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Deregulated cell proliferation and apoptosis play a major role in hepatocellular carcinoma (HCC). MicroRNAs participate in the modulation of key molecules linked to hepatocarcinogenesis. Purpose: This study aims to investigate the role of miR-221 in the modulation of Bmf, a proapoptotic BH3-only protein, and to characterize miR-221 contribution to hepatocarcinogenesis through modulation of apoptosis. Experimental Design: Transfection of miR-221 and anti-miR-221 in HCC-derived cell lines and luciferase reporter assay were used to assess Bmf as a target of miR-221. Modulation of miR-221 and Bmf expression contributed to characterize their role in anoikis. Primary HCC tissues were analyzed to assess the clinical relevance of in vitro findings. Results: Enforced miR-221 expression caused Bmf down-regulation, whereas anti-miR-221 induced its up-regulation. A luciferase reporter assay confirmed Bmf as a target of miR-221. Following matrix detachment, miR-221 silencing led to increased apoptotic cell death. The analysis of HCC tissues revealed an inverse correlation between miR-221 and Bmf expression and a direct correlation between Bmf and activated caspase-3, as a marker of apoptosis. High miR-221 levels were associated with tumor multifocality and reduced time to recurrence after surgery. Conclusions: Our results indicate that miR-221, by targeting Bmf, inhibits apoptosis. Moreover, in HCC, miR-221 overexpression is associated with a more aggressive phenotype. These findings, together with the previously reported modulation of CDKN1B/p27 and CDKN1C/p57, show that miR-221 simultaneously affects multiple pro-oncogenic pathways and suggest miR-221 as a potential target for nonconventional treatment against HCC. (Clin Cancer Res 2009;15(16):5073–81)

Background/Aims Orthotopic liver transplantation (OLT) is an important therapeutic option for HBV-related end-stage-liver disease, yet it is often hampered by a scarcity of organ availability. One option to increase organ availability is the use of virologically compromised organs from HBV-infected donors. Transplantation of anti-HBcore positive grafts has been associated with a low risk of HBV recurrence if adequately treated with nucleoside analogs, irrespective of concomitant HBV-specific immunoglobulin therapy. Experience using HBsAg positive grafts is, however, very limited. Methods Here, the analysis of the cellular and humoral HBV-specific immunity of a subject with past HBV infection (anti-HBs and anti-HBc positive) receiving an HBsAg positive liver graft is reported. Results Nine months post-OLT, the patient experienced a spontaneous anti-HBs re-seroconversion allowing the discontinuation of HBIG. The data show a concurrent increase in the cellular and humoral immunity at times of reduced viral antigenemia, demonstrating effective immune control of HBV post-OLT. Conclusions These data support the use of marginal organs in this setting, providing a potential strategy to further alleviate organ shortage.

Conventional criteria for liver transplantation for patients with hepatocellular carcinoma are single HCC

The identification of target mRNAs is a key step for assessing the role of aberrantly expressed microRNAs in human cancer. MiR-221 is upregulated in human hepatocellular carcinoma (HCC) as well as in other malignancies. One proven target of miR-221 is CDKN1B/p27, whose downregulation affects HCC prognosis. Here, we proved that the cyclin-dependent kinase inhibitor (CDKI) CDKN1C/p57 is also a direct target of miR-221. Indeed, downregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to miR-221 transfection into HCC-derived cells and a significant upregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to antimiR-221 transfection. A direct interaction of miR-221 with a target site on the 3' UTR of CDKN1C/p57 mRNA was also demonstrated. By controlling these two CDKIs, upregulation of miR-221 can promote growth of HCC cells by increasing the number of cells in S-phase. To assess the relevance of these studies in primary tumors, matched HCC and cirrhosis samples were assayed for miR-221, for CDKN1B/p27 and CDKN1C/p57 expression. MiR-221 was upregulated in 71% of HCCs, whereas CDKN1B/p27 and CDKN1C/p57 proteins were downregulated in 77% of cases. A significant inverse correlation between miR-221 and both CDKN1B/p27 and CDKN1C/p57 was found in HCCs. In conclusion, we suggest that miR-221 has an oncogenic function in hepatocarcinogenesis by targeting CDKN1B/p27 and CDKN1C/p57, hence promoting proliferation by controlling cell-cycle inhibitors. These findings establish a basis toward the development of therapeutic strategies aimed at blocking miR-221 in HCC.

Advanced donor age is a risk factor for poor outcome in liver transplantation (LT). We reviewed 553 consecutive transplants according to donor age categories [group 1 (n = 173): or =80 years]. Clinical parameters were comparable between groups. Group 5 had the highest proportion of pretransplant liver biopsy (85%), with only 1 graft showing macrovesicular steatosis > 30%, and the lowest ischemia time. Five-year graft survival was significantly higher in group 1 (75%) versus groups 3 (60%) and 4 (62%; P = 0.01 and P = 0.001, respectively) and in group 5 (81%) versus groups 3 and 4 (P = 0.04 and P = 0.01, respectively). Donor age of 60-79 years, recipient hepatitis C virus-positive status, Model for End-Stage Liver Disease score > or = 25, and emergency LT were predictors of poor survival. In hepatitis C virus-positive patients, 5-year graft survival was 72% in group 1, 85% in group 2, 52% in group 3, 65% in group 4, and 71% in group 5 (group 1 versus group 3, P = 0.04; group 2 versus group 3, P = 0.03). In conclusion, older donor grafts managed with routine graft biopsy and short ischemia time may work effectively, regardless of the severity of the recipient's liver disease.

Extramedullary myeloid tumours (EMMTs) are haematological tumours of malignant myeloid cells arising in extramedullary sites. The occurrence of EMMT in patients without leukemia is rare and in the ...

BACKGROUND.: The use of the Model for End-Stage Liver Disease (MELD) score to prioritize patients on liver waiting lists must take the bias of different laboratories into account. METHODS.: We evaluated the outcome of 418 patients listed during 1 year whose MELD score was computed by two laboratories (lab 1 and lab 2). The two labs had different normality ranges for bilirubin (maximal normal value [Vmax]: 1.1 for lab 1 and 1.2 for lab 2) and creatinine (Vmax: 1.2 for lab 1 and 1.4 for lab 2). The outcome during the waiting time was evaluated by considering the liver transplantations and the dropouts, which included deaths on the list, tumor progression, and patients who were too sick. RESULTS.: Although the clinical features of patients were similar between the two laboratories, 36 (13.1%) out of 275 were dropped from the list in lab 1, compared to 5 (3.5%) out of 143 in lab 2 (P

The best prioritization of patients with hepatocellular carcinoma (HCC) waiting for liver transplantation under the model for end-stage liver disease (MELD) allocation system is still being debated. We analyzed the impact of a MELD adjustment for HCC, which consisted of the addition of an extra score (based on the HCC stage and waiting time) to the native MELD score. The outcome was analyzed for 301 patients with chronic liver disease listed for liver transplantation between March 1, 2001 and February 28, 2003 [United Network for Organ Sharing (UNOS)-Child-Turcotte-Pugh (CTP) era, 163 patients, 28.8% with HCC] and between March 1, 2003 and February 28, 2004 (HCC-MELD era, 138 patients, 29.7% with HCC). In the HCC-MELD era, the cumulative dropout risk at 6 months was 17.6% for patients with HCC versus 22.3% for those patients without HCC (P = NS), similar to that in the UNOS-CTP era. The cumulative probability of transplantation at 6 months was 70.3% versus 39.0% (P = 0.005), being higher than that in the UNOS-CTP era for patients with HCC (P = 0.02). At the end of the HCC-MELD era, 12 patients with HCC (29.3%) versus 57 without HCC (58.8%) were still on the list (P = 0.001). Both native and adjusted MELD scores were higher (P < 0.05) and progressed more in patients with HCC who dropped out than in those who underwent transplantation or remained on the list (the initial-final native MELD scores were 17.3-23.1, 15.5-15.6, and 12.8-14.1, respectively). The patients without HCC remaining on the list showed stable MELD scores (initial-final: 15.1-15.4). In conclusion, the present data support the strategy of including the native MELD scores in the allocation system for HCC. This model allows the timely transplantation of patients with HCC without severely affecting the outcome of patients without HCC. Liver Transpl 13:857–866, 2007. © 2007 AASLD.

We investigated the sensitivity of intrahepatic cholangiocarcinoma (IHCCA) subtypes to chemotherapeutics and molecular targeted agents. Primary cultures of mucin- and mixed-IHCCA were prepared from surgical specimens (N. 18 IHCCA patients) and evaluated for cell proliferation (MTS assay) and apoptosis (Caspase 3) after incubation (72 hours) with increasing concentrations of different drugs. In vivo, subcutaneous human tumor xenografts were evaluated. Primary cultures of mucin- and mixed-IHCCA were characterized by a different pattern of expression of cancer stem cell markers, and by a different drug sensitivity. Gemcitabine and the Gemcitabine-Cisplatin combination were more active in inhibiting cell proliferation in mixed-IHCCA while Cisplatin or Abraxane were more effective against mucin-IHCCA, where Abraxane also enhances apoptosis. 5-Fluoracil showed a slight inhibitory effect on cell proliferation that was more significant in mixed- than mucin-IHCCA primary cultures and, induced apoptosis only in mucin-IHCCA. Among Hg inhibitors, LY2940680 and Vismodegib showed slight effects on proliferation of both IHCCA subtypes. The tyrosine kinase inhibitors, Imatinib Mesylate and Sorafenib showed significant inhibitory effects on proliferation of both mucin- and mixed-IHCCA. The MEK 1/2 inhibitor, Selumetinib, inhibited proliferation of only mucin-IHCCA while the aminopeptidase-N inhibitor, Bestatin was more active against mixed-IHCCA. The c-erbB2 blocking antibody was more active against mixed-IHCCA while, the Wnt inhibitor, LGK974, similarly inhibited proliferation of mucin- and mixed-IHCCA. Either mucin- or mixed-IHCCA showed high sensitivity to nanomolar concentrations of the dual PI3-kinase/mTOR inhibitor, NVP-BEZ235. In vivo, in subcutaneous xenografts, either NVP-BEZ235 or Abraxane, blocked tumor growth. In conclusion, mucin- and mixed-IHCCA are characterized by a different drug sensitivity. Cisplatin, Abraxane and the MEK 1/2 inhibitor, Selumetinib were more active against mucin-IHCCA while, Gemcitabine, Gemcitabine-Cisplatin combination, the c-erbB2 blocking antibody and bestatin worked better against mixed-IHCCA. Remarkably, we identified a dual PI3-kinase/mTOR inhibitor that both in vitro and in vivo, exerts dramatic antiproliferative effects against both mucin- and mixed-IHCCA.

AIM: To evaluate the predictors of 10-year survival of patients with hepatitis C recurrence. /// METHODS: Data from 358 patients transplanted between 1989 and 2010 in two Italian transplant centers and with evidence of hepatitis C recurrence were analyzed. A χ 2, Fisher's exact test and Kruskal Wallis' test were used for categorical and continuous variables, respectively. Survival analysis was performed at 10 years after transplant using the Kaplan-Meier method, and a log-rank test was used to compare groups. A p level less than 0.05 was considered significant for all tests. Multivariate analysis of the predictive role of different variables on 10-year survival was performed by a stepwise Cox logistic regression./// RESULTS: The ten-year survival of the entire popu lation was 61.2%. Five groups of patients were identified according to the virological response or lack of a response to antiviral treatment and, among those who were not treated, according to the clinical status (mild hepatitis C recurrence, "too sick to be treated" and patients with comorbidities contraindicating the treatment). While the 10-year survival of treated and untreated patients was not different (59.1% vs 64.7%, p = 0.192), patients with a sustained virological response had a higher 10-year survival rate than both the "non-responders" (84.7% vs 39.8%, p < 0.0001) and too sick to be treated (84.7% vs 0%, p < 0.0001). Sustained virological responders had a survival rate comparable to patients untreated with mild recurrence (84.7% vs 89.3%). A sustained virological response and young donor age were independent predictors of 10-year survival./// CONCLUSION: Sustained virological response significantly increased long-term survival. Awaiting the interferon-free regimen global availability, antiviral treatment might be questionable in selected subjects with mild hepatitis C recurrence.

Background The role of liver resection (LR) of hepatocellular carcinoma with macroscopic vascular thrombosis (MVT) remains controversial. The aim of this study is to evaluate whether the presence of MVT should still be considered a contraindication for LR. Methods Retrospective study was carried out on 62 patients who underwent LR and thrombectomy for hepatocellular carcinoma complicated by MVT. Of the 62 patients, 15 (36.5%) had tumor thrombus (TT) in the peripheral portal vein (Vp1), 5 (12.2%) in second branch (Vp2), and 21 (51.3%) in the first branch/portal vein trunk (Vp3), while on the hepatic/cava vein side, 8 (12.9%) had TT in the main trunk of the hepatic veins (Vv2) and 3 (4.8%) had TT reaching the vena cava/right atrium (Vv3). Results Perioperative major morbidity was 14.5%, while in-hospital mortality was 4.8%. Overall, 1, 3, and 5-year survival rates were 53.3%, 30.1%, and 20%, and disease-free survival rates were 31.7%, 20.8%, and 15.6%, respectively. There were no differences in survival about the MVT localized in Vp1, Vp2, or Vp3 (P = .77), while we found a statistical trend between patients with Vv2 and Vv3 (P = .06). Conclusion Surgical resection seems to be justified in these patients, and the presence of MVT should no longer be considered an absolute contraindication for LR.

Purpose We sought to evaluate liver function recovery after isolated intestinal transplantation in adults with irreversible intestinal failure. Patients and Methods Over a 5-year period, we transplanted 34 adult patients, 25 of whom received an isolated intestinal graft, 4 a multivisceral graft without a liver, and 5, a multivisceral graft with a liver. Among the group of patients transplanted with the isolated graft we selected 14 recipients with pretransplant liver dysfunction, namely, a serum bilirubin >2 mg/dL (normal value: 1.2) and/or transaminases >100 IU/mL (NV, 37/40). Other inclusion criteria were total parenteral nutrition, period > 3 months, no diagnosis of portal hypertension or cirrhosis. Two patients had biopsy-proven liver fibrosis. Results At discharge, all patients recovered liver function to normal values: mean bilirubin blood level was 0.9 ± 0.96 mg/dL (range: 0.3–1.6) and mean transaminases were 26 ± 9 and 31 ± 18 IU/mL (range: 10–44/27–65). After a mean follow-up of 2 years, only one patient has an elevated alanine aminotransferase level without clinical signs of liver disease. Type of pretransplant liver disease did not impact on survival rates. Conclusion In selected cases, an isolated intestinal or a multivisceral graft without a liver can represent a “liver salvage therapy” for an early failing liver in patients with irreversible intestinal failure. Pretransplant liver disease is not a negative prognostic factor.

Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.

About 50% of patients with colorectal cancer (CCR) are destined to develop hepatic metastases during the course of the disease. Surgery is currently the only potentially curative treatment with a five year survival rate after hepatectomy from 26% to 49%. The criteria for resectability are now less rigid than in the past and the tendency to adopt a more aggressive treatment of metastatic lesions is the rule. Systemic infusion chemotherapies based on 5-fluorouracil (5-FU), oxaliplatin (OHP) and irinotecan (CPT-11) are well tolerated and have been shown to be effective in non-operable patients. These regimens allow surgery for patients who are initially not suitable for resection, giving them a probability of survival at five years similar to that of patients operated on at diagnosis. Intra-arterial infusion chemotherapy (HAI) is very effective in inducing objective responses, but is costly, difficult to manage and encumbered by major side effects, so that its application is necessarily limited to centres with specific experience. However, despite the broader criteria and recent advances of chemotherapy, surgery is not possible in most patients. The role of other local therapeutic techniques like cryosurgery (CS) and radiofrequency ablation (RF), alone or combined with surgery or chemotherapy, is not yet established in a multidisciplinary therapeutic approach. Roughly two thirds of patients relapse during the first two years after surgery suggesting appropriate post-operative chemotherapy treatment after hepatic resection may be indicated, but no randomised studies have been published to date. In case of relapse, another hepatectomy should be considered. The role of novel targeted therapies in pre-operative, post-operative and palliative management has yet to be evaluated.

The effect of ischemic preconditioning (IPC) in orthotopic liver transplantation (OLT) has not yet been clarified. We performed a pilot study to evaluate the effects of IPC in OLT by comparing the outcomes of recipients of grafts from deceased donors randomly assigned to receive (IPC+ group, n = 23) or not (IPC- group, n = 24) IPC (10-min ischemia + 15-min reperfusion). In 10 cases in the IPC+ group and in 12 in the IPC- group, the expression of inducible nitric oxide synthase (iNOS), neutrophil infiltration, and hepatocellular apoptosis were tested by immunohistochemistry in prereperfusion and postreperfusion biopsies. Median aspartate aminotransferase (AST) levels were lower in the IPC+ group vs. the IPC- group on postoperative days 1 and 2 (398 vs. 1,234 U/L, P = 0.002; and 283 vs. 685 U/L, P = 0.009). Alanine aminotransferases were lower in the IPC+ vs. the IPC- group on postoperative days 1, 2, and 3 (333 vs. 934 U/L, P = 0.016; 492 vs. 1,040 U/L, P = 0.008; and 386 vs. 735 U/L, P = 0.022). Bilirubin levels and prothrombin activity throughout the first 3 postoperative weeks, incidence of graft nonfunction and graft and patient survival rates were similar between groups. Prereperfusion and postreperfusion immunohistochemical parameters did not differ between groups. iNOS was higher postreperfusion vs. prereperfusion in the IPC- group (P = 0.008). Neutrophil infiltration was higher postreperfusion vs. prereperfusion in both groups (IPC+, P = 0.007; IPC-, P = 0.003). Prereperfusion and postreperfusion apoptosis was minimal in both groups. In conclusion, IPC reduced ischemia/reperfusion injury through a decrease of hepatocellular necrosis, but it showed no clinical benefits.

BACKGROUND: To evaluate the role of liver resection for noncolorectal, nonneuroendocrine metastases, indications and results were retrospectively reviewed in 142 observed patients. METHODS: A curative liver resection was performed in 83 cases (58.5%), and the remaining 59 patients received palliative treatments. The primary tumor site was gastrointestinal in 18, breast in 21, genitourinary in 15, leiomyosarcoma in 10, and other in 19. The mean number of metastases was 1.4. The mean diameter of the nodules was 5.7 cm. Liver metastases were synchronous in 11 (13.3%) cases and metachronous in the remaining 72 (86.7%). RESULTS: There was no operative mortality. Postoperative morbidity was 20.5%. The median postoperative stay was 9.5 days. The 3- and 5-year actuarial survival rate was 49.5% and 34.3% in resected cases, respectively, whereas there were almost no survivors 3 years after diagnosis in unresected cases (P < .05). The 3- and 5-year disease-free survival was 41.4% and 23.8%, respectively. Among the 83 resected cases, the 3- and 5-year actuarial survival was 17.3% and 8.6% for metastases from gastrointestinal tumors, 53.9% and 24.6% from breast cancer, 63.7% and 36.4% from leiomyosarcoma, 50.4% and 37.8% from genitourinary neoplasms, and 55.6% and 42.4% from other sites, respectively. Fifteen patients (18.1%) survived longer than 5 years. CONCLUSIONS: Liver resection is an effective treatment for noncolorectal, nonneuroendocrine metastases; it allows satisfactory long-term survival with an acceptable operative risk in selected patients. Hepatic metastases from gastrointestinal carcinoma have the worst prognosis; those from genitourinary tumors show a better outcome. Patient selection is the key to achieving encouraging results.

Background and Objectives Conventional chemotherapy has not proven effective in improving long-term results of surgery for liver metastases from colorectal cancer. We assessed the usefulness of immunotherapy with tumor infiltrating lymphocytes (TIL) plus Interleukin-2 (IL-2) as adjuvant treatment. Methods Between 1995 and 1998, 47 patients were enrolled onto a prospective protocol; 25 entered the treatment group (A) and 22 entered the control group (B). All patients had undergone radical liver resection. TIL obtained from surgical specimens from group A patients were cultured and activated in vitro with IL-2, then reinfused into the patients with IL-2. We investigated pre- and post-IL-2 stimulation expression of T cell receptor (TCR) ζ- and e-chains, p56lck, Fas, and Fas-L by TIL immunostaining. Results Fourteen patients from group A (56%) received immunotherapy; 14 from group B (60%) underwent conventional chemotherapy, and the remaining 19 patients did not receive any treatment. No significant differences between the two groups were found in the actuarial and disease-free survival (DSF) rates after 1, 3, and 5 years. After IL-2 exposure, TCR ζ-chain expression significantly increased (P = 0.001); An increase in TCR e-chain expression (P = 0.04), and p56lck (P = 0.03) was detected; TCR e-chain expression was significantly increased in disease-free patients compared to those who relapsed (P = 0.04). Fas-L expression was correlated with the TCR e-chain and p56lck levels (P = 0.05). Conclusions Our data suggest that we are still a long way from being able to propose TIL + IL-2 treatment as an effective adjuvant therapy. However, the results confirm that the biological indicators examined could play an important role in modulating immunitary response against tumor cells. J. Surg. Oncol. 2004;87:46–52. © 2004 Wiley-Liss, Inc.

Although an increased incidence of de novo malignancies is reported in transplant recipients, rhabdomyosarcoma, an aggressive mesenchymal tumor typical of childhood, is not considered a neoplasm commonly related to immunosuppression. A 21-year-old woman presented with unilateral diplopia and proptosis 16 months after liver transplantation for fulminant hepatic failure. A tumoral mass originating from the medial rectus muscle was partially removed and diagnosed as being an embryonal rhabdomyosarcoma. Since the patient refused complete orbital excision, one course of radiotherapy and six courses of chemotherapy were administered, while immunosuppression was re-modulated, without interruption of the administration of cyclosporine. Complete control of tumor growth was achieved, while no alterations of graft function were observed throughout the treatment period.

BACKGROUND Although pathologic stage is currently the main prognostic indicator for patients with colorectal carcinoma (CRC), mounting evidence suggests that, in its current form, it is insufficient to predict clinical outcome. To assess biologic markers of primary CRC that may improve clinical staging and provide useful information for the application of novel therapeutic strategies, the authors investigated a panel of markers that included transforming growth factor-α (TGF-α), epithelial growth factor receptor (EGF-R; the protein product of the c-erb B2/HER-2 oncogene), matrix metalloproteinase 2 (MMP-2), insulin-like growth factor II (IGF-II), vascular endothelial growth factor (VEGF), and angiogenesis, as evaluated by microvessel density (MVD). METHODS Two groups of CRC were studied: 1) surgical samples from patients who achieved a disease free survival of at least 6 years (CRC-M0) and 2) surgical specimens of both primary tumors and synchronous or metachronous liver metastases (CRC-M1). RESULTS Chi-square analysis revealed that expression levels of TGF-α, c-erb B2/HER-2, MMP-2, IGF-II, VEGF, and MVD (but not EGF-R) were significantly higher in CRC-M1 samples compared with CRC-M0 samples (P < 0.001, P < 0.05, P < 0.001, P < 0.001, P < 0.01, and P < 0.001, respectively). Logistic regression analysis showed that TGF-α, IGF-II, and MMP-2 had significantly greater expression in CRC-M1 samples independent of the other variables (including tumor classification, histologic grade, and patient age). If all three markers had ≥ 25% expression, then the probability of developing liver metastasis was 99.5%. CONCLUSIONS Based on the evidence of this study, TGF-α MMP-2, and IGF-II seem suitable candidates for a selective panel of markers designed to provide significant additional information with respect to the current pathologic staging system for patients with colorectal carcinoma. Cancer 2002;94:647–57. © 2002 American Cancer Society. DOI 10.1002/cncr.10277

Owing to organ shortage, livers from old donors are increasingly used for transplantation. The function and duration of such transplanted livers are apparently comparable to those from young donors, suggesting that, despite some morphological and structural age-related changes, no major functional changes do occur in liver with age. We tested this hypothesis by performing a comprehensive study on proteasomes, major cell organelles responsible for proteostasis, in liver biopsies from heart-beating donors. Oxidized and poly-ubiquitin conjugated proteins did not accumulate with age and the three major proteasome proteolytic activities were similar in livers from young and old donors. Analysis of proteasomes composition showed an age-related increased of β5i/α4 ratio, suggesting a shift toward proteasomes containing inducible subunits and a decreased content of PA28α subunit, mainly in the cytosol of hepatocytes. Thus our data suggest that, proteasomes activity is well preserved in livers from aged donors, concomitantly with subtle changes in proteasome subunit composition which might reflect the occurrence of a functional remodelling to maintain an efficient proteostasis. Gender differences are emerging and they deserve further investigations owing to the different aging trajectories between men and women. Finally, our data support the safe use of livers from old donors for transplantation. Owing to organ shortage, livers from old donors are increasingly used for transplantation. The function and duration of such transplanted livers are apparently comparable to those from young donors, suggesting that, despite some morphological and structural age-related changes, no major functional changes do occur in liver with age. We tested this hypothesis by performing a comprehensive study on proteasomes, major cell organelles responsible for proteostasis, in liver biopsies from heart-beating donors. Oxidized and poly-ubiquitin conjugated proteins did not accumulate with age and the three major proteasome proteolytic activities were similar in livers from young and old donors. Analysis of proteasomes composition showed an age-related increased of β5i/α4 ratio, suggesting a shift toward proteasomes containing inducible subunits and a decreased content of PA28α subunit, mainly in the cytosol of hepatocytes. Thus our data suggest that, proteasomes activity is well preserved in livers from aged donors, concomitantly with subtle changes in proteasome subunit composition which might reflect the occurrence of a functional remodelling to maintain an efficient proteostasis. Gender differences are emerging and they deserve further investigations owing to the different aging trajectories between men and women. Finally, our data support the safe use of livers from old donors for transplantation.

During the past two decades, hepatocellular carcinoma (HCC) has been one of the most intriguing diseases to treat. The problem of treatment remains open, especially for patients with underlying cirrhosis of the liver, which substantially reduces the possibility of aggressive treatment. The management of HCC on cirrhosis has progressively involved surgeons, hepatologists, oncologists, and interventional radiologists. Consequently, several different therapies are now available for these patients: liver resection (LR), orthotopic liver transplantation (OLT), percutaneous alcohol injection (PEI), transarterial chemoembolization (TACE), and radiofrequency ablation are applied worldwide by several different specialists. The routine evaluation of patients with chronic liver disease has led to a significant increase in the number of patients found to have preserved hepatic function and relatively small HCCs. The solitary type is the most common type at presentation. 1 The disease typically occurs in the seventh decade;2 the mean age of a large cohort of patients described by our group for demographic purposes was 61.5 years. 3 In the same group, more than half the patients were Child A. 2 All these considerations explain the increased number of patients with HCC on cirrhosis who require treatment and the number of methods proposed. Unfortunately, the scientific literature lacks prospective comparative evaluations of these treatments, with the exception of those proposed for palliation, 4 and there have been no accepted guidelines for managing the disease. Further, the reference standards for results obtained by different methods often refer to historical series that reflect the medical knowledge and expertise of a particular period. 5 For these reasons, we decided to perform a retrospective evaluation of the results obtained with a single procedure (LR) over a long period, with the aim of reassessing the standards for this single therapy to be considered when evaluating the wide spectrum of treatments for patients with HCC on cirrhosis.

The upper age limit for organ donation for liver transplantation has increased over the past few years. A retrospective case control study was carried out to evaluate the outcome of 36 liver transplants (group A) performed with grafts procured from donors over 70 years old in the period 1996 to April 2000, matched with 36 transplants (group B) chronologically performed thereafter with organs procured from donors below the age of 40 yr. The groups were comparable as regards main clinical characteristics. Mean follow-up was 14.5 months. Clinical and laboratory parameters of the donors, cold ischemia period, intraoperative blood transfusions, 30-d mortality, incidence of primary graft nonfunction, acute rejection episodes, arterial complications and long-term survival of recipients were considered. The main postoperative biochemical parameters were also collected and compared. A liver biopsy was obtained in 20/36 old donors, revealing less than 25% of steatosis in all but one, which showed steatosis involving 70% of the hepatocytes. There were two postoperative deaths (5.6%) in group A and one (2.8%) in group B (p = NS). Seven postoperative arterial complications (19.4%) occurred in group A, leading to the patient's death because of rupture of the hepatic artery in one case, to successful surgical revascularization in three cases and to retransplantation in three cases. Only one patient in group B (2.8%) experienced hepatic artery thrombosis (p = 0.055). One-year patient survival rates were 77.4% for group A and 88.8% for group B (p = NS); 1-yr graft survival rates were 73.3% for group A and 85.7% for group B (p = NS). In conclusion, donors over 70 should not be excluded a priori for liver transplantation in elective settings. Great attention should be paid to the pathological conditions of arterial vessels caused by atherosclerosis, i.e. the presence of calcified plaques on the hepatic artery, which might represent the source of severe complications.

Background. In the European Multicenter Study on the Use of Aprotinin in Liver Transplantation (EIMSALT), a randomized, double-blind, placebo-controlled, prospective study, we demonstrated that aprotinin significantly reduces intraoperative blood loss during orthotopic Liver transplantation (OLT). Aprotinin is metabolized in the kidney and potentially nephrotoxic at high concentrations. Renal insufficiency is a common and serious complication after OLT. It is unknown whether aprotinin increases the risk of renal failure after OLT. Methods. We analyzed intraoperative urine output, need for postoperative dialysis, perioperative serum creatinine levels, and creatinine clearance in 93 patients enrolled in EMSALT, receiving a high dose of aprotinin, a regular dose, or placebo. Results. Peak increase in serum creatinine exceeding 0.5 mg/dl during one of the postoperative days occurred in 11 (35%) patients in the placebo group, in 11 (34%) patients in the high-dose group, but only in 1 (3%) patient in the regular-dose group (P=0.007). Furthermore, a perioperative decrease in creatinine clearance was seen in the placebo group (-23.9+/-10.1 ml/min) but not in both high-dose (-1.6+/-13.3 ml/min) and regular-dose (9.7+/-10.3 ml/min) groups (P Conclusions. Despite its potential nephrotoxicity, the use of aprotinin for reducing blood loss during OLT does not lead to a higher incidence of postoperative renal insufficiency. In combination with the observed reduction in blood loss, these findings support the prophylactic use of regular-dose aprotinin during OLT.

The aim of this study was to evaluate the incidence, radiographic appearance, time of onset, outcome and risk factors of non-infectious and infectious pulmonary complications following liver transplantation. Chest X-ray features of 300 consecutive patients who had undergone 333 liver transplants over an 11-year period were analysed: the type of pulmonary complication, the infecting pathogens and the mean time of their occurrence are described. The main risk factors for lung infections were quantified through univariate and multivariate statistical analysis. Non-infectious pulmonary abnormalities (atelectasis and/or pleural effusion: 86.7 %) and pulmonary oedema (44.7 %) appeared during the first postoperative week. Infectious pneumonia was observed in 13.7 %, with a mortality of 36.6 %. Bacterial and viral pneumonia made up the bulk of infections (63.4 and 29.3 %, respectively) followed by fungal infiltrates (24.4 %). A fairly good correlation between radiological chest X-ray pattern, time of onset and the cultured microorganisms has been observed in all cases. In multivariate analysis, persistent non-infectious abnormalities and pulmonary oedema were identified as the major independent predictors of posttransplant pneumonia, followed by prolonged assisted mechanical ventilation and traditional caval anastomosis. A “pneumonia-risk score” was calculated: low-risk score ( < 2.25) predicts 2.7 % of probability of the onset of infections compared with 28.7 % of high-risk ( > 3.30) population. The “pneumonia-risk score” identifies a specific group of patients in whom closer radiographic monitoring is recommended. In addition, a highly significant correlation (p < 0.001) was observed between pneumonia-risk score and the expected survival, thus confirming pulmonary infections as a major cause of death in OLT recipients.

Although the etiology of liver disease affects the features of hepatocellular carcinoma (HCC) diagnosed during surveillance, it is not known whether it influences patients' survival. We analyzed the impact of etiology on the characteristics and outcome of HCC detected during surveillance.In this cohort study, 742 patients with HCC detected during semiannual or annual surveillance were selected from the ITA.LI.CA database, including 1,834 consecutive patients observed in three primary and seven tertiary care settings for HCC. Patients were grouped according to etiology: hepatitis B virus (HBV, 87), hepatitis C virus (HCV, 461), alcohol (59), and multietiology (135).In all etiologic groups, most HCCs were unifocal (51-68%) and most of them wereor=3 cm (60-69%). Unifocal HCCs were less common in the multietiology group (P=0.050) and slightly more frequent in the HCV group (P=0.087). Besides etiology, only age was associated with gross pathology (P=0.023). About two-thirds of HCCs in all groups were discovered at Cancer of the Liver Italyn Program (CLIP) stage 0 or 1. The 1-, 3-, and 5-yr survival rates were comparable among groups (HBV 81%, 47%, and 22%; HCV 86%, 49%, and 24%; alcohol 76%, 41%, and 25%; multietiology 75%, 37%, and 24%; P=0.446). The surveillance interval did not influence survival, which was independently predicted by serum alpha-fetoprotein, Child-Pugh class, gross pathology, cancer size, vascular invasion, and treatment.In patients with HCC diagnosed during surveillance: (a) single nodules are less common in multietiology cases and (b) prognosis is independent of etiology, being dictated by liver function, oncologic features, and treatment.

Patients with advanced cirrhosis frequently show hemodynamic abnormalities. Autonomic dysfunction (AD) is also common and, owing to the importance of autonomic function in cardiovascular homeostasis, it may be involved in the pathogenesis of the hyperdynamic circulation. We, therefore, evaluated the hemodynamic status and autonomic function in 30 patients with cirrhosis, most of them with an advanced stage of the disease. Autonomic function was assessed with 7 cardiovascular tests exploring the vagal or sympathetic function. Each test was scored from 1 to 3 (normal, borderline, altered). Cardiac index (CI) was measured by an echocardiogram. Twenty-four (80%) patients showed an AD, this being definite in 14 (47%) patients. A vagal dysfunction (VD) was found in 19 patients (63%), this being definite in 11 patients (37%), and a sympathetic dysfunction (SD) in 7 patients (definite in 3 [10%] patients). The patients with AD showed a faster heart rate (P = .021), lower indicized peripheral vascular resistance (P = .013), and increased CI (P = .004) than patients without AD whereas mean arterial pressure did not differ. Similar results were seen by grouping patients according to the VD. AD score was directly correlated with heart rate (r = 0.53; P = .002) and CI (r = 0.45; P = .016), and inversely correlated with peripheral vascular resistance (r = 0.46; P = .013). Even closer correlations were found with vagal score. AD (mainly VD) may be involved in the pathogenesis of the hyperdynamic circulatory syndrome of patients with advanced cirrhosis.

Background/Aims: Acute hepatitis caused by recurrent or de novo hepatitis B virus (HBV) infection after liver transplantation frequently induces aggressive disease leading to liver failure. To aim of this study was to determine the efficacy and safety of lamivudine treatment in post-transplant acute hepatitis B. Method: Twelve patients with acute hepatitis B were started on lamivudine 100 mg po daily within 8 weeks of the appearance of HBsAg. One patient was excluded after 1 month because of hepatocellular carcinoma recurrence. Patients were followed for an average of 68.6 weeks (range 32–108), and were clinically and biochemically evaluated on a monthly basis. They had a histological assessment at baseline, after at least 6 months, and whenever clinically indicated. Results: Basal HBV-DNA ranged between 13 and 1288 pg/ml and serum alanine aminotransferase between 97 and 1036 U/l. HBV-DNA became undetectable within 8 weeks and transaminases normalized within 24 weeks in all cases. At the last visit, eight patients (73%) remained HBV-DNA negative by liquid hybridization and had normal or close to normal alanine aminotransferase. Five patients (45%) were also HBsAg negative and HBV-DNA negative by polymerase chain reaction. HBV-DNA and transaminase breakthrough occurred in three patients (27%). Histology after 6–9 months showed chronic hepatitis in seven patients. Lamivudine was well tolerated without serious adverse reactions. Conclusions: These results indicate that lamivudine treatment induces sustained inhibition of viral replication and normalization of transaminases in the majority of post-transplant patients with acute hepatitis B. HBsAg loss may be achieved in a considerable number of cases. Although viral resistance is relatively frequent, early initiation of lamivudine appears to be effective and safe.

Adult isolated intestinal and multivisceral transplantation is gaining acceptance as the standard treatment for patients with intestinal failure with life-threatening parenteral nutrition-related complications. We report our 4-year experience with intestinal and multivisceral transplantation. We performed 20 isolated small bowel and seven multivisceral ones, including three with liver. The underlying diseases were mainly short bowel syndrome due to intestinal infarction, chronic intestinal pseudo-obstruction, and Gardner syndrome. Indications for transplant were loss of central venous access in 14 patients, recurrent sepsis in eight patients, and major electrolyte and fluid imbalance in five patients. One-year patient actuarial survival rate was 94% for isolated intestinal transplants and 42% for multivisceral recipients (P = .003), while 1-year graft actuarial survival rate was 88.4% for isolated small bowel patients and 42.8% for multivisceral ones (P = .01). The death rate was 18.5%. Our graftectomy rate was 14.8%. Our immunosuppressive protocols were based on induction agents such as alemtuzumab, daclizumab, and antithymocyte globulins. The majority of our complications were bacterial infections, followed by rejections and relaparotomies; most rejection episodes were treated with steroid boluses and tapering. We believe that our results were due to optimal candidate and donor selection, short ischemia time, and use of induction therapy. Multivisceral transplantation is a more complex procedure with less frequent clinical indications than isolated small bowel transplant, but our data concerning multivisceral transplants include only a small number of patients and require further evaluation.

Abdominal wall closure after intestinal transplantation in adult patients can be a difficult procedure. The main possibility offered by international experience is the use of myocutaneous flaps and abdominal wall transplantation. We report our experience in intestinal/multivisceral transplantation, including four difficult cases among 27 adult transplant recipients. Three patients underwent prosthetic mesh alone and one, a myocutaneous flap for abdominal closure after primary mesh positioning. We selected a mesh with a structure that allowed us to close the abdomen without creating adhesions and, at the same time, stimulating tissue repair. Two patients experienced local mesh infection, which has been kept under clinical control by antibiotics and daily medications till neoabdominal wall formation. The mesh was then removed. Another patient underwent mesh substitution for a suspicious fever. The last patient had mesh as a bridge for a subsequent myocutaneous flap from the thigh. All patients are in good health with well-functioning grafts and no need for parenteral nutrition. No enterocutaneous fistulae were detected.

Objective Marginal statistical evidence of efficacy of adjuvant and/or perioperative chemotherapy after resection of colorectal metastases exists, but formal recommendations are still lacking. The present study evaluated the adjuvant systemic chemotherapy after the first resection of liver and lung colorectal cancer metastases. Patients and Methods We retrospectively reviewed data of 181 consecutive unselected patients with R0 resection of colorectal metastases treated simultaneously at 2 institutions from 1997 to 2004. Patients > 75 years old, with an Eastern Cooperative Oncology Group Performance Status Score ≥ 2 or unfit for adjuvant chemotherapy were excluded from the analysis. The decision on chemotherapy after surgery was left to the patient in the absence of conclusive data on the efficacy of adjuvant chemotherapy in this setting. A total of 151 patients (131 with liver metastases, 20 with lung metastases), 78 of whom underwent adjuvant chemotherapy, were evaluable for disease-free survival (DFS) and overall survival. The main prognostic factors for DFS after resection of colorectal cancer metastases were investigated in univariate and multivariate analyses. Results At the univariate analysis, the number of resected lesions, lesion volume, disease-free interval and adjuvant systemic chemotherapy were the only significant prognostic factors. At multivariate analysis, only adjuvant chemotherapy and disease-free interval were independent prognostic factors (hazard ratios 1.66 and 1.62, respectively). The median DFS of patients who underwent systemic adjuvant chemotherapy was 16 months compared with 9.7 months for patients with observation alone (hazard ratio 1.56). Estimated 5-year DFS was 17.4% and 10.5% for treated and untreated patients, respectively. Conclusion Adjuvant chemotherapy after metastasectomy in patients with colorectal cancer showed a significant benefit for DFS.

It has been suggested that certain clinical and morphological features can modify the outcome of Crohn's disease, particularly regarding recurrence after surgery. A series of 233 patiens was followed prospectively. They underwent a resectional surgical procedure for both primary and recurrent Crohn's disease during a fifteen-year period with a minimum follow-up of eighteen months. Possible risk factors for recurrence were studied. They included duration of disease before primary surgery, the type of clinical presentation at onset (whether ``Perforating'' or ``Non-perforating''), the initial anatomical location, the presence of microscopic disease at the resection edges, the type of surgical procedure (anastomosis vs stoma), post-operative surgical complications and the age of the patient. The duration of the disease before the initial operation was the only significant factor related to the recurrence rate.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with the worst survival rate among solid cancers. The pressing needs for extending life expectancy of patients are the identification of early prognostic markers and novel druggable pathways. PDAC arises generally from pancreatic intraepithelial neoplasia (PanIN) and a dynamic interactions between tumor, stromal cells and autocrine and paracrine signaling lead to epithelial to mesenchymal transition (EMT), an early process in the natural history of pancreatic cancer. Cytoskeletal reorganization, extracellular matrix (ECM) remodeling, and matrix metalloproteinases (MMPs) contribute to PDAC aggressiveness in cooperation with soluble growth factors or cytokines, with TGF-β1 as crucial player. hMENA is an actin regulatory protein whose splicing program, mediated by the epithelial splicing regulatory proteins (ESRPs), has been associated with the EMT process. Our previous studies indicated that alternative splicing of hMENA, generates hMENA11a and hMENAΔv6 isoforms with opposite roles in cell proliferation and invasion in breast and lung cancers. Alternative splicing is known to play a prominent role in tumor progression and tumorigenesis and the derived isoforms may represent powerful diagnostic and prognostic factors as we have recently shown for hMENA alternative splicing in early stage non-small cell lung cancer (NSCLC). The aim of this study is to investigate the role of TGF-β1 on the expression and function of hMENA isoforms in PDAC, and verify whether the expression pattern of hMENA isoforms may impact patient outcome. Methods: We analyzed 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, evaluating the patient outcome. The functional role of hMENA isoforms were analyzed by loss and gain of function experiments in untreated and TGF-β1-treated PDAC cell lines. Results: In a panel of pancreatic cancer cell lines, hMENA11a expression correlates with an epithelial phenotype, while hMENAΔv6 expression with a mesechymal phenotype, with low E-cadherin and high vimentin expression. hMENA11a knock-down in PDAC cell lines affected cell-cell adhesion but not cell invasion. TGF-β1 cooperated with β-catenin signalling to up-regulate hMENA and hMENAΔv6 expression but not hMENA11a. The hMENA/hMENAΔv6 up-regulation play a crucial role in cell invasiveness and in TGF-β1-induced EMT. After TGF-β1 treatment, hMENA/hMENAΔv6 were mobilized from focal adhesion to actin stress fibers, and the silencing of these isoforms significantly inhibited the TGF-β1-induced EMT in PANC-1. Functionally, in the absence of hMENA11a, the hMENA/hMENAΔv6 up-regulationis crucial for SMAD2-mediated TGF-β1 signalling, migration, invasion and MMPs activities. 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, in agreement with experimental results. Conclusions: hMENA isoforms are regulated differently by TGF-β1, and the pattern of expression of hMENA isoforms is crucial in TGF-β1-dependent EMT and cell invasion. The pattern of expression of hMENA isoforms correlates with PDAC patient outcome and it could be used in specific clinical settings for the choice of the most effective treatment of PDAC patients. Our data provide new insights into molecular pathways involved in PDAC biology and suggest that hMENA-related pathways are promising targets for the development of new prognostic and therapeutic tools in PDAC. Citation Format: Roberta Melchionna, Pierluigi Iapicca, Francesca Di Modugno, Paola Trono, Isabella Sperduti, Matteo Fassan, Ivana Cataldo, Borislav C. Rusev, Rita T. Lawlor, Maria Grazia Diodoro, Michele Milella, Gian Luca Grazi, Mina J. Bissell, Aldo Scarpa, Paola Nisticò. The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A113.

The assessment of new and more sensitive serum markers for hepatocellular carcinoma (HCC) represents a useful contribution to the diagnosis of small liver tumors, still amenable by surgery. We evaluated the efficacy of the tumor markers proposed during recent years for the study of HCC: alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), serum ferritin (SF), tissue polypeptide antigen (TPA), and, finally, the more recently proposed des-gamma-carboxy prothrombin (DCP). Of the 227 patients included in this retrospective study, 111 had HCC, and 85 of these were also cirrhotic. The remaining 116 patients, considered as the control group, included 23 patients with liver metastases from colorectal cancer, 26 with benign hepatic lesions, 20 with tumors other than HCC without hepatic metastases, and 47 with other liver diseases. For each single tumor marker, the sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and Younden index were assessed. AFP and DCP proved to be the most effective, with sensitivity, specificity, and diagnostic accuracy of 54.9%, 97.4%, and 76.6% and of 53.3%, 88.1%, and 71.1%, respectively. The same parameters evaluated for combined use of the two markers were 74.2%, 87.2%, and 80.9%, respectively. Analysis of the other markers produced no further significant contribution. Of the 111 patients with HCC, 35 (33.3%) were positive for both AFP and DCP, 43 (41%) were positive for one of them, and 27 (25.7%) were completely negative. In the 44 patients who underwent liver resection or transplantation, DCP correlated significantly with the histological presence of microvascular thrombosis, the major factor determining long-term survival after curative surgery. As a tumor marker for HCC, DCP is at least as effective as AFP; the combined use of AFP and DCP significantly improves the chances of identifying HCC by serodiagnosis.

BACKGROUND: Postoperative hepatic failure is a dreadful complication after major hepatectomy and carries high morbidity and mortality rates. In this study, we assessed the accuracy of the 50/50 criteria (bilirubin ＞2.9 mg/dL and international normalized ratio ＞1.7 on postoperative day 5) and the Mullen criteria (bilirubin peak ＞7 mg/dL on postoperative days 1-7) in predicting death from hepatic failure in patients undergoing right hepatectomy only. In addition, we identified prognostic factors linked to intra-hospital morbidity and mortality in these patients. METHODS: One hundred seventy consecutive patients underwent major right hepatectomy at a tertiary medical center from 2000 to 2008. Nineteen (11.2%) patients suffered from liver cirrhosis. Univariate and multivariate analyses were performed to identify predictors of intra-hospital mortality, morbidity and death from hepatic failure. RESULTS: The intra-hospital mortality was 6.5% (11/170). Of the six patients who died from hepatic failure, one was positive for the 50/50 criteria, but all six patients were positive for the Mullen criteria. Multivariate analysis showed that male gender, hepatitis C (HCV), hepatocellular carcinoma, postoperative bilirubin ＞7 mg/dL and ALT＜188 U/L on postoperative day 1 were predictive of death from hepatic failure in the postoperative period. Age ＞65 years, HCV, reoperation, and renal failure were significant predictors of overall intrahospital mortality on multivariate analysis. CONCLUSIONS: The Mullen criteria were more accurate than the 50/50 criteria in predicting death from hepatic failure in patients undergoing right hepatectomy. A bilirubin peak ＞7 mg/dL in the postoperative period, HCV positivity, hepatocellular carcinoma, and an ALT level ＜188 U/L on postoperative day 1 were associated with death from hepatic failure in our patient population.

Purpose Limited data suggest that second resections for colorectal cancer metastases may improve survival, but no study has compared surgery with chemotherapy in this setting. Therefore, we retrospectively compared the clinical outcome of potentially resectable patients who received a second metastasectomy with those who did not in our single-centre experience. Methods We retrospectively reviewed the clinical records of all patients treated for metastatic colorectal cancer in our centre over a period of 12 years. We selected patients who relapsed after radical resection of metastases from colorectal cancer and were deemed resectable again by our multidisciplinary team. We then compared the clinical outcome of those who received a second operation with those who refused surgery and also evaluated the role of prognostic factors. Results We identified 60 patients fulfilling the inclusion criteria. Twenty-nine underwent a second resection and 31 refused surgery. Median overall survival rates were 58.7 and 24.0 months, median times to progression were 14.4 and 6.6 months. Patients who received surgery plus perioperatory chemotherapy (18/29) had a significantly better outcome; 4/29 achieved long-term disease-free survival. Conclusions Our study suggests that in highly selected metastatic colorectal cancer patients, a multimodal treatment plan, including a second resection, can achieve longer survival with respect to medical therapy.

Background & Aims The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study. Methods From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42months (range 12–60). All recipients were HBcAb positive and were given antiviral prophylaxis. Results Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection. Conclusions OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy.

Background. The prevalence of the different hepatocellular carcinoma (HCC) macroscopic types, and the association between these types and age, gender, blood group, alcohol and coffee intake, smoking habit, hepatitis virus markers, underlying cirrhosis, and cancer histologic type were retrospectively assessed in 416 unselected patients (321 with cirrhosis), Methods. The gross pathologic types of HCC were assessed by ultrasonography combined, in most cases, with computed tomography and angiography. Results. Solitary HCC was the most common cancer type (54.8%), followed by the multinodular (31%), diffuse (7.7%), and massive (6.5%) types. Cirrhosis and blood group other than 0 were independent risk factors for multinodular HCC (relative risk [RR] 1.6, P < 0.05; and RR 1.7, P < 0.005, respectively); the absence of cirrhosis and a heavy smoking habit were risk factors for the massive type (RR 4.9, P < 0.001; and RR 3.3, P < 0.01, respectively); and blood group 0 for the solitary type (RR 1.4, P < 0.001). The prevalence of highly undifferentiated cells increased as the tumor size did, so that grade IV cell atypia was associated with massive size of the carcinoma (P < 0.05). In cirrhotic patients, advanced liver dysfunction was associated with diffuse HCC (P < 0.05). As far as solitary HCC is concerned, the tumor size was greater in noncirrhotic than in cirrhotic patients (7 k 0.4 cm versus 4.8 f 0.15, P < 0.001). Conclusions. In Italian patients, HCC presents most frequently as a solitary nodule. The presence or absence of cirrhosis, blood group, and smoking habit can influ

BACKGROUND: With substantial improvements in perioperative care and surgical technique, both mortality and morbidity after liver resection have progressively decreased; however, long-term prognosis is greatly affected by tumor recurrence, which represents the most frequent cause of death. The aim of this study is to analyze the outcome after hepatic resection in the present clinical scenario, where great improvements in diagnostic techniques, surveillance schedules, in other active treatments will potentially have a positive impact on survival. METHODS: Data from 300 consecutive hepatic resections performed on cirrhotic patients in a tertiary-care referral hospital from 1997 and 2008 were reviewed, and survival was calculated for the two periods considered. The first group of patients underwent hepatectomy between 1997 and 2002 (n = 126) and the second group of patients between 2003 and 2008 (n = 174). RESULTS: In the more recent period, tumor selection criteria for resectability included more patients with multinodular tumors so that solitary tumors decreased from 89.7 to 78.7% (P = 0.019); however, the tumor, node, metastasis (TNM) system stage remained unaffected. The 5-year recurrence rate remained similar (67.4 vs. 65.8%; P = 0.836). Despite these features, the 5-year patient survival increased from 52.6 to 65.8% (P = 0.023). This end result was related to a larger proportion of patients with tumor recurrence undergoing repeat resection or salvage transplantation that increased from 22.2 to 36.9% (P = 0.039). CONCLUSIONS: The increased survival is most likely the result of more stringent follow-up as well as increased accuracy in detecting recurrence at earlier stages, and consequently of more chances for potential cure when treating recurrent tumor.

AIM: To assess the safety and effectiveness of prophylaxis for venous thromboembolism (VTE) in a large population of patients with hepatocellular carcinoma (HCC) on cirrhosis. METHODS: Two hundred and twenty nine consecutive cirrhotic patients with HCC who underwent hepatic resection were retrospectively evaluated to assess whether there was any difference in the incidence of thrombotic or hemorrhagic complications between those who received and those who did not receive prophylaxis with low-molecular weight heparin. Differences and possible effects of the following parameters were investigated: age, sex, Child-Pugh and model for end-stage liver disease (MELD) score, platelet count, presence of esophageal varices, type of hepatic resection, duration of surgery, intraoperative transfusion of blood and fresh frozen plasma (FFP), body mass index, diabetes and previous cardiovascular disease. RESULTS: One hundred and fifty seven of 229 (68.5%) patients received antithromboembolic prophylaxis (group A) while the remaining 72 (31.5%) patients did not (group B). Patients in group B had higher Child-Pugh and MELD scores, lower platelet counts, a higher prevalence of esophageal varices and higher requirements for intraoperative transfusion of FFP. The incidence of VTE and postoperative hemorrhage was 0.63% and 3.18% in group A and 1.38% and 1.38% in group B, respectively; these differences were not significant. None of the variables analyzed including prophylaxis proved to be risk factors for VTE, and only the presence of esophageal varices was associated with an increased risk of bleeding. CONCLUSION: Prophylaxis is safe in cirrhotic patients without esophageal varices; the real need for prophylaxis should be better assessed.

BACKGROUND & AIMS: Knowledge of pre-operative tumour grade is crucial in the management of hepatocellular carcinoma (HCC) because it can influence recurrence and survival after surgery. The accuracy of pre-operative needle core biopsy (NCB) in tumour grading has been assessed in only a few studies with conflicting results. Our aim was to determine the long-term safety and the overall accuracy of NCB in assessing tumour grading in subjects who had undergone liver resection for a single HCC. METHODS: Eighty-one cirrhotic patients with HCC who had undergone NCB before liver resection were selected. Only patients with a single HCC and with at least a five-year-follow-up were included. Tumour grading was scored according to a modified Edmondson-Steiner classification: well/moderately (low grade) vs poorly-differentiated (high grade). RESULTS: In the 81 patients with a solitary HCC (mean size 4.1 ± 2.3cm) tumour grade was correctly identified by NCB in 74 out of 81 (91.4%) HCCs. NCB overall sensitivity and specificity were 65% and 98.1%, respectively, with a PPV of 92% and an NPV of 91%. No major complications (in particular tumour seeding) were observed. The overall survival rates at 1, 3, and 5 years were 83%, 62%, and 44%, respectively; the recurrence rate after a 5-year-follow-up was 56.2% for low grade and 82.3% for high grade tumours (p

Orthotopic liver transplantation (OLT) has been performed for several benign hepatic tumors. Most of these diseases are usually managed conservatively, or treated by liver resection. OLT might be required when the lesions are symptomatic, diffuse in hepatic parenchyma, causing life-threatening complications or malignant transformation cannot be ruled out. Polycystic liver disease is the most common indication for OLT. We present a review of transplantable benign hepatic lesions to evaluate the need of OLT for these diseases, to summarize in which OLT is a good therapeutic option, and to show the early and long-term survival which might be expected. Copyright © 2010 S. Karger AG, Basel.