Inferior vena cava leiomyosarcoma (IVCL) is a rare tumor with a poor prognosis, and its surgical resection remains a challenge. To date, surgery is the only potentially curative treatment for IVCL ...with a 5-year survival rate of 55%. The main challenge is to combine oncological surgery with clear margins and vascular reconstruction of the inferior vena cava (IVC). In this review, we discuss the different approaches to vascular reconstruction after IVCL resection, using a prosthetic or autologous patch, direct suture or simple ligation without IVC reconstruction. The reconstruction of IVC depends of tumor location and its extension. We recommend no reconstruction if venous collaterality is well-established. When vascular reconstruction is required, we prefer prosthetic PTFE graft. These patients should be referred to high-volume centers with a multidisciplinary team of sarcoma surgeons with cardiothoracic, vascular and hepatic specialties.
Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The ...identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well‐established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling, we demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up‐regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix, and transforming growth factor beta (TGFβ) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFβ2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFβ2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, multivariate analysis demonstrated that the stromal expression of osteopontin was an independent prognostic marker for overall and disease‐free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. (Hepatology 2013; 58:1992–2000)
Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and ...intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.
IntroductionEnd-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion ...damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally.Methods and analysisThis is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00–3:59 hour) or to the control arm (4:00–15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation.Ethics and disseminationThe protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation.Trial registration numberNL8740.
Purpose
Therapeutic drug monitoring of tacrolimus using trough concentration (C
min
) is mandatory to ensure drug efficacy and safety in solid organ transplantation. However, C
min
is just a proxy ...for the area under the curve of drug concentrations (AUC) which is the best pharmacokinetic parameter for exposure evaluation. Some studies suggest that patients may present discrepancies between these two parameters. AUC is now easily available through mini-invasive microsampling approach. The aim of this study is to evaluate the relationship between AUC and C
min
in patients benefiting from a complete pharmacokinetic profile using a microsampling approach.
Methods
Fifty-one transplant recipients benefited from a complete pharmacokinetic profile using a microsampling approach, and their 24-h AUC were calculated using the trapezoidal method. The correlation with C
min
was then explored. In parallel, we estimated AUC using the sole C
min
and regression equations according to the post-transplantation days and the galenic form.
Results
Weak correlations were found between 24-h AUC observed and the corresponding C
min
(
R
2
= 0.60) and between AUC observed and expected using the sole C
min
(
R
2
= 0.62). Therapeutic drug monitoring of tacrolimus using C
min
leads to over- or under-estimate drug exposure in 40.3% of patients.
Conclusion
Tacrolimus C
min
appears to be an imperfect reflection of drug exposure. Evaluating AUC using a microsampling approach offers a mini-invasive strategy to monitor tacrolimus treatment in transplant recipients.
Abstract Background Recently, we identified a gene signature of intrahepatic cholangiocarcinoma (ICC) stroma and demonstrated its clinical relevance for prognosis. The most upregulated genes included ...epithelial cell adhesion molecule (EpCAM), a biomarker of cancer stem cells (CSC). We hypothesized that CSC biomarkers could predict recurrence of resected ICC. Methods Both functional analysis of the stroma signature previously obtained and immunohistochemistry of 40 resected ICC were performed. The relationships between the expression of CSC markers and clinicopathologic factors including survival were assessed by univariate and multivariable analyzes. Results Gene expression profile of the stroma of ICC highlighted embryonic stem cells signature. Immunohistochemistry on tissue microarray showed at a protein level the increased expression of CSC biomarkers in the stroma of ICC compared with nontumor fibrous liver tissue. The overexpression of EpCAM in the stroma of ICC is an independent risk factor for overall (hazard ratio = 2.6; 95% confidence interval, 1.3–5.1; P = 0.005) and disease-free survival (hazard ratio = 2.2; 95% confidence interval, 1.2–4.2; P = 0.012). In addition, the overexpression of EpCAM in nontumor fibrous liver tissue is closely correlated with a worst disease-free survival ( P = 0.035). Conclusions Our findings provide new arguments for a potential role of CSC on ICC progression supporting the idea that targeting CSC biomarkers might represent a promise personalized treatment.
•An HPLC–MS/MS method was developed to quantify tacrolimus in bile.•Sample purification combined protein precipitation and liquid–liquid extraction.•The assay fulfilled acceptance criteria for ...bio-analytical method validation.•The method was successfully applied to the analysis of bile from liver transplants.•Drug monitoring in bile could be an alternative approach for treatment optimization.
Tacrolimus whole-blood concentrations imperfectly reflect concentrations at the effect site. Tacrolimus concentrations in the transplanted organ could be more relevant to predict rejection events. Because liver biopsy cannot be repeatedly performed after liver transplantation, we suggested measuring tacrolimus in the bile to have a cost-effective and clinically implementable surrogate marker of intra-hepatic tacrolimus concentration. We developed and fully validated a liquid chromatography–tandem mass spectrometry method for the determination of tacrolimus in human bile. Sample purification was achieved using protein precipitation and liquid–liquid extraction with ethyl-acetate. Gradient elution was performed using a C18 analytical column with a 5min run-time. The method was linear from 0.5ng/mL to 20ng/mL. In this concentration range, within-day and between-day precisions as well as overall bias were within ±15%. Matrix effect was fully corrected by the internal standard (ascomycin). The assay was optimized to achieve good selectivity in this complex biological matrix. Tacrolimus was found to be stable in bile stored 6 months at −80°C, after 3 freeze and thaw cycles, 20h at room temperature and 24h in extracts kept at 15°C in the auto-sampler. The method was applied to quantify tacrolimus in bile from liver transplant recipients. It allowed getting preliminary data about tacrolimus excretion profile in bile and showed the lack of correlation between tacrolimus whole blood concentration and tacrolimus liver exposition. This alternative and innovative analytical approach of tacrolimus bio-analysis appears suitable for further studies evaluating relevance of biliary tacrolimus concentration as a new pharmacological marker of immunosuppressive activity.
Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be ...associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury.
HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage.
We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing.
ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.
Background In patients with intrahepatic cholangiocarcinoma (ICC), extended liver resections (ELRs) increase the rate of resectability. The aims of the present study were to evaluate the morbidity ...and oncologic outcomes of ELR compared with other liver resections (LR) for ICC. Methods All LR for ICC that were performed in our center between January 1997 and September 2013 and conducted with curative intent were included in this retrospective analysis. ELRs were defined by resections of ≥5 liver segments. The factors that influenced the occurrence of major complications (Clavien ≥ 3) and overall survival (OS) were tested with univariate and multivariate analyses. Results One hundred seven patients (82 men and 25 women) were resected, and 27 (25.3%) underwent ELRs. Compared with the LRs, the ELRs were performed in larger tumors ( P = .003) and were significantly associated with more complex surgeries such as vascular ( P < .001) or biliary reconstructions ( P < .001). Multivariate analysis revealed that ELR was an independent risk factor for major complications (odds ratio OR, 6.2; 95% CI, 2.11–19.62; P < .001). Compared with the other LRs, ELRs had no effects on OS or disease-free survival ( P = .881 and P = .228, respectively). Perioperative blood transfusion (Hazard ratio (HR), 2.51; 95% CI, 1.49–4.23; P < .001), the presence of >1 nodule (HR, 3.17; 95% CI, 1.67–5.97; P < .001), and age ≥65 years (HR, 1.72; 95% CI, 1.03–2.86; P = .036) were independent prognostic factors for OS. Conclusion This study suggests that ELRs performed for large ICCs do not affect negatively oncologic outcomes, despite the increased risk of major complications.
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