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IMPORTANCE: Indication for liver resection (LR) for localized hepatic metastases from breast cancer (BC) is still a matter of debate. OBJECTIVE: A literature review of recent scientific papers pertaining to hepatectomies for BC liver metastases (LM). EVIDENCE REVIEW: We based our systematic review on case series on literature reviews, comparative studies and cost-utility analysis which have been selected based on criteria regarding surgery, possible prognostic factors and evaluation of long-term survival. FINDINGS: There is a strong inhomogeneity in the reported data, with 5-year survivals ranging from 21% to 58%. There is no agreement in the evaluation of prognostic variables predicting good survival, with the only exception of the time of treatment of the primary BC until the diagnosis of metastases. Three out of the four comparative studies report better survivals for patients who underwent a hepatectomy in comparison to those treated with chemotherapy alone, but their strength in terms of scientific evidence is weak. The only cost-utility analysis revealed that 2 out of the 3 scenarios considered were in favor of the treatment with surgery followed by conventional chemotherapy. CONCLUSIONS: There is no definitive proof on the effectiveness of LRs for BC LM. Surgery can be proposed when it is possible to perform radical surgery, with R0 margins and saving at least 30% of the liver with its vascular and biliary connections. Stable skeletal metastases are not a contraindication. The interval between treatment of the primary location and diagnosis of hepatic metastases is the only prognosis criteria available.

Background and aims: We investigated the clinical impact of the newly defined metabolic-associated fatty liver disease (MAFLD) in patients undergoing hepatectomy for HCC (MAFLD-HCC) comparing the characteristics and outcomes of patients with MAFLD-HCC to viral- and alcoholic-related HCC (HCV-HCC, HBV-HCC, A-HCC). Methods: A retrospective analysis of patients included in the He.RC.O.Le.S. Group registry was performed. The characteristics, short- and long-term outcomes of 1315 patients included were compared according to the study group before and after an exact propensity score match (PSM). Results: Among the whole study population, 264 (20.1%) had MAFLD-HCC, 205 (15.6%) had HBV-HCC, 671 (51.0%) had HCV-HCC and 175 (13.3%) had A-HCC. MAFLD-HCC patients had higher BMI (p < 0.001), Charlson Comorbidities Index (p < 0.001), size of tumour (p < 0.001), and presence of cirrhosis (p < 0.001). After PSM, the 90-day mortality and severe morbidity rates were 5.9% and 7.1% in MAFLD-HCC, 2.3% and 7.1% in HBV-HCC, 3.5% and 11.7% in HCV-HCC, and 1.2% and 8.2% in A-HCC (p = 0.061 and p = 0.447, respectively). The 5-year OS and RFS rates were 54.4% and 37.1% in MAFLD-HCC, 64.9% and 32.2% in HBV-HCC, 53.4% and 24.7% in HCV-HCC and 62.0% and 37.8% in A-HCC (p = 0.345 and p = 0.389, respectively). Cirrhosis, multiple tumours, size and satellitosis seems to be the independent predictors of OS. Conclusion: Hepatectomy for MAFLD-HCC seems to have a higher but acceptable operative risk. However, long-term outcomes seems to be related to clinical and pathological factors rather than aetiological risk factors.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and its incidence is correlated with infections, chronic inflammation, diet, and genetic factors. An emerging aspect is that microbial dysbiosis and chronic infections triggered by certain bacteria can be risk factors for tumor progression. Recent data suggest that certain bacterial toxins implicated in DNA attack or in proliferation, replication, and death can be risk factors for insurgence and progression of CRC. In this study, we recruited more than 300 biopsy specimens from people undergoing colonoscopy, and we analyzed to determine whether a correlation exists between the presence of bacterial genes coding for toxins possibly involved in CRC onset and progression and the different stages of CRC. We also analyzed to determine whether CRC-predisposing genetic factors could contribute to bacterial toxins response. Our results showed that CIF toxin is associated with polyps or adenomas, whereas pks+ seems to be a predisposing factor for CRC. Toxins from Escherichia coli as a whole have a higher incidence rate in adenocarcinoma patients compared to controls, whereas Bacteroides fragilis toxin does not seem to be associated with pre-cancerous nor with cancerous lesions. These results have been obtained irrespectively of the presence of CRC-risk loci.

Background: Hepatocellular carcinoma (HCC) is frequently diagnosed as multinodular. This study aims to assess prognostic factors for survival and identify patients with multiple HCC who may benefit from surgery beyond the Barcelona Clinic Liver Cancer classification indications. Methods: This retrospective study included all the consecutive patients from 4 Italian tertiary centers receiving liver resection for naive multiple HCC between 1990 and 2012 to have a potential follow-up of 5 years. Results: Included patients were 144. Ninety-day morbidity and mortality rates were 38.3% and 8.3%, respectively. The 5-year overall and disease-free survival rates were 33.3% and 19.1%, respectively. Tumor size

Primary leiomyoma of the liver (PLL) is a rare benign tumor occurring in immunosuppressed people. From 1926 less than fifty cases are reported in the scientific literature and about half are in immunocompetent patients. Etiology of this kind of lesion is not yet well known. We report a case of primary hepatic leiomyoma in a 60-year-old immunocompetent woman. The patient presented with lipothymia with unexpected vomiting. She underwent an ultrasound (US), and a computed tomography (CT) scan that revealed the presence of a single, solid lesion about 9 cm located between the S5 and S8 segment of the liver. It showed a well-defined, heterogeneous hypodensity with internal and peripheral enhancement and various central hypoattenuating areas and no wash-out in the portal and the late phases. Because of her symptoms and the risk of malignancy, the patient underwent a surgical liver resection. Histological diagnosis was primary leiomyoma of the liver. The patient had an uneventful recovery and was discharged after 7 days. At 30 months follow-up there were no symptoms and no evidence of disease. Leiomyoma of the liver is a rare benign neoplasm of which clinical symptoms are nonspecific and the exact radiological diagnosis still remains a challenge for radiologists. Etiology is still unclear and usually PLL represents an incidental diagnosis. Surgery plays a primary role not only in the treatment algorithm, but also in the diagnostic workout.

Background: Laparoscopic surgery is a choice of treatment for liver diseases; it can decrease postoperative morbidity and length of hospital stay (LOS). Hepatocellular carcinoma (HCC) in patients w...

Background and aimsAbout 15% of intrahepatic cholangiocarcinoma (iCCA) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), most often in concert with mutationally inactivated TP53, CDKN2A or BAP1. FFs span residues 1-768 of FGFR2 fused to sequences encoded by any of a long list (>60) of partner genes, a configuration sufficient to ignite oncogenic FF activation. In line, FGFR-specific tyrosine kinase inhibitors (F-TKI) were shown to provide clinical benefit in FF+ iCCA, although responses were partial and/or limited by resistance mechanisms, including the FF V565F gatekeeper mutation. Herein we present an FF-driven murine iCCA model and exploit its potential for pre-clinical studies on FF therapeutic targeting.MethodsFour iCCA FFs carrying different fusion sequences were expressed in Tp53-/- mouse liver organoids. Tumorigenic properties of genetically modified liver organoids were assessed by intrahepatic/subcutaneous transplantation in immuno-deficient mice. Cellular models derived from neoplastic lesions were exploited for pre-clinical studies.ResultsTumors diagnosed as CCA were obtained upon transplantation of FF-expressing liver organoids. The penetrance of this tumorigenic phenotype was influenced by FF identity. Tumor organoids and 2D cell lines derived from CCA lesions were addicted to FF signaling via Ras-Erk, regardless of FF identity or presence of V565F mutation. Double blockade of FF-Ras-Erk pathway by concomitant pharmacological inhibition of FFs and Mek1/2 provided greater therapeutic efficacy than single agent F-TKI in vitro and in vivo.ConclusionsFF-driven iCCA pathogenesis was successfully modelled in murine Tp53-/- background. This model revealed biological heterogeneity among structurally different FFs. Double blockade of FF-Erk signaling deserves consideration for improving precision-based approaches against human FF+ iCCA.Abbreviations used in this paper: ANOVA, analysis of variance; Bap1, BRCA1-Associated-Protein 1; Cdkn2a, cyclin-dependent kinase inhibitor 2A; Cftr, cystic fibrosis transmembrane conductance regulator; Ck19, cytokeratin 19; Cyp3A, cytochrome P450, family 3, subfamily A; EGF, Epidermal growth factor; EGFR, Epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; Erk, extracellular signal–regulated kinase; FGFR2, fibroblast growth factor receptor 2; FRS2, fibroblast growth factor receptor substrate 2; GRB2, growth factor receptor-bound 2; GSEA, gene set enrichment analysis; GSVA, gene set variation analysis; H&E, hematoxylin and eosin; HepPar1, hepatocyte Paraffin 1; Hnf4α-7, hepatocyte nuclear factor 4 alpha; Hprt, hypoxanthine-guanine phosphoribosyl transferase; LGR5, leucine-rich repeat-containing G-protein coupled receptor 5; NTRK, neurotrophic Tyrosine Kinase; Parp, Poly (ADP-ribose) polymerase; RECIST, response evaluation criteria in solid tumors; SHP2, Src homology phosphatase 2; Ttr, transthyretin.

Background: We aimed to assess the ability of comprehensive complication index (CCI) and Clavien-Dindo complication (CDC) scale to predict excessive length of hospital stay (e-LOS) in patients undergoing liver resection for hepatocellular carcinoma. Methods: Patients were identified from an Italian multi-institutional database and randomly selected to be included in either a derivation or validation set. Multivariate logistic regression models and ROC curve analysis including either CCI or CDC as predictors of e-LOS were fitted to compare predictive performance. E-LOS was defined as a LOS longer than the 75th percentile among patients with at least one complication. Results: A total of 2669 patients were analyzed (1345 for derivation and 1324 for validation). The odds ratio (OR) was 5.590 (95%CI 4.201, 7.438) for CCI and 5.507 (4.152, 7.304) for CDC. The AUC was 0.964 for CCI and 0.893 for CDC in the derivation set and 0.962 vs. 0.890 in the validation set, respectively. In patients with at least two complications, the OR was 2.793 (1.896, 4.115) for CCI and 2.439 (1.666, 3.570) for CDC with an AUC of 0.850 and 0.673, respectively in the derivation cohort. The AUC was 0.806 for CCI and 0.658 for CDC in the validation set. Conclusions: When reporting postoperative morbidity in liver surgery, CCI is a preferable scale.

In our study, we investigated the role of CD39 on tumor-infiltrating CD8+ T lymphocytes (CD8+ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T-cell exhaustion, we demonstrated a divergent functional activity in CD39+ CD8+ TILs. On the one hand, CD39+ CD8+ TILs (as compared to their CD39- counterparts) produced significantly lower IFN-γ and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39+ CD8+ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8+ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39+ CD8+ T-cell effector function ex vivo, and that CD39+ CD8+ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39+ CD8+ T-cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8+ TILs.

OBJECTIVE: The aim of this study was to evaluate correlation between centers' volume and incidence of failure to rescue (FTR) following liver resection for hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: FTR, defined as the probability of postoperative death among patients with major complication, has been proposed to assess quality of care during hospitalization. Perioperative management is challenging in cirrhotic patients and the ability to recognize and treat a complication may be fundamental to rescue patients from the risk of death. METHODS: Patients undergoing liver resection for HCC between 2008 and 2018 in 18 Centers enrolled in the He.Rc.O.Le.S. Italian register. Early results included major complications (Clavien ≥3), 90-day mortality, and FTR and were analyzed according to center's volume. RESULTS: Among 1935 included patients, major complication rate was 9.4% (8.6%, 12.3%, and 7.0% for low-, intermediate- and high-volume centers, respectively, P = 0.001). Ninety-day mortality rate was 2.6% (3.7%, 4.2% and 0.9% for low-, intermediate- and high-volume centers, respectively, P < 0.001). FTR was significantly higher at low- and intermediate-volume centers (28.6% and 26.5%, respectively) than at high-volume centers (6.1%, P = 0.002). Independent predictors for major complications were American Society of Anesthesiologists (ASA) >2, portal hypertension, intraoperative blood transfusions, and center's volume. Independent predictors for 90-day mortality were ASA >2, Child-Pugh score B, BCLC stage B-C, and center's volume. Center's volume and BCLC stage were strongly associated with FTR. CONCLUSIONS: Risk of major complications and mortality was related with comorbidities, cirrhosis severity, and complexity of surgery. These factors were not correlated with FTR. Center's volume was the only independent predictor related with severe complications, mortality, and FTR.

Background: Recently, the minimally invasive surgical approach has been available for performing liver resections (LRs) with laparoscopic and robotic techniques. The robotic approach for LRs seems to overcome several laparoscopic limitations, which is a valid alternative when performed in high volume and specialized centers. Laparoscopic difficulty score systems (DSSs) should serve to guide the surgeon's choice in the best surgical approach to adopt for every single patient, giving the possibility to switch to the open approach when needed. To this day, no specific robotic difficulty scores exist. The aim of our study was to verify the feasibility of applying these scores and related updates on robotic LRs performed in our Institute.Materials and Methods: Out of a total of 683 LRs performed from June 2010 to July 2019, 60 were performed through using a mini invasive approach and of these 18 were performed robotically. The Ban DSS and subsequently the modified Iwate DSS were applied to our cases.Results: Based on our findings, applying the DSS we divided our series into two groups: a low difficulty level group (1-3) made up of 5 patients, and an intermediate difficulty level group (4-6) consisting of 13 patients. Average Ban DSS and subsequently updated score system results were 4.6 +/- 1.5 points (range 2-6) for both scores.Conclusions: Difficulties were encountered in applying the score when simultaneous multiple wedge resections were performed. The laparoscopic DSS is applicable to robotic LRs with some limitations due to the peculiarity of the two different minimally invasive approaches. A specific robotic difficulty rating score could be necessary to include these elements.

Background: To analyze long-term results and risk of relapse in the clinical TNM stages II and III, mid-low rectal cancer patients (RC pts), treated with transanal local excision (LE) after major response to neoadjuvant chemoradiation (n-CRT). Methods: Thirty-two out of 345 extraperitoneal cT3–4 or N+ RC pts (9.3%) underwent LE. Inclusion criteria: extraperitoneal RC, adenocarcinoma, ECOG Performance Status ≤2. Pts with distant metastases were excluded. Results: All pts showed histologically clear margins of resection and 81.2% were restaged ypT0/mic/1. Nine out of 32 (28.1%) pts relapsed: 7 (21.8%) showed a local recurrence, of which 5 (15.6%) at the endorectal suture, 1 (3.1%) pelvic and 1 (3.1%) mesorectal. Two pts (6.2%) relapsed distantly. Among the pT0/1, 11.5% relapsed vs 100% of the pT2 and pT4 ones. The six pts relapsing locally or in the mesorectal fat underwent a salvage total mesorectal excision surgery. The old patient with pelvic recurrence relapsed after 108 months and underwent a re-irradiation; the two pts with distant metastases were treated with chemotherapy followed by radical surgery. Conclusions: Presently combined approach seems a valid option in major responders, confirming its potential curative impact in the ypT0/mic/1 pts. A strict selection of pts is basic to obtain favourable results.

An appraisal of recent data highlighting aspects inspired by the new Geroscience perspective are here discussed. The main findings are summarized as follows: i) liver has to be considered an immunological organ, and new studies suggest a role for the recently described cells named telocytes; ii) the liver-gut axis represents a crucial connection with environment and life style habits and may influence liver diseases onset; iii) the physiological aging of liver shows relatively modest alterations. Nevertheless, several molecular changes appear to be relevant: a) an increase of microRNA-31-5p; -141-3p; -200c-3p expressions after 60 years of age; b) a remodeling of genome-wide DNA methylation profile evident until 60 years of age and then plateauing; c) changes in transcriptome including the metabolic zones of hepatocyte lobules; d) liver undergoes an accelerated aging in presence of chronic inflammation/liver diseases in a sort of continuum, largely as a consequence of unhealthy life styles and exposure to environmental noxious agents. We argue that chronic liver inflammation has all the major characteristics of "inflammaging" and likely sustains the onset and progression of liver diseases. Finally, we propose to use a combination of parameters, mostly obtained by omics such as transcriptomics and epigenomics, to evaluate in deep both the biological age of liver (in comparison with the chronological age) and the effects of donor-recipient age-mismatches in the context of liver transplants.

Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0–2.5 μM) of OCA were added to culture media and, after 3–10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 μM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.

Transgenic mouse models designed to recapitulate genetic and pathologic aspects of cancer are useful to study early stages of disease as well as its progression. Among several, two of the most sophisticated models for pancreatic ductal adenocarcinoma (PDAC) are the LSL-Kras(G12D/+);Pdx-1-Cre (KC) and LSL-Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre (KPC) mice, in which the Cre-recombinase regulated by a pancreas-specific promoter activates the expression of oncogenic Kras alone or in combination with a mutant p53, respectively. Non-invasive in vivo imaging offers a novel approach to preclinical studies introducing the possibility to investigate biological events in the spatio/temporal dimension. We recently developed a mouse model, MITO-Luc, engineered to express the luciferase reporter gene in cells undergoing active proliferation. In this model, proliferation events can be visualized non-invasively by bioluminescence imaging (BLI) in every body district in vivo. Here, we describe the development and characterization of MITO-Luc-KC- and -KPC mice. In these mice we have now the opportunity to follow PDAC evolution in the living animal in a time frame process. Moreover, by relating in vivo and ex vivo BLI and histopathological data we provide evidence that these mice could represents a suitable tool for pancreatic cancer preclinical studies. Our data also suggest that aberrant proliferation events take place early in pancreatic carcinogenesis, before tumour appearance.

Background: The role of liver transplant (LT) for neuroendocrine liver metastasis (NELM) has not been completely defined. While international guidelines included LT as a potential treatment for highly selected patients with advanced NELM, recently, LT has been proposed as an alternative curative treatment for NELM for patients meeting restrictive criteria (Milan criteria). Methods: Using a multi-institutional cohort of patients undergoing liver resection for NELM, the long-term outcomes of patients meeting Milan criteria (resected NET drained by the portal system, stable disease/response to therapies for at least 6 months, metastatic diffusion to < 50% of the total liver volume, a confirmed histology of low-grade, and ≤ 60 years) were investigated. Results: Among the 238 patients included in the study, 28 (12%) patients met the Milan criteria for LT with a 5-year OS of 83%. Furthermore, among patients meeting Milan criteria, subsets of patients with favorable clinic-pathological characteristics had 5-year OS rates greater than 90% including G1 patients (5-year OS, 92%), patients undergoing minor liver resection (5-year OS, 94%), patients with low number of NELM (1–2 NELM), and small tumor size (< 3 cm) (for both groups of patients, 5-year OS, 100%). Conclusions: In our series, only 12% of patients met Milan criteria, and the 5-year OS after liver resection for this small selected group of patients was comparable with that reported in the literature for patients undergoing LT for NELM within Milan criteria. While LT might be the optimal treatment for patients with unresectable NELM, surgical resection should be the first option for patients with resectable NELM.

The tumor regression grade (TRG) role was investigated by multiple correspondence analysis (MCA) in 174 low rectal cancer patients undergone neoadjuvant chemoradiation and radical surgery, with a minimum follow-up of 10 years. The TRG 1 and 2 showed better survival than TRG 4 and 5 subgroups. MCA allocated TRG 3 together with other prognostic variables better than multivariate analysis. Background: The role of Mandard's tumor regression grade (TRG) classification is still controversial in defining the prognostic role of patients who have undergone neoadjuvant chemoradiation (CRT) and total mesorectal excision. The present study evaluated multiple correspondence analysis (MCA) as a tool to better cluster variables, including TRG, for a homogeneous prognosis. Patients and Methods: A total of 174 patients with a minimum follow-up period of 10 years were stratified into 2 groups: group A (TRG 1-3) and group B (TRG 4-5) using Mandard's classification. Overall survival and disease-free survival were analyzed using univariate and multivariate analysis. Subsequently, MCA was used to analyze TRG plus the other prognostic variables. Results: The overall response to CRT was 55.7%, including 13.2% with a pathologic complete response. TRG group A correlated strictly with pN status (P =.0001) and had better overall and disease-free survival than group B (85.1% and 75.6% vs. 71.1% and 67.3%; P =.06 and P =.04, respectively). The TRG 3 subset (about one third of our series) showed prognostically heterogeneous behavior. In addition to multivariate analysis, MCA separated TRG 1 and TRG 2 versus TRG 4 and TRG 5 well and also allocated TRG 3 patients close to the unfavorable prognostic variables. Conclusion: TRG classification should be used in all pathologic reports after neoadjuvant CRT and radical surgery to enrich the prognostic profile of patients with an intermediate risk of relapse and to identify patients eligible for more conservative treatment. Thus, MCA could provide added value.

Introduction The aim of this study is to analyze the evolution of pancreatectomy with venous resection in 10 referral Italian centers in the last 25 years. Methods A multicenter database of 425 patients submitted to pancreatectomy with venous resection between 1991 and 2015 was retrospectively analyzed. Patients were classified in 5 periods: 1 (1991–1995); 2 (1996–2000); 3 (2001–2005); 4 (2006–2010); 5 (2011–2015). Indications and outcomes were compared according to the period of surgery. Results Nineteen patients were operated in period 1, 28 in period 2, 91 in period 3, 140 in period 4, and 147 in period 5. Use of neoadjuvant therapy increased from 0% in period 1 and 2–12.1% in period 5. Postoperative complications ranged from 46.3% to 67.8%, and mortality from 5.3% to 9.2%. Median survival progressively increased, from 6 months in period 1–16 months in period 2, 24 months in period 3 and 4 and 35 months in period 5 (p = 0.004). Period, venous and nodal invasion were significant prognostic factors for survival. Conclusion Management and outcomes of pancreatectomy with venous resection have evolved in the last 25 years in Italy. Improvement in patients' multidisciplinary management has lead to significant improvement of median survival.

The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8,823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria, we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally, we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt-signaling pathways in the aging of human liver.

Cholangiocarcinomas (CCAs) comprise a mucin-secreting form, intrahepatic or perihilar, and a mixed form located peripherally. We characterized cancer stem cells (CSCs) in CCA subtypes and evaluated their cancerogenic potential. CSC markers were investigated in 25 human CCAs in primary cultures and established cell lines. Tumorigenic potential was evaluated in vitro or in xenografted mice after s.c. or intrahepatic injection in normal and cirrhotic (carbon tetrachloride-induced) mice. CSCs comprised more than 30% of the tumor mass. Although the CSC profile was similar between mucin-intrahepatic and mucin-perihilar subtypes, CD13 + CSCs characterized mixed-intrahepatic, whereas LGR5 + characterized mucin-CCA subtypes. Many neoplastic cells expressed epithelial-mesenchymal transition markers and coexpressed mesenchymal and epithelial markers. In primary cultures, epithelial-mesenchymal transition markers, mesenchymal markers (vimentin, CD90), and CD13 largely predominated over epithelial markers (CD133, EpCAM, and LGR5). In vitro , CSCs expressing epithelial markers formed a higher number of spheroids than CD13 + or CD90 + CSCs. In s.c. tumor xenografts, tumors dominated by stromal markers were formed primarily by CD90 + and CD13 + cells. By contrast, in intrahepatic xenografts in cirrhotic livers, tumors were dominated by epithelial traits reproducing the original human CCAs. In conclusion, CSCs were rich in human CCAs, implicating CCAs as stem cell–based diseases. CSC subpopulations generate different types of cancers depending on the microenvironment. Remarkably, CSCs reproduce the original human CCAs when injected into cirrhotic livers.

International audience; BACKGROUND:Choice of calcineurin inhibitor may influence response to antiviral therapy in liver transplant patients with hepatitis C virus (HCV) infection.MATERIAL AND METHODS:In a randomized, multicenter, 80-week trial, liver transplant recipients (>6 months and £10 years post-transplant) with recurrent HCV infection received cyclosporine (n=50) or tacrolimus (n=42) with a 48-week course of pegylated interferon (peg-IFNα2a) and ribavirin. Twenty-three patients in each group completed the trial on study medication. The primary endpoint was sustained virological response (SVR) 24 weeks after the end of antiviral therapy, for which 43 patients were eligible for analysis.RESULTS:The rate of SVR was 60.0% (12/20) with cyclosporine and 43.5% (10/23) with tacrolimus (adjusted odds ratio 1.85; 95% CI 0.53-6.43; p=0.331). There were no significant intergroup differences for rapid or early virological response, relapse, HCV RNA viral load, or fibrosis progression. One cyclosporine-treated patient experienced acute rejection. One patient died in each group. Adverse events, treatment-related adverse events, and serious adverse events were similar between groups.CONCLUSIONS:Since fewer patients were recruited than planned (92 versus 355), the study was underpowered and robust conclusions cannot be drawn regarding the effect of cyclosporine and tacrolimus on virological responses to antiviral treatment for recurrent HCV after liver transplantation. However, as reported in other trials, SVR was higher in cyclosporine-treated patients.

Background The UICC/AJCC TNM staging system classifies lymph nodes as N0 and N1 in pancreatic cancer. Aim of the study is to determine whether the number of examine nodes, the nodal ratio (NR) and the logarithm odds of positive lymph nodes (LODDS) may better stratify the prognosis of patients undergoing pancreatectomy combined with venous resection for pancreatic cancer with venous involvement. Methods A multicenter database of 303 patients undergoing pancreatectomy in 9 Italian referral centers was analyzed. The prognostic impact of number of retrieved and examined nodes, NR, LODDS was analyzed and compared with ROC curves analysis, Pearson test, univariate and multivariate analysis. Results The number of metastatic nodes, pN, the NR and LODDS was significantly correlated with survival at multivariate analyses. The corresponding AUC for the number of metastatic nodes, pN, the NR and LODDS were 0.66, 0.69, 0.63 and 0.65, respectively. The Pearson test showed a significant correlation between the number of retrieved lymph nodes and number of metastatic nodes, pN and the NR. LODDS had the lower coefficient correlation. Concerning N1 patients, the NR, the LODDS and the number of metastatic nodes were able to significantly further stratify survival (p = 0.040; p = 0.046; p = 0.038, respectively). Conclusions The number of examined lymph nodes, the NR and LODDS are useful for further prognostic stratification of N1 patients in the setting of pancreatectomy combined with PV/SMV resection. No superiority of one over the others methods was detected.

// Davide Gentilini 1 , Stefania Scala 2 , Germano Gaudenzi 3 , Paolo Garagnani 4, 5 , Miriam Capri 4, 5 , Matteo Cescon 6 , Gian Luca Grazi 7 , Maria Giulia Bacalini 8 , Serena Pisoni 1 , Alessandra Dicitore 1 , Luisa Circelli 9 , Sara Santagata 2 , Francesco Izzo 10 , Anna Maria Di Blasio 1 , Luca Persani 1, 3 , Claudio Franceschi 4, 5, 8 and Giovanni Vitale 1, 3 1 Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy 2 Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS Fondazione “G. Pascale”, Napoli, Italy 3 Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy 4 Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna, Bologna, Italy 5 Interdepartmental Center "L. Galvani", University of Bologna, Bologna, Italy 6 DIMEC-Department of General Surgery and Medicine Sciences, S. Orsola-Malpighi Hospital, Bologna, Italy. 7 Regina Elena National Cancer Institute Via Elio Chianesi 53, Rome, Italy 8 IRCCS Institute of Neurological Sciences, Bologna, Italy 9 Department of Experimental Oncology, Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, Napoli, Italy 10 Department of Surgical Oncology, Abdominal and Hepatobiliary Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS Fondazione “ G. Pascale”, Napoli, Italy Correspondence to: Giovanni Vitale, email: giovanni.vitale@unimi.it Keywords: hepatocellular carcinoma, stochastic epigenetic mutation, epigenetics, DNA methylation, genome-wide Received: January 27, 2017 Accepted: April 15, 2017 Published: April 27, 2017 ABSTRACT Hepatocellular carcinoma (HCC) results from accumulation of both genetic and epigenetic alterations. We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical approach has been adopted to identify Stochastic Epigenetic Mutations (SEMs) in HCC. HCC and peritumoral tissues showed a different epigenetic profile, mainly characterized by loss of DNA methylation in HCC. Total number of SEMs was significantly higher in HCC tumor (median: 77,370) than in peritumoral (median: 5,656) tissues and correlated with tumor grade. A significant positive association emerged between SEMs measured in peritumoral tissue and hepatitis B and/or C virus infection status. A restricted number of SEMs resulted to be shared by more than 90% of HCC tumor samples and never present in peritumoral tissue. This analysis allowed the identification of four epigenetically regulated candidate genes (AJAP1, ADARB2, PTPRN2, SDK1), potentially involved in the pathogenesis of HCC. In conclusion, HCC showed a methylation profile completely deregulated and very far from adjacent non-cancerous liver tissues. The SEM analysis provided valuable clues for further investigations in understanding the process of tumorigenesis in HCC.

Summary To understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12–92 years before transplants and in 11 biopsies after transplants with high donor–recipient age-mismatch. We also assessed liver function in 36 age-mismatched recipients. The major findings were the following: (i) miR-31-5p, miR-141-3p, and miR-200c-3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT–qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age-dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR-31-5p and miR-200c-3p, and both its mRNA (RT–qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR-31-5p, miR-141-3p and miR-200c-3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor–recipient extreme age-mismatch; (v) the analysis of recipients plasma by N-glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age-mismatch, and recipients apparently ‘rejuvenated’ according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor–recipient age-mismatches in transplantation, and offered positive evidence for the use of organs from old donors.

// Valeria Canu 1,* , Andrea Sacconi 1,* , Laura Lorenzon 2 , Francesca Biagioni 1 , Federica Lo Sardo 1 , Maria Grazia Diodoro 4 , Paola Muti 5 , Alfredo Garofalo 3 , Sabrina Strano 5,6 , Antonietta D’Errico 7 , Gian Luca Grazi 3 , Mario Cioce 1 and Giovanni Blandino 1,5 1 Oncogenomic and Epigenetic Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy 2 Faculty of Medicine and Psychology, Surgical and Medical Department of Clinical Sciences, Biomedical Technologies and Translational Medicine, University of Rome ‘La Sapienza’, Sant’Andrea Hospital, Rome, Italy 3 HepatoBiliary Pancreatic Surgery, ‘Regina Elena’ National Cancer Institute, Rome, Italy 4 Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy 5 Department of Oncology, Juravinski Cancer Center, McMaster University Hamilton, Hamilton, Ontario, Canada 6 Molecular Chemoprevention Group, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy 7 Department of Medical and Surgical Sciences, Pathology Unit, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna, Italy * These authors have equally contributed to this work Correspondence to: Giovanni Blandino, email: // Keywords : gastric cancer, cholangiocarcinoma, micro-RNA, miR-204, prognostic Received : September 18, 2016 Accepted : January 27, 2017 Published : February 11, 2017 Abstract Background & Aims: There is high need of novel diagnostic and prognostic tools for tumors of the digestive system, such as gastric cancer and cholangiocarcinoma. We recently found that miR-204 was deeply downregulated in gastric cancer tissues. Here we investigated whether this was common to other tumors of the digestive system and whether this elicited a miR-204-dependent gene target signature, diagnostically and therapeutically relevant. Finally, we assessed the contribution of the identified target genes to the cell cycle progression and clonogenicity of gastric cancer and cholangiocarcinoma cell lines. Methods: We employed quantitative PCR and Affymetrix profiling for gene expression studies. In silico analysis aided us to identifying a miR-204 target signature in publicly available databases (TGCA). We employed transient transfection experiments, clonogenic assays and cell cycle profiling to evaluate the biological consequences of miR-204 perturbation. Results: We identified a novel miR-204 gene target signature perturbed in gastric cancer and in cholangiocarcinoma specimens. We validated its prognostic relevance and mechanistically addressed its biological relevance in GC and CC cell lines. Conclusions: We suggest that restoring the physiological levels of miR-204 in some gastrointestinal cancers might be exploited therapeutically.

Objective: To optimize the results of low-volume (LV) centers for hepatopancreaticobiliary (HPB) surgery. Background: High-volume (HV) centers for HPB surgery have lower mortality than LV. Strategies for collaboration between HV and LV centers are not well investigated. Methods: Postoperative outcomes of patients undergoing curative HPB resection were evaluated at an LV hospital before (2006-2008) and during the collaboration (2009-2012) and at 2 hospitals with HV for either liver or pancreatic resection (2009-2012). Itinerant tutor surgeons from the HV centers were involved in the pre-, intra- And postoperative course of HPB patients at the LV hospital. Results: HPB cases at the LV center increased from 18 to 40 patients per year from 2006 to 2012, whereas 6-month postoperative mortality decreased from 17.8% (2006-2008) to 6% (2009-2012), P < 0.05 (liver: 10.3% vs 4.7% and pancreas: 29.4% vs 7.9%). During the collaborative study period, outcomes for hepatectomy were similar for LV and HV (85 vs 507 cases): postoperative Clavien-Dindo scores 4 and 5 were 2% and 0.2% for HV versus 2.4% and 1.2% for LV, respectively. Outcomes for pancreatic procedures (LV 63 vs HV 269 cases) showed better postoperative Clavien-Dindo scores 4 and 5 in the HV (0.7% score 4 and 1.5% score 5 for HV vs 3.2% and 6.3%, respectively, for LV) but the difference disappeared in the last 2 years (2011-2012) and matching the cases. Conclusions: Our partnership model helped improve postoperative outcomes at the LV center. Results at the LV hospital were comparable with the HV centers, although 2 years of partnership were required to achieve this in pancreatic surgery.

Even though surgery remains the only potentially curative option for patients with neuroendocrine liver metastases, the factors determining a patient's prognosis following hepatectomy are poorly understood. Using a multicentric database including patients who underwent hepatectomy for NELMs at seven tertiary referral hepato-biliary-pancreatic centers between January 1990 and December 2014, we sought to identify the predictors of survival and develop a clinical tool to predict patient's prognosis after liver resection for NELMs. The median age of the 238 patients included in the study was 61.9 years (interquartile range 51.5-70.1) and 55.9 % (n = 133) of patients were men. The number of NELMs (hazard ratio = 1.05), tumor size (HR = 1.01), and Ki-67 index (HR = 1.07) were the predictors of overall survival. These variables were used to develop a nomogram able to predict survival. According to the predicted 5-year OS, patients were divided into three different risk classes: 19.3, 55.5, and 25.2 % of patients were in low (> 80 % predicted 5-year OS), medium (40-80 % predicted 5-year OS), and high (< 40 % predicted 5-year OS) risk classes. The 10-year OS was 97.0, 55.9, and 20.0 % in the low, medium, and high-risk classes, respectively (p < 0.001). We developed a novel nomogram that accurately (c-index > 70 %) staged and predicted the prognosis of patients undergoing liver resection for NELMs.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease in need of prognostic markers to address therapeutic choices. We have previously shown that alternative splicing of the actin regulator, hMENA, generates hMENA11a, and hMENAΔv6 isoforms with opposite roles in cell invasion. We examined the expression pattern of hMENA isoforms by immunohistochemistry, using anti-pan hMENA and specific anti-hMENA11a antibodies, in 285 PDACs, 15 PanINs, 10 pancreatitis, and normal pancreas. Pan hMENA immunostaining, absent in normal pancreas and low-grade PanINs, was weak in PanIN-3 and had higher levels in virtually all PDACs with 64% of cases showing strong staining. Conversely, the anti-invasive hMENA11a isoform only showed strong staining in 26% of PDAC. The absence of hMENA11a in a subset (34%) of pan-hMENA-positive tumors significantly correlated with poor outcome. The functional effects of hMENA isoforms were analyzed by loss and gain of function experiments in TGF-β1-treated PDAC cell lines. hMENA11a knock-down in PDAC cell lines affected cell–cell adhesion but not invasion. TGF-β1 cooperated with β-catenin signaling to upregulate hMENA and hMENAΔv6 expression but not hMENA11a In the absence of hMENA11a, the hMENA/hMENAΔv6 up-regulation is crucial for SMAD2-mediated TGF-β1 signaling and TGF-β1-induced EMT. Since the hMENA isoform expression pattern correlates with patient outcome, the data suggest that hMENA splicing and related pathways are novel key players in pancreatic tumor microenvironment and may represent promising targets for the development of new prognostic and therapeutic tools in PDAC.

none 12 no Purpose: The role of pancreatectomy with en bloc venous resection and the prognostic impact of pathological venous invasion are still debated. The authors analyzed perioperative, survival results, and prognostic factors of pancreatectomy with en bloc portal (PV) or superior mesenteric vein (SMV) resection for borderline resectable pancreatic carcinoma, focusing on predictive factors of histological venous invasion and its prognostic role. Methods: A multicenter database of 406 patients submitted to pancreatectomy with en bloc SMV and/or PV resection for pancreatic adenocarcinoma was analyzed retrospectively. Univariate and multivariate analysis of factors related to histological venous invasion were performed using logistic regression model. Prognostic factors were analyzed with log-rank test and multivariate proportional hazard regression analysis. Results: Complications occurred in 51.9 % of patients and postoperative death in 7.1 %. Histological invasion of the resected vein was confirmed in 56.7 % of specimens. Five-year survival was 24.4 % with median survival of 24 months. Vein invasion at preoperative computed tomography (CT), N status, number of metastatic lymph nodes, preoperative serum albumin were related to pathological venous invasion at univariate analysis, and vein invasion at CT was independently related to venous invasion at multivariate analysis. Use of preoperative biliary drain was significantly associated with postoperative complications. Multivariate proportional hazard regression analysis demonstrated a significant correlation between overall survival and histological venous invasion and administration of adjuvant therapy. Conclusions: This study identifies predictive factors of pathological venous invasion and prognostic factors for overall survival, including pathological venous invasion, which may help with patients’ selection for different treatment protocols. Ramacciato, Giovanni; Nigri, Giuseppe; Petrucciani, Niccolò; Pinna, Antonio Daniele; Ravaioli, Matteo; Jovine, Elio; Minni, Francesco; Grazi, Gian Luca; Chirletti, Piero; Tisone, Giuseppe; Napoli, Niccolò; Boggi, Ugo Ramacciato, Giovanni; Nigri, Giuseppe; Petrucciani, Niccolò; Pinna, Antonio Daniele; Ravaioli, Matteo; Jovine, Elio; Minni, Francesco; Grazi, Gian Luca; Chirletti, Piero; Tisone, Giuseppe; Napoli, Niccolò; Boggi, Ugo

Introduction To report our experience on associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in patients with liver tumors. Methods ALPPS is a surgical technique that allows hepatic resection after rapid liver hypertrophy. Results Thirteen operations were performed: 8 for hepatocellular carcinoma (HCC) with liver cirrhosis (LC) and 5 for colorectal liver metastases (CRLM, n = 3) and cholangiocarcinoma (CC, n = 2) in normal livers (NL). Of the 11 men (85%), the median age was 60 years (range 36–74). Six (75%) HCC patients had BCLC stage C and 2 (25%) had BCLC stage B disease. The median % future liver remnant (FLR) volume increase was 71.7% in patients with LC and 64.8% in NL (p = 0.44). Twelve patients achieved a sufficient FLR growth after the first stage (92.3% efficacy). Four right trisectorectomies and 9 right hepatectomies were performed. All patients completed the second stage (100% feasibility). R0 resection was achieved in all cases. The 90-day mortality rate was 23.1% (12.5% for HCC patients with LC vs 40% for CRLM and CC patients with NL, p = 0.13). After the first stage the overall morbidity rates were 62.5% and 80% (p = 0.61), whereas after the second stage they were 87.5% and 80% in patients with LC and NL respectively (p = 0.99). At a median follow-up of 15 months (range 1–27), the median DFS was 9 months (CI95% 6–12), and the 1yr-DFS was 42%. The median survival was 25 months (CI95% 10–40), and the 1-yr overall survival was 74%. Conclusions ALPPS induced a considerable and comparable FLR growth in HCC patients with liver cirrhosis and patients with CRLM and CC with normal liver parenchyma. HCC patients who underwent ALPPS had a high rate of macrovascular tumor involvement. A high rate of R0 resection is expected in properly selected patients.

Background: Posthepatectomy liver failure is one of the most feared complications in extended hepatic resections. In 2012, a novel two-stage liver resection was developed, able to induce rapid and extensive hypertrophy by portal vein ligation and in situ liver splitting - Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS). The technique became more widely employed but its use remained controversial due to reporting of high complication and mortality rates. Method: A national audit was performed to gather information about the safety of the procedure and to better understand the complications. The audit was offered to all high-volume hepatobiliary centers in Italy. Results: Of all Italian centers approached in January 2012, 12 centers with experience in ALPPS enrolled and participated in collection of data. Fifty patients underwent ALPPS between 2012 and 2014. In 48/50 patients completion of hepatectomy was performed successfully. Major morbidity occurred in 54% with a 20% 90-day mortality. Uni- and multivariate analysis showed that ALPPS for cholangiocarcinoma and a peak of bilirubin over 5 mg/dl between stages was associated with increase of 90 day mortality and worse survival. Discussion: It is proposed that a moratorium be introduced for classic ALPPS in cholangiocarcinoma and to abort ALPPS in patients who develop an interstage increase in bilirubin, due to the high risk of liver failure and mortality.

CDKN1C/P57 is a cyclin-dependent kinase inhibitor implicated in different human cancers, including hepatocellular carcinoma (HCC); however, little is known regarding the role of CDKN1C/P57 and its regulation in HCC. In this study, we show that the down-regulation of Notch1 and Notch3 in two HCC cell lines resulted in Hes1 down-regulation, CDKN1C/P57 up-regulation, and reduced cell growth. In line with these data, we report that CDKN1C/P57 is a target of transcriptional repression by the Notch effector, Hes1. We found that the up-regulation of CDKN1C/P57 by cDNA transfection decreased tumor growth, as determined by growth curve, flow cytometry analysis, and cyclin D1 down-regulation, without affecting the apoptosis machinery. Indeed, the expression of Bax , Noxa , PUMA , BNIP 3, and cleaved caspase-3 was not affected by CDKN1C/P57 induction. Morphologically CDKN1C/p57-induced HCC cells became flat and lengthened in shape, accumulated the senescence-associated β-galactosidase marker, and increased P16 protein expression. Evaluation of senescence in cells depleted both for Hes1 and CDKN1C/P57 revealed that the senescent state really depends on the accumulation of CDKN1C/p57. Finally, we validated our in vitro results in primary HCCs, showing that Hes1 protein expression inversely correlates with CDKN1C/P57 mRNA levels. In addition, reduced Hes1 protein expression is accompanied by a shorter time to recurrence after curative resection, suggesting that Hes1 may represent a biomarker for prediction of patients with poor prognosis.

BACKGROUND:The impact of advanced donor age on hepatic artery thrombosis (HAT) after liver transplantation (LT) is controversial. METHODS: We analyzed the incidence of and risk factors for HAT in LT with donors aged 70 years or older. Eighty patients were transplanted between 1998 and 2002 (group A) and 132 between 2003 and 2008 (group B). RESULTS:In the more recent approach to hepatic artery (HA) reconstruction, the donor HA was systematically preferred to the Carrel patch/celiac trunk, the reconstruction of donor accessory right HA on the donor gastroduodenal artery significantly increased, and the use of interposition grafts was minimized. Group B showed higher Model for End-stage Liver Disease score, lower ischemia time, and lower use of the folding technique/mesenteric conduits. There were 10 cases of HAT (4.7%): 8 (10%) in group A and 2 (1.5%) in group B (P=0.007). Early HAT occurred in 7 (8.8%) patients in group A and in 2 (1.5%) in group B (P=0.02). Group A (P=0.01), anatomical variations of HA (P=0.005), and the use of interposition grafts (P=0.004) were all factors independently affecting HAT. CONCLUSIONS:A low incidence of late HAT was observed in single-center LTs with very old donors. Early HAT decreased over time to largely acceptable rates because of more appropriate technical management.

BACKGROUND: Systemic inflammation markers, such as neutrophil-to-lymphocyte ratio (NLR), have recently emerged as the prognostic factors for recurrence of liver tumors. METHODS: We assessed the ability of NLR and of other variables to predict the outcomes of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). A retrospective analysis was performed in 219 patients with HCC who underwent OLT between 1997 and 2009, with a median follow-up of 40 months. RESULTS: Overall 3- and 5-year patient survival rates were 76.6% and 70.7%, respectively. Overall 3- and 5-year recurrence-free survival (RFS) rates were 83.8% and 82.1%, respectively. On univariate analysis, the factors affecting overall survival were α-fetoprotein more than 30 ng/mL (P=0.006), NLR more than or equal to 5 (P

OBJECTIVE: To evaluate the evolution of liver transplantation (LT) in cases with partial and total portal vein thrombosis (PVT). BACKGROUND: Portal vein thrombosis and in particular total PVT are still surgically demanding conditions, which can exclude patients from LT or increase the postoperative complications after LT. METHODS: We reviewed our 10-year experience (first era 1998–2002 and second era 2003–2008), comparing the outcome of patients with PVT to a group without PVT. RESULTS: Among 889 LTs, we intraoperatively diagnosed 91 PVTs (10.2%):51 partial PVTs (56%) and 40 total PVTs (44%). The rate of complete PVTs increased from the first to the second era (2.2% vs. 6.7%, P < 0.005). Partial PVTs were mainly treated with thrombectomy while complete PVTs were managed with thrombectomy in 26 cases (63%), jumping graft in 6 (15%), portocaval hemitransposition in 6 (15%), and anastomosis to varix in 3 (7%). Among cases of PVT and no-PVT, the postoperative mortality was comparable (6.6% vs. 5.8%), as were the 1- and 5-year patient survival rates (85% and 68% PVT vs. 86% and 73% non-PVT). The postoperative outcome was similar in the PVT group between patients with partial and complete PVT, but in this last group, patient survival differed significantly between the 1st and 2nd era (57% vs. 89% at 1 year, P < 0.05). CONCLUSIONS: Liver transplantation offers good survival in patients with partial PVT but also in selected cases with total PVT, where surgical innovation has improved the results.

We describe the first case of West Nile virus (WNV) infection in Europe with transmission from donor to recipient following liver transplantation. The infection was detected in the recipient 3 days after transplantation, during the asymptomatic phase. We also report an innovative prophylactic strategy based on infusion of WNV hyperimmune plasma and gamma globulins that could be effective in preventing the appearance of a neuroinvasive disease.

OBJECTIVE: To evaluate the results of surgical therapy for intrahepatic cholangiocarcinoma (ICC), the incidence and the management of recurrence, and to analyze the change in approach during 2 different periods. DESIGN: Retrospective study. PATIENTS AND METHODS: Patient and tumor characteristics, and overall and disease-free survival were analyzed in a series of 72 consecutive patients who underwent hepatic resection for ICC. Several factors likely to influence survival after resection were evaluated. Patients were divided into 2 groups according to the year of operation (before and after 1999). Management of recurrence and survival after recurrence were also analyzed. RESULTS: The 3- and 5-year overall survival rates were 62% and 48%, whereas the 3- and 5-year disease-free survival rates were 30% and 25%, respectively. The median survival time was 57.1 months. Patient and histologic characteristics before and after 1999 were similar. Survival was significantly better among patients operated after 1999, who were node-negative, did not receive blood transfusion, and underwent adjuvant chemotherapy. The overall recurrence rates before and after 1999 were comparable (66.6% and 50%, P = 0.49). The most frequent site of recurrence was the liver. A significantly large number of patients received treatment for recurrence after 1999 (81.5%) compared with the first period (8.3%). The overall 3-year survival rate after recurrence was 46%. After 1999, there was a significant improvement in 3-year survival after recurrence (56%) compared with patients operated before 1999 (0%, P = 0.004); the median survival time from the diagnosis of recurrence increased from 20 months to 66 months in the second group. CONCLUSIONS: Although recurrence rate represents a frequent problem in ICC, an aggressive approach to recurrence can significantly prolong survival.

MicroRNAs (miRNA) have rapidly emerged as modulators of gene expression in cancer in which they may have great diagnostic and therapeutic import. MicroRNA-199a-3p (miR-199a-3p) is downregulated in several human malignancies including hepatocellular carcinoma (HCC). Here, we show that miR-199a-3p targets mammalian target of rapamycin (mTOR) and c-Met in HCC cells. Restoring attenuated levels of miR-199a-3p in HCC cells led to G1-phase cell cycle arrest, reduced invasive capability, enhanced susceptibility to hypoxia, and increased sensitivity to doxorubicin-induced apoptosis. These in vitro findings were confirmed by an analysis of human HCC tissues, which revealed an inverse correlation linking miR-199a-3p and mTOR as well as a shorter time to recurrence after HCC resection in patients with lower miR-199a-3p expression. These results suggest that tactics to regulate mTOR and c-Met by elevating levels of miR-199a-3p may have therapeutic benefits in highly lethal cancers such as HCC. Cancer Res; 70(12); 5184–93. ©2010 AACR.

Many prognostic systems have been devised to predict the outcome of liver transplantation (LT) candidates. Today, the Model for End-Stage Liver Disease (MELD) is widely used for organ allocation, but it has shown some limitations. The aim of this study was to investigate the performance of MELD compared to 5 different score models. We evaluated the prognostic ability of MELD, modified Child-Turcotte-Pugh, MELD-sodium, United Kingdom MELD, updated MELD, and integrated MELD in 487 candidates with cirrhosis for LT at the Bologna Transplant Centre, Bologna, Italy, between 2003 and 2008. Calibration analysis by Hosmer-Lemeshow test, calibration curves, and concordance c-statistics (area under the receiver operating characteristic curve [AUC]) were calculated at 3, 6, and 12 months. Actual cumulative survival curves, taking into account the event of interest in the presence of competing risk, were obtained using the best cutoffs identified by AUC. For each score, the Hosmer-Lemeshow test revealed a good calibration. Integrated MELD showed calibration curves closer to the line of perfect predicting ability, followed by MELD-sodium at 3 months and modified Child-Turcotte-Pugh at 6 months. MELD-sodium AUCs at 3 and 6 months (0.798 and 0.765, respectively) and integrated MELD AUC at 6 months (0.792) were better than standard MELD (P < 0.05). Actual survival curves showed that these 2 scores were able to identify the patients with the highest drop-out risk. In conclusion, MELD-sodium and integrated MELD were the best prognostic models to predict drop-out rates among patients awaiting LT.