Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report.

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.

The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells.

The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcinoma tissues showed increased levels of COX-2 as well as phospho-Akt (Thr (308)), a protein kinase activated by COX-2-mediated prostaglandins, in human cholangiocarcinoma cells. Treatment of cultured human cholangiocarcinoma cells (HuCCT1, SG231, and CCLP1) with celecoxib resulted in a dose- and time-dependent reduction of cell viability. Fluorescence microscopy, Western blot, and caspase activity assays demonstrated that celecoxib induced morphological features of apoptosis, activation of caspase-9 and caspase-3, and release of cytochrome c. The celecoxib-induced cell death was significantly blocked by N-benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone, a wide-spectrum caspase inhibitor. Furthermore, cholangiocarcinoma cells treated with celecoxib showed significant reduction of Akt phosphorylation, whereas the levels of Bcl-2 and Bax were not altered. Inhibition of Akt activation by LY294002 significantly decreased the viability of human cholangiocarcinoma cells. These findings suggest that celecoxib inhibits cholangiocarcinoma growth partly through induction of apoptosis and inhibition of Akt phosphorylation.

Distinguishing between recurrent primary sclerosing cholangitis and chronic rejection.

KEY CONCEPTS: 1. Recurrent primary sclerosing cholangitis (PSC) is extremely difficult, if not impossible, to distinguish from other causes of biliary strictures or sclerosing cholangitis in allografts using needle biopsy evaluation alone. Technical problems with biliary reconstruction, long cold ischemic times, non-heart beating donors, ABO blood group incompatibility, antibody-mediated rejection, and small-for-size syndrome in reduced-size or living donor livers can also cause similar manifestations in a peripheral core biopsy. 2. Some difficulties in distinguishing between sclerosing cholangitis and chronic rejection (CR) arise because: a) at risk populations are similar; b) both can cause "cholestatic" elevation of liver injury tests; and c) both can lead to intrahepatic cholestasis and small bile duct loss. 3. Etiopathogenesis and pathology of CR and sclerosing cholangitis have some overlapping features, but show distinct differences that result in significantly different and discriminating pathologic manifestations. 4. Clues in the clinical history, evaluation of serial biopsies, and histopathology can be used to distinguish with confidence between sclerosing cholangitis and CR. 5. Potential discriminating features include liver size and gross appearance, and histopathology findings in the arterial tree, hilar lymph nodes, large and small bile ducts, interface zone, lobular, and perivenular regions.