Simultaneous trans-hepatic portal and hepatic vein embolization before major hepatectomy: the liver venous deprivation technique

Purpose

To assess technical feasibility, safety, and efficacy of the liver venous deprivation (LVD) technique that combines both portal and hepatic vein embolization during the same procedure for liver preparation before major hepatectomy.

Materials and methods

Seven patients (mean age:63.6y[42-77y]) underwent trans-hepatic LVD for liver metastases (n?=?2), hepatocellular carcinoma (n?=?1), intrahepatic cholangiocarcinoma (n?=?3) and Klatskin tumour (n?=?1). Assessment of future remnant liver (FRL) volume, liver enzymes and histology was performed.

Results

Technical success was 100 %. No complication occurred before surgery. Resection was performed in 6/7 patients. CT-scan revealed hepatic congestion in the venous-deprived area (6/7 patients). A mean of 3 days (range: 1–8 days) after LVD, transaminases increased (AST: from 42?±?24U/L to 103?±?118U/L, ALT: from 45?±?25U/L to 163?±?205U/L). Twenty-three days (range: 13–30 days) after LVD, FRL increased from 28.2 % (range: 22.4–33.3 %) to 40.9 % (range: 33.6–59.3 %). During the first 7 days, venous-deprived liver volume increased (+13.4 %) probably reflecting vascular congestion, whereas it strongly decreased (-21.3 %) at 3-4 weeks. Histology (embolized lobe) revealed sinusoidal dilatation, hepatocyte necrosis and important atrophy in all patients.

Conclusion

Trans-hepatic LVD technique is feasible, well tolerated and provides fast and important hypertrophy of the FRL. This new technique needs to be further evaluated and compared to portal vein embolization.

Key Points

? Twenty-three days after LVD, FRL increased from 28.2 % (range:22.4-33.3 %) to 40.9 % (range:33.6–59.3 %) ? During the first 7 days, venous-deprived liver volume increased (+13.4 %) ? Venous-deprived liver volume strongly decreased (mean atrophy:229 cc; -21.3 %) at 3-4 weeks ? Histology of venous-deprived liver revealed sinusoidal dilatation, hepatocyte necrosis and important atrophy

     

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.     

Edoxaban drug–drug interactions with ketoconazole,erythromycin, and cyclosporine

AimsEdoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition.MethodsIn each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study.ResultsCoadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed.ConclusionsAdministration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.     

Variable selection for distribution‐free models for longitudinal zero‐inflated count responses

Zero‐inflated count outcomes arise quite often in research and practice. Parametric models such as the zero‐inflated Poisson and zero‐inflated negative binomial are widely used to model such responses. Like most parametric models, they are quite sensitive to departures from assumed distributions. Recently, new approaches have been proposed to provide distribution‐free, or semi‐parametric, alternatives. These methods extend the generalized estimating equations to provide robust inference for population mixtures defined by zero‐inflated count outcomes. In this paper, we propose methods to extend smoothly clipped absolute deviation (SCAD)‐based variable selection methods to these new models. Variable selection has been gaining popularity in modern clinical research studies, as determining differential treatment effects of interventions for different subgroups has become the norm, rather the exception, in the era of patent‐centered outcome research. Such moderation analysis in general creates many explanatory variables in regression analysis, and the advantages of SCAD‐based methods over their traditional counterparts render them a great choice for addressing this important and timely issues in clinical research. We illustrate the proposed approach with both simulated and real study data. Copyright © 2016 John Wiley & Sons, Ltd.     

Employee Health in the Mental Health Workplace: Clinical,Administrative, and Organizational Perspectives

Issues of mental health and employee health have risen to increasing prominence in recent years. However, there have been few explorations of the clinical and administrative challenges that these issues raise, particularly in settings that are themselves mental health workplaces. In order to identify and understand such challenges, a brief case of acute employee illness in a mental health workplace is described followed by a discussion of salient clinical, administrative, and organizational considerations. The case raises questions about medicolegal responsibilities and relationships between clinicians and patients in mental health settings, illuminates tensions between clinical staff and human resources processes, and draws attention to the need for illness prevention and mental health promotion initiatives in the workplace. Increased awareness of these issues, complications, and potential solutions would benefit clinicians, administrators, and mental health institutions.