Intrahepatic cholangiocarcinoma (CCA) is characterized by an abundant desmoplastic environment. Poor prognosis of CCA has been associated with the presence of alpha‐smooth muscle actin ...(α‐SMA)‐positive myofibroblasts (MFs) in the stroma and with the sustained activation of the epidermal growth factor receptor (EGFR) in tumor cells. Among EGFR ligands, heparin‐binding epidermal growth factor (HB‐EGF) has emerged as a paracrine factor that contributes to intercellular communications between MFs and tumor cells in several cancers. This study was designed to test whether hepatic MFs contributed to CCA progression through EGFR signaling. The interplay between CCA cells and hepatic MFs was examined first in vivo, using subcutaneous xenografts into immunocompromised mice. In these experiments, cotransplantation of CCA cells with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and metastastic dissemination of tumors. These effects were abolished by gefitinib, an EGFR tyrosine kinase inhibitor. Immunohistochemical analyses of human CCA tissues showed that stromal MFs expressed HB‐EGF, whereas EGFR was detected in cancer cells. In vitro, HLMFs produced HB‐EGF and their conditioned media induced EGFR activation and promoted disruption of adherens junctions, migratory and invasive properties in CCA cells. These effects were abolished in the presence of gefitinib or HB‐EGF‐neutralizing antibody. We also showed that CCA cells produced transforming growth factor beta 1, which, in turn, induced HB‐EGF expression in HLMFs. Conclusion: A reciprocal cross‐talk between CCA cells and myofibroblasts through the HB‐EGF/EGFR axis contributes to CCA progression. (Hepatology 2013; 58:2001–2011)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Patients with hepatocellular adenomas are, in selected cases, candidates for liver resection, which can be approached via laparoscopy or laparotomy. The present study aimed to investigate ...the effects of the surgical approach on the postoperative morbidities of both minor and major liver resections.
Methods
In this multi-institutional study, all patients who underwent open or laparoscopic hepatectomies for hepatocellular adenomas between 1989 and 2013 in 27 European centers were retrospectively reviewed. A multiple imputation model was constructed to manage missing variables. Comparisons of both the overall rate and the types of complications between open and laparoscopic hepatectomy were performed after propensity score adjustment (via the standardized mortality ratio weighting method) on the factors that influenced the choice of the surgical approach.
Results
The laparoscopic approach was selected in 208 (38%) of the 533 included patients. There were 194 (93%) women. The median age was 38.9 years. After the application of multiple imputation, 208 patients who underwent laparoscopic operations were compared with 216 patients who underwent laparotomic operations. After adjustment, there were 20 (9.6%) major liver resections in the laparoscopy group and 17 (7.9%) in the open group. The conversion rate was 6.3%. The two surgical approaches exhibited similar postoperative morbidity rates and severities. Laparoscopic resection was associated with significantly less blood loss (93 vs. 196 ml,
p
< 0.001), a less frequent need for pedicle clamping (21 vs. 40%,
p
= 0.002), a reduced need for transfusion (8 vs. 24 red blood cells units,
p
< 0.001), and a shorter hospital stay (5 vs. 7 days,
p
< 0.001). The mortality was nil.
Conclusions
Laparoscopy can achieve short-term outcomes similar to those of open surgery for hepatocellular adenomas and has the additional benefits of a reduced blood loss, need for transfusion, and a shorter hospital stay.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background Although recent reports have suggested the potential advantages of laparoscopy in patients undergoing major hepatectomy, the benefits of this approach in elderly patients remain unclear. ...This study aimed to compare the short-term outcomes of laparoscopic major hepatectomy (LMH) and open major hepatectomy (OMH) in elderly patients. Study Design All patients aged 55 years and older undergoing laparoscopic LMH between 2000 and 2013 at 2 centers were retrospectively analyzed and divided into 3 groups (group 1: 55 to 64 years old; group 2: 65 to 74 years old; and group 3: 75 years and older). Risk factors for postoperative complications were determined on multivariable analysis in the overall LMH population and in each LMH group. Outcomes of LMH patients were compared with those of patients of similar age undergoing OMH at another center after propensity score matching. Results Laparoscopic major hepatectomy was performed in 174 patients, including 72 (41.4%) in group 1, 67 (38.5%) in group 2, and 35 (20.1%) in group 3. On multivariable analysis, diabetes (odds ratio OR = 2.349; 95% CI, 1.251–2.674; p = 0.047), American Society of Anesthesiologists status (OR = 2.881; 95% CI, 2.193–3.71; p = 0.017), cirrhosis (OR = 1.426; 95% CI, 1.092–2.025; p = 0.043), right-sided resection (OR = 2.001; 95% CI, 1.492–2.563; p = 0.037), conversion (OR = 1.950; 95% CI, 1.331–2.545; p = 0.024), and intraoperative transfusion (OR = 2.338, 95% CI, 1.738–2.701, p = 0.032) were associated with increased risk of postoperative complications in the whole LMH population. After propensity score matching, laparoscopy was associated with significantly decreased rates of pulmonary complications and shorter hospital stays in all groups, decreased rates of overall complications in group 2 and group 3, and decreased rates of postoperative confusion in group 3. Conclusions The current study supports the benefits of laparoscopy in decreasing postoperative complications in elderly patients requiring major hepatectomy.
Patients affected by hepatocellular carcinoma (HCC) represent a vulnerable population during the COVID-19 pandemic and may suffer from altered allocation of healthcare resources. The aim of this ...study was to determine the impact of the COVID-19 pandemic on the management of patients with HCC within 6 referral centres in the metropolitan area of Paris, France.
We performed a multicentre, retrospective, cross-sectional study on the management of patients with HCC during the first 6 weeks of the COVID-19 pandemic (exposed group), compared with the same period in 2019 (unexposed group). We included all patients discussed in multidisciplinary tumour board (MTB) meetings and/or patients undergoing a radiological or surgical programmed procedure during the study period, with curative or palliative intent. Endpoints were the number of patients with a modification in the treatment strategy, or a delay in decision-to-treat.
After screening, n = 670 patients were included (n = 293 exposed to COVID, n = 377 unexposed to COVID). Fewer patients with HCC presented to the MTB in 2020 (p = 0.034) and fewer had a first diagnosis of HCC (n = 104 exposed to COVID, n = 143 unexposed to COVID, p = 0.083). Treatment strategy was modified in 13.1% of patients, with no differences between the 2 periods. Nevertheless, 21.5% vs. 9.5% of patients experienced a treatment delay longer than 1 month in 2020 compared with 2019 (p <0.001). In 2020, 7.1% (21/293) of patients had a diagnosis of an active COVID-19 infection: 11 (52.4%) patients were hospitalised and 4 (19.1%) patients died.
In a metropolitan area highly impacted by the COVID-19 pandemic, we observed fewer patients with HCC, and similar rates of treatment modification, but with a significantly longer treatment delay in 2020 vs. 2019.
During the coronavirus disease 2019 (COVID-19) pandemic era, fewer patients with hepatocellular carcinoma (HCC) presented to the multidisciplinary tumour board, especially with a first diagnosis of HCC. Patients with HCC had a treatment delay that was longer in the COVID-19 period than in 2019.
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•During the COVID-19 period, fewer patients with HCC presented to the multidisciplinary tumour board.•Globally, modification in the treatment strategy was observed in 13.1% of patients.•More than 21% of patients experienced a treatment delay >1 month in the COVID-19 period compared with 9.5% in 2019.•COVID-19 infection was the main reason for treatment delays in 2020.•In 2020, 7.1% of patients had a diagnosis of an active COVID-19 infection and 4/21 (19.1%) died.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Schedule of enrolment, interventions, and assessments in the HOPExt trial STAGES V1 Screening V2 Inclusion V3 V4 V5 –V11 V12 V13-V16 Time point Actions At inscription for LT or at pre LT visit D0 At ...hospitalization for LT D0 HOPE group only D0 + 6 h (± 2 h) after LT D0 + 12 h (± 2 h) after LT Day 1 to day 7 (± 1 day) End of hospital stay M3; M6: M9 and M12 (± 30 days) Inclusion / non-inclusion criteria X X Informed consent X Medical history and patient characteristics1 X MELD score X At inscription X Randomization2 X Clinical examination3 X X X Biological analyses4 X (before LT) X X X X X CHILD–PUGH score X (before LT) Donor characteristics5 X HOPE perfusion parameters6 X Bacteriological and fungal analyses7 X X Intra-operative data8 X Liver Biopsy9 X both groups X Machine perfusate sample10 X ICU and hospital stay X Morbidity (Clavien-Dindo Score, CCI) X X At M3 only Concomitant Medication X X X X X X Adverse events X X X X X X Abdominal contrast enhanced MRI/MRCP X At M12 only 1patient characteristics: age, gender, height, weight, BMI, blood group, cause of cirrhosis, indication for transplantation, medical history (diabetes mellitus, arterial hypertension, transjugular intrahepatic portosystemic shunt) pretransplant status of residence (home, hospital ward or intensive care unit (ICU)) 2Randomization will be performed after the harvesting team has macroscopically assessed the graft and confirmed that the graft will be harvested. Randomization will be stratified by center and MELD score at the time of transplantation with a cut-off of 30 3Clinical examination: vital signs (temperature, blood pressure, heart rate), body weight, height, BMI 4Biological analyses: AST, ALT, GGT, Alkaline Phosphatase, bilirubin, factor V, INR, platelets, creatinine, GFR, lactates At V2 only, a pregnancy test (beta HCG) will be done for women of childbearing age 5Donor characteristics: age, gender, height, weight, BMI, blood group, length of stay in intensive care unit, cause of death, occurrence of cardiac arrest, biological test (AST, ALT, natremia) 6Parameters measured during HOPE perfusion (only in HOPE group): perfusion pressure, flow, temperature, duration of machine perfusion, perfusate oxygenation (partial pressure O2) and CO2 content (partial pressure CO2) at the beginning and at the end of machine perfusion; perfusate AST and ALT, LDH, hyaluronic acid, lactate levels at 30 minutes and at the end of machine perfusion 7Bacteriological and fungal samplings will be taken on static storage solution (IGL-1) at the end of the back-table in both groups, and of the perfusion solution at the end of machine perfusion for HOPE group 8Intra-operative data: surgical technique of transplantation (piggy-back vs. vena cava resection), length of procedure, transfusion needs (fresh frozen plasma, red blood cell, thrombocyte concentrate), occurrence of post-reperfusion syndrome (decrease of 50% of the median arterial pressure during the 5 minutes after the revascularisation), cold ischemia time, circulatory support at the end of transplantation (noradrenaline (mg/h)) 9A biopsy will be taken on the back-table before machine perfusion in both study groups, immediately after liver machine perfusion in the HOPE group, and after reperfusion of the liver in both groups 103ml sample will be taken from machine perfusion solution during HOPE perfusion (only in HOPE group), at 30 minutes and at the end of machine perfusion The original article has been corrected. End-ischemic hypothermic oxygenated perfusion for extended criteria donors in liver transplantation: a multicenter, randomized controlled trial—HOPExt.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
The outcomes of liver resection (LR) with a narrow margin in patients with transplantable hepatocellular carcinoma (HCC) have not been studied. The aim was to assess whether narrow margin ...following up-front LR impacts the incidence, timing, pattern, and transplantability of tumor recurrence in patients with initially transplantable HCC.
Methods
All initially transplantable HCC patients undergoing hepatectomy with either narrow (<10 mm) or wide (≥10 mm) margins from 2007 to 2016 at four Western university centers were compared in terms of recurrence, transplantability of recurrence, recurrence-free survival (RFS), and intention-to-treat overall survival (ITT-OS). Independent predictors of non-transplantability of recurrence were assessed.
Results
This study included 187 patients (narrow group,
n
= 107 vs. wide group,
n
= 80). Recurrence was significantly more frequent in the narrow margin group (44% vs. 26%;
p
= 0.01) with a shorter RFS (
p
= 0.03). The transplantability of recurrence and ITT-OS were, however, not different between the two groups. The presence of satellite nodules on the resected specimens emerged as the sole independent predictor of non-transplantability of tumor recurrence. The stratification of the analysis according to the presence of cirrhosis achieved essentially the same results as in the whole study population.
Conclusions
Narrow margin was associated with a higher tumor recurrence rate and a shorter RFS for patients with initially transplantable HCC. However, transplantability of recurrence and long-term ITT-OS were not impaired.
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EMUNI, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Transection methods and hemostasis achievement have an impact on blood loss, and consequently on outcome and survival. However, no consensus exists on parenchymal transection or hemostasis techniques ...in laparoscopic liver resection (LLR). The aim of this review is to clarify the role of energy devices (ED) in LLR. ED is a generator of mechanic or electric energy transfer to an operating tool, used for transection, sealing or both. Searches were performed in PubMed, PubMed Central, Cochrane, Embase, Google Scholar in human or animal experimental models. Each study quality was graded following the GRADE system. From 1996 to 2014, 30 studies were found: five comparative, one prospective, two case‐control, and 16 case series and some case reports, with level of evidence ranging from Moderate to Very Low. Since 2012, the Research and Development of new tools raised quicker than clinical studies could follow. The two main techniques emerged are blind transection versus sharp dissection: due to the low quality and heterogeneity of the studies, no firm conclusion can be drawn, but meticulous dissection of vessels usually never leads to vascular damage. As a matter of fact, ED, though efficient and reliable, cannot replace the basic skills of hepatic surgery: sharp dissection, vascular control and elective sealing.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Normothermic perfusion provides a means to rescue steatotic liver grafts, including by pharmacological defatting. In this study, we tested the potential of new drug combinations to trigger defatting ...in three human culture models, primary hepatocytes with induced steatosis, primary hepatocytes isolated from steatotic liver, and precision-cut liver slices (PCLS) of steatotic liver. Forskolin, L-carnitine and a PPARα agonist were all combined with rapamycin, an immunosuppressant that induces autophagy, in a D-FAT cocktail. D-FAT was tested alone or in combination with necrosulfonamide, an inhibitor of mixed lineage kinase domain like pseudokinase involved in necroptosis. Within 24 h, in all three models, D-FAT induced a decrease in triglyceride content by 30%, attributable to an upregulation of genes involved in free fatty acid β-oxidation and autophagy, and a downregulation of those involved in lipogenesis. Defatting was accompanied by a decrease in endoplasmic reticulum stress and in the production of reactive oxygen species. The addition of necrosulfonamide increased the efficacy of defatting by 8%-12% in PCLS, with a trend towards increased autophagy. In conclusion, culture models, notably PCLS, are insightful to design strategies for liver graft rescue. Defatting can be rapidly achieved by combinations of drugs targeting mitochondrial oxidative metabolism, macro-autophagy and lipogenesis.
Biliary tract carcinomas are divided into intrahepatic, perihilar, distal extrahepatic cholangiocarcinomas, and gallbladder adenocarcinomas. Therapies targeting
ROS1
,
ALK
,
MET
, and
HER2
...alterations are currently evaluated in clinical trials. We assessed
ROS1
and
ALK
translocations/amplifications as well as
MET
and
HER2
amplifications for each tumor subtype by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in 73 intrahepatic, 40 perihilar bile duct, 36 distal extrahepatic cholangiocarcinomas, and 45 gallbladder adenocarcinomas (
n
= 194). By FISH, we detected targetable alterations in 5.2% of cases (
n
= 10):
HER2
and
MET
amplifications were found in 4.1% (
n
= 8) and 1.0% (
n
= 2), respectively. The
HER2
-amplified cases were mostly gallbladder adenocarcinomas (
n
= 5). The
MET
- and
HER2
-amplified cases were all positive by IHC. Fourteen cases without
MET
amplification were positive by IHC, whereas HER2 over-expression was detected by IHC only in
HER2
-amplified cases. We detected no
ALK
or
ROS1
translocation or amplification. Several alterations were consistent with aneuploidy: 24 cases showed only one copy of
ROS1
gene, 4 cases displayed a profile of chromosomal instability, and an over-representation of centromeric alpha-satellite sequences was found in five cases. We confirm a relatively high rate of
HER2
amplifications in gallbladder adenocarcinomas and the efficacy of IHC to screen these cases. Our results also suggest the value of IHC to screen
MET
amplification. Contrary to initial publications,
ROS1
rearrangements seem to be very rare in biliary tract adenocarcinomas. We confirm a relatively high frequency of aneuploidy and chromosomal instability and reveal the over-representation of centromeric alpha-satellite sequences in intrahepatic cholangiocarcinomas.
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