Review article: liver transplantation for HCC. Treatment options on the waiting list

The most widely adopted criteria to admit and maintain patients with HCC and cirrhosis in the waiting list for liver transplantation are the Milano criteria, consisting in the presence of a single tumour ≤ 5 cm in diameter or up to three tumours, none exceeding 3 cm in diameter. Since the average time to transplantation has become longer than 10-12 months in most European and American Centers, the exclusion from the list during the waiting period due to increase of the neoplasm over the established criteria is not uncommon at present. It is mandatory, therefore, to seek an effective therapeutic strategy for patients with HCC waiting for transplantation. Surgical resection and eventual subsequent salvage transplantation seems a cost-effective strategy in resectable HCC. In unresectable neoplasms both transarterial chemoembolization and percutaneous ablation techniques are currently used and one or the other are chosen according to individual applicability, limitations and specific risks. However, although positive trends were reported, no definitive evidence has been produced so far about their efficacy in increasing patient's survival and decreasing tumour recurrence rates after transplantation. Adult-to-adult living donor liver transplantation is one possible way to shorten the waiting list, but this strategy involves important ethical implications. At present it appears justified to take it into consideration only if the waiting time for cadaveric OLT is expected to exceed 7 months. A more general and definitive attempt to overcome problems related to long waiting times for patients with HCC and relatively preserved hepatic function has been introduced in the USA very recently and consists in prioritizing patients with HCC. However, the overall efficacy of this approach will be established only in some years

Skeletal muscle contraction. The thorough definition of the contractile event requires both load acceleration and load mass to be known

<p>Abstract</p> <p>Background</p> <p>The scope of this work is to show that the correct and complete definition of the system of muscle contraction requires the knowledge of both the mass and the acceleration of the load.</p> <p>Results</p> <p>The aim is achieved by making use of a model of muscle contraction that operates into two phases. The first phase considers the effects of the power stroke in the absence of any hindrance. In the second phase viscous hindrance is introduced to match the experimental speed and yield of the contraction. It is shown that, at constant force of the load, changing load acceleration changes the time course of the pre-steady state of myofibril contraction. The decrease of the acceleration of the load from 9.8 m.s^-2to 1 m.s^-2increases the time length of the pre-steady state of the contraction from a few microseconds to many hundreds of microseconds and decreases the stiffness of the active fibre.</p> <p>Conclusions</p> <p>We urge that in the study of muscle contraction both the mass and the acceleration of the load are specified.</p

Crystalline D -Gluconate 6-Phosphate Dehydrogenase"

A method for t.he purification of n-gluconate 6-phosphate dchydrogenase from brewers' yeast has been described by Horecker and Smyrniotis. (1). The enzyme preparation also catalyzed the oxidation of n-glucose 6-phosphate and isocitrate and in addition contained significant amounts of n-ribose 5-phosphate isomerasc. The utility of the enzyme for the assay of n-gluconate 6-phosphato and for the preparation of n-ribulose 5-phosphate was seriously affected by the prcsencc of thcsc contaminating activitics. For a further investigation of the properties of the enzyme and of the nature of the two-step reaction, a more highly purified preparation was necessary. A method has now been developed which yields from Candida yeast a crystalline preparation which is free of detectable quantitics of I)-glucose 6-phosphata dchydrogenase and r)-ribose 5-phosphate isomerasc. To remove the former enzyme, advantage was taken of its lability to heat after treatment with charcoal (2, 3). n-Glucose 6-phosphate dchydrogcnasc is known to bc unstable in t,he absence of triphosphopyridine nuclcotidc. With the purified enzyme, only n-ribulosc 5-phosphate is formed, and this ester can thus be obtained free of n-ribose 5-phosphate and n-xylulose j-phosphate. Since the crystalline enzyme preparation catalyzes the osidation of reduced triphosphopyridine nucleotide by CO, and o-ribulose phosphate at a rate equal to that observed with crude enzyme preparations, wc have concluded that a single enzyme is rcsponsible for both oxidation and decarboxylation reactions. We have also undertaken an investigation of the specificity of the Mg++ requirement (1) and havn found that at high concentrations of NaCl, full activity is obtained in the absence of Mg++. There is reason to believe that the nature of t,he anion plays a role in the activation of the enzyme

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

Liver transplantation for hepatocellular carcinoma: further considerations on selection criteria

The selection criteria in liver transplantation for HCC are a matter of debate. We reviewed our series, comparing two periods: before and after 1996, when we started to apply the Milan criteria. The study population was composed of patients with a preoperative diagnosis of HCC, confirmed by the pathological report and with a survival of &gt; 1 year. Preoperative staging as revealed by radiological imagining was distinguished from postoperative data, including the variable of tumor volume. After 1996 tumor recurrences significantly decreased (6 out of 15 cases, 40% vs. 3 out of 48, 6.3%, P &lt; .005) and 5-year patient survival improved (42% vs. 83%, P &lt; .005). Not meeting the Milan criteria was significantly related to higher recurrence rate (37.5% vs. 12.7%, P &lt; .05) and to lower 5-year patient survival (38% vs. 78%, P &lt; .005%) in the preoperative analysis, but not in the postoperative one. The alfa-fetoprotein level of more than 30 ng/dL and the preoperative tumor volume of more than 28 cm3 predicted HCC recurrences in the univariate and mutivariate analysis (P &lt; .005 and P &lt; .05, respectively). The ROC curve showed a linear correlation between preoperative tumor volume and HCC recurrence. Milan criteria significantly reduced tumor recurrences after liver transplantation, improving long-term survival. In conclusion, the efficacy of tumor selection criteria must be analyzed with the use of preoperative data, to avoid bias of the postoperative evaluation. Tumor volume and alfa-fetoprotein level may improve the selection of patients. Copyright © 2004 by the American Association for the Study of Liver Diseases

Anti-HBs re-seroconversion after liver transplantation in a patient with past HBV infection receiving a HBsAg positive graft

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The social cost of chronic kidney disease in Italy

This study aims to estimate the mean annual social cost per patient with chronic kidney disease (CKD) by stages 4 and 5 pre-dialyses and cost components in Italy. The multicenter cross-sectional study included all adult outpatients in charge of the 14 main Nephrology Centers of Tuscany Region during 7 weeks from 2012 to 2013. Direct medical costs have been estimated using tariffs for laboratory tests, diagnostic exams, visits, hospitalization and prices for drugs. Non-medical costs included expenses of low-protein special foods, travel, and formal and informal care. Patients' and caregivers' losses of productivity have been estimated as indirect costs using the human capital approach. Costs have been expressed in Euros (2016). Totals of 279 patients in stage 4 and 205 patients in stage 5 have been enrolled. The estimated mean annual social cost of a patient with CKD were a,notsign7422 (+/- a,notsign6255) for stage 4 and a,notsign8971 (+/- a,notsign6503) for stage 5 (p &lt; 0.05). Direct medical costs were higher in stage 5 as compared to stage 4; direct non-medical costs and indirect costs accounted, respectively, for 41 and 5 % of the total social cost of CKD stage 4 and for 33 and 9 % of CKD stage 5. In Italy, the overall annual social cost of CKD was a,notsign1,809,552,398 representing 0.11 % of the Gross Domestic Product. Direct non-medical costs and indirect costs were weighted on the social cost of CKD almost as much as the direct medical cost. Patients, their families and the productivity system sustain the burden of the disease almost as much as the healthcare system. © 2016, The Author(s)

Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids

Approximately 20-50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need