Clinical Presentation, Cholangiographic Features, Natural History, and Outcome: A Series of 16 Cases

Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an important differential diagnosis in patients presenting with cholestasis and PSC-like cholangiographic changes in endoscopic retrograde cholangiography (ERC). As a relatively newly described entity, SSC-CIP is still underdiagnosed, and the diagnosis is often delayed. The present study aims to improve the early detection of SSC-CIP and the identification of its complications. A total of 2633 records of patients who underwent or were listed for orthotopic liver transplantation at the University Hospital Charité, Berlin, were analyzed retrospectively. The clinical presentation and outcome (mean follow-up 62.7 months) of the 16 identified SSC-CIP cases were reviewed. Cholestasis was the first sign of SSC-CIP. GGT was the predominant enzyme of cholestasis. Hypercholesterolemia occurred in at least 75% of the patients. SSC-CIP provoked a profound weight loss (mean 18 kg) in 94% of our patients. SSC-CIP was diagnosed by ERC in all patients. The 3 different cholangiographic features detected correspond roughly to the following stages: (I) evidence of biliary casts, (II) progressive destruction of intrahepatic bile ducts, and (III) picture of pruned tree. Biliary cast formation is a hallmark of SSC-CIP and was seen in 87% of our cases. In 75% of the patients, the clinical course was complicated by cholangiosepsis, cholangitic liver abscesses, acalculous cholecystitis, or gallbladder perforation. SSC-CIP was associated with worse prognosis; transplant-free survival was ∼40 months (mean). Because of its high rate of serious complications and unfavorable prognosis, it is imperative to diagnose SSC-CIP early and to differentiate SSC-CIP from other types of sclerosing cholangitis. Specific characteristics enable identification of SSC-CIP. Early cooperation with a transplant center and special attention to biliary complications are required after diagnosis of SSC-CIP

Transplant conditioning by the prior therapy of brain-dead organ donors with methylprednisolone (Urbason ®)

Die traumatischen pathophysiologischen Ereignisse während des Hirntodes haben einen negativen Einfluss auf die Qualität und spätere Funktionalität der periphereren Organe, unter anderem durch die gesteigerte Expression der proinflammatorischen Zytokine in den peripheren Organen sowie der höheren Spiegel zirkulierender proinflammatorischen Zytokine im Serum hirntoter Spender. Diese Zytokine generieren eine proinflammatorische Aktivierung der Organe, haben einen Anteil an der Leukozyten-Endothelaktivierung, der T-Zell- Stimulierung, der Sekretion weiterer Zytokine, der Induktion von Zellapoptosen und der Antigenprozessierung. Durch die chirurgische Manipulation sowie die folgende Ischämie/Reperfusion-Phase werden die zu transplantierenden Organe beeinträchtigt. Durch die frühe Expression proinflammatorischer Zytokine erfahren die Organe einen intensiveren I/R-Schaden. Die Empfänglichkeit für eine nachfolgende Immunreaktion wird dadurch erhöht. In dieser Studie wurden die Organspender einer Methylprednisolon-Stoßtherapie vor der Organentnahme unterzogen. Es wurde untersucht, ob sich die durch den Hirntod hervorgerufene Inflammation der peripheren Organe sowie die systemische Inflammation supprimieren lässt. Hierzu wurde die Expression proinflammatorischer Zytokine in den Lebertransplantaten sowie deren Serumkonzentration bei Organspendern gemessen. Ferner wurde untersucht, ob eine Korrelation dieser Ergebnisse mit der Organfunktion und der Frequenz akuter Abstoßungsepisoden im weiteren klinischen Verlauf besteht. Für die Beurteilung des frühen postoperativen Verlaufs wurden die Serumkonzentrationen der Organempfänger von ALT, AST und Bilirubin bestimmt. Für die Beurteilung des klinischen Verlaufs in den ersten sechs Monaten nach der Transplantation wurde die ITBL- und die Rejektionsrate während dieses Zeitabschnitts ausgewertet. Passend zu den bereits vorliegenden experimentellen Daten konnte mittels der Vortherapie der Organspender mit Methylprednisolon sowohl die Expression proinflammatorischer Zytokine in den Lebertransplantaten als auch die Serumkonzentration der proinflammatorischen Zytokine bei den Organspendern signifikant gesenkt werden. Somit kann die Vortherapie der Organspender mit Methylprednisolon die durch den Hirntod hervorgerufene Inflammation der Peripherie supprimiert werden. Passend zu den bereits vorliegenden klinischen Daten konnte mittels der Vortherapie der Organspender mit Methylprednisolon eine signifikante Verbesserung der Transplantatfunktion sowie eine signifikante Senkung von postoperativen Transplantatschäden bei Organempfängern erreicht werden. Die ITBL- sowie die Rejektionsraten bei Organempfängern konnten durch die Vortherapie der Organspender ebenfalls signifikant gesenkt werden, ebenfalls in Übereinstimmung mit den bisher klinisch erhobenen Daten. Somit ist es möglich, mit der Vortherapie der Organspender mit Methylprednisolon eine bessere Qualität und eine bessere Funktionalität der Transplantate zu erreichen. Insbesondere die Empfänger marginaler Organe würden von der Vortherapie der Organspender mit Methylprednisolon profitieren. Die Vortherapie der Organspender mit Methylprednisolon ist in der Durchführung bei Menschen ungefährlich und einfach.The traumatic pathophysiological events during the brain death have a negative influence on the quality and functionality of the peripheral organs, among other known factors although through the increased expression of proinflammatory cytokines in peripheral organs as well as higher levels of circulating proinflammatory cytokines in the serum of the brain dead donors. These cytokines generate a proinflammatory activation of human organs, have an influence on the T-cell stimulation, secretion of other cytokines, the induction of cell apoptosis and antigen processing. The surgical manipulation and the subsequent ischemia/reperfusion phase affects the organs to be transplanted. By the early expression of proinflammatory cytokines, the human organs undergo a more intensive I/R-injury. The susceptibility to a subsequent immune response is increased. In this study, the organ donor were treated with methylprednisolone before organ removal. It was investigated, whether the inflammation of the peripheral organs and systemic inflammation caused by brain death, can be suppressed. To this end, the expression of proinflammatory cytokines was measured in liver tissue and in serum of organ donors. It was also investigated whether there is a correlation of these results with the organ function and the frequency of acute rejection episodes in the further clinical course. To evaluate the early postoperative course, serum concentrations of recipients of ALT, AST and bilirubin were determined. To assess the clinical course in the first six months after transplantation, the ITBL and the rate of rejections was evaluated during this period. According to the experimental data already available, the expression of proinflammatory cytokines in liver tissue as well as the serum concentration of proinflammatory cytokines could be significantly reduced in organ donors by means of the prior therapy of organ donors with methylprednisolone. Thus, the prior therapy of organ donors with methylprednisolone suppresses the inflammation of the peripherial organ tissue, caused by the brain death. According to the experimental data already available, the significant improvement of the graft function and a significant reduction of postoperative graft damage is achieved by recipients, got the organs from donors, that underwent the prior therapy with methylprednisolone. The ITBL rates as well as the rates of rejections were reduced by the recipients, got the organs from donors, that underwent the prior therapy with methylprednisolone. This data is also in accordance with the previously collected clinical data. Thus, it is possible to achieve a better quality and better functionality of the grafts with the prior therapy of organ donors with methylprednisolone. Particularly the recipients of marginal organs would benefit from the organ donor prior therapy with methylprednisolone. The therapy of organ donors with methylprednisolone is in the implementation harmless and easy

Implications of Imaging Criteria for the Management and Treatment of Intraductal Papillary Mucinous Neoplasms - Benign versus Malignant Findings

OBJECTIVES Evaluation of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiation of pancreatic intraductal papillary mucinous neoplasm (IPMN) subtypes based on objective imaging criteria. METHODS Fifty-eight patients with 60 histologically confirmed IPMNs were included in this retrospective study. Eighty-three imaging studies (CT,n = 42; MRI,n = 41) were analysed by three independent blinded observers (O1-O3), using established imaging criteria to assess likelihood of malignancy (-5, very likely benign; 5, very likely malignant) and histological subtype (i.e., low-grade (LGD), moderate-grade (MGD), high-grade dysplasia (HGD), early invasive carcinoma (IPMC), solid carcinoma (CA) arising from IPMN). RESULTS Forty-one benign (LGD IPMN,n = 20; MGD IPMN,n = 21) and 19 malignant (HGD IPMN,n = 3; IPMC,n = 6; solid CA,n = 10) IPMNs located in the main duct (n = 6), branch duct (n = 37), or both (n = 17) were evaluated. Overall accuracy of differentiation between benign and malignant IPMNs was 86/92 % (CT/MRI). Exclusion of overtly malignant cases (solid CA) resulted in overall accuracy of 83/90 % (CT/MRI). The presence of mural nodules and ductal lesion size ≥30 mm were significant indicators of malignancy (p = 0.02 and p < 0.001, respectively). CONCLUSIONS Invasive IPMN can be identified with high confidence and sensitivity using CT and MRI. The diagnostic problem that remains is the accurate radiological differentiation of premalignant and non-invasive subtypes. KEY POINTS • CT and MRI can differentiate benign from malignant forms of IPMN. • Identifying (pre)malignant histological IPMN subtypes by CT and MRI is difficult. • Overall, diagnostic performance with MRI was slightly (not significantly) superior to CT

Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma

Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a "cirrhotic" methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals