Hepatitis B virus recurrence after liver transplantation: An old tale or a clear and present danger?

Hepatitis B virus(HBV) recurrence after liver transplantation(LT) has been described more than 50 years ago. Similarly, to other clinical conditions, in which impairment of host immune defense favors viral replication, early reports described in details recurrence and reactivation of HBV in liver transplant recipients. The evidence of a possible, severe, clinical evolution of HBV reappearance in a significant percentage of these patients, allowed to consider,for some years, HBV positivity a contraindication for LT. Moving from the old to the new millennium this picture has changed dramatically. Several studies contributed to establish efficient prophylactic protocols for HBV recurrence and with the advent of more potent anti-viral drugs an increased control of infection was achieved in transplanted patients as well as in the general immunecompetent HBV population. Success obtained in the last decade led some authors to the conclusion that HBV is now to consider just as a "mere nuisance".However, with regard to HBV and LT, outstanding issues are still on the table:(1)A standard HBV prophylaxis protocol after transplant has not yet been clearly defined;(2) The evidence of HBV resistant strains to the most potent antiviral agents is claiming for a new generation of drugs;and(3) The possibility of prophylaxis withdrawal in some patients has been demonstrated, but reliable methods for their selection are still lacking. The evolution of LT for HBV is examined in detail in this review together with the description of the strategies adopted to prevent HBV recurrence and their pros and cons.

Ultraviolet-induced alloantigen-specific immunosuppression in transplant immunity

After the first observation of the immunosuppressive effects of ultraviolet(UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells(Tregs). Antigen-specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40th anniversary of its discovery.

Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma:Review of the literature

Cholangiocarcinoma(CCA)is a malignant tumor of the biliary system and includes,according to the anatomical classification,intra hepatic CCA(iCCA),hilar CCA(hCCA)and distal CCA(dCCA).Hilar CCA is the most challenging type in terms of diagnosis,treatment and prognosis.Surgery is the only treatment possibly providing long-term survival,but only few patients are considered resectable at the time of diagnosis.In fact,tumor’s extension to segmentary or subsegmentary biliary ducts,along with large lymph node involvement or intrahepatic metastases,precludes the surgical approach.To achieve R0 margins is mandatory for the disease-free survival and overall survival.In case of unresectable locally advanced hCCA,radiochemotherapy(RCT)as neoadjuvant treatment demonstrated to be a therapeutic option before either hepatic resection or liver transplantation.Before liver surgery,RCT is believed to enhance the R0 margins rate.For patients meeting the Mayo Clinic criteria,RCT prior to orthotopic liver transplant(OLT)has proved to produce acceptable 5-years survivals.In this review,we analyze the current role of neoadjuvant RCT before resection as well as before OLT.

Moving forward in the treatment of cholangiocarcinoma

Despite being the second most frequent primary liver tumor in humans,early diagnosis and treatment of cholangiocarcinoma(CCA)are still unsatisfactory.In fact,survival after 5 years is expected in less than one fourth of patients diagnosed with this disease.Rare incidence,late appearance of symptoms and heterogeneous biology are all factors contributing to our limited knowledge of this cancer and determining its poor prognosis in the clinical setting.Several efforts have been made in the last decades in order to achieve an improved classification/understanding with regard to the diverse CCA forms.Location within the biliary tree has helped to distinguish between intrahepatic,perihilar and distal CCA types.Sequence analysis contributed to identifying several characteristic genetic aberrations in CCA that may also serve as possible targets for therapy.Novel findings are expected to significantly improve the management of this malignancy in the near future.In this changing scenario our review focuses on the current and future strategies for CCA treatment.Both systemic and surgical treatments are discussed in detail.The results of the main studies in this field are reported,together with the ongoing trials.The current findings suggest that an integrated multidisciplinary approach to this malignancy would be helpful to improve its outcome.

Spontaneous necrosis of solid gallbladder adenocarcinoma accompanied with pancreaticobiliary maljunction

A 71-year-old Japanese man with acute cholecystitis and an incarcerated gallbladder （GB） stone was admitted. Plain ultrasonography （US） incidentally detected a mass-like lesion in the fundus. Doppler US revealed that this elevated lesion had no blood flow. Computed tomography showed a relatively low-density mass, measuring 5 cm x 4 cm in diameter, with no positive enhancement. Magnetic resonance imaging showed a mass in the fundus with a slightly low intensity on Tl-weighted images and a slightly high intensity on T2-weighted images. We were agonized in making the qualitative diagnosis of mass-like lesions of the fundus, such as a benign tumor, cancer, or debris. We performed laparoscopic cholecystectomy, because the incarcerated GB stone clearly caused acute cholecystitis. Intra-operative cholangiography clearly revealed pancreaticobiliary maljunction. Amylase levels in the common bile duct and gallbladder were quite high. The elevated lesion in the fundus dearly showed severe necrosis. Although this necrotic nodule included non-viable adenocarcinoma cells, viable cancer cell nests were located in the muscularis propria and subcutaneous layer. Histopathological examination confirmed a solid adenocarcinoma. Thus, we diagnosed it as a gallbladder cancer, based on histopathological analysis of the resected specimen. We therefore undertook radical surgery, including wedge resection of the liver, radical dissection of regional lymph nodes, and resection of the extrahepatic bile duct. Histopathological findings revealed no cancer, hyperplasia or dysplasia in the additionally resected specimens. The patient was finally staged as T2, N0, H0, P0, M（-）, stage Ⅱ. We present the first case of spontaneous necrosis of solid gallbladder adenocarcinoma, with a review of previous studies.

Anterior transhepatic approach for total caudate lobectomy including spigelian lobe,paracaval portion and caudate process:A Brazilian experience

To the Editor:Nowadays,because of the infiltration of cholangiocarcinoma to the parenchyma and/or bile ducts of the caudate lobe,the inclusion of caudate lobe combined with a major hepatectomy remains the gold standard approach for a resectable hilar cholangiocarcinoma.Since the last years of the 20th century,some authors have begun to report isolated caudate lobe resection for hepatocellular

Pancreatic neuroendocrine tumor accompanied with multiple liver metastases

Pancreatic neuroendocrine tumor(P-NET) is rare and slow-growing. Current classifications predict its progno-sis and postoperative recurrence. Curative resection is ideal, although often difficult, because over 80% of pa-tients have unresectable multiple liver metastases and extrahepatic metastasis. Aggressive surgery for liver metastases is important to improve survival. Aggressive or cytoreductive surgery for liver metastases is indi-cated to reduce hormone levels and improve symptoms and prognosis. Liver transplantation was originally con-ceived as an ideal therapy for unresectable liver metas-tases. Unfortunately, there is no clear consensus on the role and timing of surgery for primary tumor and liver metastases. Surgeons still face questions in deciding the best surgical scenario in patients with P-NET with unresectable liver metastases.

Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria:a meta-analysis of 18,421 patients

Background:Outcomes after liver resection(LR)and liver transplantation(LT)for hepatocellular carcinoma(HCC)are heterogenous and may vary by region,over time periods and disease burden.We aimed to compare overall survival(OS)and disease-free survival(DFS)between LT versus LR for HCC within the Milan criteria.Methods:Two authors independently searched Medline and Embase databases for studies comparing survival after LT and LR for patients with HCC meeting the Milan criteria.Meta-analyses and meta-regression were conducted using random-effects models.Results:We screened 2,278 studies and included 35 studies with 18,421 patients.LR was associated with poorer OS[hazard ratio(HR)=1.44;95%confidence interval(CI):1.14-1.81;P<0.01]and DFS(HR=2.71;95%CI:2.23-3.28;P<0.01)compared to LT,with similar findings among intention-to-treat(ITT)studies.In uninodular disease,OS in LR was comparable to LT(P=0.13)but DFS remained poorer(HR=2.95;95%CI:2.30-3.79;P<0.01).By region,LR had poorer OS versus LT in North America and Europe(P≤0.01),but not Asia(P=0.25).LR had inferior survival versus LT in studies completed before 2010(P=0.01),but not after 2010(P=0.12).Cohorts that underwent enhanced surveillance had comparable OS after LT and LR(P=0.33),but cohorts undergoing usual surveillance had worse OS after LR(HR=1.95;95%CI:1.24-3.07;P<0.01).Conclusions:Mortality after LR for HCC is nearly 50%higher compared to LT.Survival between LR and LT were similar in uninodular disease.The risk of recurrence after LR is threefold that of LT.