Portal vein tumor thrombosis (PVTT) is an intractable condition but common phenomenon in hepatocellular carcinoma (HCC). HCC patients with PVTT may have worse liver function, a higher chance of comorbidity related to portal hypertension, lower tolerance to treatment and poorer prognoses. In Western guidelines, patients are offered palliative treatment with sorafenib or other systemic agents because HCC with PVTT is grouped together with metastatic HCC during the planning of its management. In recent years, various treatment options have become available for patients with HCC and PVTT. Therapy has also shifted toward evidence-based treatment. However, policies for the management of HCC with PVTT have not been established. This comprehensive literature review aims to present current and available management options for patients with HCC and PVTT. Evidence is mainly based on studies published after 2010.

Slow coronary flow (SCF) is an angiographically observed phenomenon that is characterized by slow antegrade progression of radio-opaque contrast agent in the epicardial arteries and without any evidence of obstructive coronary artery disease. Published reports suggest that apart from having several established clinical and physical etiological factors, SCF might have some genetic determinants, along with some easily detectible biochemical correlates.

We set out to consolidate the information from all published articles exploring genetic determinants, specifically, single nucleotide polymorphisms (SNPs), and/or biochemical correlates of SCF, employing a systematic review and possibly a meta-analysis.

After a rigorous, well-defined, online database search, we identified 25 relevant original articles published up to December 2016. These articles reported on a total of 60 studies, including 14 for genetic determinants (nst=14) and 46 for biochemical correlates of SCF (nst=46). The present meta-analysis evaluating genetic determinants indicated statistically significant associations of two SNPs with SCF: nitric oxide synthase 3 (NOS3) gene variations of −849 G>T (rs1799983) and the 4b/a 27 base pair (bp) variable number tandem repeat (VNTR). Both of these SNPs provide dominant as well as allelic genetic models. For rs1799983 (nst=2), the odds ratio (OR) range was 2.11–2.71, with a Z value range of 2.91–3.00 and a p-value range of 0.003–0.004. For 27bp VNTR (nst=2), the OR range was 2.18–2.37, with a Z value range of 3.02–3.10 and p-value range of 0.002–0.003. We also noted possible involvement of some other SNPs which were reported to be associated with SCF in single studies. Our meta-analysis also aimed to assess biochemical correlates of SCF and deduced some noteworthy results. Plasma/serum levels of homocysteine [nst=10, standard mean difference (SMD): 1.45 (95% CI: 0.95–1.95, p<0.00001], endothelin-1 [nst=3, SMD: 2.33 (95%CI: 0.16–4.49), p=0.03] and C-reactive protein [nst=2, SMD: 0.39 (95% CI: 0.06–0.72), p=0.02] were found to be positively correlated with SCF, yielding statistically significant results. On the other hand, plasma levels of nitric oxide [nst=8, SMD: −0.93 (95%CI: −1.59 to −0.28), p=0.005] and folate [nst=3, SMD: −0.62 (95%CI=−0.88 to −0.36), p<0.00001] were found to be significantly, but negatively, correlated with SCF. A few lesser-known biochemical entities reported to be associated with SCF were also identified by single studies.

The results of this first ever review and meta-analysis on SCF identify its few genetic determinants as well as some biochemical correlates. Implicated biochemical correlates have the potential to be used for early detection of SCF. Published studies evaluating the genetic determinants responsible for this condition, however, are very few and sporadic. Several large and statistically-powered genetic-association studies are required to substantiate our findings.

Influenza continues to pose significant threats to global health. The disease remains life-threatening, especially in children, the elderly and immunocompromised patients. High mutation rate and genetic reassortment enhance antigenic diversity and generation of novel strains. These, and other related factors, have made influenza viruses more resistant to control strategies and have necessitated the need for development of novel and effective strategies for prevention and treatment of influenza. While vaccination is the preferred method for prevention of influenza virus infections, preparation of influenza vaccines has to be carried out annually, and this takes several months. Anti-influenza drugs would, therefore, be the most immediate resource for combating newly emerging influenza viruses, especially if available vaccines proved ineffective. This review discusses the prospects of using small interfering RNAs (siRNAs) for treatment of influenza. Challenges associated with anti-influenza RNA interference (RNAi) and future directions are also highlighted

Guillain-Barre Syndrome (GBS) is an autoimmune inflammatory polyneuropathy, which usually develops following infectious diseases. It is a known complication of dengue fever, in particular; however, GBS following combined Dengue and Chikungunya infection is extremely rare. We hereby report a patient with combined Dengue and Chikungunya fever, without associated thrombocytopenia. The main concern in this case was the sudden development of GBS, which was responsive to double immunoglobulin therapy and required a percutaneous dilatational tracheostomy (PCT) to facilitate weaning from ventilation.

In the United States, the fight to eradicate hepatitis C virus (HCV) infection has been ongoing for many years, but the results have been less than ideal. Historically, patients with chronic hepatitis C (CHC) were treated with interferon-based regimens, which were associated with frequent adverse effects, suboptimal response rates, and long durations of treatment – of up to 48 weeks. Expertise from specialist-physicians, such as hepatologists and gastroenterologists, was needed to closely follow patients on these medications so as to monitor laboratory values and manage adverse effects. However, the emergence of direct-acting antiviral (DAA) agents against HCV infection have heralded outstanding progress in terms of safety, tolerability, lack of adverse effects, efficacy, and truncated duration of therapy – 12 weeks or less – thereby making the need for close monitoring by specialist-physicians obsolete. With the recent approval of DAA agents by the Food and Drug Administration, the treatment model for CHC no longer relies on the limited number of specialist-physicians, which represented a major barrier to treatment access in the past, especially in underserved areas of the United States. We propose and share our experiences in adapting a task-shifting treatment model, one that utilizes a relatively larger pool of non-specialist healthcare providers, such as nursing staff (medical assistants, vocational licensed nurses, registered nurses, etc.) and advanced practice providers (nurse practitioners and physician assistants), to perform a variety of important clinical functions in an effort to make DAA-based antiviral therapy widely available against HCV infection. Most recently, task-shifting was implemented by the United States and World Health Organization in the fight against the human immunodeficiency virus and showed encouraging results. Based on our experiences in implementing this model at our outreach clinics, the majority of HCV-infected patients treated with DAA agents can be easily monitored by non-specialist healthcare providers and physician extenders. Task-shifting can effectively address one of the major rate-limiting factors in expanding treatment access for HCV infection.

Vascular diseases of the spleen are relatively uncommon in the clinical practice. However, the reported incidence has been progressively increasing, probably due to advances in the imaging modalities used to detect them. This disease condition often presents with non-specific clinical manifestations, but can be associated with significant morbidity and mortality. This review article aims to provide updated clinical information on the different vascular diseases of the splenic vasculature—splenic vein thrombosis, splenic vein aneurysm, splenic artery aneurysm, splenic arteriovenous fistula, and spontaneous splenorenal shunt—in order to aid clinicians in early diagnosis and management.

Nonalcoholic fatty liver disease (NAFLD) represents a major public health epidemic. Pharmacologic therapies for this condition are scarce, but multiple agents with novel mechanisms of action are in development. Here we review the pathophysiology and natural history of NALFD, diagnostic testing and data for currently available treatment strategies. We then turn our attention to promising developmental drugs and their respective trials. As the prevalence of fatty liver disease increases, clinicians will have more tools at hand for management of this condition. We conclude the horizon is bright for patients and doctors who deal with NAFLD.

Background and Aims: Due to the shortage of donor livers, minor ABO-incompatible liver transplantations are commonly performed. Together with the allograft, immunocompetent B-lymphocytes, called passenger lymphocytes, are transplanted. In case of minor ABO-incompatibility, these passenger lymphocytes produce antibodies directed towards the recipient’s red blood cells, which causes immune-mediated hemolysis, also known as the passenger lymphocyte syndrome (PLS). Although this is a self-limiting disorder, serious complications can occur, including graft failure. Retrospectively, we evaluated the role of PLS in minor ABO-incompatible liver transplantations performed at our center.

Methods: A retrospective analysis was conducted for all minor ABO-incompatible liver transplantations performed at the Antwerp University Hospital between 2003 and 2015. All patient files were inspected for clinical and laboratory findings. In cases of PLS diagnosis, the applied treatment was also studied.

Results: In total, 10 patients underwent a minor ABO-incompatible liver transplantation and 4 showed signs of PLS. All 4 PLS patients were treated with different therapeutic strategy, corresponding to the severity of hemolysis. In all 4 cases, PLS resolved following treatment.

Conclusion: When performing minor ABO-incompatible liver transplantations, knowledge of PLS is elemental. Next to a high index of clinical suspicion, we suggest routine screening for markers of hemolysis, with emphasis on haptoglobin level and direct antiglobulin test, weekly in the first 4 weeks post-transplantation as well as in case of a sudden hemoglobin drop within the first 3 months after transplantation. Peri- and postoperative transfusion support using donor-compatible blood has been suggested to prevent the occurrence or limit the extent of hemolysis.

Cirrhosis due to any etiology disrupts the homeostatic role of liver in the body. Cirrhosis-associated immune dysfunction leads to alterations in both innate and acquired immunity, due to defects in the local immunity of liver as well as in systemic immunity. Cirrhosis-associated immune dysfunction is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, and is responsible for 30% mortality. It also plays an important role in acute as well as chronic decompensation. Immune paralysis can accompany it, which is characterized by increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines. There is also presence of increased gut permeability, reduced gut motility and altered gut flora, all of which leads to increased bacterial translocation. This increased bacterial translocation and consequent endotoxemia leads to increased blood stream bacterial infections that cause systemic inflammatory response syndrome, sepsis, multiorgan failure and death. The gut microbiota of cirrhotic patients has more pathogenic microbes than that of non-cirrhotic individuals, and this disturbs the homeostasis and favors gut translocation. Prompt diagnosis and treatment of such infections are necessary for better survival. We have reviewed the various mechanisms of immune dysfunction and its consequences in cirrhosis. Recognizing the exact pathophysiology of immune dysfunction will help treating clinicians in avoiding its complications in their patients and can lead to newer therapeutic interventions and reducing the morbidity and mortality rates.

Background and Aims: The lack of specificity has limited the role of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) screening among patients with cirrhosis related to hepatitis C virus (HCV) infection. We sought to examine whether AFP may decrease after achieving a sustained virological response (SVR) in patients with HCV-related cirrhosis.

Methods: We performed a retrospective study of patients with HCV-related cirrhosis who were cured with direct-acting antiviral (DAA) therapy at the University of California, Los Angeles. Laboratory values, including serum AFP, were measured before and after completing the DAA treatment.

Results: Fifty-six patients met the inclusion criteria, with median (interquartile range [IQR]) age of 67 (58–69) years and with 51.8% being male. All patients received DAA therapy without interferon. AFP decreased from median (IQR) 7.2 (4.2–13.4) ng/mL before DAAs to 4.2 (2.7–6.3) ng/mL at the end of treatment and 4.2 (2.9–6.8) ng/mL at 12 weeks after treatment (p < 0.001). Model for end-stage liver disease (MELD), fibrosis-4 (FIB4), and aspartate transaminase (AST) to platelet ratio index (APRI) scores at baseline were not significantly associated with AFP reduction. On multivariate analysis, platelet count, AST and total bilirubin at baseline were significantly correlated to AFP reduction (p = 0.04, 0.009 and 0.04, respectively). The higher the baseline AFP, the greater the reduction in AFP. There was no statistically significant correlation between baseline AFP and MELD, FIB4 or APRI scores.

Conclusion: There was a significant decrease in AFP in patients with cirrhosis who achieved a SVR with DAAs. Given a reduction in AFP after DAA treatment, AFP should be further studied as a screening modality for HCC in patients with cirrhosis.

Herein, we summarize the background data that has led to a new class of antimicrobial amphiphiles and present recent results showing reversal of resistance to antibiotics in an Escherichia coli strain incorporating a tetracycline-selective efflux pump. In addition, two types of amphiphiles that show antibiotic potency enhancement or resistance reversal are discussed, along with our knowledge on the evolution that led to the active structures. One family is based on macrocyclic crown polyethers, which are known to insert into both liposomal and bacterial bilayers; these compounds are termed as hydraphiles and consist of three diazacrown rings linked by alkyl spacers and terminated by benzyl groups. In contrast, the second type of amphiphiles use tryptophans as the terminal, membrane anchoring residues; in this group of amphiphiles, two tryptophans are connected by alkyl chains or aryl groups. In both cases, however, the antibacterial activity of certain members of each family was apparent. Further, the amphiphiles have been shown to act as adjuvants that increase the potency of such antimicrobials as tetracycline and even to have re-sensitized a tetracycline-resistant E. coli strain to the antibiotic.

The advent of targeted biologic therapies for debilitating disorders such as Crohn’s disease (CD) and Ulcerative Colitis (UC) has changed management and significantly improved outcomes. However, biologic agents are expensive, and the introduction of biosimilar medications for the treatment of inflammatory bowel diseases presents a lower-cost alternative. In this review, the mechanism of action, pharmacokinetics, efficacy and adverse effects associated with biosimilar CT-P13 in the treatment of inflammatory bowel disease are discussed.

Background and Aims: Platelet-to-lymphocyte ratio (PLR) has been shown to predict prognosis of cancers. We aimed to evaluate the prognostic value of stratification of PLR in patients after curative liver resection (CLR) for hepatocellular carcinoma (HCC).

Methods: A total of 1804 patients who underwent CLR for suspected HCC between January 2007 and January 2014 were screened for the study. All of the patients were categorized into equal tertiles according to the number of patients and the distribution of PLR. Prognostic significance was determined for overall survival (OS) and was assessed using Kaplan–Meier analysis. Univariate and multivariate Cox proportional hazard regression analyses were evaluated for association of all independent parameters with disease prognosis.

Results: The optimal cut-off points of preoperative PLR were: (T1) 11.98–75.00, (T2) 75.00–113.33 and (T3) 113.33–567.50. There were obvious differences in each PLR tertile with mortality within 36 months of CLR (plog-rank < 0.001). Multivariable analysis suggested that the level of PLR (HR = 1.004, 95%CI: 1.001–1.008, p = 0.006), portal vein thrombosis (HR = 3.406, 95%CI: 1.185–9.794, p = 0.023), number of nodules (HR = 1.810, 95%CI: 1.345–2.437, p < 0.001), Child-Turcotte-Pugh score (HR = 1.741, 95%CI: 1.129–2.684, p = 0.012) and microvascular invasion (HR = 2.730, 95%CI: 1.777–4.196, p < 0.001) were significant predictors of mortality. Kaplan–Meier analysis of overall survival (OS) demonstrated that each PLR tertile showed a progressively worse OS and apparent separation (plog-rank = 0.016). The highest 5-year OS rate following CLR (58%) was revealed in tertile 1. In contrast, the lowest 5-year OS rate (30%) was revealed in tertile 3.

Conclusion: Stratified preoperative PLR could strengthen the predictive power for OS in HCC patients with CLR.

Background and Aims: Hepatitis C virus (HCV) hepatotropism is associated with intra-peripheral blood mononuclear cell (PBMC) infection that causes post-treatment relapse in RNA seronegative patients. Our understanding of the association of non-viremic hepatic fibrosis with positive anti-HCV IgG antibodies and active hepatocellular damage might be increased by PBMCs screening for intracellular infection. Thus, the goals of this study included evaluation of PBMCs PCR for diagnosing HCV infection, addressing PBMCs plus serum real-time (SRT) PCR benefits over SRT-PCR alone, studying intra-PBMCs distribution of RNA sense and antisense strands, and identifying treatment feasibility in solitary intracellular infection.

Methods: Enzyme-linked immunosorbent assay, SRT-PCR and PBMCs PCR were used to evaluate HCV infection in 401 subjects. The patients were classified into groups of negative controls (n = 30), positive controls (n = 63), non-viremia post-treatment (experienced; n = 166) and naïve (n = 49) cases, and non-viremia positive PBMCs PCR naïve (n = 35) and experienced (n = 58) patients.

Results: The diagnosis of true positive and negative by PBMCs PCR and SRT-PCR had 100% and 96.7% compatibility respectively. PBMCs PCR detected intracellular HCV infection in 49 out of 215 non-viremia patients; among them, naïve cirrhotics had significantly higher number of intracellular infection than the naïve non-cirrhotic (p < 0.001) and experienced patients (p < 0.0001). Antisense and sense strands were respectively recognized in naïve and experienced cases (p = 0.01218). Intracellular HCV strands were detected in 18.02% of experienced patients. Recognition of intracellular RNA strands showed significant decline in experienced compared to naïve patients (p < 0.05).

Conclusion: PBMCs PCR is a valid diagnostic test that can diagnose intracellular HCV when SRT-PCR is negative. Antisense and sense strands are respectively recognized more often in naïve and experienced patients. The expected overall relapsing rate in our cohort was 18.02%. Intra-PBMC infections are associated with liver cirrhosis in naïve non-viremia patients. Eradication of intracellular strands is recommended to avoid RNA seroconversion.

Ethical approval certificate: Registration number 10231.

Background and Aims: Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer worldwide. Knowledge and adherence to HCC surveillance guidelines has been associated with earlier detection. We sought to evaluate characteristics and outcomes following HCC diagnosis in patients screened for HCC in a large academic liver center versus patients diagnosed and referred from the community.

Methods: We reviewed the records of patients diagnosed with HCC in the liver center of an academic institution from January 1999 till December 2013. Patients were classified into two groups: patients followed in our hepatology clinic and patients with HCC recently referred to our center. Univariate analysis was performed using chi-squared test and multivariate analysis was performed using SPSS 22.0.

Results: The records of 410 patients were reviewed, and included 77.3% of patients referred from the community and 22.7% of patients followed in our clinic. In the clinic group, 75.6% were identified with one nodule at initial diagnosis, compared to 65.6% in the referral group. Patients in the referral group were more likely to present with tumors ≥5 cm at diagnosis, with 28.7% compared to 5.4% in the clinic group (p < 0.0001). Patients referred from the community were also less likely to undergo transplant, with 32.2% as compared to 48.4% of the clinic group (p < 0.004).

Conclusion: Patients with chronic liver disease managed in an academic liver center present in the early stage of HCC diagnosis and are more likely to meet the Milan criteria and undergo transplant. Early referral to a specialized transplant center, if feasible, where a multidisciplinary approach is utilized might be essential in the management of chronic liver disease.

Background and Aims: Cloning of ATP7B provided evidence that Wilson’s disease is a hepatic copper toxicosis with a variety of extrahepatic complications. Affected siblings with the same genetic background and exposure to similar environmental factors may be a good model for the study of genotype-phenotype correlation.

Methods: Twenty-three affected siblings in 11 families were selected from a database. The first phenotypes were determined according to the international proposal. The final types of chronic organ damage were re-evaluated for life-long management.

Results: Phenotypes were identical in 5 of the families and different in 6 of the families. The acute hepatic phenotype H1 was found in 3 younger siblings and 1 older sibling. All survived an acute episode of hemolysis with underlying chronic liver disease. One also presented complication with neurological disease. The neurological phenotype N1 with neuropsychiatric symptoms and hepatic disease was found in 2 aged siblings of 1 family, in an older sibling in 3 families and in the oldest sibling in 1 family. Phenotypes in siblings were mainly split by either H1 occurring in random order or age-dependent N1. Types of chronic organ damage were identical in 8 of the families and different in 3 of the families. The same combination of chronic liver disease was found in 6 families and chronic liver disease complicated with neurological disease in 2 families. Split organ damage in siblings was found when an older sibling was complicated by neurological disease. There was no reverse combination of a younger sibling being complicated by neurological disease in any of the families.

Conclusion: Phenotype combinations of siblings were mainly modified by externally-induced hemolytic episodes, while chronic organ damage in siblings was split by age-dependent neurological complications.

Background and Aims: Patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) who are dialysis-dependent form a unique group, in which safety, tolerability and efficacy of sofosbuvir (SOF)-based direct-acting antivirals (DAAs) need further evaluation.

Methods: We performed a retrospective analysis of 14 patients with CHC and ESRD on dialysis who received 15 courses of SOF-based therapy. We evaluated dose escalation to standard-dose SOF in this proof-of-principle experience.

Results: Sustained virological response (defined as undetectable viral load at 12 weeks, SVR-12) was achieved in 13 out of the 15 (86.7%) treatment courses. Seven (46.6%) patients received reduced half dose as conservative proof-of-principal to mitigate potential toxicity. In 13 out of 15 treatment courses, patients completed the designated treatment duration. One patient was treated twice and developed SVR-12 with the retreatment. One patient was lost to follow-up and counted as a non-responder. Premature discontinuations were not due to DAA-related adverse effects. There were no reports of severe adverse effects or drug interactions.

Conclusion: We treated CHC patients with ESRD using dose escalation to standard-dose SOF in this proof-of-principle experience and achieved SVR rates comparable to general population.

Background: Impairment of the ability to adapt to stress in animals may contribute to some stress-related psychiatric disorders, such as anxiety and depression. A growing body of evidence has suggested that the brain’s serotonin (5-HT) nervous system may play an important role in the etiology, expression and treatment of anxiety and depression. The aim of the present study was to examine whether brain 5-HT7 receptors are involved in the formation of stress adaptation.

Methods: Male ICR mice were either exposed to repeated restraint stress for 60 or 240 min/day (stressed group) or left in their home cage (non-stressed group) for 1 or 14 days. The emotionality of mice was estimated by the hole-board test. The levels of 5-HT7 receptor expression and extracellular signal-regulated kinase 1/2 (ERK) phosphorylation were assessed by western blot analysis.

Results: A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response was not observed in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. Increases in 5-HT7 receptor protein and ERK phosphorylation were observed in the frontal cortex and hippocampus of stress-adaptive, but not stress-maladaptive, mice. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with LP-12, a selective 5-HT7 receptor agonist, immediately after daily exposure to stress.

Conclusion: The present findings suggest that the brain 5-HT7 receptor-ERK system may play an important role in the formation of stress adaptation. Furthermore, stimulation of 5-HT7 receptors may have a beneficial effect on stress adaptation and alleviate the emotional abnormality observed under conditions of excessive stress.