The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma.

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.

Tumor Biology as Predictor of Mortality in Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver tumor, with the Milan criteria considered to be the gold standard for patient selection for liver transplantation (LT). MATERIALS AND METHODS: We performed a descriptive observational study, reviewing 20 years of experience of LT in patients with HCC in the Fundacion Valle del Lilí in Cali, Colombia. Subgroup analysis was undertaken for periods 1999 to 2007 and 2008 to 2015. RESULTS: Fifty-seven cases with a pretransplant HCC diagnosis were reviewed. In the first period patients within the Milan criteria had a recurrence-free survival at 5 years of 66.6%, and in those who exceeded the Milan criteria, recurrence-free survival was 75%. In the second period, patients within the Milan criteria, recurrence-free survival at 5 years was 93.5%, and in those who exceeded the Milan criteria, recurrence-free survival was 75.7%. No statistically significant difference was found in either period. For patients with mild and moderate tumor differentiation, the relapse survival rate at 5 years was 69.4% (95% confidence interval [CI] 35.8-87.8) and 74.7% (95% CI 44.5-90), respectively. All patients with poor tumor differentiation relapsed and died within 3 years. CONCLUSION: Global and recurrence-free survival among patients who met and patients who exceeded the Milan criteria was not significantly different, suggesting an expansion of the Milan criteria to include potential recipients who were previously excluded. Obtaining histologic differentiation and identifying vascular invasion will provide a more worthwhile contribution to LT decision making.

Kidney transplantation for end-stage renal disease in lupus nephritis, a very safe procedure: a single Latin American transplant center experience.

Background Lupus nephritis (LN) is one of the most frequent complications of SLE and occurs in up to 50% of cases depending on the studied population. Of these, approximately 20% progress to end-stage renal disease (ESRD), with the treatment of choice being a kidney transplant. Objective The objective of this study was to describe the clinical outcome of patients transplanted due to LN, compared with patients transplanted for other causes, in a Latin American population from the Fundación Valle del Lili in Cali, Colombia. Methods Observational, retrospective case study with controls matched by age, sex and type of donor in a single center between 1996 and 2014. Results Sixty-five kidney transplants were performed in patients with LN and ESRD. The survival of patients with LN was 98% at 1, 10 and 15 years ( p = .99). For controls by age and sex, survival was also 98% at 15 years post-transplant, and for controls by donor, the survival rate was 100% at 5 years and 98% at 15 years. Graft survival in patients with LN to 1, 5 and 15 years was 92%, 83% and 71%, respectively; for controls by age and sex, it was 90%, 84% and 64%, respectively, and for the controls by donor, it was 89%, 86% and 79%, respectively ( p = .7718). There were no statistically significant differences found in the cumulative incidence of acute graft rejection in the first year, but it was found that acute rejection is a factor that relates to the loss of function of the renal graft ( p = .032). Of the patients transplanted for LN, two (3.1%) experienced a recurrence of the disease. One patient died after a diagnosis of recurrence of LN due to an infection. Conclusions Kidney transplantation is a good option for patients with ESRD due to LN. In this Hispanic population, the survival of patients, graft survival, and cumulative incidence of graft rejection are not different from those of other transplanted patients. In addition, recurrence of LN was rare, showing the benefits of renal transplantation in LN patients with ESRD.

[Evaluation of the effectiveness of a nutrition education intervention performed by primary school teachers]. / Valutazione d'efficacia di un intervento di educazione alimentare condotto da insegnanti di scuola media inferiore.

This study values the effectiveness of nutrition education interventions carried out by teachers with active didactic methodologies. The research was carried out by administering a frequency of food intake questionnaire, before and after the intervention. To compare the answers given before and after the educational intervention the Wilcoxon-test was applied to dependent data. Our research confirmed that a substantial percentage of children do not show a correct nutrition and therefore nutrition education interventions are opportune and necessary. In the group with "insufficient execution" particular variations are not taken place. In the group with "sufficient execution" increase the number of subjects having breakfast, particularly with milk and biscuits, and decrease the snakes intake. Moreover there is a general decrease of intake food as meat, fish, vegetables, salami and legumes. So this educational intervention seems to have only partial effectiveness.

[Top medical management and levels of knowledge about the application of the D.lgs. 626/94]. / Dirigenza medica apicale e livelli di consapevolezza circa l'applicazione del D.lgs. 626/94.

The incorporation into Italian legislation of the European Community directives on the improvement of health and safety at work imposes new duties on the department heads of hospital departments. Their level of knowledge and information on several safety problems--occupational infections, exposure to chemical agents, use of antineoplastic and antiviral drugs, use of protective garments and devices, exposure to ionizing and non ionizing radiations, use of electric devices, lifting and loading, fire prevention--was surveyed in a large teaching hospital in northern Italy, via a check-list derived from Italian and international experience. Both knowledge and information resulted rather low, with particular regard to chemical, electric and fire hazards. The ignorance of department heads about common safety and prevention procedures in hospital work does not allow them to carry out their role according to the new requirements of Italian legislation. However, as they "must" know and have criminal responsibility in case of accidents or diseases due to their unawareness, appropriate courses are needed to fulfil law and safety requirements.

[Stromal tumors of the stomach. Review of the literature and description of a case of "uncommitted" stromal tumor]. / Tumori stromali dello stomaco. Revisione della letteratura e descrizione di un caso di tumore stromale "uncommitted".

Non-epithelial non-lymphomatous neoplasms of the gastrointestinal tract are known as stromal tumors (GISTs) because of the tissues in which they originate (4), (16). These neoplasms are rare and account for about 4% of all the tumors of the stomach. Their malignancy and biological and anatomopathological behaviour are related to clinical problems, since their histopathological picture is both complex and controversial. Modern immunohistochemical and ultrastructural (12), (26) studies have identified forms of myogenic or neural origin, which are more differentiated, as well as mixed types with both components, and types, though surely stromal, of uncertain origin, therefore called "uncommitted" (22), (25). The latter are extremely rare and, since it is not yet possible to classify them, some Authors use the term GIST only for these groups. A report of a clinical case of "uncommitted" GIST offers the opportunity to review the literature, highlighting the increased incidence of these tumors (which is probably related partially to the improved diagnostic techniques (3)), their potential malignancy and the difficulty of a correct classification and, therefore, a clear prognosis.