Surgical Strategies for Combined Hepatocellular-Cholangiocarcinoma (cHCC-CC).

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a tumor entity presenting features of hepatocellular and cholangiocellular epithelial differentiation. Due to the likeness between cHCC-CC, HCC and CC, accurate pretherapeutical diagnosis is challenging and advanced stages are prevalent. Radical oncological surgery is the only curative therapeutical option in patients with cHCC-CC. To reach this goal a profound understanding of this rare liver tumor is crucial. Factors such as clinicopathological characteristics, growth patterns and biological behavior are of central importance. To explore onco-surgical strategies and aspects for complete resection of cHCC-CC and to answer important key questions, an extensive review of the literature was conducted to answer the following questions: What are the best surgical options? Is there a significance for nonanatomical resections? Is there a prognostic value of concomitant lymphadenectomy? What about multimodal concepts in local advanced cHCC-CC? The role of minimally invasive liver surgery (MILS) including the role of robotic liver surgery for cHCC-CC will be discussed. While liver transplantation (LT) is standard for patients with unresectable HCC, the role of LT in cHCC-CC patients is still controversial. How can patients with high risk for early tumor recurrence be identified to avoid aggressive surgical treatment without clinical benefit? The comprehensive understanding of this challenging liver tumor will help to improve future treatment options for these patients.

YKL-40-gene polymorphism affects acute cellular rejection and fibrosis progression after transplantation for hepatitis C virus-induced liver disease.

BACKGROUND AND AIM: The development of end-stage graft disease is suspected to be partially determined by an individual genetic background. The aim of our study was to determine the prevalence of YKL-40-gene polymorphism in hepatitis C virus (HCV)-positive patients and its impact on the incidence of acute cellular rejection (ACR), graft fibrosis and antiviral treatment response. METHODS: A total of 149 patients, who underwent liver transplantation for HCV-induced liver disease, were genotyped for YKL-40 (rs4950928; G/C) by TaqMan Genotyping Assay. The results were correlated with 616 post-transplant graft biopsies regarding inflammation, fibrosis and evidence for ACR. RESULTS: No association of YKL-40-genotypes was observed regarding mean inflammation grade (P = 0.216) and antiviral treatment outcome (P = 0.733). However, the development of advanced fibrosis (F3-4) was significantly faster in patients with YKL-40-G-allele: t(CC) = 4.6 versus t(CG/GG) = 2.4 years; P = 0.006. Patients with lower fibrosis (F0-2) compared to advanced fibrosis (F3-4) received significantly more frequent dual immunosuppression (calcineurin inhibitors [CNIs]/mofetile mycophenolate [MMF] vs CNIs; P = 0.003). ACR-occurrence was associated with YKL-40-genotypes (ACR: CC = 60.4%, CG = 25.0% and GG = 14.6% vs non-ACR: CC = 74.2%, CG = 23.8% and GG = 2.0%; P = 0.009) and with gender compatibility between donor and recipient (P = 0.012). CONCLUSION: Fibrosis progression and ACR-incidence after transplantation for HCV-induced liver disease seem to be under genetic control. The negative impact of G-allele on post-transplant events observed in our study, deserves attention and should be verified in larger liver transplantation-cohorts.

Induction of bona fide regulatory T cells after liver transplantation - the potential influence of polyclonal antithymocyte globulin.

T-cell-depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting. Besides prevention of alloreactivity, treatment with rabbit antithymocyte globulin (rATG) has been related to the induction of immunoregulatory T cells (Treg) in vitro and in vivo. To investigate Treg induced by rATG, we prospectively studied the effect of rATG induction therapy in liver-transplanted recipients in vivo (n = 28). Treg induction was further evaluated by means of Treg-specific demethylation region (TSDR) analysis within the FOXP3 locus. Whereas no induction of CD4(+) CD25(high) CD127(-) Treg could be observed by phenotypic analysis, we could demonstrate an induction of TSDR(+) T cells within CD4(+) T cells exclusively for rATG-treated patients in the long-term (day 540) compared with controls (P = NS). Moreover, although in vitro experiments confirm that rATG primarily led to a conversion of CD4(+) CD25(-) into CD4(+) CD25(+) T cells displaying immunosuppressive capacities, these cells cannot be classified as bona fide Treg based on their FOXP3 demethylation pattern. Consequently, the generation of Treg after rATG co-incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined.

Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study.

Hepatitis B re-infection prophylaxis is crucial for graft and recipient survival for transplanted patients and is administered routinely after liver transplantation for hepatitis B. Aim of the current study was the investigation of efficacy, safety and feasibility of home-treatment of a novel human hepatitis B immunoglobulin BT088 (Zutectra) after weekly subcutaneous application in liver-transplanted patients. A total of 23 patients (5 female, 18 male, median age 51 years) were enrolled and switched from monthly IV to weekly SC hepatitis B immunoglobulin administration. During a period of 18 weeks (optional 24 weeks) anti-HBs levels, signs of re-infection, adverse events and feasibility of self-administration were studied. After 8 weeks of training patients showing good compliance and stable antibody titres were allowed to start self-administration at home. All patients maintained a safety level of >100 U/l anti-HBs. No failure was noted, no re-infection occurred. A total of 10 treatment-emergent events were assessed as related to study drug application (injection-site haematoma, headache, abdominal pain, fatigue and haematuria). High numbers of self-administration (287 vs. 122 by staff) demonstrated general feasibility of SC administration. Weekly subcutaneous administration of BT088 (Zutectra - registered trade mark in the EU) is effective, safe and presents an easy-to-apply treatment option for combined hepatitis B virus re-infection prophylaxis in liver transplant patients (Eudra CT Number: 2005-003737-40).

Loss of receptor on tuberculin-reactive T-cells marks active pulmonary tuberculosis.

BACKGROUND: Tuberculin-specific T-cell responses have low diagnostic specificity in BCG vaccinated populations. While subunit-antigen (e.g. ESAT-6, CFP-10) based tests are useful for diagnosing latent tuberculosis infection, there is no reliable immunological test for active pulmonary tuberculosis. Notably, all existing immunological tuberculosis-tests are based on T-cell response size, whereas the diagnostic potential of T-cell response quality has never been explored. This includes surface marker expression and functionality of mycobacterial antigen specific T-cells. METHODOLOGY/PRINCIPAL FINDINGS: Flow-cytometry was used to examine over-night antigen-stimulated T-cells from tuberculosis patients and controls. Tuberculin and/or the relatively M. tuberculosis specific ESAT-6 protein were used as stimulants. A set of classic surface markers of T-cell naïve/memory differentiation was selected and IFN-gamma production was used to identify T-cells recognizing these antigens. The percentage of tuberculin-specific T-helper-cells lacking the surface receptor CD27, a state associated with advanced differentiation, varied considerably between individuals (from less than 5% to more than 95%). Healthy BCG vaccinated individuals had significantly fewer CD27-negative tuberculin-reactive CD4 T-cells than patients with smear and/or culture positive pulmonary tuberculosis, discriminating these groups with high sensitivity and specificity, whereas individuals with latent tuberculosis infection exhibited levels in between. CONCLUSIONS/SIGNIFICANCE: Smear and/or culture positive pulmonary tuberculosis can be diagnosed by a rapid and reliable immunological test based on the distribution of CD27 expression on peripheral blood tuberculin specific T-cells. This test works very well even in a BCG vaccinated population. It is simple and will be of great utility in situations where sputum specimens are difficult to obtain or sputum-smear is negative. It will also help avoid unnecessary hospitalization and patient isolation.