Mesenchymal stem cells: A novel treatment option for primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a progressive liver disease for which there is no effective therapy. Hepatocytes and cholangiocytes from a PSC patient were cocultured with mesenchymal stem cells (MSCs) to assess in vitro change. A single patient with progressive PSC was treated with 150 million MSCs via direct injection into the common bile duct. Coculture of MSCs with cholangiocytes and hepatocytes showed in vitro improvement. Local delivery of MSCs into a single patient with progressive PSC was safe. Radiographic and endoscopic evaluation showed stable distribution of multifocal structuring in the early postoperative period. MSCs may be effective for the treatment of PSC.

Tocilizumab therapy in 5 solid and composite tissue transplant recipients with early ARDS due to SARS-CoV-2.

There are emerging data depicting the clinical presentation of coronavirus disease 19 (COVID-19) in solid organ transplant recipients but negligible data-driven guidance on clinical management. A biphasic course has been described in some infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), beginning with a flu-like illness followed by an intense inflammatory response characterized by elevated c-reactive protein (CRP), interleukin 6 (IL-6), and acute respiratory distress syndrome (ARDS) associated with high mortality. The exuberant and possibly dysregulated immune response has prompted interest in therapeutic agents that target the cytokines involved, particularly IL-6. Tocilizumab is an IL-6 receptor antagonist with a record of use for a variety of rheumatologic conditions and cytokine release syndrome due to chimeric antigen receptor T-cell therapy but experience in solid organ and composite tissue transplant recipients (SOT/CTTRs) with SARS-CoV-2-related ARDS has not been previously reported in detail. We present the clinical course of 5 SOT/CTTRs with SARS-CoV-2-related ARDS that received tocilizumab with favorable short-term outcomes in 4. Responses were characterized by reductions in CRP, discontinuation of vasopressors, improved oxygenation and respiratory mechanics, and variable duration of ventilator support. Four bacterial infections occurred within 2 weeks of tocilizumab administration. We discuss safety concerns and the need for randomized comparative trials to delineate tocilizumab's clinical utility in this population.

Coronavirus disease 2019 in an orthotopic liver transplant recipient living with human immunodeficiency virus.

Coronavirus disease 2019 (COVID-19), mediated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with flu-like illness and severe pneumonia with acute respiratory distress syndrome (ARDS). Immunocompromised patients merit particular attention as altered host immunity may influence both disease severity and duration of viral shedding as is described with several other ribonucleic acid respiratory viruses. Yet immunocompromised status alone, in the absence of other comorbidities, may not necessarily predict severe illness presentations and poorer clinical outcomes as indicated by recent reports of COVID-19-infected solid organ transplant recipients and people living with human immunodeficiency virus (HIV). Such patients may even be spared the robust inflammatory response that precipitates ARDS associated with COVID-19, complicating the management of iatrogenic immunosuppression in this setting. We present a case of an orthotopic liver transplant recipient with well-controlled HIV who successfully recovered from a mild, flu-like illness attributed to SARS-CoV-2.

Single-Center Comparison of Overall Survival and Toxicities in Patients with Infiltrative Hepatocellular Carcinoma Treated with Yttrium-90 Radioembolization or Drug-Eluting Embolic Transarterial Chemoembolization.

PURPOSE: To compare overall survival and toxicities after yttrium-90 (90Y) radioembolization and chemoembolization with drug-eluting embolics (DEE) in patients with infiltrative hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Retrospective review of 50 patients with infiltrative HCC without main portal vein invasion who were treated with 90Y radioembolization (n = 26) or DEE chemoembolization (n = 24) between March 2007 and August 2012 was completed. Infiltrative tumors were defined by cross-sectional imaging as masses that lacked well-demarcated boundaries, and treatment allocations were made by a multidisciplinary tumor board. Median age was 63 years; median tumor diameter was 9.0 cm; and there were no significant differences between groups in performance status, severity of liver disease, or HCC stage. Toxicities were graded by Common Terminology Criteria for Adverse Events v4.03. Overall survival from treatment was assessed by Kaplan-Meier analysis, with analysis of potential predictors of survival with log-rank test. RESULTS: There was no difference in the average number of procedures performed in each treatment group (DEE, 1.5 ± 1.1; 90Y, 1.6 ± 0.5; P = .97), and technical success was achieved in all cases. Abdominal pain (73% vs 33%; P = .004) and fever (38% vs 8%; P = .01) were more frequent after DEE chemoembolization. There was no significant difference in median overall survival between treatment groups after treatment (DEE, 9.9 months; 90Y, 8.1 months; P = .11). CONCLUSIONS: 90Y radioembolization and DEE chemoembolization provided similar overall survival in the treatment of infiltrative HCC without main portal vein invasion. Abdominal pain and fever were more frequent after DEE chemoembolization.

Serum albumin predicts survival in patients with hilar cholangiocarcinoma.

BACKGROUND AND AIMS: Hilar cholangiocarcinoma is a devastating malignancy with incidence varying by geography and other risk factors. Rapid progression of disease and delays in diagnosis restrict the number of patients eligible for curative therapy. The objective of this study was to determine prognostic factors of overall survival in all patients presenting with hilar cholangiocarcinoma. METHODS: All adult patients with histologically confirmed hilar cholangiocarcinoma from 2003 to 2013 were evaluated for predictors of survival using demographic factors, laboratory data, symptoms and radiological characteristics at presentation. RESULTS: A total of 116 patients were identified to have pathological diagnosis of hilar cholangiocarcinoma and were included in the analysis. Patients with a serum albumin level >3.0 g/dL (P < 0.01), cancer antigen 19-9 ≤200 U/mL (P = 0.03), carcinoembryonic antigen ≤10 ìg/L (P < 0.01) or patients without a history of cirrhosis (P < 0.01) or diabetes (P = 0.02) were associated with a greater length of overall survival. A serum albumin level >3.0 g/dL was identified as an independent predictor of overall survival (hazard ratio 0.31; 95% confidence interval 0.14-0.70) with a survival benefit of 44 weeks. CONCLUSION: This study was the largest analysis to date of prognostic factors in patients with hilar cholangiocarcinoma. A serum albumin level >3.0 g/dL conferred an independent survival advantage with a significantly greater length of survival.

Healthcare utilization and costs associated with cholangiocarcinoma.

BACKGROUND AND AIMS: Cholangiocarcinoma is a rare but devastating malignancy associated with a poor prognosis and a high mortality rate. With the recent advances in detection and treatment, it is unclear if the incidence and outcomes of cholangiocarcinoma are improving in the United States. The aim of this study was to evaluate the trends in the incidence, costs and mortality rates of cholangiocarcinoma- related hospital admissions in the USA. METHODS: We utilized the National Inpatient Sample Database (NIS) from 1997-2012 for all patients in whom cholangiocarcinoma (ICD-9 code 155.1, 156) was the principal discharge diagnosis. The temporal trends in the number of hospital admissions, length of stay and, hospitalization costs along with mortality rates over the study period were determined by using regression analysis for trends. RESULTS: There was a significant increase in the number of hospital admissions for cholangiocarcinoma as the principal diagnosis from 1997 to 2012 (10 357 vs 11 970, P<0.001). The mean length of stay for cholangiocarcinoma decreased by 17 % between 1997 and 2012 from 9.5 days to 7.9 days (P<0.001). However, during the same period, the mean hospital charges per patient (adjusted for inflation) increased 113.25% from $36 460 in 1997 to $77 753 in 2012. The in-hospital mortality rate decreased from 9.3% in 1997 to 6.4% in 2012 (P<0.001). CONCLUSIONS: There was a significant increase in the number of hospital admissions and associated costs from cholangiocarcinoma in the USA between 1997 and 2012. However, this was accompanied by a decrease in the inpatient mortality rates from cholangiocarcinoma.

Safety and efficacy of sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation.

INTRODUCTION: Recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT) carries a poor prognosis. The aim of our study was to assess the safety and efficacy of sorafenib in patients with recurrent HCC following LT. METHODS: A prospectively maintained LT database was retrospectively analyzed for patients with recurrent HCC following LT between 2001 and 2011-34 patients. Patients were divided into two groups based on whether they were prescribed sorafenib (n = 17) or not prescribed sorafenib (n = 17). The primary endpoint was overall survival. RESULTS: There were no significant differences between the two groups analyzed. Seventeen patients were on sorafenib for recurrent HCC, with a mean daily dose of ~444 mg. Mean duration of treatment was ~10 months. Side effects included: thrombocytopenia, diarrhea, rising transaminases, fatigue, hand-foot skin reaction, and nausea. Survival in the sorafenib vs. non-sorafenib group was greater at three-, six-, nine-, and 12-month intervals and overall survival. CONCLUSION: Sorafenib can be well tolerated and safe in patients with recurrent HCC following LT and may be associated with a modest survival benefit. To our knowledge, this is the largest single-center retrospective analysis of patients prescribed sorafenib for recurrent HCC after LT.

Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma.

PURPOSE: Intermediate-stage hepatocellular carcinoma (HCC) is usually treated with locoregional therapy using transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using ß-emitting yttrium-90 integral to the glass matrix of the microspheres is an alternative to TACE. This retrospective case-control study compared the outcomes and safety of TARE versus TACE in patients with unresectable HCC. MATERIALS AND METHODS: Patients with unresectable HCC without portal vein thrombosis treated with TARE between 2005 and 2008 (n = 61) were retrospectively frequency-matched by age, sex, and liver dysfunction with TACE-treated patients (n = 55) in the Mayo Clinic Hepatobiliary Neoplasia Registry. Imaging studies were reviewed, and clinical and safety outcomes were abstracted from the medical records. RESULTS: Complete tumor response was more common after TARE (12 %) than after TACE (4 %) (p = 0.17). When complete response was combined with partial response and stable disease, there was no difference between TARE and TACE. Median survival did not differ between the two groups (15.0 months for TARE and 14.4 months for TACE; p = 0.47). Two-year survival rates were 30 % for TARE and 24 % for TACE. TARE patients received fewer treatments (p < 0.001). Fifty-nine (97 %) TARE patients received outpatient treatment. In contrast, 53 (98 %) TACE patients were hospitalized for ≥1 day (p < 0.001). Compared with TACE, TARE was more likely to induce fatigue (p = 0.003) but less likely to cause fever (p = 0.02). CONCLUSION: There was no significant difference in efficacy between TARE and TACE. TARE patients reported more fatigue but had less fever than TACE patients. Treatment with TARE required less hospitalization than treatment with TACE. These findings require confirmation in randomized trials.

Factor XII deficiency acquired by orthotopic liver transplantation: case report and review of the literature.

Transmission of congenital clotting factor deficiencies after orthotopic liver transplantation is rare. There are published reports of liver donor-to-recipient transmission of protein C deficiency with dysfibrinogenemia, protein S, factor VII and factor XI deficiencies. We report a case of transmission of factor XII deficiency with liver transplantation in a patient with Budd-Chiari syndrome. There was a persistent elevation of the activated partial thromboplastin time (aPTT), but no evidence of bleeding while the patient was maintained on warfarin. The presence of a persistently abnormal aPTT may raise suspicion for the presence of a clotting factor deficiency; however, deficiencies of other clotting factors may not be readily apparent on routine blood tests performed in a donor. Being aware of the possibilities of transmission of these inherited deficiencies of coagulation factors will aid in their early detection and management in the transplant donor and recipient.

MELD and other factors associated with survival after liver transplantation.

Allocation of cadaveric livers for transplantation in the United States is now based on the severity of illness as determined by the model for end-stage liver disease (MELD) score, a function of bilirubin, creatinine and international normalized ratio (INR). The aim of our study was to determine the association of various pre-transplant risk factors, including the MELD score, on patient survival after orthotopic liver transplantation (OLT). The medical records of 499 consecutive patients (233 female, 266 males, mean age 50.9 +/- 10.6 years) undergoing cadaveric OLT at our institution between June 1990 and February 1998 were reviewed. In the 407 patients alive at the latest contact, follow-up was 4.7 years, with a minimum of 20 months (maximum of 9.4 years). Variables considered for analysis included MELD score, age, pre-transplant renal dysfunction requiring dialysis, Child-Pugh classification, underlying liver disease, diabetes mellitus, and heart disease (ischemic/valvular/other). There were 92 deaths during follow-up. In univariate analysis, the MELD score, renal failure requiring hemodialysis pre-OLT, age > 42 years, and underlying etiology of liver disease were significantly associated with death during long-term follow-up. In multivariate models, age, underlying etiology of liver disease and renal failure requiring hemodialysis were independent predictors of death after OLT.

Non-A to E hepatitis.

PURPOSE OF THE REVIEW: The list of possible hepatotropic viruses continues to grow with the discovery of the GB virus-C, the TT virus and the SEN virus. There is emerging data on the biology of these newly discovered :In spite of continuing research into the pathogenicity of the GB virus-C and the TT virus, definite evidence linking them to acute or chronic liver disease is lacking. The SEN virus was reported in 2000, and although there seems to be an association between virus and transfusion-related hepatitis, more data are awaited before definite conclusions can be drawn. The effect of GB virus-C, the TT virus and the SEN virus co-infection on other viral and non-viral hepatitides has also been studied in some detail. Again, there is no definite evidence so far that these viruses modify other liver diseases. SUMMARY: At the present time, diagnostic testing for these viruses does not seem to be warranted outside of clinical studies. The discovery of these viruses, however, paves the way for further research into novel viral agents that infect humans, other among hosts.

Etiology and natural history of primary sclerosing cholangitis.

The etiology of primary sclerosing cholangitis remains unknown. Bacteria, toxins, viral infections, and immunological and genetic factors have all been proposed as etiological agents. Portal bacteremia, toxins absorbed from the diseased colon in inflammatory bowel disease, and cytomegalovirus and reovirus infections have been implicated by various investigators but there is little evidence to support these hypotheses. The close association between primary sclerosing cholangitis and various human leukocyte antigen haplotypes is now well established and lends support to the theory that immunologic and genetic mechanisms may be involved in its pathogenesis. Patients with primary sclerosing cholangitis may have elevated levels of circulating immune complexes, immunoglobulins, and non-organ specific autoantibodies. The association between ulcerative colitis and primary sclerosing cholangitis remains unexplained and both groups of patients have a high prevalence of antibodies to the perinuclear cytoplasmic antigen. The long-term prognosis in primary sclerosing cholangitis is tempered by the development of cholangiocarcinoma in 6%-30% of patients when followed over long periods of time. Detecting cholangiocarcinoma early in a patient with primary sclerosing cholangitis is one of the most frustrating problems faced by a clinician while caring for these patients. The long-term outlook for patients with primary sclerosing cholangitis and cholangiocarcinoma remains dismal, whatever the treatment modality employed. However, the development of a multivariate statistical survival model from long-term survival data from the Mayo Clinic and other centers has been a major step in identifying individual primary sclerosing cholangitis patients at low, moderate, and high risk of dying. Such models have been useful for stratifying patients in therapeutic trials, for in patient counseling, and in patient selection and timing of liver transplantation.