[Articolo su rivista]
Deltenre, P.; Zanetto, A.; Saltini, D.; Moreno, C.; Schepis, F.
abstract
In selected patients with cirrhosis and ascites, transjugular intrahepatic portosystemic shunt (TIPS) placement improves control of ascites and may reduce mortality. In this review, we summarize the current knowledge concerning the use of TIPS for the treatment of ascites in patients with cirrhosis, from pathophysiology of ascites formation to hemodynamic consequences, patient selection, and technical issues of TIPS insertion. The combination of these factors is important to guide clinical decision-making and identify the best strategy for each individual patient. There is still a need to identify the best timing for TIPS placement in the natural history of ascites (recurrent vs. refractory) as well as which type and level of renal dysfunction is acceptable when TIPS is proposed for the treatment of ascites in cirrhosis. Future studies are needed to define the optimal stent diameter according to patient characteristics and individual risk of shunt-related side effects, particularly hepatic encephalopathy and insufficient cardiac response to hemodynamic consequences of TIPS insertion.
2022
- Baveno VII – Renewing consensus in portal hypertension
[Articolo su rivista]
de Franchis, R.; Bosch, J.; Garcia-Tsao, G.; Reiberger, T.; Ripoll, C.; Abraldes, J. G.; Albillos, A.; Baiges, A.; Bajaj, J.; Banares, R.; Barrufet, M.; Benajiba, L.; Berzigotti, A.; Bureau, C.; Calvaruso, V.; Cardenas, A.; D'Amico, G.; De Gottardi, A.; Dell'Era, A.; Escorsell, A.; Fallowfield, J.; Ferral, H.; Francque, S.; Gaba, R.; Garcia-Pagan, J. C.; Genesca, J.; Rodrigues, S. G.; Gracia-Sanscho, J.; Han, G.; Hernandez-Gea, V.; Jia, J.; Kiladjian, J. J.; Krag, A.; Laleman, W.; La Mura, V.; Lens, S.; Luo, X.; Mandorfer, M.; Murad, S. D.; Paradis, V.; Patch, D.; Piano, S.; Pinzani, M.; Plessier, A.; Primignani, M.; Procopet, B.; Rautou, P. E.; Rudler, M.; Sarin, S. K.; Schepis, F.; Senzolo, M.; Shah, V.; Shukla, A.; Tandon, P.; Tellez, L.; Thabut, D.; Thiele, M.; Trebicka, J.; Tripathi, D.; Tsochatzis, E.; Turco, L.; Turon, F.; Valla, D.; Villanueva, C.; Wanless, I.; Yoshiji, H.
abstract
To expand on the work of previous meetings, a virtual Baveno VII workshop was organised for October 2021. Among patients with compensated cirrhosis or compensated advanced chronic liver disease (cACLD – defined at the Baveno VI conference), the presence or absence of clinically significant portal hypertension (CSPH) is associated with differing outcomes, including risk of death, and different diagnostic and therapeutic needs. Accordingly, the Baveno VII workshop was entitled “Personalized Care for Portal Hypertension”. The main fields of discussion were the relevance and indications for measuring the hepatic venous pressure gradient as a gold standard, the use of non-invasive tools for the diagnosis of cACLD and CSPH, the impact of aetiological and non-aetiological therapies on the course of cirrhosis, the prevention of the first episode of decompensation, the management of an acute bleeding episode, the prevention of further decompensation, as well as the diagnosis and management of splanchnic vein thrombosis and other vascular disorders of the liver. For each of these 9 topics, a thorough review of the medical literature was performed, and a series of consensus statements/recommendations were discussed and agreed upon. A summary of the most important conclusions/recommendations derived from the workshop is reported here. The statements are classified as unchanged, changed, and new in relation to Baveno VI.
2022
- Corrigendum to ‘Baveno VII – Renewing consensus in portal hypertension’ [J Hepatol (2022) 959-974, (S0168827821022996), (10.1016/j.jhep.2021.12.022)]
[Articolo su rivista]
de Franchis, R.; Bosch, J.; Garcia-Tsao, G.; Reiberger, T.; Ripoll, C.; Abraldes, J. G.; Albillos, A.; Baiges, A.; Bajaj, J.; Banares, R.; Barrufet, M.; Benajiba, L.; Berzigotti, A.; Bureau, C.; Calvaruso, V.; Cardenas, A.; D'Amico, G.; De Gottardi, A.; Dell'Era, A.; Escorsell, A.; Fallowfield, J.; Ferral, H.; Francque, S.; Gaba, R.; Garcia-Pagan, J. C.; Genesca, J.; Rodrigues, S. G.; Gracia-Sanscho, J.; Han, G.; Hernandez-Gea, V.; Jia, J.; Kiladjian, J. J.; Krag, A.; Laleman, W.; La Mura, V.; Lens, S.; Luo, X.; Mandorfer, M.; Murad, S. D.; Paradis, V.; Patch, D.; Piano, S.; Pinzani, M.; Plessier, A.; Primignani, M.; Procopet, B.; Rautou, P. E.; Rudler, M.; Sarin, S. K.; Schepis, F.; Senzolo, M.; Shah, V.; Shukla, A.; Tandon, P.; Tellez, L.; Thabut, D.; Thiele, M.; Trebicka, J.; Tripathi, D.; Tsochatzis, E.; Turco, L.; Turon, F.; Valla, D.; Villanueva, C.; Wanless, I.; Yoshiji, H.
abstract
It has come to our attention that on page 974 in the Baveno VII Faculty section, one of the faculty member's names was misspelled “Guogong Han (Xi'an, China)”. The correct spelling is “Guohong Han (Xi'an, China)”. We apologise for any inconvenience caused.
2022
- Decompensation in Advanced Nonalcoholic Fatty Liver Disease May Occur at Lower Hepatic Venous Pressure Gradient Levels Than in Patients With Viral Disease
[Articolo su rivista]
Bassegoda, O.; Olivas, P.; Turco, L.; Mandorfer, M.; Serra-Burriel, M.; Tellez, L.; Kwanten, W.; Laroyenne, A.; Farcau, O.; Alvarado, E.; Moga, L.; Vuille-Lessard, E.; Fortea, J. I.; Ibanez, L.; Tosetti, G.; Vanwolleghem, T.; Larrue, H.; Burgos-Santamaria, D.; Stefanescu, H.; Paternostro, R.; Cippitelli, A.; Lens, S.; Augustin, S.; Llop, E.; Laleman, W.; Trebicka, J.; Chang, J.; Masnou, H.; Zipprich, A.; Miceli, F.; Semmler, G.; Forns, X.; Primignani, M.; Banares, R.; Puente, A.; Berzigotti, A.; Rautou, P. E.; Villanueva, C.; Gines, P.; Garcia-Pagan, J. C.; Procopet, B.; Bureau, C.; Albillos, A.; Francque, S.; Reiberger, T.; Schepis, F.; Graupera, I.; Hernandez-Gea, V.
abstract
Background & Aims: Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension–related decompensation in patients with advanced NAFLD (aNAFLD). Methods: Multicenter cross-sectional study included 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels. Results: Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and Model for End-Stage Liver Disease score. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25%; P =.019) than in the aHCV group. For any of the HVPG cutoff analyzed (<10, 10–12, or 12 mmHg) the prevalence of decompensation was higher in the aNAFLD group than in the aHCV group. Conclusions: Patients with aNAFLD have higher prevalence of portal hypertension–related decompensation at any value of HVPG as compared with aHCV patients. Longitudinal studies aiming to identify HVPG thresholds able to predict decompensation and long-term outcomes in aNAFLD population are strongly needed.
2022
- Endothelial angiopoietin-2 overexpression in explanted livers identifies subjects at higher risk of recurrence of hepatocellular carcinoma after liver transplantation
[Articolo su rivista]
Lasagni, Simone; Leonardi, Filippo; Pivetti, Alessandra; Di Marco, Lorenza; Ravaioli, Federico; Serenari, Matteo; Gitto, Stefano; Critelli, Rosina Maria; Milosa, Fabiola; Romanzi, Adriana; Mancarella, Serena; Dituri, Francesco; Riefolo, Mattia; Catellani, Barbara; Magistri, Paolo; Romagnoli, Dante; Celsa, Ciro; Enea, Marco; de Maria, Nicola; Schepis, Filippo; Colecchia, Antonio; Cammà, Calogero; Cescon, Matteo; D'Errico, Antonietta; di Benedetto, Fabrizio; Giannelli, Gianluigi; Martinez-Chantar, Maria Luz; Villa, Erica
abstract
Background Though the precise criteria for accessing LT are consistently being applied, HCC recurrence (HCC-R_LT) still affects more than 15% of the patients. We analyzed the clinical, histopathological, and biological features of patients with HCC to identify the predictive factors associated with cancer recurrence and survival after LT.Methods We retrospectively analyzed 441 patients with HCC who underwent LT in our center. Overall, 70 (15.8%) of them developed HCC-R_LT. We matched them by age at transplant and etiology with 70 non-recurrent patients. A comparable cohort from the Liver Transplant Centre of Bologna served as validation. The clinical and biochemical characteristics and pre-LT criteria (Milan, Metroticket, Metroticket_AFP, and AFP model) were evaluated. Histological analysis and immunohistochemistry for angiopoietin-2 in the tumor and non-tumor tissue of explanted livers were performed. Patients' follow-up was until death, last clinical evaluation, or 31 December 2021. In patients with HCC-R_LT, the date of diagnosis of recurrence and anatomical site has been reported; if a biopsy of recurrence was available, histologic and immunohistochemical analyses were also performed.Results Patients were followed up for a mean period of 62.7 54.7 months (median, 39 months). A higher risk of HCC-R_LT was evident for factors related indirectly (AFP) or directly (endothelial angiopoietin-2, microvascular invasion) to biological HCC aggressiveness. In multivariate analysis, only angiopoietin-2 expression was independently associated with recurrence. Extremely high levels of endothelial angiopoietin-2 expression were also found in hepatic recurrence and all different metastatic locations. In univariate analysis, MELD, Metroticket_AFP Score, Edmondson-Steiner grade, microvascular invasion, and endothelial angiopoietin-2 were significantly related to survival. In multivariate analysis, angiopoietin-2 expression, Metroticket_AFP score, and MELD (in both training and validation cohorts) independently predicted mortality. In time-dependent area under receiver operating characteristic curve analysis, the endothelial angiopoietin-2 expression had the highest specificity and sensitivity for recurrence (AUC 0.922, 95% CI 0.876-0.962, p < 0.0001).Conclusions Endothelial angiopoietin-2 expression is a powerful independent predictor of post-LT tumor recurrence and mortality, highlighting the fundamental role of tumor biology in defining the patients' prognosis after liver transplantation. The great advantage of endothelial angiopoietin-2 is that it is evaluable in HCC biopsy before LT and could drive a patient's priority on the waiting list.
2022
- Portosystemic shunt is an effective treatment for complications of portal hypertension in hepatic myeloid metaplasia and improves nutritional status
[Articolo su rivista]
Aspite, S.; Schepis, F.; Roccarina, D.; Gitto, S.; Citone, M.; Di Bonaventura, C.; Bianchini, M.; Arena, U.; Vannucchi, A. M.; Guglielmelli, P.; Campani, F.; Fanelli, F.; Marra, F.; Vizzutti, F.
abstract
In patients affected by myelofibrosis with hepatic myeloid metaplasia (HMM), portal hypertension (PHT) complications may develop. In this case series, we analysed the efficacy and safety of transjugular portosystemic shunt (TIPS) in the treatment of PHT-related complications and its effects on the nutritional status. Six patients were evaluated and the average follow-up period after TIPS was 33 (IQR 5) months. None of the patients developed hepatic failure, nor any recurrence of variceal bleeding was recorded. No additional paracentesis or endoscopic prophylactic treatment for PHT-related complications were required. In all subjects, the average dose of diuretics was almost halved three months after TIPS. Three patients died during the follow-up, but none for liver-related causes. All patients showed an improvement in the global nutritional status. In conclusion, TIPS represent an effective and safe treatment option for patients affected by complications of PHT secondary to HMM and drives to an improvement of the nutritional status.
2022
- Predictors of solid extra-hepatic non-skin cancer in liver transplant recipients and analysis of survival: a long-term follow-up study
[Articolo su rivista]
Gitto, Stefano; Magistri, Paolo; Marzi, Luca; Mannelli, Nicolò; De Maria, Nicola; Mega, Andrea; Vitale, Giovanni; Valente, Giovanna; Vizzutti, Francesco; Villa, Erica; Marra, Fabio; Andreone, Pietro; Di Benedetto, Fabrizio; Falcini, Margherita; Catellani, Barbara; Guerrini, Gian Piero; Serra, Valentina; Di Sandro, Stefano; Ballarin, Roberto; Piai, Guido; Schepis, Filippo; Margotti, Marzia; Cursaro, Carmela; De Simone, Paolo; Petruccelli, Stefania; Carrai, Paola; Forte, Paolo; Campani, Claudia; Zoller, Heinz
abstract
Introduction and objectives: De novo malignancies represent an important cause of death for liver transplant recipients. Our aim was to analyze predictors of extra-hepatic non-skin cancer (ESNSC) and the impact of ESNSC on the long-term outcome. Patients: We examined data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics with a retrospective observational cohort study. Cox Regression was performed to identify predictors of ESNSC. A 1:2 cohort sub-study was developed to analyze the impact of ESNSC on 10-year survival. Results: We analyzed data from 367 subjects (median follow-up: 15 years). Patients with ESNSC (n=47) more often developed post-LT diabetes mellitus (DM) (57,4% versus 35,9%, p=0,004). At multivariate analysis, post-LT DM independently predicted ESNSC (HR 1.929, CI 1.029-3.616, p=0.040). Recipients with ESNSC showed a lower 10-year survival than matched controls (46,8% versus 68,1%, p=0,023). Conclusions: Post-LT DM seems to be a relevant risk factor for post-LT ESNSC. ESNSC could have a noteworthy impact on the long-term survival of LT recipients.
2022
- Quality of life in liver transplant recipients during the Corona virus disease 19 pandemic: A multicentre study
[Articolo su rivista]
Gitto, S.; Golfieri, L.; Mannelli, N.; Tame, M. R.; Lopez, I.; Ceccato, R.; Montanari, S.; Falcini, M.; Vitale, G.; De Maria, N.; Presti, D. L.; Marzi, L.; Mega, A.; Valente, G.; Borghi, A.; Foschi, F. G.; Grandi, S.; Forte, P.; Cescon, M.; Di Benedetto, F.; Andreone, P.; Arcangeli, G.; De Simone, P.; Bonacchi, A.; Sofi, F.; Morelli, M. C.; Petranelli, M.; Lau, C.; Marra, F.; Chiesi, F.; Vizzutti, F.; Vero, V.; Di Donato, R.; Berardi, S.; Pianta, P.; D'Anzi, S.; Schepis, F.; Gualandi, N.; Miceli, F.; Villa, E.; Piai, G.; Valente, M.; Campani, C.; Lynch, E.; Magistri, P.; Cursaro, C.; Chiarelli, A.; Carrai, P.; Petruccelli, S.; Dinu, M.; Pagliai, G.
abstract
Background: Liver transplant recipients require specific clinical and psychosocial attention given their frailty. Main aim of the study was to assess the quality of life after liver transplant during the current pandemic. Methods: This multicentre study was conducted in clinically stable, liver transplanted patients. Enrollment opened in June and finished in September 2021. Patients completed a survey including lifestyle data, quality of life (Short Form health survey), sport, employment, diet. To examine the correlations, we calculated Pearson coefficients while to compare subgroups, independent samples t-tests and ANOVAs. To detect the predictors of impaired quality of life, we used multivariable logistic regression analysis. Results: We analysed data from 511 patients observing significant associations between quality of life’s physical score and both age and adherence to Mediterranean diet (p <.01). A significant negative correlation was observed between mental score and the sedentary activity (p <.05). Female patients scored significantly lower than males in physical and mental score. At multivariate analysis, females were 1.65 times more likely to report impaired physical score than males. Occupation and physical activity presented significant positive relation with quality of life. Adherence to Mediterranean diet was another relevant predictor. Regarding mental score, female patients were 1.78 times more likely to show impaired mental score in comparison with males. Sedentary activity and adherence to Mediterranean diet were further noteworthy predictors. Conclusions: Females and subjects with sedentary lifestyle or work inactive seem to show the worst quality of life and both physical activity and Mediterranean diet might be helpful to improve it.
2022
- Upregulation of the oestrogen target gene SIX1 is associated with higher growth speed and decreased survival in HCV-positive women with hepatocellular carcinoma
[Articolo su rivista]
Critelli, Rosina Maria; Milosa, Fabiola; Romanzi, Adriana; Lasagni, Simone; Marcelli, Gemma; Di Marco, Lorenza; Pivetti, Alessandra; Schepis, Filippo; Romagnoli, Dante; Mancarella, Serena; Dituri, Francesco; Martinez-Chantar, Maria-Luz; Giannelli, Gianluigi; Villa, Erica
abstract
The male/female ratio of patients with hepatocellular carcinoma (HCC) is often unbalanced towards the male sex, indicating a sex predisposition for HCC development. A possible explanation may be attributed to different hormonal statuses, including the pro-inflammatory action of androgens in men and the protective effects of oestrogen against excessive inflammation in women. Although several studies have studied gene expression in patients with HCC, very few have attempted to identify features that could be distinctive between male and female patients. The present study aimed to identify distinctive signalling mechanisms between men and women that may be associated with HCC progression. The present study analysed a detailed microarray database that was obtained from the prospective study of 78 patients with HCC to study gene expression according to sex. In addition, the present study aimed to evaluate whether the differentially expressed genes were known oestrogen targets. Moreover, RNAs from the HCC cohort were evaluated for microRNA (miRNA/miR) expression, and a relationship between miRNA and gene expression according to sex was investigated. One gene, sineoculis homeobox homolog 1 (SIX1), which is known to be an oestrogen target gene, was revealed to be highly upregulated in hepatitis virus C (HCV)-positive female patients with HCC but not in HCV-positive male patients. In addition, SIX1 upregulation had a significant relationship with tumour growth speed (assessed as tumour doubling time in two CTs performed 6 weeks apart) and survival (P=0.009 and P=0.042, respectively) in female patients only. Furthermore, SIX1 upregulation was related with miR-421 and miR-9-5p only in male patients; however, in female patients, SIX1 upregulation had a direct relationship with miR-181b, miR-503-5p and miR-125b (miRNAs with potential oncogenic capacity), and an inverse correlation with miR139-5p, miR-26b, let7c-3p and let7c-5p (putatively oncosuppressive microRNAs). These data suggested a distinctive model for liver carcinogenesis in HCV-positive women, with downregulation of protective mechanisms against tumour progression and the activation of potential oncogenes, in relation to the oestrogen target gene SIX1. (IRB10/08_CE_UniRer; ClinicalTrials ID: NCT01657695).
2021
- Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis
[Articolo su rivista]
Ferrusquía-Acosta, José; Bassegoda, Octavi; Turco, Laura; Reverter, Enric; Pellone, Monica; Bianchini, Marcello; Campuzano, Valeria; Ripoll, Enric; García-Criado, Ángeles; Graupera, Isabel; García-Pagán, Juan Carlos; Schepis, Filippo; Senzolo, Marco; Hernández-Gea, Virginia
abstract
BACKGROUND & AIMS: Wedge hepatic vein pressure (WHVP) accurately estimates portal pressure (PP) in alcohol or viral hepatitis-related cirrhosis. Whether this also holds true in cirrhosis due to non-alcoholic steatohepatitis (NASH) is unknown. We aimed to evaluate the agreement between WHVP and PP in patients with NASH cirrhosis in comparison with patients with alcohol or hepatitis C virus (HCV)-related cirrhosis.METHODS: All consecutive patients with NASH cirrhosis treated with a transjugular intrahepatic porto-systemic shunt (TIPS) in 3 European centers were included (NASH group; n=40) and matched with two controls (one with alcohol-related and one with HCV-related cirrhosis) treated with TIPS contemporaneously (control group; n=80). Agreement was assessed by Pearson's correlation (R), intraclass correlation coefficient (ICC) and Bland-Altman method. Disagreement between WHVP and PP occurred when both pressures differed by > 10% of PP value. A binary logistic regression analysis was performed to identify factors associated with this disagreement.RESULTS: Correlation between WHVP and PP was excellent in the control group (R: 0.92, p<0.001; ICC 0.96, p<0.001) and moderate in the NASH group (R: 0.61, p<0.001; ICC: 0.74, p<0.001). Disagreement between WHVP and PP was more frequent in the NASH group (37.5% vs 14%, p=0.003) and was mainly caused by PP underestimation. In univariate and multivariate analyses, only NASH etiology was associated with disagreement between WHVP and PP [OR: 4.03 (95% CI 1.60-10.15); p=0.003].CONCLUSIONS: In patients with decompensated NASH cirrhosis, WHVP does not estimate PP as accurately as in patients with alcohol or HCV-related cirrhosis, mainly due to PP underestimation. Further studies aimed to assess this agreement in patients with compensated NASH cirrhosis are needed.
2021
- Controlled underdilation using novel VIATORR® controlled expansion stents improves survival after transjugular intrahepatic portosystemic shunt implantation
[Articolo su rivista]
Praktiknjo, M.; Abu-Omar, J.; Chang, J.; Thomas, D.; Jansen, C.; Kupczyk, P.; Schepis, F.; Garcia-Pagan, J. C.; Merli, M.; Meyer, C.; Strassburg, C. P.; Pieper, C. C.; Trebicka, J.
abstract
Background & Aims: Smaller 8-mm diameter transjugular intrahepatic portosystemic shunts (TIPS) appear to be more beneficial than larger 10-mm TIPS stent-grafts, but lack the ability for secondary dilation in cases of clinical ineffectiveness. Underdilated VIATORR® TIPS stent grafts (VTS) expand passively, whereas novel VIATORR Controlled Expansion (VCX) stent grafts do not. This study evaluated the impact on survival of underdilated VCX compared with VTS in patients with decompensated cirrhosis. Methods: This was a prospective case-control study including patients with cirrhosis receiving TIPS using 10-mm VCX underdilated to 8 mm. Patients with cirrhosis receiving 10-mm VTS underdilated to 8 mm were matched for age, sex, indication for TIPS, and liver function. Results: A total of 114 patients (47 VCX, 47 VTS, and 20 fully dilated VCX/VTS) were included. After TIPS implantation, underdilated VCX diameter was 8.0 (7.8–9.2) mm at a median time of 359 (87–450) days, compared with VTS at 9.9 (9.7–10.0) mm (p <0.001). The portosystemic pressure gradient immediately after TIPS procedure and after 7 days did not change significantly in VCX [mean 9.4 (± 0.8) vs. 10.4 (± 0.7) mmHg, p = 0.115). Hospital readmission rates for hepatic encephalopathy were 23% (n = 11) vs 51% (n = 24) for VCX and VTS (p <0.001), respectively. Patients with VCX had significantly lower rates of large-volume paracentesis (n = 5 [11%] vs. n = 10 [21%], p = 0.017) and heart failure (n = 1 [2%] vs. n = 7 [15%], p = 0.015). One-year mortality for underdilated VCX and VTS was 15% (n = 7) and 30% (n = 14) and, for fully dilated VCX/VTS, was 45% (n = 9) (log-rank p = 0.008), respectively. Conclusions: This study demonstrated that VCX stent grafts underdilated to 8 mm do not passively expand to nominal diameter and suggests reduced hospital readmissions because of hepatic encephalopathy, uncontrolled ascites, and heart failure, and improved 1-year survival compared with underdilated VTS. Lay summary: Transjugular intrahepatic portosystemic shunt (TIPS) improves survival in selected patients with liver cirrhosis and acute variceal bleeding or refractory ascites. Smaller 8-mm diameter TIPS stent grafts appear to improve patient outcome compared with larger 10-mm diameter stent grafts. Novel VIATORR® Controlled Expansion (VCX) stent grafts facilitate safe and stable underdilation to 8 mm of large 10-mm diameter stent grafts with improved patient outcome (survival, hepatic encephalopathy, ascites and heart failure) compared with legacy VIATORR TIPS stent graft (VTS). Thus, the use of underdilated VCX could preserve heart function. Clinical Trials Registration: The study is registered at Clinicaltrials.gov NCT03628807.
2021
- Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19
[Articolo su rivista]
Villa, E.; Critelli, R.; Lasagni, S.; Melegari, A.; Curatolo, A.; Celsa, C.; Romagnoli, D.; Melegari, G.; Pivetti, A.; Di Marco, L.; Casari, F.; Arioli, D.; Turrini, F.; Zuccaro, V.; Cassaniti, I.; Riefolo, M.; de Santis, E.; Bernabucci, V.; Bianchini, M.; Lei, B.; de Maria, N.; Carulli, L.; Schepis, F.; Gozzi, C.; Malaguti, S.; Del Buono, M.; Brugioni, L.; Torricelli, P.; Trenti, T.; Pinelli, G.; Bertellini, E.; Bruno, R.; Camma, C.; D'Errico, A.
abstract
This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n 5 187 patients; validation cohort, n 5 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P 5 .004) with AUROC 5 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P # .0001) with AUROC 5 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.
2021
- Effects of sildenafil on right ventricle remodelling in Portopulmonary hypertension
[Articolo su rivista]
Rossi, R.; Talarico, M.; Schepis, F.; Coppi, F.; Sgura, F. A.; Monopoli, D. E.; Minici, R.; Boriani, G.
abstract
Portopulmonary hypertension (PoPH) is a clinical condition associated with end‐stage liver disease, described by the coexistence of pulmonary arterial hypertension (PAH) and portal hypertension. In PoPH patients, there is a right ventricle (RV) remodeling to compensate for the increased resistance in the lung circulation. There are no studies on the effects of the PAH-targeted pharmacological treatment on the RV dimension and function. The present study summarizes our experience in patients with PoPH treated with sildenafil in a period of 6 years (from 2013 to 2019). We enrolled 64 consecutive patients identified as PoPH, all treated with sildenafil (57.6% in monotherapy; in the other cases in association with macitentan; in 19.0% with initial combination therapy). A hemodynamic invasive cardiopulmonary study was performed at baseline and after 6 months of sildenafil treatment. In our population we showed a significative improvement in RV performance, with a significant increase in RV stroke volume (+33%), RV ejection fraction (+31%) and RV stroke work index (+17.5%). We registered the reduction of the RV cavity dimension over time in all patients treated with sildenafil (RV end diastolic diameter decreased by 15% after 6 months of follow-up). Regarding diastolic function, we highlighted a very significant reduction in RV end-diastolic pressure (−50% concerning baseline). Sildenafil was effective both when used as monotherapy and in combination with macitentan. In conclusion, Sildenafil had a positive impact on RV systolic and diastolic function in patients with PoPH and was able to conditionate the reverse remodeling of the RV.
2021
- Endoscopic radiofrequency ablation for the treatment of severe gastric antral vascular ectasia in patients with cirrhosis
[Articolo su rivista]
Senzolo, M.; Realdon, S.; Zanetto, A.; Simoncin, B.; Schepis, F.; Caronna, S.; Saracco, G. M.; De Angelis, C. G.; Debernardi Venon, W.
abstract
INTRODUCTION: Gastric antral vascular ectasia is a significant cause of gastrointestinal bleeding in patients with cirrhosis. AIM: To assess safety/efficacy and cost/advantages of radiofrequency ablation for the treatment of gastric antral vascular ectasia in patients with cirrhosis. MATERIALS AND METHODS: Patients with cirrhosis and severe gastric antral vascular ectasia who underwent radiofrequency ablation were enrolled. Clinical data, gastric antral vascular ectasia grade, and gastric antral vascular ectasia-related hospitalizations were collected. Primary outcome was defined as the absence of transfusion over the 6 months after radiofrequency. An economic analysis was performed in the same period. RESULTS: Forty patients (50% Child B) were enrolled (80% refractory to argon plasma coagulation). Gastric antral vascular ectasia eradication was obtained in all patients and 65% of these patients achieved primary outcome. After radiofrequency, mean number of red blood cells transfusions dropped (from 25 to 0.9, P < 0.0001), with a parallel increase in hemoglobin (from 8 to 10.5 g/dL, P < 0.0001). No major complication occurred and liver function remained stable in all patients. The cost-analysis demonstrated a profound reduction of health care cost (from € 536.084 to € 189.044 in the 6 months before vs. after radiofrequency, respectively). These results were confirmed in the subgroup analysis in patients refractory to argon plasma coagulation. CONCLUSIONS: Radiofrequency ablation is safe and effective for the treatment of gastric antral vascular ectasia in patients with cirrhosis, including those refractory to argon plasma coagulation. Although the cost of single radiofrequency ablation is relatively high, the cost-analysis demonstrated considerable saving.
2021
- Guide-wire replacement of a mini-midline catheter with a central venous catheter: A retrospective study on 63 cases
[Articolo su rivista]
Brugioni, L.; Bertellini, E.; Ravazzini, M.; Barchetti, M.; Borsatti, A.; Martella, P.; Girardis, M.; Serra, F.; Tricoli, A.; Nicolini, M.; Bianchini, M.; Schepis, F.; Tazzioli, G.; Pinelli, G.; Romagnoli, E.; Gelmini, R.
abstract
Background: Achieving a reliable venous access in a particular subset of patients and/or in emergency settings can be challenging and time-consuming. Furthermore, many hospitalized patients do not meet the criteria for central venous catheter positioning, unless an upgrade of the treatment is further needed. The mini-midline catheter has already showed to be reliable and safe as a stand-alone device, since it is easily and rapidly inserted and can indwell up to 1 month. Methods: In this further case series, we retrospectively evaluated data from 63 patients where a previously inserted mini-midline catheter was upgraded to a central venous catheter (the devices inserted in the arm replaced by peripherally inserted central catheter and others inserted “off-label” in the internal jugular replaced by single lumen centrally inserted central catheter), being used as introducer for the Seldinger guidewire. Results: The guidewire replacement was been made even early (after 1 day) or late (more than 10 days), usually following a need for an upgrade in treatment. No early or late complications were reported. Conclusion: According to the preliminary data we collected, this converting procedure seems to be feasible and risk-free, since neither infectious nor thrombotic complications were reported.
2021
- Portal Hypertension and Ascites: Patient-and Population-centered Clinical Practice Guidelines by the Italian Association for the Study of the Liver (AISF)
[Articolo su rivista]
Bruno, R.; Camma, C.; Caraceni, P.; D'Amico, G.; Grattagliano, I.; La Mura, V.; Riggio, O.; Schepis, F.; Senzolo, M.; Angeli, P.; de Franchis, R.
abstract
Portal hypertension and ascites are two crucial events in the natural history of liver cirrhosis, whose appearance marks a downward shift in the prognosis of the disease. Over the years, several international and national societies have issued clinical practice guidelines for the diagnosis and management of portal hypertension and ascites. The present document addresses the needs of an updated guidance on the clinical management of these conditions. Accordingly, the AISF Governing Board appointed a multi-disciplinary committee of experts for drafting an update of the most recent EASL Clinical Practice Guidelines. The aim of this work was to adapt the EASL recommendations to national regulations and resources, local circumstances and settings, infrastructure, and cost/benefit strategies to avoid duplication of efforts and optimize resource utilization. The committee defined the objectives, the key issues and retrieved the relevant evidence by performing a systematic review of the literature. Finally, the committee members (chosen on the basis of their specific expertise) identified the guidelines’ key questions and developed them following the PICO format (Population, Intervention, Comparison, Outcomes). For each of the PICO questions, the systematic review of the literature was made on the most important scientific databases (Pubmed, Scopus, Embase)
2021
- Proximal Splenic Artery Embolization to Treat Refractory Ascites in a Patient With Cirrhosis
[Articolo su rivista]
Caporali, C.; Turco, L.; Prampolini, F.; Quaretti, P.; Bianchini, M.; Saltini, D.; Miceli, F.; Casari, F.; Felaco, D.; Garcia-Pagan, J. C.; Trebicka, J.; Senzolo, M.; Guerrini, G. P.; Di Benedetto, F.; Torricelli, P.; Villa, E.; Schepis, F.
abstract
2021
- Relevance of spontaneous portosystemic shunts detected with CT in patients with cirrhosis
[Articolo su rivista]
Nardelli, S.; Riggio, O.; Turco, L.; Gioia, S.; Puzzono, M.; Bianchini, M.; Ridola, L.; Aprile, F.; Gitto, S.; Pelle, G.; Di Martino, M.; Marzocchi, G.; Caporali, C.; Spagnoli, A.; Di Rocco, A.; Schepis, F.
abstract
Background: Cirrhosis leads to portal hypertension and to the consequent formation of spontaneous portosystemic shunts (SPSSs), leading to complications related to the diversion of portal blood into the systemic circulation, which is called portosystemic shunt syndrome. Purpose: To investigate the characteristics of patients with cirrhosis and an SPSS and secondarily to assess the prognostic impact of SPSSs on portal hypertension–related complications and transplant-free survival. Materials and Methods: A retrospective database review of patients with cirrhosis (observed from March 2015 to July 2019) was performed to identify patients with CT imaging and outcomes data. For each patient, clinical and biochemical data were collected, and the presence, types, and sizes of SPSSs were investigated with CT. Patients were followed for a mean of 27.5 months 6 22.8. Multivariable logistic analysis was used to identify the clinical characteristics associated with the presence of SPSSs (any size) and presence of SPSSs 1 cm or larger. Competitive risk analysis (Fine and Gray model) was used to identify the association between SPSSs and complications and mortality. Results: Two hundred twenty-two patients with cirrhosis (157 male, 65 female; mean age, 62 years 6 12 [standard deviation]) were evaluated. An SPSS was found in 141 of 222 patients (63.5%), and 40 of 222 (18%) had a shunt diameter of at least 1 cm. At presentation, variables independently associated with the presence of SPSSs (any size) were portal vein thrombosis (odds ratio, 5.5; P = .008) and Child-Pugh class C (odds ratio, 3.0; P = .03). Previous hepatic encephalopathy (odds ratio, 4.4; P = .001) and portal vein thrombosis (odds ratio, 5.3; P = .001) were the only variables associated with SPSSs larger than 1 cm. Patients with SPSSs of any size had higher mortality (subdistribution hazard ratio, 1.9; P , .001) and higher frequency of hepatic encephalopathy (subdistribution hazard ratio, 2.3; P = .023), gastrointestinal bleeding (subdistribution hazard ratio, 2.9; P = .039), and portal vein thrombosis (subdistribution hazard ratio, 7.6; P = .005). Conclusion: The presence of spontaneous portosystemic shunts on CT images in patients with cirrhosis was associated with higher mortality and complications, including portal vein thrombosis, hepatic encephalopathy, and gastrointestinal bleeding.
2021
- Reply to: “The clinical advantage of fixed 8-mm diameter VCX stents over underdilated VTS stents is not established in refractory ascites”
[Articolo su rivista]
Praktiknjo, M.; Witt, A.; Schepis, F.; Garcia-Pagan, J. C.; Merli, M.; Trebicka, J.
abstract
2020
- Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure
[Articolo su rivista]
Praktiknjo, M.; Monteiro, S.; Grandt, J.; Kimer, N.; Madsen, J. L.; Werge, M. P.; William, P.; Brol, M. J.; Turco, L.; Schierwagen, R.; Chang, J.; Klein, S.; Uschner, F. E.; Welsch, C.; Moreau, R.; Schepis, F.; Bendtsen, F.; Gluud, L. L.; Moller, S.; Trebicka, J.
abstract
Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P =.011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.
2020
- Erratum: Alcoholic and nonalcoholic liver disease: Diagnostic assessment and therapeutic perspectives (BioMed Research International (2019) 2019 (8691502) DOI: 10.1155/2019/8691502)
[Articolo su rivista]
Gitt, S.; Bihl, F.; Schepis, F.; Caputo, F.; Berenguer, M.
abstract
In the article titled “Alcoholic and Nonalcoholic Liver Disease: Diagnostic Assessment and Therapeutic Perspectives” [1], the affiliation “University of Valencia, Hospital La Fe, Valencia, Spain” was incorrectly assigned to the author Dr. Marina Berenguer. The correct affiliations for this author are shown below, and they have been added as affiliations 6, 7, and 8 in the author information above: CIBER-EHD, Instituto de Salud Carlos III, Madrid, Spain Hepatology and Liver Transplantation Unit, IIS La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain Faculty of Medicine, University of Valencia, Valencia, Spain.
2020
- Liver steatosis and non-alcoholic fatty liver disease with fibrosis are predictors of frailty in people living with HIV
[Articolo su rivista]
Milic, Jovana; Menozzi, Valentina; Schepis, Filippo; Malagoli, Andrea; Besutti, Giulia; Franconi, Iacopo; Raimondi, Alessandro; Carli, Federica; Mussini, Cristina; Sebastiani, Giada; Guaraldi, Giovanni
abstract
2020
- Pre-transplant diabetes predicts atherosclerotic vascular events and cardiovascular mortality in liver transplant recipients: a long-term follow-up study
[Articolo su rivista]
Gitto, S.; De Maria, N.; Marzi, L.; Magistri, P.; Falcini, M.; Vitale, G.; Olivieri, T.; Guerrini, G. P.; Serra, V.; Forte, P.; Carrai, P.; De Simone, P.; Mega, A.; Zoller, H.; Piai, G.; Schepis, F.; Marocchi, M.; Villa, E.; Marra, F.; Andreone, P.; Di Benedetto, F.; Vizzutti, F.; Laffi, G.; Borelli, E.; Ballarin, R.; Tarantino, G.; Di Sandro, S.; Puntili, R.; Petruccelli, S.; Valente, G.; Turco, L.
abstract
Background Early after surgery, liver transplant (LT) recipients often develop weight gain. Metabolic disorders and cardiovascular disease represent main drivers of morbidity and mortality. Our aim was to identify predictors of atherosclerotic vascular events (AVE) and to assess the impact of AVE on the long-term outcome. Methods We retrospectively analyzed data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics. Cox Regression analysis was performed to identify predictors of AVE, global mortality, and cardiovascular mortality. Survival analysis was performed using the Kaplan-Meier method. Results We analyzed data from 367 subjects during a median follow-up of 14 years. Thirty-seven post-LT AVE were registered. Patients with AVE more frequently showed pre-LT diabetes mellitus (DM) (48.6 vs 13.9%, p=0.000). In the post-LT period, patients with AVE satisfied criteria of metabolic syndrome in 83.8% vs. 36.7% of subjects without AVE (p=0.000). At multivariate analysis, pre-LT DM independently predicted AVE (HR 2.250, CI 4.848-10.440, p=0.038). Moreover, both pre-LT DM and AVE strongly predicted cardiovascular mortality (HR 5.418, CI 1.060-29.183, p=0.049, and HR 86.097, CI 9.510-779.480, p=0.000, respectively). Conclusions Pre-LT DM is the main risk factor for post-LT AVE. Pre-LT DM and post-LT AVE are strong, long-term predictors of cardiovascular mortality. Patients with pre-LT DM should obtain a personalized follow-up for prevention or early diagnosis of AVE.
2020
- Prediction of Esophageal Varices by Liver Stiffness and Platelets in Persons with HIV infection and Compensated Advanced Chronic Liver Disease
[Articolo su rivista]
Merchante, Nicolas; Saroli Palumbo, Chiara; Mazzola, Giovanni; Pineda, Juan A; Téllez, Francisco; Rivero-Juárez, Antonio; Ríos-Villegas, Maria José; Maurice, James B; Westbrook, Rachel H; Judge, Rebekah; Guaraldi, Giovanni; Schepis, Filippo; Perazzo, Hugo; Rockstroh, Juergen; Boesecke, Christoph; Klein, Marina B; Cervo, Adriana; Ghali, Peter; Wong, Philip; Petta, Salvatore; De Ledinghen, Victor; Macías, Juan; Sebastiani, Giada
abstract
Human immunodeficiency virus (HIV)-infected individuals are at increased risk of cirrhosis and esophageal varices. Baveno VI criteria, based on liver stiffness measurement (LSM) and platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for esophageal varices needing treatment (EVNT). This approach has not been validated in HIV-infected patients.
2020
- Prevalence, Predictors, and Severity of Lean Nonalcoholic Fatty Liver Disease in Patients Living With Human Immunodeficiency Virus
[Articolo su rivista]
Cervo, Adriana; Milic, Jovana; Mazzola, Giovanni; Schepis, Filippo; Petta, Salvatore; Krahn, Thomas; Lebouche, Bertrand; Deschenes, Marc; Cascio, Antonio; Guaraldi, Giovanni; Sebastiani, Giada
abstract
The burden of non-alcoholic fatty liver disease (NAFLD) is growing in people with HIV. NAFLD is associated with obesity, however it can occur in normoweight (lean) patients. We aimed to investigate lean NAFLD in HIV-infected patients.
2020
- The use of intrahepatic portosystemic shunt in HIV positive patients: A retrospective multicentric study
[Articolo su rivista]
Lombardi, A.; Rossotti, R.; Rockstroh, J. K.; Airoldi, A.; Schepis, F.; Bruno, R.
abstract
2020
- Transjugular intrahepatic portosystemic shunt (TIPS): current indications and strategies to improve the outcomes
[Articolo su rivista]
Vizzutti, F.; Schepis, F.; Arena, U.; Fanelli, F.; Gitto, S.; Aspite, S.; Turco, L.; Dragoni, G.; Laffi, G.; Marra, F.
abstract
Transjugular intrahepatic portosystemic shunt (TIPS) represents a very effective treatment of complications of portal hypertension. Established indications to TIPS in cirrhotic patients include portal hypertensive bleeding and refractory ascites. Over the years additional indications have been proposed, such as the treatment of vascular disease of the liver, hepatic hydrothorax, hepatorenal syndrome and bleeding from ectopic varices. Indications under evaluation include treatment of portal hypertension prior to major abdominal surgery and treatment of portal vein thrombosis. In spite of these advances, there are still uncertainties regarding the appropriate workup for patients to be scheduled for TIPS. Moreover, prevention and management of post-TIPS complications including hepatic encephalopathy and heart failure are still suboptimal. These issues are particularly relevant considering aging in TIPS candidates in Western countries. Correct selection of patients is mandatory to prevent complications which may eventually frustrate the good hemodynamic results and worsen the patient’s quality of life or even life expectancy. The possible role of small diameter TIPS to prevent post-procedural complications is discussed.
2019
- A new device for ultrasound-guided peripheral venous access
[Articolo su rivista]
Brugioni, Lucio; Marco, Barchetti; Tazzioli, Giovanni; Gelmini, Roberta; Girardis, Massimo; Bianchini, Marcello; Schepis, Filippo; Nicolini, Matteo; Giovanni, Pinelli; Pietro, Martella; Marco, Barozzi; Mori, Francesca; Scarabottini, Serena; Righetti, Andrea; Mirco Ravazzini and Elisabetta Bertellini,
abstract
Background: In patients with difficult peripheral venous access, alternative techniques require expertise and are invasive, expensive, and prone to serious adverse events. This brought us to designing a new venous catheter (JLB® Deltamed, Inc.) for the cannulation of medium and large bore veins; it is echogenic, and available in different lengths (60 / 70 / 80 mm) and Gauges (14 / 16 / 17 / 18). Methods: We led a multi-center observational convenience sampling study to evaluate safety and effectiveness of JLB. Data was collected from June 2015 to February 2018. Inclusion criteria were age ⩾ 18, difficulty in obtaining superficial venous access in the veins of the arm, need for rapid infusion, or patient’s preference. Results: We enrolled 1000 patients, mean age 66.8 years. In total, 951 (95.1%) had the device placed in internal jugular vein, 28 in basilic or cephalic vein, 15 in femoral vein, 5 in axillary vein (infra-clavicular tract), and 1 in the external jugular vein. The procedure was performed by attending physicians or emergency medicine residents under US guidance. Mean procedure time (from disinfection to securing) was approximately 240 s. Mean attempts number was 1.21. Early complications (<24 h) occurred in four patients, consisting in two soft tissue hematoma, one phlebitis, and one atrial tachyarrhythmia. No major complications (such as pneumothorax) were reported. Mean indwelling time was 168 h (7 days); early occlusion/dislocation occurred in four cases. Conclusion: According to preliminary data, the application of JLB appears to be safe, cost-effective, and rapid to place bedside.
2019
- Alcoholic and Nonalcoholic Liver Disease: Diagnostic Assessment and Therapeutic Perspectives
[Articolo su rivista]
Gitto, S.; Bihl, F.; Schepis, F.; Caputo, F.; Berenguer, M.
abstract
2019
- Angiopoietin-2/Tie2 Inhibition by Regorafenib Associates With Striking Response in a Patient With Aggressive Hepatocellular Carcinoma
[Articolo su rivista]
Todesca, P.; Marzi, L.; Critelli, R. M.; Cuffari, B.; Caporali, C.; Turco, L.; Pinelli, G.; Schepis, F.; Carulli, L.; de Maria, N.; Casari, F.; Scaglioni, R.; Villa, E.
abstract
2019
- Reply to: “It takes two “eyes” to see in depth”
[Articolo su rivista]
Turco, L.; Garcia-Tsao, G.; Rossi, R.; Villa, E.; Schepis, F.
abstract
2019
- Retraction: The OMICs Window into Nonalcoholic Fatty Liver Disease (NAFLD) (Metabolites 2019, 9(2), 25)
[Articolo su rivista]
Carulli, L.; Zanca, G.; Schepis, F.; Villa, E.
abstract
As the authors of the title paper [1], it is with great regret that we inform the readership of Metabolites that we have asked the journal’s publisher, MDPI, to retract the paper from the scientific literature. Due to human error, we included contents similar to article [2], which has already been published by Pirola et al. We apologize to the readership of Metabolites and to the authors of [2] for any inconvenience caused. MDPI is a member of the Committee on Publication Ethics (COPE) and takes the responsibility to enforce strict ethical policies and standards very seriously. To ensure the integrity of the publication record, [1] is retracted and shall be marked accordingly.
2019
- The OMICs window into nonalcoholic fatty liver disease (NAFLD)
[Articolo su rivista]
Carulli, L.; Zanca, G.; Schepis, F.; Villa, E.
abstract
Nonalcoholic fatty liver disease (NAFLD) is a common cause of hepatic abnormalities worldwide. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD and leads to progressive liver disease, such as cirrhosis and hepatocellular carcinoma. In NASH patient, fibrosis represents the major predictor of liver-related mortality; therefore, it is important to have an early and accurate diagnosis of NASH. The current gold standard for the diagnosis of NASH is still liver biopsy. The development of biomarkers able to predict disease severity, prognosis, as well as response to therapy without the need for a biopsy is the focus of most up-to-date genomic, transcriptomic, proteomic, and metabolomic research. In the future, patients might be diagnosed and treated according to their molecular signatures. In this short review, we discuss how information from genomics, proteomics, and metabolomics contribute to the understanding of NAFLD pathogenesis.
2019
- Transient elastography and ultrasonography: Optimal evaluation of liver fibrosis and cirrhosis in patients with chronic hepatitis B concurrent with nonalcoholic fatty liver disease
[Articolo su rivista]
Zhang, G. -L.; Zhao, Q. -Y.; Lin, C. -S.; Hu, Z. -X.; Zhang, T.; Gao, Z. -L.; Schepis, F.
abstract
Background and Aims. Concordance between transient elastography (TE) and ultrasonography (US) in assessing liver fibrosis in patients with chronic hepatitis B (CHB) and concurrent nonalcoholic fatty liver disease (NAFLD) has been rarely studied. This study aimed to evaluate the individual and combined performances of TE and US in assessing liver fibrosis and cirrhosis. Patients and Methods. Consecutive CHB patients with NAFLD were prospectively enrolled. TE and US examinations were performed, with liver biopsy as a reference standard. Receiver operating characteristic (ROC) curves were obtained to evaluate the diagnostic performance. Differences between the areas under the ROC curves (AUCs) were compared using DeLong's test. Results. TE and US scores correlated significantly with the histological fibrosis staging scores. TE was significantly superior to US in the diagnosis of significant fibrosis (AUC, 0.84 vs 0.73; P=0.02), advanced fibrosis (AUC, 0.95 vs 0.76; P<0.001), and cirrhosis (AUC, 0.96 vs 0.71; P<0.001). Combining TE with US did not increase the accuracy of detecting significant fibrosis, advanced cirrhosis, or cirrhosis (P=0.62, P=0.69, and P=0.38, respectively) compared to TE alone. However, TE combined with US significantly increased the positive predictive value for significant fibrosis when compared to TE alone. The optimal cut-off values of TE for predicting advanced fibrosis and cirrhosis were 8.7 kPa and 10.9 kPa, with negative predictive values of 92.4% and 98.7%, respectively. Conclusions. TE is useful for predicting hepatic fibrosis and excluding cirrhosis in CHB patients with NAFLD. A combination of TE and US does not improve the accuracy in assessing liver fibrosis or cirrhosis.
2019
- Transjugular intrahepatic portosystemic shunt does not affect the efficacy and safety of direct-acting antivirals in patients with advanced cirrhosis: a real-life, case-control study
[Articolo su rivista]
Gitto, Stefano; Vizzutti, Francesco; Schepis, Filippo; Turco, Laura; Aspite, Silvia; Vitale, Giovanni; Arena, Umberto; Villa, Erica; Laffi, Giacomo; Debernardi-Venon, Wilma; Fanelli, Fabrizio; Andreone, Pietro; Marra, Fabio
abstract
Background: Transjugular Intrahepatic Portosystemic Shunt (TIPS) is a well-established treatment
for complications of portal hypertension. Aims: To analyze the impact of TIPS on virologic
response and safety profile in patients treated with direct-acting antivirals (DAA). Methods: We
analyzed data from HCV-positive cirrhotic patients treated with DAAs. Twenty-one patients with previous TIPS placement were compared with 42 matched subjects without TIPS. Logistic
regression was used to identify predictors of hepatic function worsening and adverse events.
Results: No differences were found between the two groups in particular regarding sustained
virologic response (92.5 and 97.6% in TIPS vs no-TIPS, p=0.559). Model for End-stage Liver
Disease (MELD) of both TIPS and no-TIPS groups declined from baseline to week 24 of follow-up
(from 12.5±3.5 to 10.8±3.4 and from 11.1±3.5 to 10.3±3.4, p=0.044 and 0.025). There were no
differences in adverse event rates. At univariate analysis, age was associated with MELD increase
from baseline to week 24 (OR 1.111, 95% CI 1.019-1.211, p=0.017), and patients with higher
baseline MELD developed serious adverse events more frequently (OR 0.815, 95% CI 0.658-1.010,
p=0.062). Patients with or without TIPS did not show differences in transplant-free survival.
Conclusion: TIPS placement does not affect virologic response and clinical outcome of patients
receiving DAAs.
2018
- Cardiopulmonary hemodynamics and c-reactive protein as prognostic indicators in compensated and decompensated cirrhosis
[Articolo su rivista]
Turco, Laura; Garcia-Tsao, Guadalupe; Magnani, Ilenia; Bianchini, Marcello; Costetti, Martina; Caporali, Cristian; Colopi, Stefano; Simonini, Emilio; De Maria, Nicola; Banchelli, Federico; Rossi, Rosario; Villa, Erica; Schepis, Filippo
abstract
The main stages of cirrhosis (compensated and decompensated) have been substaged based on clinical, endoscopic, and portal pressure (determined by the hepatic venous pressure gradient, HVPG) features. Vasodilatation leading to a hyperdynamic circulatory state is central in the development of a late decompensated stage with inflammation being currently considered a key driver. We aimed to assess hepatic/systemic hemodynamics and inflammation (by C reactive protein, CRP) among the different substages of cirrhosis and to investigate their interrelationship and prognostic relevance.
2018
- Correction: The Role of Anticoagulation in Treating Portal Hypertension
[Articolo su rivista]
Turco, Laura; Schepis, Filippo; Villa, Erica
abstract
: [This corrects the article DOI: 10.1007/s11901-018-0406-x.].
2018
- De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients
[Articolo su rivista]
Gitto, Stefano; de Maria, Nicola; di Benedetto, Fabrizio; Tarantino, Giuseppe; Serra, Valentina; Maroni, Lorenzo; Cescon, Matteo; Pinna, Antonio D; Schepis, Filippo; Andreone, Pietro; Villa, Erica
abstract
Patients who have undergone transplantation often develop metabolic syndrome (MetS) and de-novo nonalcoholic fatty liver disease (NAFLD). Our aim was to evaluate the impact of metabolic disease on cardiovascular and neoplastic risk and survival.
2018
- Liver Angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after HCV direct-acting antivirals
[Articolo su rivista]
Faillaci, Francesca; Marzi, Luca; Critelli, Rosina; Milosa, Fabiola; Schepis, Filippo; Turola, Elena; Andreani, Silvia; Vandelli, Gabriele; Bernabucci, Veronica; Lei, Barbara; D'Ambrosio, Federica; Bristot, Laura; Cavalletto, Luisa; Chemello, Liliana; Sighinolfi, Pamela; Manni, Paola; Maiorana, Antonino; Caporali, Cristian; Bianchini, Marcello; Marsico, Maria; Turco, Laura; de Maria, Nicola; Del Buono, Mariagrazia; Todesca, Paola; di Lena, Luca; Romagnoli, Dante; Magistri, Paolo; di Benedetto, Fabrizio; Bruno, Savino; Taliani, Gloria; Giannelli, Gianluigi; Martinez-Chantar, Maria-Luz; Villa, Erica
abstract
Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC).In Study 1,we studied the proangiogenic liver microenvironment in 242 DAAs-treated chronic Hepatitis C patients with advanced fibrosis.Angiopoietin-2 expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent,de novo,non-recurrent HCC or patients never developing HCC.Circulating Angiopoietin-2,vascular-endothelial growth factor (VEGF),and C-reactive protein were also measured. In Study 2,we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical,clinical,hemodynamic,endoscopic, elastographic,and echo-Doppler work-up was performed in both studies.In Study 1,none without cirrhosis developed HCC.Of 183 patients with cirrhosis,14/28 (50.0%) with previous HCC recurred while 21/155 (13.5%) developed de novo HCC.Recurrent and de novo HCCs had significantly higher liver fibrosis scores,portal pressure,and systemic inflammation than non-recurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients,tumor and non-tumor Angiopoietin-2 showed an inverse relationship with portal vein velocity (r=-0.412,p=0.037 and r= -0.409,p=0.047,respectively) and a positive relationship with liver stiffness (r=0.526,p=0.007;r=0.525,p=0.003,respectively).Baseline circulating VEGF and cirrhotic liver Angiopoietin-2 were significantly related (r=0.414,p=0.044).VEGF increased during DAAs, remaining stably elevated at 3 months follow-up, when it significantly related with serum Angiopoietin-2 (r=0.531,p=0.005).Angiopoietin-2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with the risk of HCC recurrence (OR 1.137,95%CI 1.044-1.137,p=0.003) or occurrence (OR 1.604,95% CI 1.080-2.382;p=0.019).In Study 2,DAA treatment (OR 4.770,95%CI 1.395-16.316,p=0.013) and large varices (OR 3.857,95%CI 1.127-13.203,p=0.032) were independent predictors of de novo HCC.
2018
- Low molecular weight heparin does not increase bleeding and mortality post endoscopic variceal band ligation in cirrhotic patients
[Articolo su rivista]
Bianchini, Marcello; Cavani, Giulia; Bonaccorso, Ambra; Turco, Laura; Vizzutti, Francesco; Sartini, Alessandro; Gitto, Stefano; Merighi, Alberto; Banchelli, Federico; Villa, Erica; Schepis, Filippo
abstract
Anticoagulants are commonly indicated in cirrhotic patients due to high rate of (pro)thrombotic conditions. Low molecular weight heparin (LMWH) is safe in patients with esophageal varices. However, the safety of LMWH is unknown in patients undergoing prophylactic endoscopic variceal ligation (EVL).
2018
- Non-alcoholic fatty liver disease phenotypes in patients with inflammatory bowel disease
[Articolo su rivista]
Sartini, Alessandro; Gitto, Stefano; Bianchini, Marcello; Chiara Verga, Maria; Di Girolamo, Maria; Bertani, Angela; Del Buono, Mariagrazia; Schepis, Filippo; Lei, Barbara; De Maria, Nicola; Villa, Erica
abstract
Non-alcoholic fatty liver disease (NAFLD) can be detected in up to 33.6% of inflammatory bowel disease (IBD) patients, often in absence of metabolic risk factors. Nevertheless, most of previous studies on such issue were conducted within the IBD population only. The primary aim of this study was to compare clinical and metabolic features of NAFLD in patients with and without IBD (w/o IBD) and to identify specific NAFLD phenotypes within the IBD population. Among 223 NAFLD patients, 78 patients with IBD were younger compared to 145 without (w/o) IBD, were less likely to have altered liver enzymes, had lower mean body weight, smaller waist circumference and lower body mass index (BMI); at the same time, MetS was more prevalent among patients w/o IBD (56.6 vs. 23.1%, p < 0.001). Within IBD population, patients with severe IBD showed more often severe steatosis (S3) at ultrasound (US) (32.1 vs. 16.6%, p = 0.01), compared to mild-to-moderate disease. Independent risk factors for S3 US steatosis in IBD patients at the multivariate logistic regression analysis were: more than 1 IBD relapse per year during disease history (OR 17.3, 95% CI 3.6-84), surgery for IBD (OR 15.1, 95% CI 3.1-73.7) and more extensive intestinal involvement (OR 19.4, 95% CI 3.4-110.9); the ongoing anti-Tumor Necrosis Factor alpha (antiTNFα) therapy was the only independent factor which protect toward the presence of altered liver enzymes (OR 0.15, 95% CI 0-0.8, p = 0.02). In conclusion, NAFLD in IBD patients is different from that in patients w/o IBD, who seem to develop different NAFLD phenotypes according to intestinal disease clinical course. More severe IBD seem to predict the presence of more severe steatosis. Therapy with antiTNFα antibodies could prevent alteration of liver enzymes in such population.
2018
- Obese zebrafish: A small fish for a major human health condition
[Articolo su rivista]
Faillaci, Francesca; Milosa, Fabiola; Critelli, Rosina Maria; Turola, Elena; Schepis, Filippo; Villa, Erica
abstract
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 long‐term 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 non‐alcoholic 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.
2018
- Prevention and Management of Bleeding Risk Related to Invasive Procedures in Cirrhosis
[Articolo su rivista]
Schepis, Filippo; Turco, Laura; Bianchini, Marcello; Villa, Erica
abstract
Cirrhosis represents the end stage of chronic liver disease and its transition from a compensated to a decompensated status is mainly driven by portal hypertension and systemic inflammation. Although relevant modifications in the evaluation of the coagulative balance in cirrhosis across its natural history have occurred and alterations in routine indices of hemostasis have lost their role as indicators of the hemorrhagic risk of patients with liver cirrhosis, these are still perceived as prone to bleed when admitted to invasive procedures. This view, which is still present in guidelines addressing the management of bleeding risk, makes preprocedural transfusion of plasma and platelets still an ongoing clinical practice. In this review, we describe the limitations of both bleeding risk assessment in cirrhotic patients admitted to radiologic and endoscopic invasive procedures and evaluate whether preventive strategies indicated by current guidelines can affect the procedure-related hemorrhagic events.
2018
- Reply to: “Relationship of hyperdynamic circulation and cardiodynamic states in cirrhosis”
[Articolo su rivista]
Turco, Laura; Garcia-Tsao, Guadalupe; Rossi, Rosario; Villa, Erica; Schepis, Filippo
abstract
N/A
2018
- Study of the Serum Metabolomic Profile in Nonalcoholic Fatty Liver Disease: Research and Clinical Perspectives
[Articolo su rivista]
Gitto, Stefano; Schepis, Filippo; Andreone, Pietro; Villa, Erica
abstract
In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects.
2018
- The Role of Anticoagulation in Treating Portal Hypertension
[Articolo su rivista]
Turco, Laura; Schepis, Filippo; Villa, Erica
abstract
Purpose of review: To revise experimental and clinical data supporting a less traditional role of anticoagulation for treating portal hypertension in patients with cirrhosis. Recent findings: Portal hypertension is the main driver of complications such as ascites, variceal hemorrhage, and hepatic encephalopathy, with inflammation as a key component. The traditional view of cirrhosis as a pro-hemorrhagic condition has recently changed, prothrombotic complications being recognized as frequently as the hemorrhagic ones. Several data indicate a close relationship between inflammation, prothrombotic status, worsening of hepatic fibrosis, and portal hypertension both in animal models and in patients with chronic liver disease. These findings indicate that anticoagulation may represent a potent tool to act on fibrogenesis and therefore consequently to treat portal hypertension. All anticoagulants have good to optimal safety profiles and can be used in patients with advanced chronic liver disease with confidence. Summary: Anticoagulation has a role as a pleiotropic treatment of portal hypertension in cirrhosis.
2018
- Under-dilated TIPS Associate With Efficacy and Reduced Encephalopathy in a Prospective, Non-randomized Study of Patients With Cirrhosis
[Articolo su rivista]
Schepis, Filippo; Vizzutti, Francesco; Garcia-Tsao, Guadalupe; Marzocchi, Guido; Rega, Luigi; De Maria, Nicola; Di Maira, Tommaso; Gitto, Stefano; Caporali, Cristian; Colopi, Stefano; De Santis, Mario; Arena, Umberto; Rampoldi, Antonio; Airoldi, Aldo; Cannavale, Alessandro; Fanelli, Fabrizio; Mosconi, Cristina; Renzulli, Matteo; Agazzi, Roberto; Nani, Roberto; Quaretti, Pietro; Fiorina, Ilaria; Moramarco, Lorenzo; Miraglia, Roberto; Luca, Angelo; Bruno, Raffaele; Fagiuoli, Stefano; Golfieri, Rita; Torricelli, Pietro; Di Benedetto, Fabrizio; Saverio Belli, Luca; Banchelli, Federico; Laffi, Giacomo; Marra, Fabio; Villa, Erica
abstract
Portosystemic encephalopathy (PSE) is a major complication of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement. Most devices are self-expandable polytetrafluoroethylene-covered stent grafts (PTFE-SGs) that are dilated to their nominal diameter (8 or 10 mm). We investigated whether PTFE-SGs dilated to a smaller caliber (under-dilated TIPS) reduce PSE yet maintain clinical and hemodynamic efficacy. We also studied whether under-dilated TIPS self-expand to nominal diameter over time.
METHODS:
We performed a prospective, non-randomized study of 42 unselected patients with cirrhosis who received under-dilated TIPS (7 and 6 mm) and 53 patients who received PTFE-SGs of 8 mm or more (controls) at referral centers in Italy. After completion of this study, dilation to 6 mm became the standard and 47 patients were included in a validation study. All patients were followed for 6 months; Doppler ultrasonography was performed 2 weeks and 3 months after TIPS placement and every 6 months thereafter. Stability of PTFE-SG diameter was evaluated by computed tomography analysis of 226 patients with cirrhosis whose stent grafts increased to 6, 7, 8, 9, or 10 mm. The primary outcomes were incidence of at least 1 episode of PSE grade 2 or higher during follow up, incidence of recurrent variceal hemorrhage or ascites (based on need for at least 1 large-volume paracentesis by 4 weeks after TIPS placement), incidence of shunt dysfunction requiring TIPS recanalization, and reduction in porto-caval pressure gradient.
RESULTS:
PSE developed in a significantly lower proportion of patients with under-dilated TIPS (46%) than controls (73%) during the first year after the procedure (P=.015), but the proportions of patients with recurrent variceal hemorrhage or ascites did not differ significantly between groups. No TIPS occlusions were observed. These results were confirmed in the validation cohort. In an analysis of self-expansion of stent grafts, during a mean follow-up period of 252 days after placement, none of the PTFE-SGs self-expanded to the nominal diameter in hemodynamically relevant sites (such as portal and hepatic vein vascular walls).
CONCLUSION:
In prospective, non-randomized study of patients with cirrhosis, we found under-dilation of PTFE-SGs during TIPS placement to be feasible, associated with lower rates of PSE, and effective
2017
- Consensus conference on TIPS management: Techniques, indications, contraindications
[Articolo su rivista]
Fagiuoli, Stefano; Bruno, Raffaele; Debernardi Venon, Wilma; Schepis, Filippo; Vizzutti, Francesco; Toniutto, Pierluigi; Senzolo, Marco; Caraceni, Paolo; Salerno, Francesco; Angeli, Paolo; Cioni, Roberto; Vitale, Alessandro; Grosso, Maurizio; De Gasperi, Andrea; D'Amico, Gennaro; Marzano, Alfredo
abstract
The trans jugular intrahepatic Porto systemic shunt (TIPS) is no longer viewed as a salvage therapy or a bridge to liver transplantation and is currently indicated for a number of conditions related to portal hypertension with positive results in survival. Moreover, the availability of self-expandable polytetrafluoroethylene (PTFE)-covered endoprostheses has dramatically improved the long-term patency of TIPS. However, since the last updated International guidelines have been published (year 2009) new evidence have come, which have open the field to new indications and solved areas of uncertainty. On this basis, the Italian Association of the Study of the Liver (AISF), the Italian College of Interventional RadiologyâItalian Society of Medical Radiology (ICIR-SIRM), and the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI) promoted a Consensus Conference on TIPS. Under the auspices of the three scientific societies, the consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Bergamo on June 4th and 5th, 2015. The final statements presented here were graded according to quality of evidence and strength of recommendations and were approved by an independent jury. By highlighting strengths and weaknesses of current indications to TIPS, the recommendations of AISF-ICIR-SIRM-SIAARTI may represent the starting point for further studies.
2017
- JLB: a flexible and effective device in critical patients. Review of clinical cases
[Articolo su rivista]
Brugioni, L.; Tazzioli, G.; Elisabetta, Bertellini; Girardis, M.; Nicolini, M.; Barchetti, M.; Pinelli, G.; Barozzi, M.; Schepis, F.; Bianchini, M.; Martella, P.; Borsatti, A.; de NIederhausern, F.; Mori, F.; Scarabottini, S.; Ravazzini, M.; Piani, Federica; Righetti, A.; Buda, Marina; Carella, Elena; Campanale, Sergio
abstract
JLB catheter (Deltamed Inc) is an alternative way to manage difficult venous access; it is placed under US-guidance in large bore veins, with an easy-sterile approach. Internal jugular vein (IJV) is the first choice for cannulation, followed by subclavian or deep upper-arm veins. The catheter is available in different lengths and gauges, it allows high flow rates and can be left in place up to 30 days.
From June 2015 to March 2017, JLB has been positioned in 409 patients: in 354 as primary access in IJV, brachial or subclavian vein; in 55 cases JLB became an introducing line for the Seldinger guidewire and further CVC positioning. All clinical cases were reviewed selecting those with greater clinical relevance.
We report 8 cases in which JLB resulted determinant for the patient treatment:
a 16 years old obese girl born with perinatal distress,
a 78 years old obese woman with hemorrhagic shock caused by gastrointestinal bleeding,
a 40 years old man with severe hypokalemia,
a 30 years old man with severe sepsis,
a 40 years old man with Becker’s muscular dystrophy and severe sepsis,
a 40 years old man with multiple myeloma who had to carry out cycles of chemotherapy,
a 76 years old man with CMV pancolitis and myelofibrosis who needed parenteral nutrition, antiviral therapy and frequent blood and platelets transfusion.
Moreover, it has been useful in elderly patients who needed to carry out palliative care for seniority or cancer lasting up to 30 days .
In our experience the JLB catheter is safe, easy to place, quick and cost –effective. It is a valid solution either in unstable patients requiring an immediate access in emergency and stable patients with difficult venous access, in which invasive devices can be considered an over-treatment.
2017
- Microenvironment inflammatory infiltrate drives growth speed and outcome of hepatocellular carcinoma: a prospective clinical study
[Articolo su rivista]
Critelli, Rosina; Milosa, Fabiola; Faillaci, Francesca; Condello, Rosario; Turola, Elena; Marzi, Luca; Lei, Barbara; Dituri, Francesco; Andreani, Silvia; Sighinolfi, Pamela; Manni, Paola; Maiorana, Antonino; Caporali, Cristian; di Benedetto, Fabrizio; Del Buono, Mariagrazia; De Maria, Nicola; Schepis, Filippo; Martinez-Chantar, Maria-Luz; Giannelli, Gianluigi; Villa, Erica
abstract
In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune-mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-β1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial-mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast-growing HCCs are associated with TGF-β signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFβ1 signaling in a general background of long-standing and permanent inflammatory state.
2017
- Validating, deconstructing and refining Baveno criteria for ruling out high-risk varices in patients with compensated cirrhosis
[Articolo su rivista]
Jangouk, Parastoo; Turco, Laura; De Oliveira, Ana; Schepis, Filippo; Villa, Erica; Garcia-Tsao, Guadalupe
abstract
Background: Guidelines recommend variceal screening in patients with cirrhosis to identify varices at high risk of bleeding requiring primary prophylaxis. Non-invasive criteria to rule out high-risk varices will avoid unnecessary endoscopies. Recent Baveno VI criteria define patients with compensated cirrhosis in whom endoscopy can be avoided as those with a liver stiffness by transient elastography <20 kPa and a platelet count >150Â 000/mm3. Aims: To validate Baveno criteria in two cohorts with a different prevalence of high-risk varices and to determine whether alternate parameters not including liver stiffness would be equal/more accurate in ruling out high-risk varices. Methods: Retrospective study evaluating patients with liver stiffness >10 kPa who had liver stiffness and endoscopy within 1Â year of each other. Results: This study included 161 patients from the US cohort (14 [9%] with high-risk varices) and 101 patients from an Italian cohort (17 [17%] with high-risk varices). Of patients meeting Baveno criteria (41 in the US, 16 in Italy), none had high-risk varices and therefore 26% (US) and 16% (Italy) endoscopies could have been avoided. Sensitivity and negative predictive value were 100%. A stepwise strategy using platelet count >150Â 000 and MELD=6, increased the number of endoscopies avoided to 54% (US) while maintaining a sensitivity and negative predictive value of 100%. Excellent sensitivity and negative predictive value were validated in the Italian cohort and in another cohort of patients with a clinical diagnosis of cirrhosis. Conclusions: This study validates Baveno VI criteria, particularly in sites with a low prevalence of high-risk varices and describes a new accurate strategy that does not include liver stiffness.
2016
- Akt1/Akt2 inhibition and development of hepatocellular carcinoma
[Articolo su rivista]
Critelli, R. M.; Schepis, F.; Villa, E.
abstract
2016
- Complete resolution of non-necrotizing lung granuloma and pyoderma gangrenosum after restorative proctocolectomy in a woman with severe ulcerative colitis and cytomegalovirus infection
[Articolo su rivista]
Sartini, Alessandro; Bianchini, Marcello; Schepis, Filippo; Marzi, Luca; De Maria, Nicola; Villa, Erica
abstract
Here, we report the unusual case of an ulcerative colitis female patient presenting together with cytomegalovirus infection, pyoderma gangrenosum and a noncaseating lung granuloma, both resistant to immunomodulatory drugs which dramatically obtained a clinical stable remission after restorative proctocolectomy.
2016
- Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference
[Articolo su rivista]
Andriulli, Angelo; Tripodi, Armando; Angeli, Paolo; Senzolo, Marco; Primignani, Massimo; Giannini, Edoardo G.; Riggio, Oliviero; Colli, Agostino; Prati, Daniele; Sacerdoti, David; Merkel, Carlo; Basili, Stefania; Ferro, Domenico; Villa, Erica; Di Minno, Giovanni; Caraceni, Paolo; Marzioni, Marco; Mannucci, Pier Mannuccio; Violi, Francesco; Piscaglia, Fabio; Calvaruso, Vincenza; De Pietri, Lesley; Falcone, Marco; Feltracco, Paolo; Grandone, Elvira; La Mura, Vincenzo; Licata, Anna; Lucidi, Cristina; Maimone, Sergio; Marietta, Marco; Morisco, Filomena; Napoleone, Laura; Piano, Salvatore; Raparelli, Valeria; Rebulla, Paolo; Ribero, Dario; Sartori, Maria Teresa; Scalera, Antonella; Schepis, Filippo; Sicilianom, Massimo; Baroni, Gianluca Svegliati; Tufano, Antonella; Vitale, Alessandro; Zuin, Massimo
abstract
Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.
2016
- LOW MOLECULAR WEIGHT HEPARIN TREATMENT DOES NOT INCREASE THE RISK OF BLEEDING AFTER PROPHYLACTIC ENDOSCOPIC VARICEAL BAND LIGATION IN PATIENTS WITH CIRRHOSIS
[Abstract in Atti di Convegno]
Bianchini, M; Cavani, G; Bonaccorso, A; Turco, L; Merighi, A; Villa, E; Schepis, F
abstract
Introduction. Anticoagulants are commonly indicated in cirrhotics due to their high rate of thrombotic events. It’s not known if anticoagulants are safe in cirrhotics undergoing elective Endoscopic Variceal band Ligation (EVL).
Aim. to define the short-term risk of bleeding after prophylactic EVL in cirrhotics treated with LMWH.
Materials and Methods. All primary and secondary prophylactic EBL performed from January 2009 to September 2015 were restrospectively analyzed. Inclusion criteria: diagnosis of cirrhosis, age 18-85, EVL procedures started and completed at the same Institution during the observation period. Exclusion criteria: active bleeding at first endoscopy. Patients treated with LMWH were classified as Cases, the remaining as Controls. Clinical characteristics including ascites, hepatic encephalopathy and MELD, endoscopic features at the beginning and at the end of EVL treatment, number of EVL sessions, mean number of bands per session were recorded. EVL related bleeding was defined as endoscopic evidence of hemorrhage within 30 days from the procedure.
Results. Among 26742 upper endoscopies, 542 were prophylactic EVLs performed in 245 (200 primary and 45 secondary prophylaxis) cirrhotics. 197 EVL sessions were performed in 76 Cases (4.81±0.92 bands/session) and 345 in 169 Controls (4.80±1.03; p=ns). 48 Cases (63%) were treated with 100 U/Kg/bid while the remaining with 70 U/Kg/bid. Clinical and endoscopic features were similar between the groups at the time of the first EVL and at the last treatment. Overall 5 patients bled (2%), 3 Cases (3.9%) and 2 Controls (1.2%, Log-Rank test 0.161). F2 and F3 varices with red marks (100% vs 54,7%, p 0.044) and the number of bands used at index EVL (5.8±0.4 vs 4.6±1.1, p=0.003) were different between bleeders and non-bleeders, respectively.
Conclusions. Anticoagulation with LMWH does not increase the risk of post-procedural bleeding in cirrhotic patients undergoing prophylactic EBL.
2016
- Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study
[Articolo su rivista]
Villa, Erica; Critelli, Rosina Maria; Lei, Barbara; Marzocchi, Guido; Cammà, Calogero; Giannelli, Gianluigi; Pontisso, Patrizia; Cabibbo, Giuseppe; Enea, Marco; Colopi, Stefano; Caporali, Cristian; Pollicino, Teresa; Milosa, Fabiola; Karampatou, Aimilia; Todesca, Paola; Bertolini, Elena; Maccio, Livia; Martinez Chantar, Maria Luz; Turola, Elena; Del Buono, Mariagrazia; De Maria, Nicola; Ballestri, Stefano; Schepis, Filippo; Loria, Paola; Gerunda, Giorgio Enrico; Losi, Luisa; Cillo, Umberto
abstract
Objective: The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide highthroughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC. Design: Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model. Results: Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54-82 days (n=20), 83-110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2(ANGPT2), delta-like ligand 4(DLL4), neuropilin (NRP)/tolloid (TLL)-like 2(NETO2), endothelial cell-specific molecule-1(ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001). Conclusions: The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC. Trial registration number ClinicalTrials.gov Identifier: NCT01657695.
2016
- PROGRESSIVE ALTERATIONS IN SYSTEMIC AND CARDIOPULMONARY HEMODYNAMICS OCCUR IN PATIENTS WITH CIRRHOSIS AND PREDICT DEATH IN DECOMPENSATED CIRRHOSIS
[Abstract in Atti di Convegno]
Turco, L; Garcia-Tsao, G; Magnani, I; Bianchini, M; Costetti, M; Rossi, R; Villa, E; Schepis, F
abstract
Background and Aims: The main stages of cirrhosis (compensated and decompensated) have been substaged based on clinical, endoscopic, and portal pressure (determined by the hepatic venous pressure gradient, HVPG) features. Vasodilation leading to a hyperdynamic circulatory state is central in the development of a late decompensated stage with inflammation being currently considered a key driver. We aimed to assess hepatic/systemic hemodynamics and inflammation (by C reactive protein, CRP) among the different substages of cirrhosis and to investigate their interrelationship and prognostic relevance.
Methods: Single center, prospective cohort of patients with cirrhosis undergoing per protocol hepatic and right-heart catheterization and CRP measurement, classified into recently defined prognostic stages (PS) of compensated (PS1: HVPG ≥6mmHg but <10mmHg; PS2: HVPG ≥10 mmHg without gastroesophageal varices; PS3: patients with gastroesophageal varices) and decompensated (PS4: diuretic-responsive ascites; PS5: refractory ascites) disease. Cardiodynamic states based on cardiac index (L/min/m2) were created: relatively-hypodynamic (<3.2), normodynamic (3.2-4.2) and hyperdynamic (>4.2).
Results: 238 patients, 151 compensated (PS1=25; PS2=36; PS3=90), 87 decompensated (PS4=48; PS5=39). Mean arterial pressure decreased progressively from PS1 to PS5, cardiac index increased progressively from PS1-to-PS4 but decreased in PS5. HVPG, MELD, and CRP increased progressively from PS1-to-PS5. Among compensated patients, age, HVPG, relatively-hypodynamic/hyperdynamic state and CRP were predictive of decompensation. Among patients with ascites, MELD, relatively-hypodynamic/hyperdynamic state, post-capillary pulmonary hypertension, and CRP were independent predictors of death/liver transplant.
Conclusions: Our study demonstrates that, in addition to known parameters, cardiopulmonary hemodynamics and CRP are predictive of relevant outcomes in patients with both compensated and decompensated cirrhosis.
2015
- Paradoxical embolization in TIPS: take a closer look to the heart
[Articolo su rivista]
Vizzutti, Francesco; Rega, Luigi; Arena, Umberto; Romanelli, Roberto Giulio; Meucci, Francesco; Barletta, Giuseppe; Schepis, Filippo; Tsalouchos, Aris; Laffi, Giacomo; Marra, Fabio
abstract
No definitive indications are provided in the literature for pre-TIPS patient workup, which is often limited to prevent the incidence of refractory hepatic encephalopathy or unacceptable deterioration of liver function. Concerning cardiologic workup, efforts are generally limited at excluding ventricular failure or porto pulmonary hypertension. The cases presented herein focus the attention of the readers on the possible occurrence of post-TIPS paradoxical embolization in the presence of a patent foramen ovale, frequently recognized in adult population. In conclusion, although this complication has been already reported in literature, in the present manuscript we concentrate on possible additional risk factors which may allow to identify a subset of patients with a higher likelihood to experience paradoxical embolization following TIPS. Another important line of information presented herein is the feasibility of percutaneous closure of a patent foramen ovale before TIPS deployment in the presence of portal vein thrombosis and possibly with additional risk factors.
2015
- The Coiled-Coil Domain Containing 80 (ccdc80) gene regulates gadd45β2 expression in the developing somites of zebrafish as a new player of the hedgehog pathway
[Articolo su rivista]
Della Noce, Isabella; Carra, Silvia; Brusegan, Chiara; Critelli, Rosina Maria; Frassine, Andrea; De Lorenzo, Carlo; Giordano, Antonio; Bellipanni, Gianfranco; Villa, Erica; Cotelli, Franco; Pistocchi, Anna; Schepis, Filippo
abstract
The Coiled-Coil Domain Containing 80 (CCDC80) gene has been identified as strongly induced in rat thyroid PC CL3 cells immortalized by the adenoviral E1A gene. In human, CCDC80 is a potential oncosoppressor due to its down-regulation in several tumor cell lines and tissues and it is expressed in almost all tissues. CCDC80 has homologous in mouse, chicken, and zebrafish. We cloned the zebrafish ccdc80 and analyzed its expression and function during embryonic development. The in-silico translated zebrafish protein shares high similarity with its mammalian homologous, with nuclear localization signals and a signal peptide. Gene expression analysis demonstrates that zebrafish ccdc80 is maternally and zygotically expressed throughout the development. In particular, ccdc80 is strongly expressed in the notochord and it is under the regulation of the Hedgehog pathway. In this work we investigated the functional effects of ccdc80-loss-of-function during embryonic development and verified its interaction with gadd45β2 in somitogenesis.
2015
- The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias
[Articolo su rivista]
Leone, Vincenza; Ferraro, Angelo; Schepis, Filippo; Federico, Antonella; Sepe, Romina; Arra, Claudio; Langella, Concetta; Palma, Giuseppe; De Lorenzo, Carlo; Troncone, Giancarlo; Masciullo, Valeria; Scambia, Giovanni; Fusco, Alfredo; Pallante, Pierlorenzo
abstract
We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80(-/-) mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80(-/-) mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.
2015
- Thrombophilic genetic risk factors for liver fibrosis: To screen or not to screen?
[Articolo su rivista]
Schepis, Filippo; Villa, Erica
abstract
Invited Editorial
2013
- Erratum: Unusual association between Budd-Chiari syndrome secondary to antiphospholipid syndrome and relapsing polychondritis: A case report and review of the literature (Clinical Rheumatology (2013) 32 (905-907) DOI: 10.1007/s10067-013-2229-z)
[Articolo su rivista]
Sebastiani, M.; Manzini, C. U.; Campomori, F.; Spinella, A.; Vacchi, C.; Giuggioli, D.; Schepis, F.; Ferri, C.
abstract
2013
- Hemodynamic response to propranolol in patients with recurrent hepatitis C virus-related cirrhosis after liver transplantation: A case-control study
[Articolo su rivista]
Schepis, Filippo; Vukotic, Ranka; Berzigotti, Annalisa; Carriõn, José A.; Forns, Xavier; Abraldes, Juan G.; García Valdecasas, Juan Carlos; Navasa, Miguel; García Pagán, Juan Carlos; Bosch, Jaime
abstract
Cirrhosis recurrence is frequent after orthotopic liver transplantation for hepatitis C virus (HCV). Because transplantation causes liver denervation, we hypothesized that the response to propranolol might differ in transplant patients versus nontransplant patients with cirrhosis and portal hypertension. Twenty-one patients with cirrhosis recurrence after orthotopic liver transplantation with portal hypertension were compared to 20 nontransplant patients with cirrhosis, HCV, and portal hypertension, and they were matched by sex, age, presence of varices, and Child-Pugh score. The patients underwent systemic and hepatic hemodynamic measurements at the baseline and 20 minutes after intravenous propranolol (0.15 mg/kg). At the baseline, the transplant patients with cirrhosis had a lower hepatic venous pressure gradient (HVPG) than the nontransplant patients with cirrhosis (14.8 ± 2.9 versus 17.3 ± 4.4 mm Hg, P = 0.03) but a higher mean arterial pressure (MAP; 100.3 ± 12.3 versus 91.8 ± 11.6 mm Hg, P = 0.04) and higher systemic vascular resistance (2253 ± 573 versus 1883 ± 525 dyn/second/cm-5, P = 0.03). There were no differences in the cardiac index (CI). Propranolol significantly decreased HVPG to similar extents in transplant patients and nontransplant patients with cirrhosis (-14.1% ± 8.0% versus -16.9% ± 9.5%, P > 0.99). MAP tended to increase in transplant patients with cirrhosis, whereas it slightly decreased in nontransplant patients (5.1% ± 14.2% versus -4.8% ± 6.4%, P = 0.007); however, the reduction in CI was less marked in transplant patients with cirrhosis (-18.6% ± 7.6% versus -26.9% ± 9.0%, P = 0.005). In conclusion, patients with HCV-related cirrhosis and portal hypertension after orthotopic liver transplantation have lower baseline HVPG values but similar HVPG responses to propranolol infusions in comparison with nontransplant patients with cirrhosis. In contrast to nontransplant patients, propranolol increases the systemic vascular resistance and arterial pressure in transplant patients with cirrhosis and attenuates the fall in CI. Liver Transpl 19:450-456, 2013. © 2013 AASLD. Copyright
2013
- Tumor suppressor role of the CL2/DRO1/CCDC80 gene in thyroid carcinogenesis
[Articolo su rivista]
Ferraro, Angelo; Schepis, Filippo; Leone, Vincenza; Federico, Antonella; Borbone, Eleonora; Pallante, Pierlorenzo; Berlingieri, Maria Teresa; Chiappetta, Gennaro; Monaco, Mario; Palmieri, Dario; Chiariotti, Lorenzo; Santoro, Massimo; Fusco, Alfredo
abstract
Context: Thyroid carcinoma is one of the mostcommonmalignancies of the endocrine system, and, despite the high frequency of oncogene activation in thyroid neoplastic lesions, the tumor suppressor genes involved in thyroid carcinogenesis remain unidentified.Ourprevious data implicated a link between the CL2/CCDC80 gene and thyroid cancer. Objective: The objective of the study was to examine the expression of the CL2/CCDC80 gene in human thyroid carcinomas in the attempt to determine whether it plays a role in thyroid carcinogenesis. Design: Weevaluated the expression of CL2/CCDC80 in a large number of thyroid neoplastic tissue samples differing in degree of malignancy. We also investigated the effects of its restoration in 2 human thyroid carcinoma cell lines characterized by very low levels of CL2/CCDC80 expression. Results: CL2/CCDC80 expression was much lower in almost all the thyroid carcinomas analyzed than in normal thyroid tissues and was lowest in follicular variants of papillary carcinomas. Loss of heterozygosity partially accounted for CL2/CCDC80 down-regulation in thyroid carcinoma samples. Restoration of CL2/CCDC80 expression in the 2 human thyroid anaplastic carcinoma cell lines resulted in a higher susceptibility to apoptosis and suppression of the malignant phenotype. CL2/CCDC80 expression positively regulated the expression of E-cadherin, thereby halting cancer progression. Conclusions: These results indicate that CL2/CCDC80 is a putative tumor suppressor gene in thyroid carcinogenesis. Copyright © 2013 by The Endocrine Society.
2013
- Unusual association between Budd–Chiari syndrome secondary to antiphospholipid syndrome and relapsing polychondritis: a case report and review of the literature
[Articolo su rivista]
Sebastiani, Marco; C. U., Manzini; Campomori, Federica; Spinella, Amelia; C., Vacchi; D., Giuggioli; Schepis, Filippo; Ferri, Clodoveo
abstract
Relapsing polychondritis is a rare immune-mediated condition, characterized by episodic inflammation of the cartilaginous tissue, in particular the ears, nose, and eyes, and involvement of joints and respiratory tract. Nearly one third of patients showed other associated diseases, such as systemic vasculitides, connective tissue diseases, or myelodysplastic syndromes. Antiphospholipid antibodies can be found in relapsing polychondritis in patients with no clinical thrombotic disease. However, when antiphospholipid syndrome is present, its clinical manifestations can be severe and life threatening. We describe the case of a patient with relapsing polychondritis associated to Budd–Chiari syndrome due to antiphospholipid syndrome. The present clinical observations together with the updated review of the literature suggest a search for antiphospholipid antibodies in all patients with relapsing polychondritis.
2012
- Ccdc80-l1 Is involved in axon pathfinding of zebrafish motoneurons.
[Articolo su rivista]
Brusegan, C; Pistocchi, A; Frassine, A; DELLA NOCE, Isabella; Schepis, Filippo; Cotelli, F.
abstract
Axon pathfinding is a subfield of neural development by which neurons send out axons to reach the correct targets. In particular, motoneurons extend their axons toward skeletal muscles, leading to spontaneous motor activity. In this study, we identified the zebrafish Ccdc80 and Ccdc80-like1 (Ccdc80-l1) proteins in silico on the basis of their high aminoacidic sequence identity with the human CCDC80 (Coiled-Coil Domain Containing 80). We focused on ccdc80-l1 gene that is expressed in nervous and non-nervous tissues, in particular in territories correlated with axonal migration, such as adaxial cells and muscle pioneers. Loss of ccdc80-l1 in zebrafish embryos induced motility issues, although somitogenesis and myogenesis were not impaired. Our results strongly suggest that ccdc80-l1 is involved in axon guidance of primary and secondary motoneurons populations, but not in their proper formation. ccdc80-l1 has a differential role as regards the development of ventral and dorsal motoneurons, and this is consistent with the asymmetric distribution of the transcript. The axonal migration defects observed in ccdc80-l1 loss-of-function embryos are similar to the phenotype of several mutants with altered Hedgehog activity. Indeed, we reported that ccdc80-l1 expression is positively regulated by the Hedgehog pathway in adaxial cells and muscle pioneers. These findings strongly indicate ccdc80-l1 as a down-stream effector of the Hedgehog pathway.
2012
- Enoxaparin prevents portal vein thrombosis and liver decompensation in patients
with advanced cirrhosis
[Articolo su rivista]
Villa, Erica; C., Cammà; M., Marietta; Luongo, Monica; Critelli, Rosina Maria; S., Colopi; C., Tata; Zecchini, Ramona; S., Gitto; S., Petta; B., Lei; Bernabucci, Veronica; Vukotic, Ranka; N., De Maria; Schepis, Filippo; A., Karampatou; C., Caporali; L., Simoni; M., Del Buono; B., Zambotto; Turola, Elena; G., Fornaciari; S., Schianchi; A., Ferrari; D., Valla
abstract
BACKGROUND & AIMS: We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis.
METHODS: In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment
(controls, n = 36). Ultrasonography (every 3 months) and computed tomography
(every 6 months) were performed to check the portal vein axis. The primary
outcome was prevention of PVT. Radiologists and hepatologists that assessed
outcomes were blinded to group assignments. Analysis was by intention to treat.
RESULTS: At 48 weeks, none of the patients in the enoxaparin group had developed
PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient
developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P
= .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin
group and 27.7% of controls developed PVT (P = .048). The actuarial probability
of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was
less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P <
.0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The
actuarial probability of liver decompensation was lower in the enoxaparin group
(P < .0001). Eight patients in the enoxaparin group and 13 controls died. The
actuarial probability of survival was higher in the enoxaparin group (P = .020).
No relevant side effects or hemorrhagic events were reported.
CONCLUSIONS: In a small randomized controlled trial, a 12-month course of
enoxaparin was safe and effective in preventing PVT in patients with cirrhosis
and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of
hepatic decompensation and to improve survival.
2011
- A RANDOMIZED TRIAL OF THE SAFETY AND HEPATIC HEMODYNAMIC EFFECTS OF INTRAVENOUS CONIVAPTAN IN EUVOLEMIC OR HYPERVOLEMIC CIRRHOTIC PATIENTS
[Abstract in Atti di Convegno]
Bosch, J; Erice, E; Llop, E; Abeyratne, A; Tanaka, M; Whitcomb, D; Schepis, F; Mcnutt, B
abstract
A RANDOMIZED TRIAL OF THE SAFETY AND HEPATIC HEMODYNAMIC EFFECTS OF INTRAVENOUS CONIVAPTAN IN EUVOLEMIC OR HYPERVOLEMIC CIRRHOTIC PATIENTS
2011
- ENOXAPARIN PREVENTS PORTAL VEIN THROMBOSIS (PVT) AND DECOMPENSATION IN ADVANCED CIRRHOTIC PATIENTS: FINAL REPORT OF A PROSPECTIVE RANDOMIZED CONTROLLED STUDY
[Abstract in Atti di Convegno]
Villa, E; Zecchini, R; Marietta, M; Bernabucci, V; Lei, B; Vukotic, R; Ferrari, A; De Maria, N; Schepis, F; Fornaciari, G; Schianchi, S
abstract
BACKGROUND & AIMS:
We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis.
METHODS:
In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat.
RESULTS:
At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported.
CONCLUSIONS:
In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.
2010
- ANTICOAGULANT THERAPY IS SAFE AND EFFECTIVE IN PREVENTING PORTAL VEIN THROMBOSIS (PVT) IN ADVANCED CIRRHOTIC PATIENTS: A PROSPECTIVE RANDOMIZED CONTROLLED STUDY
[Abstract in Atti di Convegno]
Zecchini, R; Ferrari, A; Bernabucci, V; Lei, B; Vukotic, R; De Maria, N; Schepis, F; Marietta, M; Fornaciari, G; Schianchi, S; Villa, E
abstract
BACKGROUND & AIMS:
We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis.
METHODS:
In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat.
RESULTS:
At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported.
CONCLUSIONS:
In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.
2010
- PROCALCITONIN IS THE BEST DIAGNOSTIC AND PROGNOSTIC MARKER OF SEPSIS IN DECOMPENSATED CIRRHOTIC PATIENTS
[Abstract in Atti di Convegno]
Schepis, F; Bianchini, M; Ferretti, I; Marino, M; Bonfreschi, Silvia; Dattomo, G; Agnello, F; Wratten, Ml; De Maria, N; Villa, E
abstract
PROCALCITONIN IS THE BEST DIAGNOSTIC AND PROGNOSTIC MARKER OF SEPSIS IN DECOMPENSATED CIRRHOTIC PATIENTS
2009
- 30 Days of continuous olanzapine infusion determines energy imbalance, glucose intolerance, insulin resistance, and dyslipidemia in mice.
[Articolo su rivista]
R., Coccurello; Brina, Daniela; A., Caprioli; R., Conti; O., Ghirardi; Schepis, Filippo; A., Moles
abstract
The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.
2009
- Pathophysiology of portal hypertension and variceal bleeding
[Relazione in Atti di Convegno]
Bosch, J; de Gottardi, A; Chang, J; Berzigotti, A; Schepis, F
abstract
Descrizione della fisiopatologia dell'ipertensione portale e del sanguinamento da varici esofagee.
2007
- Baveno IV Consensus Statements: Predictive Models in Portal Hypertension
[Capitolo/Saggio]
D'Amico, G.; Garcia-Tsao, G.; Abraldes, J. G.; Christensen, E.; Gines, P.; Kim, W. R.; Merli, M.; Schepis, F.
abstract
Predictive models in portal hypertension
2007
- Monitoring Treatment of Cirrhosis and Portal Hypertension
[Capitolo/Saggio]
Annalisa, Berzigotti; Schepis, Filippo; JUAN CARLOS GARCIA, Pagan
abstract
Monitoring Treatment of Cirrhosis and Portal Hypertension
2007
- Session 2: Predictive Models in Portal Hypertension
[Capitolo/Saggio]
Garcia-Tsao, G.; D'Amico, G.; Abraldes, J. G.; Schepis, F.; Merli, M.; Kim, W. R.; Christensen, E.
abstract
2005
- Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors.
[Articolo su rivista]
D. D., Vizio; L., Cito; A., Boccia; P., Chieffi; L., Insabato; G., Pettinato; M. L., Motti; Schepis, Filippo; W., D'Amico; F., Fabiani; B., Tavernise; S., Venuta; A., Fusco; G., Viglietto
abstract
PTEN/MMAC1/TEP1: (hereafter PTEN) is a tumor suppressor gene (located at 10q23) that is frequently mutated or deleted in sporadic human tumors. PTEN encodes a multifunctional phosphatase, which negatively regulates cell growth, migration and survival via the phosphatidylinositol 3'-kinase/AKT signalling pathway. Accordingly, Pten+/- mice develop various types of tumors including teratocarcinomas and teratomas. We have investigated PTEN expression in 60 bioptic specimens of germ cell tumors (32 seminomas, 22 embryonal carcinomas and six teratomas) and 22 intratubular germ cell neoplasias (ITGCN) adjacent to the tumors for PTEN protein and mRNA expression. In total, 10 testicular biopsies were used as controls. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56\% of seminomas as well as from 86\% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not an early event in testicular tumor development. The loss of PTEN expression occurs mainly at the RNA level as determined by in situ hybridization of cellular mRNA (17/22) but also it may involve some kind of post-transcriptional mechanisms in the remaining 25\% of cases. Analysis of microsatellites D10S551, D10S541 and D10S1765 in GCTs (n=22) showed LOH at the PTEN locus at 10q23 in at least 36\% of GCTs (three embryonal carcinoma, three seminoma, two teratoma); one seminoma and one embryonal (9\%) carcinoma presented an inactivating mutation in the PTEN gene (2/22). Finally, we demonstrated that the phosphatidylinositol 3'-kinase/AKT pathway, which is regulated by the PTEN phosphatase, is crucial in regulating the proliferation of the NT2/D1 embryonal carcinoma cells, and that the cyclin-dependent kinase inhibitor p27(kip1) is a key downstream target of this pathway.
2004
- Chemoprevention of hepatocellular carcinoma
[Capitolo/Saggio]
Antonio, Craxì; Schepis, Filippo; Calogero, Camma'
abstract
Chemoprevention of hepatocellular carcinoma
2004
- Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data.
[Articolo su rivista]
C., Camma; D., Di Bona; Schepis, Filippo; E. J., Heathcote; S., Zeuzem; P. J., Pockros; P., Marcellin; L., Balart; A., Alberti; A., Craxi
abstract
Multicenter randomized trials have shown that once-weekly pegylated interferon (peginterferon) alfa-2a is more efficacious than conventional interferon alfa-2a (IFN) in patients with chronic hepatitis C. We performed a meta-analysis of 1,013 previously untreated patients (from 3 randomized trials) with pretreatment and post-treatment liver biopsies to assess the differences between peginterferon alfa-2a and IFN in terms of their effects on liver histology. Reported values were standardized mean differences (SMD) between patients receiving peginterferon alfa-2a and those receiving IFN (post-treatment value minus baseline value for each group). We used a random-effects model to quantify the average effect of peginterferon alfa-2a on liver histology. Peginterferon alfa-2a significantly reduced fibrosis compared with IFN (SMD, -0.14; 95% CI: -0.27, -0.01; P = .04). A reduction in fibrosis was observed among sustained virologic responders (SMD, -0.59; 95% CI: -0.89, -0-30; P < .0001) and patients with recurrent disease (SMD, -0.34; 95% CI: -0.54, -0.14; P = .0007), whereas no significant reduction was observed among nonresponders (SMD, -0.13; 95% CI: -0.32, 0.05; P = .15). Logistic regression analysis indicated that patients with sustained virologic responses (SVRs) had an odds ratio (OR) of 1.61 (95% CI: 1.14, 2.29) for reduction in fibrosis compared with patients without SVRs, whereas obese patients (body mass index [BMI] > 30 kg/m(2)) had an OR of 0.56 (95% CI: 0.35, 0.90) compared with normal-weight (BMI < 25 kg/m(2)) and overweight patients (BMI, 25-30 kg/M-2). In conclusion, in patients with chronic hepatitis C with or without cirrhosis, peginterferon alfa-2a (relative to IFN) significantly reduced fibrosis. The beneficial effects of peginterferon on liver histology are closely related to virologic response.
2004
- Natural history of chronic HBV in northern Italy: Morbidity and morality after 30 years
[Articolo su rivista]
M., Manno; C., Camma; Schepis, Filippo; F., Bassi; Gelmini, Roberta; F., Giannini; F., Miselli; Grottola, Antonella; I., Ferretti; C., Vecchi; M., De Palma; Villa, Erica
abstract
Background & Aims: Increased morbidity and mortality from liver disease have been reported in chronic hepatitis B surface antigen (HBsAg) carriers, but data on survival are equivocal. To assess the impact of hepatitis B virus (HBV) infection on survival and liver-related complications, we re-evaluated, after a mean follow-up of 30 years, a cohort of 296 blood donors excluded from donation 30 years ago when HBsAg screening became mandatory. Methods: Clinical and ultrasound examination and biochemical and virologic tests were performed. The cause of death was recorded and survival was compared with a control population of 157 HBV-negative blood donors selected at baseline. Results: Thirty-two (10.8%) cases and 14 controls (8.9%) (P = 0.625) had died; 3 of 32 (9.3%) and 1 of 14 (7.1%) deaths were liver-related. Hepatocellular carcinoma (HCC) caused death in 2 of 296 and 1 of 157 subjects (0.6% in each group). Alcohol-induced cirrhosis occured in the remaining subject. By Cox regression analysis, survival was independently predicted by older age, abnormal gamma-glutamyl transpeptidase (GGT) levels, and presence of medical comorbidities at baseline. Unequivocal liver disease was found in 4 carriers only. No disease decompensation occurred during follow-up. Fifty-nine (32.2%) carriers cleared HBsAg (yearly incidence, 1.0%). Full-length serum HBV DNA was present in 32.2% of persistently HBsAg-positive individuals (average titer always <10(5) copies/mL). Conclusions: Over a 30-year period, chronic HBV carrier blood donors from Northern Italy did not develop clinically significant liver disease, hepatocellular cancer, or other liver-related morbidity or mortality at a higher rate than uninfected controls. The presence of medical comorbidities, older age at diagnosis, and abnormal GGT levels were independent predictors of death among chronic HBV carriers.
2004
- Preoperative chemoradiotherapy for oesophageal cancer: A systematic review and meta-analysis
[Articolo su rivista]
F., Fiorica; D. D., Bona; Schepis, Filippo; A., Licata; L., Shahied; A., Venturi; A. M., Falchi; A., Craxì; C., Cammà
abstract
BACKGROUND: The benefit of neoadjuvant chemoradiotherapy in oesophageal cancer has been extensively studied but data on survival are still equivocal. OBJECTIVE: To assess the effectiveness of chemoradiotherapy followed by surgery in the reduction of mortality in patients with resectable oesophageal cancer. METHODS: Computerised bibliographic searches of MEDLINE and CANCERLIT (1970-2002) were supplemented with hand searches of reference lists. STUDY SELECTION: Studies were included if they were randomised controlled trials (RCTs) comparing preoperative chemoradiotherapy plus surgery with surgery alone, and if they included patients with resectable histologically proven oesophageal cancer without metastatic disease. Six eligible RCTs were identified and included in the meta-analysis. DATA EXTRACTION: Data on study populations, interventions, and outcomes were extracted from each RCT according to the intention to treat method by three independent observers and combined using the DerSimonian and Laird method. RESULTS: Chemoradiotherapy plus surgery compared with surgery alone significantly reduced the three year mortality rate (odds ratio (OR) 0.53 (95\% confidence interval (CI) 0.31-0.93); p = 0.03) (number needed to treat = 10). Pathological examination showed that preoperative chemoradiotherapy downstaged the tumour (that is, less advanced stage at pathological examination at the time of surgery) compared with surgery alone (OR 0.43 (95\% CI 0.26-0.72); p = 0.001). The risk for postoperative mortality was higher in the chemoradiotherapy plus surgery group (OR 2.10 (95\% CI 1.18-3.73); p = 0.01). CONCLUSIONS: In patients with resectable oesophageal cancer, chemoradiotherapy plus surgery significantly reduces three year mortality compared with surgery alone. However, postoperative mortality was significantly increased by neoadjuvant chemoradiotherapy. Further large scale multicentre RCTs may prove useful to substantiate the benefit on overall survival.
2003
- An adenovirus carrying the rat protein tyrosine phosphatase eta suppresses the growth of human thyroid carcinoma cell lines in vitro and in vivo.
[Articolo su rivista]
R., Iuliano; F., Trapasso; I. L., Pera; Schepis, Filippo; I., Samà; A., Clodomiro; K. R., Dumon; M., Santoro; L., Chiariotti; G., Viglietto; A., Fusco
abstract
We demonstrated previously that rat tyrosine phosphatase r-PTPeta expression was suppressed in rat and human thyroid neoplastic cells, and that restoration of r-PTPeta expression reverted the malignant phenotype. To investigate the potential of this gene for cancer therapy, we generated an adenovirus carrying the r-PTPeta cDNA (Ad-r-PTPeta). This virus infected human thyroid carcinoma cells and overexpressed the r-PTPeta protein. Overexpression of r-PTPeta significantly inhibited the growth of four thyroid carcinoma cell lines. Cell growth inhibition was associated with down-regulation of extracellular signal-regulated kinase 1/2 activity, with increased levels of the cell-cycle inhibitor p27(kip1) protein and with dephosphorylation of PLCgamma1, a substrate of DEP-1, the human homologue of r-PTPeta. Finally, the growth of xenograft tumors induced in athymic mice by anaplastic thyroid carcinoma ARO cells transduced with the Ad-r-PTPeta virus was drastically reduced. These data suggest that gene therapy based on restoration of PTPeta function has potential in the treatment of human thyroid malignant neoplasias.
2003
- Cloning and molecular characterization of a novel gene strongly induced by the adenovirus E1A gene in rat thyroid cells.
[Articolo su rivista]
Visconti, R.; Schepis, F.; Iuliano, R.; Pierantoni, G. M.; Zhang, L.; Carlomagno, F.; Battaglia, C.; Martelli, M. L.; Trapasso, F.; Santoro, M.; Fusco, A.
abstract
Expression of the adenovirus E1A gene in the rat thyroid differentiated cell line PC Cl 3 induces thyrotropin-independent cell growth and impairs differentiation. However, the malignant phenotype is achieved only when the PC E1A cells are infected with other murine retroviruses carrying the v-abl, v-raf or polyoma middle-T genes. To determine through which genes E1A affects thyroid cells, we differentially screened PC Cl 3 and PC E1A cells. Here we report a new gene, named CL2, that is upregulated in PC E1A cells. The CL2 transcript is 4.4 kb long and encodes a 949 amino-acid protein. Conceptual translation of the open reading frame showed one product with a signal peptide, multiple nuclear localization signals and three newly described domains. Furthermore, in vivo, this protein was located juxtanuclear, which is suggestive of Golgian localization, and also in cytoplasm and nucleus/nucleolus. Finally, CL2 gene expression was drastically downregulated in human thyroid neoplastic cell lines and tissues.
2003
- Meta-analysis of Transarterial Embolization in Patients with Unresectable Hepatocellular Carcinoma: Dr Camma and colleagues respond
[Articolo su rivista]
C., Camma; Schepis, Filippo; M., Cottone; A., Craxi
abstract
Meta-analysis of Transarterial Embolization in Patients with Unresectable Hepatocellular Carcinoma: Dr Camma and colleagues respond
2003
- The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity.
[Articolo su rivista]
S., Cortellino; D., Turner; V., Masciullo; Schepis, Filippo; D., Albino; R., Daniel; A. M., Skalka; N. J., Meropol; C., Alberti; L., Larue; A., Bellacosa
abstract
Cytotoxicity of methylating agents is caused mostly by methylation of the O6 position of guanine in DNA to form O6-methylguanine (O6-meG). O6-meG can direct misincorporation of thymine during replication, generating O6-meG:T mismatches. Recognition of these mispairs by the mismatch repair (MMR) system leads to cell cycle arrest and apoptosis. MMR also modulates sensitivity to other antitumor drugs. The base excision repair (BER) enzyme MED1 (also known as MBD4) interacts with the MMR protein MLH1. MED1 was found to exhibit thymine glycosylase activity on O6-meG:T mismatches. To examine the biological significance of this activity, we generated mice with targeted inactivation of the Med1 gene and prepared mouse embryonic fibroblasts (MEF) with different Med1 genotype. Unlike wild-type and heterozygous cultures, Med1-/- MEF failed to undergo G2-M cell cycle arrest and apoptosis upon treatment with the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Similar results were obtained with platinum compounds' 5-fluorouracil and irinotecan. As is the case with MMR-defective cells, resistance of Med1-/- MEF to MNNG was due to a tolerance mechanism because DNA damage accumulated but did not elicit checkpoint activation. Interestingly, steady state amounts of several MMR proteins are reduced in Med1-/- MEF, in comparison with Med1+/+ and Med1+/- MEF. We conclude that MED1 has an additional role in DNA damage response to antitumor agents and is associated with integrity of the MMR system. MED1 defects (much like MMR defects) may impair cell cycle arrest and apoptosis induced by DNA damage.
2003
- When and how to treat acute hepatitis C?
[Articolo su rivista]
A., Licata; D. D., Bona; Schepis, Filippo; L., Shahied; A., Craxí; C., Cammà
abstract
BACKGROUND: Appropriate treatment of acute hepatitis C is still a matter of controversy due to the lack of large controlled trials. AIM: To assess the effectiveness of interferon as treatment for acute hepatitis C by meta-analysis. METHODS: MEDLINE search (1985-2002) was supplemented with manual searches of reference lists. Studies were included if they were controlled trials comparing interferon to no treatment and if they included patients with either post-transfusion or sporadic acute hepatitis C. Twelve trials were analyzed (414 patients). The outcome assessed was the sustained virological response (SVR) rate (undetectable hepatitis C virus RNA in serum at least 6 months after cessation of therapy). RESULTS: Interferon significantly increased the SVR (risk difference 49\%; 95\% confidence interval 32.9-65\%) in comparison to no treatment. The risk difference of SVR increased from 5 to 90\% when trials were ordered by increasing interferon weekly dose. Delaying therapy by 8-12 weeks after the onset of disease does not compromise the SVR rate. CONCLUSIONS: Current evidence is sufficient to recommend interferon treatment of patients with acute hepatitis C. A later initiation of therapy yields the same likelihood of response as early treatment. A daily induction dose during the 1st month is the best option of treatment.
2002
- Protection of human endothelial cells from oxidative stress: Role of Ras-ERK1/2 signaling
[Articolo su rivista]
G., Cuda; R., Paterno; R., Ceravolo; M., Candigliota; N., Perrotti; F., Perticone; M. C., Faniello; Schepis, Filippo; A., Ruocco; E., Mele; S., Cassano; M., Bifulco; M., Santillo; E. V., Avvedimento
abstract
BACKGROUND: Reactive oxygen species play a critical role in inducing apoptosis. The small GTPase p21 Ras and the ERK1/2 MAPK have been proposed as key regulators of the signaling cascade triggered by oxidative stress (H2O2). Harvey-Ras (Ha-Ras) and Kirsten-Ras (Ki-Ras) isoforms are so far functionally indistinguishable, because they activate the same downstream effectors, including ERK1/2. Moreover, ERK1/2 signaling has been involved in both protection and induction of apoptosis. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were subjected to H2O2, and apoptosis was detected by fluorescence-activated cell sorting analysis, fluorescence microscopy, and caspase-3 activation. Transfection of Ha-Ras and Ki-Ras genes in HUVECs was performed to evaluate the response to H2O2. We have found that, whereas Ha-Ras decreases tolerance to oxidative stress, Ki-Ras has a potent antiapoptotic activity. Both effects are mediated by ERK1/2. Tolerance to H2O2 is encoded by a unique stretch of lysines at the COOH terminus of the Ki-Ras, lacking in Ha-Ras, and it is relatively independent of the farnesylated anchor. Inhibition of p21 Ras signaling by farnesylation inhibitors increased the resistance to apoptosis in Ha-Ras-expressing cells. CONCLUSIONS: These findings explain the opposite effects of ERK1/2 stimulation on apoptosis found in different cell types and suggest that local activation of ERK1/2 signaling may account for the opposing response to oxidative stress by Ha-Ras or Ki-Ras-expressing cells. Modulation of cell reactivity to oxidative stress by p21 Ras points to the specific and predictive effects of Ras inhibitors in vivo as potential therapeutic drugs in disorders produced by increase of reactive oxygen species inside the cells
2002
- Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data.
[Articolo su rivista]
Cammà, C.; Bruno, S.; Schepis, Filippo; Iacono, O. L.; Andreone, P.; Gramenzi, A. G.; Mangia, A.; Andriulli, A.; Puoti, M.; Spadaro, A.; Freni, M.; Marco, V. D.; Cino, L.; Saracco, G.; Chiesa, A.; Crosignani, A.; Caporaso, N.; Morisco, F.; Rumi, M. G.; Craxì, A.
abstract
BACKGROUND AND AIMS: Retreatment with a combination of alpha interferon (IFN) plus ribavirin of patients with chronic hepatitis C who did not respond to IFN monotherapy has not been assessed in large controlled studies. METHODS: To assess the effectiveness and tolerability of IFN/ribavirin retreatment of non-responders to IFN and to identify predictors of complete (biochemical and virological) sustained response, we performed a meta-analysis of individual data on 581 patients from 10 centres. Retreatment with various IFN schedules (mean total dose 544 mega units) and a fixed ribavirin dose (1000-1200 mg/daily depending on body weight) was given for 24-60 (mean 39.5) weeks. RESULTS: Biochemical end of treatment and sustained responses were observed in 271/581 (46.6\%; 95\% confidence interval (CI) 42.6-50.7\%) and in 109/581 (18.7\%; 95\% CI 15.6-22.0\%) cases, respectively. Two hundred and six of 532 patients (38.7\%; 95\% CI 34.6-42.9\%) had an end of treatment complete response to retreatment while a complete sustained response occurred in 88 of 559 (15.7\%; 95\% CI 12.8-18.8\%). Fifty four of 581 patients (9.2\%; 95\% CI 7.0-11.7\%) stopped retreatment due to adverse effects. By logistic regression, complete sustained response was predicted independently by age <45 years (p=0.04), by normal pretreatment gamma-glutamyltransferase levels (p=0.01), and by a second course total IFN dose of at least 432 mega units (p=0.008). CONCLUSIONS: The overall low probability of effectiveness argues against indiscriminate retreatment of all IFN monotherapy non-responders with IFN/ribavirin. Patients less than 45 years old with normal gamma-glutamyltransferase levels who were retreated with high dose long course combination therapy had a complete sustained response rate of 30\%.
2002
- Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials
[Articolo su rivista]
C., Cammà; Schepis, Filippo; A., Orlando; M., Albanese; L., Shahied; F., Trevisani; P., Andreone; A., Craxì; M., Cottone
abstract
PURPOSE: To review the available evidence of chemoembolization for unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Computerized bibliographic searches with MEDLINE and CANCERLIT databases from 1980 through 2000 were supplemented with manual searches, with the keywords "hepatocellular carcinoma," "liver cell carcinoma," "randomized controlled trial [RCT]," and "chemoembolization." Studies were included if patients with unresectable HCC were enrolled and if they were RCTs in which chemoembolization was compared with nonactive treatment (five RCTs) or if different transarterial modalities of therapy (13 RCTs) were compared. Data were extracted from each RCT according to the intention-to-treat method. Five of the RCTs with a nonactive treatment arm were combined by using the random-effects model, whereas all 18 RCTs were pooled from meta-regression analysis. RESULTS: Chemoembolization significantly reduced the overall 2-year mortality rate (odds ratio, 0.54; 95\% CI: 0.33, 0.89; P =.015) compared with nonactive treatment. Analysis of comparative RCTs helped to predict that overall mortality was significantly lower in patients treated with transarterial embolization (TAE) than in those treated with transarterial chemotherapy (odds ratio, 0.72; 95\% CI: 0.53, 0.98; P =.039) and that there is no evidence that transarterial chemoembolization is more effective than TAE (odds ratio, 1.007; 95\% CI: 0.79, 1.27; P =.95), which suggests that the addition of an anticancer drug did not improve the therapeutic benefit. CONCLUSION: In patients with unresectable HCC, chemoembolization significantly improved the overall 2-year survival compared with nonactive treatment, but the magnitude of the benefit is relatively small.
2001
- Effects of simvastatin treatment on sICAM-1 and sE-selectin levels in hypercholesterolemic subjects.
[Articolo su rivista]
M. A., Sardo; M., Castaldo; M., Cinquegrani; M., Bonaiuto; A., Maesano; Schepis, Filippo; M. C., Zema; G. M., Campo; F., Squadrito; A., Saitta
abstract
This study was performed to determine whether the levels of soluble intercellular adhesion molecule-1 (sICAM-l) and soluble endothelial molecule-1 (sE-selectin) were elevated in subjects with hypercholesterolemia who presented with no other risk factors or evidence of atherosclerosis. The effects of administration of an HMG-CoA reductase inhibitor on the serum levels of these molecules were also examined. Forty hypercholesterolemic subjects (HCh) (19 males and 21 females), without hypertension or cardiovascular disease, received placebo for 4 weeks. The patients were then randomized in two groups; 20 of them (simvastatin group) were treated with simvastatin (20 mg/day) and the other 20 (placebo group) continued placebo administration. After 12 and 24 weeks of either simvastatin or placebo treatment, sICAM-1 and sE-selectin levels were measured. The same parameters were measured in 20 control subjects (C) with normal cholesterol levels, matched for sex and age. HCh had sICAM-1 basal values higher than C (352.4+/-57.9 ng/ml versus 114.9+/-89.6 ng/ml; P<0.001); however, sE-selectin basal values were not different in the two groups. No correlation was observed between HCh sICAM-1 levels and cholesterol levels (total and low-density lipoprotein). Furthermore, cholesterol-lowering treatment with simvastatin did not significantly diminish sICAM-1 levels. Our findings would support the hypothesis that patients with isolated hypercholesterolemia and without clinical atherosclerosis may be silent carriers of arterial subendothelial inflammation, expressed as an increase of sICAM-1.
2001
- Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection?
[Articolo su rivista]
Schepis, Filippo; C., Cammà; D., Niceforo; A., Magnano; S., Pallio; M., Cinquegrani; G., D'Amico; L., Pasta; A., Craxì; A., Saitta; G., Raimondo
abstract
Our aims were to develop a noninvasive predictive tool to identify cirrhotic patients with esophageal varices and to evaluate whether portal Doppler ultrasonographic parameters may improve the value of other predictors. One hundred forty-three consecutive compensated cirrhotic patients underwent upper gastrointestinal endoscopy. Fourteen clinical, biochemical, ultrasonographic, and Doppler ultrasonographic parameters of each patient were also recorded. Esophageal varices were detected in 63 of the 143 patients examined (44\%; 95\% confidence interval [CI] 36.2-52.6). Medium and large esophageal varices were observed in 28 subjects (44\%; 95\% CI 31.4-58.4). Using stepwise logistic regression, presence of esophageal varices was independently predicted by prothrombin activity less than 70\% (odds ratio [OR]: 5.83; 95\% CI: 2.6-12.8), ultrasonographic portal vein diameter greater than 13 mm (OR: 2.92; 95\% CI: 1.3-6.4), and platelet count less than 100 x 10(9)/L (OR: 2.83; 95\% CI: 1.27-6.28). Variables included in the model were used to generate a simple incremental rule to evaluate each individual patient. The discriminating ability of the prediction rule was relevant (area under the curve: 0.80) and did not change by replacing ultrasonographic portal vein diameter with congestion index of portal vein. We concluded that compensated cirrhotic patients should be screened by upper gastrointestinal endoscopy when prothrombin activity less than 70\%, platelet count less than 100 x 10(9)/L, and ultrasonographic portal vein diameter greater than 13 mm are observed, whereas those without any of these predictors should not undergo endoscopy. The contribution provided by portal Doppler ultrasonographic parameters does not appear of practical utility.
1999
- MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1
[Articolo su rivista]
A. A., Bellacosa; L., Cicchillitti; Schepis, Filippo; A., Riccio; A. T., Yeung; Y., Matsumoto; E. A., Golemis; M., Genuardi; G., Neri
abstract
The DNA mismatch repair (MMR) is a specialized system, highly conserved throughout evolution, involved in the maintenance of genomic integrity. To identify novel human genes that may function in MMR, we employed the yeast interaction trap. Using the MMR protein MLH1 as bait, we cloned MED1. The MED1 protein forms a complex with MLH1, binds to methyl-CpG-containing DNA, has homology to bacterial DNA repair glycosylases/lyases, and displays endonuclease activity. Transfection of a MED1 mutant lacking the methyl-CpG-binding domain (MBD) is associated with microsatellite instability (MSI). These findings suggest that MED1 is a novel human DNA repair protein that may be involved in MMR and, as such, may be a candidate eukaryotic homologue of the bacterial MMR endonuclease, MutH. In addition, these results suggest that cytosine methylation may play a role in human DNA repair.
1998
- Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors.
[Articolo su rivista]
M., Bernardi; S., Calandra; A., Colantoni; F., Trevisani; M. L., Raimondo; G., Sica; Schepis, Filippo; M., Mandini; P., Simoni; M., Contin; G., Raimondo
abstract
Prolonged Q-T interval predicts severe arrhythmias and sudden death, and has been shown to occur in alcoholic liver disease and cirrhotic patients who are candidates for liver transplantation. This study first evaluated the prevalence of prolonged Q-T interval in a large population of unselected patients with cirrhosis, and assessed the relationship between abnormal Q-T, etiology, and severity of liver disease and mortality of patients. Possible causes of Q-T abnormality were also explored. Ninety-four patients with cirrhosis without overt heart disease and 37 control subjects with mild chronic active hepatitis were enrolled. Rate-corrected Q-T interval (Q-Tc) was assessed along with routine liver tests, Child-Pugh score, serum bile salts, electrolytes and creatinine, plasma renin activity, aldosterone, norepinephrine, atrial natriuretic factor and, gonadal hormones. Q-Tc was longer in patients with cirrhosis than in controls (440.3 +/- 3.2 vs. 393.6 +/- 3.7 ms; P < .001) and prolonged (> 440 ms) in 44 patients (46.8\%) and 2 controls (5.4\%; P < .001). Q-Tc length was not influenced by the etiology of cirrhosis and correlated with Child-Pugh score (r = .53; P < .001), liver tests such as prothrombin activity, and serum concentrations of albumin and bilirubin, plasma bile salts, and plasma norepinephrine. Multivariate analysis showed that only Child-Pugh score and plasma norepinephrine were independently correlated with Q-Tc duration. Over a median follow-up period of 19 months (range, 2-33 months), patients with Q-Tc longer than 440 ms had a significantly lower survival rate than those with normal Q-Tc. Q-T interval is frequently prolonged in patients with cirrhosis, regardless the etiology of the disease, worsens in parallel with the severity of the disease, and may have an important prognostic meaning. In addition to other undefined factors related to the severity of cirrhosis, sympathoadrenergic hyperactivity may play a pathogenetic role.
1997
- Outcome of liver disease and response to interferon treatment are not influenced by hepatitis B virus core gene variability in children with chronic type B hepatitis.
[Articolo su rivista]
Schepis, Filippo; G., Verucchi; T., Pollicino; L., Attard; S., Brancatelli; G., Longo; G., Raimondo
abstract
BACKGROUND/AIMS: Hepatitis B virus (HBV) core gene heterogeneity may influence the outcome of liver disease and the response to interferon (IFN) therapy in adult HBV carriers. The aim of this study was to evaluate the possible association between HBV core gene variability and evolution of chronic hepatitis in children. METHODS: We examined serum samples from 25 children with HBV chronic hepatitis and HBe antigen (HBeAg) positivity who were followed-up for a mean of 7.4 years. Seven cases spontaneously seroconverted to anti-HBe, becoming HBV healthy carriers; nine cases were successfully treated with IFN; nine cases were non-responders to IFN therapy. HBV-DNA was extracted from one serum sample ("I") collected during the HBeAg positive phase, and from a second sample ("II") collected after the anti-HBe seroconversion or, in non-responders, after stopping therapy. The entire core gene of the HBV isolates was amplified and sequenced. RESULTS: Each isolate showed single or no missense mutation independently of the clinical behavior of the patients. HBeAg-defective viruses were detected in one case in both samples and in two cases only in sample "II". CONCLUSIONS: Core gene variability does not seem to be involved either in the outcome of infection or in the response to IFN treatment in children with HBV chronic hepatitis. Considering that most of the HBV carriers in our area acquire the infection in childhood, our data suggest that core gene heterogeneity is not a major cause of progression to chronicity.