Search

Extra-hepatic portal vein obstruction can cause severe portal hypertension. Meso-rex shunting is a surgical option to bypass the extrahepatic portal venous obstruction, connecting the superior mesenteric vein to the left portal vein, restoring hepato-petal blood flow. This is an alternative to porto-systemic shunts (e.g. spleno-renal shunt)in a setting of normal liver function and intrahepatic vasculature. Our case is of a 3yo patient who underwent meso-rex shunt creation, which was complicated by thrombosis and recurrent varices and ascites. Percutaneous recanalization and stenting via a trans-splenic approach was successful, and the shunt remained patent at follow up at 1,3, and 5 months.

The complement system has long been recognized as a potential druggable target for a variety of inflammatory conditions. Very few complement inhibitors have been approved for clinical use, but a great number are in clinical development, nearly all of which systemically inhibit complement. There are benefits of targeting complement inhibition to sites of activation/disease in terms of efficacy and safety, and here we describe P-selectin targeted complement inhibitors, with and without a dual function of directly blocking P-selectin-mediated cell-adhesion. The constructs are characterized in vitro and in murine models of hindlimb ischemia/reperfusion injury and hindlimb transplantation. Both constructs specifically targeted to reperfused hindlimb and provided protection in the hindlimb ischemia/reperfusion injury model. The P-selectin blocking construct was the more efficacious, which correlated with less myeloid cell infiltration, but with similarly reduced levels of complement deposition. The blocking construct also improved tissue perfusion and, unlike the nonblocking construct, inhibited coagulation, raising the possibility of differential application of each construct, such as in thrombotic vs. hemorrhagic conditions. Similar outcomes were obtained with the blocking construct following vascularized composite graft transplantation, and treatment also significantly increased graft survival. This is outcome may be particularly pertinent in the context of vascularized composite allograft transplantation, since reduced ischemia reperfusion injury is linked to a less rigorous alloimmune response that may translate to the requirement of a less aggressive immunosuppressive regime for this normally nonlife-threatening procedure. In summary, we describe a new generation of targeted complement inhibitor with multi-functionality that includes targeting to vascular injury, P-selectin blockade, complement inhibition and anti-thrombotic activity. The constructs described also bound to both mouse and human P-selectin which may facilitate potential translation.

IntroductionDonor brain death (BD) is an unavoidable component of vascularized composite allograft (VCA) transplantation and a key contributor to ischemia-reperfusion injury (IRI). Complement is activated and deposited within solid organ grafts as a consequence of BD and has been shown to exacerbate IRI, although the role of BD and complement in VCA and the role it plays in IRI and VCA rejection has not been studied.MethodsBD was induced in Balb/c donors, and the VCA perfused prior to graft procurement with UW solution supplemented with or without CR2-Crry, a C3 convertase complement inhibitor that binds at sites of complement activation, such as that induced on the endothelium by induction of BD. Following perfusion, donor VCAs were cold stored for 6 hours before transplantation into C57BL/6 recipients. Donor VCAs from living donors (LD) were also procured and stored. Analyses included CR2-Crry graft binding, complement activation, toxicity, injury/inflammation, graft gene expression and survival.ResultsCompared to LD VCAs, BD donor VCAs had exacerbated IRI and rejected earlier. Following pretransplant in-situ perfusion of the donor graft, CR2-Crry bound within the graft and was retained post-transplantation. CR2-Crry treatment significantly reduced complement deposition, inflammation and IRI as compared to vehicle-treated BD donors. Treatment of BD donor VCAs with CR2-Crry led to an injury profile not dissimilar to that seen in recipients of LD VCAs.ConclusionPre-coating a VCA with CR2-Crry in a clinically relevant treatment paradigm provides localized, and therefore minimally immunosuppressive, protection from the complement-mediated effects of BD induced exacerbated IRI.

ABSTRACT IMPACT: Our work unveils a novel mechanism of ischemia repurfusion injury driven by pre-existing autoimmunity following lung transplant and a potential therapeutic strategy for blocking complement-dependent injury thereby reducing risk of lung transplant rejection. OBJECTIVES/GOALS: Our goal was to determine if pre-existing autoimmune autoantibodies, such as those resulting from cigarette smoke (CS), contribute to graft rejection in lung transplantation (LTx) and if autoreactive-mediated graft injury is complement-dependent. METHODS/STUDY POPULATION: For in vivo experiments, we utilized our emphysema mouse model. Briefly, eight-week-old C57BL/6J mice are exposed to 3R4F reference cigarette smoke 5 hours per day, 5 days a week for 6 months. Upon completion, cigarette smoked (CS) mice and control (NS) mice received syngeneic orthotopic left-lung transplant from age-matched C57BL/6J donors. To determine if pre-existing autoreactivity mediated graft injury was complement-dependent we treated CS-LTx mice with a novel, bifunctional complement inhibitor. Autoantibody levels were measured by ELISA and lung injury was assessed by blinded histopathological analyses. Complement inhibition was verified by immunofluorescence. RESULTS/ANTICIPATED RESULTS: We found that CS-exposure leads to production of autoreactive antibodies towards extracellular matrix (ECM) components and contributes to graft injury. Interestingly, LTx into CS exposed mice further increased de-novo ECM autoantibody development. Lastly, treatment with our novel, bifunctional complement inhibitor blocked autoantibody spreading and significantly reduced graft rejection. DISCUSSION/SIGNIFICANCE OF FINDINGS: These data demonstrate that smoking induces pre-LTx autoreactivity to ECM proteins that promotes graft injury following LTx. Furthermore, complement inhibition reduces autoantibody production and protects the graft from injury.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare but aggressive pediatric tumor. Historically, treatment for UESL has consisted of combination therapy with surgical resection and chemotherapy. In some cases, surgical resection is not appropriate due to limiting factors such as tumor size, location, and lack of response to treatment. Orthotopic liver transplant (OLT) has been suggested as a promising alternative in these cases. We present a case of an 8 year-old boy with a large undifferentiated embryonal sarcoma of the liver who experienced disease progression after initial neoadjuvant chemotherapy. His tumor was considered unresectable after internal tumor board review due to its size and significant vascularity, ultimately making OLT the only curative option for this patient. Keywords: Undifferentiated embryonal sarcoma of the liver, Pediatric liver tumors, Orthotopic liver transplant, Pediatric liver transplantation

Background and Study Aims: The prevalence of gallbladder cancer (GBC) varies between different parts of the world. This study is a review of literature and an update of a previously published study conducted in our university and aims to reassess the incidence of GBC over the past 2 decades. Patients and Methods: We conducted a retrospective study between 2002 and 2016. Data regarding demographics, clinical presentation, risk factors, histopathology, investigations, and treatments were obtained. A diagnosis of GBC established during surgery or primarily detected in the surgical specimen was classified as incidental. Results: Of 11 391 cholecystectomies performed, 31 cases (0.27%) of GBC were found. The mean age of patients with GBC was 68 years (43-103 years), 74% were women. The annual incidence of GBC was 0.2/100 000 (men: 0.1/100 000; women: 0.3/100 000). Biliary colic and acute cholecystitis were the main presentations. Diagnosis of GBC was “incidental” in 67% of cases. About 75% of patients with GBC had gallstones, 13% had polyps, and 3% had porcelain gallbladder. Adenocarcinoma was the dominant (87%) histologic type. Conclusions: The GBC rate in our region, similar to others parts of the world, is still low and has not changed over the past 2 decades. This study consolidates the previously published recommendations regarding the high index of suspicion of GBC in elderly with cholelithiasis.