Organized proteomic heterogeneity in colorectal liver metastases and implications for therapies
Turtoi, Andrei ; Blomme, Arnaud ; Debois, Delphine et al
in Acta Gastro-Enterologica Belgica (2014, March), 77(1), 07
Introduction : Tumor heterogeneity is a major obstacle for developing effective anti-cancer treatments. Recent studies have pointed at large stochastic genetic heterogeneity within cancer lesions, where ... [more ▼]
Introduction : Tumor heterogeneity is a major obstacle for developing effective anti-cancer treatments. Recent studies have pointed at large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Aim : Because to date no similar information is available at the protein (phenotype) level, we aimed at characterising the proteomic heterogeneity in human colorectal carcinoma (CRC) liver metastases. Methods & Results : We employed MALDI imaging-guided proteomics and explored the heterogeneity of extracellular distribution of over 1000 proteins we found unexpectedly that all liver metastasis lesions displayed a reproducible, zon- ally delineated, pattern of functional and therapeutic biomarker heterogeneity. Peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement and drug metabolism whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA- repair activity. From the aspect of therapeutic targeting zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. Conclusions : proteome heterogeneity has a distinct, organized, pattern. This particular hallmark can now be used as a part of the strategy for developing rational therapies based on multiple sets of targetable antigens. [less ▲]Detailed reference viewed: 46 (3 ULg)
TGF-B induced protein IG-H3 is essential for the growth of human liver metastases
Castronovo, Vincenzo ; ; Delvenne, Philippe et al
in Acta Gastro-Enterologica Belgica (2014, March), 77(1), 05
Introduction : Transforming growth factor-beta-induced protein ig-h3 (TGFBI) is extracellular matrix component known to be important for cell-collagen interaction. We and others have reported elevated ... [more ▼]
Introduction : Transforming growth factor-beta-induced protein ig-h3 (TGFBI) is extracellular matrix component known to be important for cell-collagen interaction. We and others have reported elevated expression of TGFBI in sev- eral human cancers, where its role remains controversial. Aim Current study aims at clarifying the function of TGFBI to date. Methods &Results : CRC-LM and in liver metastases originating from breast, lung and pancreatic tumors. We have next focused on func- tional aspects and have silenced TGFBI expression in SW1222 human colorectal carcinoma cells. The suppression of TGFBI protein led to a marked decrease in cell migration (-70%) and proliferation (-30%) in vitro. To study the effects in vivo we have developed a novel animal model of colorectal carcinoma based on chicken chorioallantoic membrane (CAM) that mimics human CRC-LM. TGFBI silencing resulted in 50% reduction of tumor volume in the CAM tumor model. Notably, the tumors displayed a marked inhibition of vascularization, suggesting an additional anti-angiogenic effect. Indeed, SW1222 cells silenced for TGFBI expression secreted lower levels of VEGFA in vitro. Finally, we have investigated if TGFBI can be used as systemically reachable target for antibody-drug delivery. For this purpose we have The in vivo data demonstrated that TGFBI is an accessible tumor target. Conclusions : Taken together, the present study shows that TGFBI is essential for promoting the development of CRC- LM and therefore represents a promising target for designing novel therapeutic approaches. [less ▲]Detailed reference viewed: 59 (10 ULg)
A More Than 20% Increase in Deceased-Donor Organ Procurement and Transplantation Activity After the Use of Donation After Circulatory Death.
; MONARD, Josée ; DELBOUILLE, Marie-Hélène et al
in Transplantation proceedings (2014), 46(1), 9-13
BACKGROUND: Organ procurement and transplant activity from controlled donation after circulatory death (DCD) was evaluated over an 11-year period to determine whether this program influenced the ... [more ▼]
BACKGROUND: Organ procurement and transplant activity from controlled donation after circulatory death (DCD) was evaluated over an 11-year period to determine whether this program influenced the transplant and donation after brain death (DBD) activities. MATERIAL AND METHODS: Deceased donor (DD) procurement and transplant data were prospectively collected in a local database for retrospective review. RESULTS: There was an increasing trend in the potential and actual DCD numbers over time. DCD accounted for 21.9% of the DD pool over 11 years, representing 23.7% and 24.2% of the DD kidney and liver pool, respectively. The DBD retrieval and transplant activity increased during the same time period. Mean conversion rate turning potential into effective DCD donors was 47.3%. Mean DCD donor age was 54.6 years (range, 3-83). Donors >/=60 years old made up 44.1% of the DCD pool. Among referred donors, reasons for nondonation were medical contraindications (33.7%) and family refusals (19%). Mean organ yield per DCD donor was 2.3 organs. Mean total procurement warm ischemia time was 19.5 minutes (range, 6-39). In 2012, 17 DCD and 37 DBD procurements were performed in the Liege region, which has slightly >1 million inhabitants. CONCLUSIONS: This DCD program implementation enlarged the DD pool and did not compromise the development of DBD programs. The potential DCD pool might be underused and seems to be a valuable organ donor source. [less ▲]Detailed reference viewed: 50 (18 ULg)
Does comfort therapy during controlled donation after circulatory death shorten the life of potential donors?
LEDOUX, Didier ; DELBOUILLE, Marie-Hélène ; DE ROOVER, Arnaud et al
in Clinical transplantation (2014), 28(1), 47-51
INTRODUCTION: Controlled donation after circulatory death (DCD) remains ethically controversial. The authors developed a controlled DCD protocol in which comfort therapy is regularly used. The aim of this ... [more ▼]
INTRODUCTION: Controlled donation after circulatory death (DCD) remains ethically controversial. The authors developed a controlled DCD protocol in which comfort therapy is regularly used. The aim of this study was to determine whether this policy shortens the DCD donors' life. METHODS: The authors retrospectively analyzed prospectively collected data on patients proposed for DCD at the University Hospital of Liege, Belgium, over a 56-month period. The survival duration of these patients, defined as duration between the time of proposal for DCD and the time of circulatory arrest, was compared between patients who actually donated organs and those who did not. RESULTS: About 128 patients were considered for controlled DCD and 54 (43%) became donors. Among the 74 non-donor patients, 34 (46%) objected to organ donation, 38 patients (51%) were denied by the transplant team for various medical reasons, and two potential DCD donors did not undergo procurement due to logistical and organizational reasons. The survival durations were similar in the DCD donor and non-donor groups. No non-donor patient survived. CONCLUSIONS: Survival of DCD donors is not shortened when compared with non-donor patients. These data support the ethical and respectful approach to potential DCD donors in the authors' center, including regular comfort therapy. [less ▲]Detailed reference viewed: 36 (8 ULg)
Mesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion.
Erpicum, Pauline ; DETRY, Olivier ; WEEKERS, Laurent et al
in Nephrology Dialysis Transplantation (2014), 29
Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbi-mortality. AKI treatment mostly relies on supportive manoeuvres in the absence of ... [more ▼]
Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbi-mortality. AKI treatment mostly relies on supportive manoeuvres in the absence of specific target-oriented therapy. The pathophysiology of AKI commonly involves ischaemia/reperfusion (I/R) events, which cause both immune and metabolic consequences in renal tissue. Similarly, at the time of kidney transplantation (KT), I/R is an unavoidable event which contributes to early graft dysfunction and enhanced graft immunogenicity. Mesenchymal stromal cells (MSCs) represent a heterogeneous population of adult, fibroblast-like multi-potent cells characterized by their ability to differentiate into tissues of mesodermal lineages. Because MSC have demonstrated immunomodulatory, anti-inflammatory and tissue repair properties, MSC administration at the time of I/R and/or at later times has been hypothesized to attenuate AKI severity and to accelerate the regeneration process. Furthermore, MSC in KT could help prevent both I/R injury and acute rejection, thereby increasing graft function and survival. In this review, summarizing the encouraging observations in animal models and in pilot clinical trials, we outline the benefit of MSC therapy in AKI and KT, and envisage their putative role in renal ischaemic conditioning. [less ▲]Detailed reference viewed: 66 (32 ULg)
Rationale for the potential use of mesenchymal stromal cells in liver transplantation.
VANDERMEULEN, Morgan ; GREGOIRE, Céline ; BRIQUET, Alexandra et al
in World journal of gastroenterology : WJG (2014), 20(44), 16418-32
Mesenchymal stromal cells (MSCs) are multipotent and self-renewing cells that reside essentially in the bone marrow as a non-hematopoietic cell population, but may also be isolated from the connective ... [more ▼]
Mesenchymal stromal cells (MSCs) are multipotent and self-renewing cells that reside essentially in the bone marrow as a non-hematopoietic cell population, but may also be isolated from the connective tissues of most organs. MSCs represent a heterogeneous population of adult, fibroblast-like cells characterized by their ability to differentiate into tissues of mesodermal lineages including adipocytes, chondrocytes and osteocytes. For several years now, MSCs have been evaluated for their in vivo and in vitro immunomodulatory and 'tissue reconstruction' properties, which could make them interesting in various clinical settings, and particularly in organ transplantation. This paper aims to review current knowledge on the properties of MSCs and their use in pre-clinical and clinical studies in solid organ transplantation, and particularly in the field of liver transplantation. The first available clinical data seem to show that MSCs are safe to use, at least in the medium-term, but more time is needed to evaluate the potential adverse effects of long-term use. Many issues must be resolved on the correct use of MSCs. Intensive in vitro and pre-clinical research are the keys to a better understanding of the way that MSCs act, and to eventually lead to clinical success. [less ▲]Detailed reference viewed: 25 (11 ULg)
Prognostic value of 18f-fdg PET - CT in liver transplantation for hepatocarcinoma
MEURISSE, Nicolas ; DETRY, Olivier ; et al
Poster (2014)Detailed reference viewed: 23 (14 ULg)
Alcoholic liver disease: when to consider liver transplantation?
Scientific conference (2013, December 07)Detailed reference viewed: 23 (3 ULg)
DONATION AFTER CIRCULATORY DEATH INCREASES THE CADAVERIC DONOR POOL
; DE ROOVER, Arnaud ; SQUIFFLET, Jean-Paul et al
in Transplant International (2013, December), 26(S2), 54-101
Background: There is a controversy on the possibility to increase the organ donor pool by donation-after-circulatory-death (DCD) and the possible decrease in donation-after-brain-death (DBD) by DCD ... [more ▼]
Background: There is a controversy on the possibility to increase the organ donor pool by donation-after-circulatory-death (DCD) and the possible decrease in donation-after-brain-death (DBD) by DCD programs. Our aim is to report the DCD experience at the University Hospital of Liege, Belgium, from 2002 through 2012, in a donor region of about 1 million inhabitants. Methods: The prospective organ donor and recipient databases were retrospectively reviewed. Results: 94 and 331 procurements were performed from controlled DCD and DBD donors in the time period, respectively. DCD donors contributed to 22.1% of the deceased donor (DD) organ procurement activity from Jan 2002 to Dec 2012, and up to one-third annually since 2009. DCD liver and kidneys contributed 23.7% and 24.2% of the DD liver and kidney transplantation activity, respectively. There was no decrease of the DBD procurement in the study period. In 2012, overall 54 DD were procured in the Liege region, reaching a high procurement activity.Conclusions: Controlled DCD donors are a valuable source of transplantable liver and kidney grafts, and in our experience do not adversely affect DBD organ procurement activity. [less ▲]Detailed reference viewed: 106 (7 ULg)
DONATION AFTER CIRCULATORY DEATH LIVER TRANSPLANTATION: IS DONOR AGE AN ISSUE?
DETRY, Olivier ; ; HONORE, Pierre et al
in Transplant International (2013, December), 26(s2), 112-228
Background: Donation after circulatory death (DCD) donors > 55 years are usually not considered suitable for liver transplantation (LT). At our institute, age is not an absolute exclusion criterion to ... [more ▼]
Background: Donation after circulatory death (DCD) donors > 55 years are usually not considered suitable for liver transplantation (LT). At our institute, age is not an absolute exclusion criterion to refuse DCD liver grafts. We retrospectively compared the transplant outcome of patients receiving older DCD liver grafts to the younger ones. Methods: 70 DCD liver transplants have been performed from 2003 to 2012, which includes 32 liver grafts from younger donors <55y (group A), 20 between 56 and 69 years (group B), and 18 from older donors ≥70 years (group C). The three groups were compared in terms of donor and recipient demographics, procurement and transplantation conditions, peak laboratory values during the first post-transplant week and results at one and three years. Results are expressed as median IQR. Results: No difference other than age in donor and recipient characteristics as well as procurement conditions was noted between both groups. Median donor age of the group A was 44 (38-45) years, in group B 62 (60-64) years and 73 (71-75) in group C. Median primary warm ischemia time (WIT) were 20 (17-22), 21 (19-25) and 19 (16-23) min, respectively (NS). Median cold ischemia time (CIT) was 236 (229-294), 245 (227-290) and 210 (195-277) min, respectively (NS). Peak AST (UI/ml) was 1162 (1072-3971), 1416 (1006-2752), and 1067 (902-4037), respectively (NS). There was no primary nonfunction and one patient needed retransplantation for artery thrombosis. Biliary complications occurred similarly in both groups, without graft loss secondary to ischemic cholangiopathy. Graft and patient survivals were not different at one and three years. Conclusion: This study shows comparable results between DCD liver transplants from younger and older donors. Therefore donor age >55 years should not be a contraindication to DCD liver transplantation if other donor risk factors (such as WIT, CIT) are minimized. [less ▲]Detailed reference viewed: 40 (6 ULg)
IS ULTRA-SHORT COLD ISCHEMIA THE KEY TO ISCHEMIC CHOLANGIOPATHY AVOIDANCE IN DCD- LT?
DETRY, Olivier ; DE ROOVER, Arnaud ; et al
in Transplant International (2013, December), 26(S2), 53-98
Introduction: Donation after circulatory death (DCD) donors have been proposed to partially overcome the organ donor shortage. DCD-LT remains controversial, with reported increased risk of ischemic ... [more ▼]
Introduction: Donation after circulatory death (DCD) donors have been proposed to partially overcome the organ donor shortage. DCD-LT remains controversial, with reported increased risk of ischemic cholangiopathy leading to graft loss. The authors retrospectively reviewed a single centre experience with DCD-LT in a 9-year period. Patients and Methods: 70 DCD-LT were performed from 2003 to November 2012. All DCD procedures were performed in operative rooms. Median donor age was 59 years. Most grafts were flushed with HTK solution. Allocation was centre-based. Median total DCD warm ischemia was 19.5 min. Mean follow-up was 36 months. No patient was lost to follow-up. Results: Median MELD score at LT was 15. Median cold ischemia was 235 min. Median peak AST was 1,162 U/L. Median peak bilirubin was 31.2 mg/dL. Patient and graft survivals were 92.8% and 91.3% at one year and 79% and 77.7% at 3 years, respectively. One graft was lost due to hepatic artery thrombosis. No PNF or graft loss due to ischemic cholangiopathy was observed in this series. Causes of death were malignancies in 8 cases. Discussion: In this series, DCD LT appears to provide results equal to classical LT. Short cold ischemia and recipient selection with low MELD score may be the keys to good results in DCD LT, in terms of graft survival and avoidance of ischemic cholangiopathy. [less ▲]Detailed reference viewed: 35 (6 ULg)
Effects of Parecoxib on The Prevention of Postoperative Peritoneal Adhesions in Rats.
; ; et al
in Journal of Investigative Surgery : The Official Journal of the Academy of Surgical Research (2013), 26(6), 340-346
ABSTRACT Background: No systemic preventive therapy has been successful in inhibiting the development of postoperative peritoneal adhesions (PPAs). Objective: The aim of this study was to evaluate the ... [more ▼]
ABSTRACT Background: No systemic preventive therapy has been successful in inhibiting the development of postoperative peritoneal adhesions (PPAs). Objective: The aim of this study was to evaluate the potential effects of 5 day administration of parecoxib, on PPA prevention and on suture or wound healing in rats. Methods: In a model of PPAs induced by peritoneal electrical burn, 30 rats were randomized into 3 groups according to parecoxib administration route (control; intraperitoneal (IP); intramuscular (IM)). Plasma and peritoneal levels of PAI-1 and tPA were measured at T0, after 90 min of surgery (T90), and on postoperative day 10 (D10). In a cecum resection model, 20 rats were randomized into two groups (control and IP parecoxib), and abdominal wound healing and suture leakage were assessed at D10. In both models, PPAs were evaluated quantitatively and qualitatively on D10. Results: Administration of parecoxib significantly decreased the quantity (p < .05) and the severity (p < .01) of PPAs in both models. In addition, parecoxib administration did not cause healing defects or infectious complications in the two models. In the peritoneal burn model, IP or IM parecoxib administration inhibited the increase of postoperative plasma and peritoneum PAI-1 levels, an increase that was observed in the control group (p < .01). No anastomosis leakage could be demonstrated in both groups in the cecum resection model. Conclusion: This study showed that, in these rat models, parecoxib might reduce PPA formation. Confirmation of the safety of parecoxib on intestinal anastomoses is required and should be investigated in further animal models. [less ▲]Detailed reference viewed: 39 (6 ULg)
The key to success of the ULG DCD organ procurement program : the points of view of the intensivist, the anaesthesiologist and the surgeon
LEDOUX, Didier ; JORIS, Jean ; DETRY, Olivier
Scientific conference (2013, September 23)Detailed reference viewed: 38 (5 ULg)
How to perform the most minimal invasive cholecystectomy?
Conference (2013, September 20)
Twenty years ago, laparoscopy has totally transformed the surgical approach of the gallbladder. For those who were not in surgery at that time, it has to be reminded that most open cholecystectomies ... [more ▼]
Twenty years ago, laparoscopy has totally transformed the surgical approach of the gallbladder. For those who were not in surgery at that time, it has to be reminded that most open cholecystectomies performed in the 80’s required nasogastric tube for several days, surgical drain, and 5 to 8 days of hospitalisation. For these obvious advantages, laparoscopic cholecystectomy has become the “Gold Standard” without evidence by a randomised controlled study comparing open and laparoscopic techniques. These last years, some groups proposed variations of laparoscopic cholecystectomies that they presented as less invasive. In robotic surgery, the Da-Vinci device has been proposed without significant improvement since more than 10 years. To date, no interest of this Da-Vinci robot has been demonstrated in abdominal surgery. Its cost for acquisition, its yearly fee and the cost for each use render its use without proof of results totally inappropriate. Single-Incision Laparoscopic Surgery (SILS) has also been described to perform cholecystectomy with only one larger umbilical incision. Until now, no superiority of SILS on classical cholecystectomy has been demonstrated. The Natural Orifice Transluminal Endoscopic Surgery (NOTES) proposes to use the vagina, the stomach or the colon to remove the gallbladder. No prospective controlled comparison has proved the superiority of these approaches that sometimes do not reach common sense or usual surgical principles. What is a minimal invasive cholecystectomy? A safe and un expensive cholecystectomy, with a good anatomical exposure, a cholangiography, and a good surgical comfort allowing to perform several procedures in the same day; a cholecystectomy that can be performed as a day-case without complications; a cholecystectomy that can be performed laparoscopically in acute settings; a cholecystectomy without the risk of postoperative incisional hernia. In necessary, in young and thin woman, laparoscopic cholecystectomy may be performed using 2 mm trocars that allow a good triangulation but with minimal scars. [less ▲]Detailed reference viewed: 31 (2 ULg)
Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Fourth Meeting: Lessons Learned from First Clinical Trials.
; ; et al
in Transplantation (2013), 96(3), 234-238
The Fourth Expert Meeting of the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Consortium took place in Barcelona on October 19 and 20, 2012. This meeting focused on the translation of ... [more ▼]
The Fourth Expert Meeting of the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Consortium took place in Barcelona on October 19 and 20, 2012. This meeting focused on the translation of preclinical data into early clinical settings. This position paper highlights the main topics explored on the safety and efficacy of mesenchymal stem cells as a therapeutic agent in solid organ transplantation and emphasizes the issues (proper timing, concomitant immunossupression, source and immunogenicity of mesenchymal stem cells, and oncogenicity) that have been addressed and will be followed up by the MiSOT Consortium in future studies. [less ▲]Detailed reference viewed: 39 (4 ULg)
Mosquito net for abdominal wall repair: a comparison of their chemical, physical, morphological and mechanical properties to commercial meshes
Sevrin, Chantal ; ; et al
in Biomedica proceedings (2013, June 23)
Meshes are the actual standard in abdominal wall repair. Commercial medical meshes are however either unavailable or unaffordable too expensive for developing countries. Therefore in most resource-poor ... [more ▼]
Meshes are the actual standard in abdominal wall repair. Commercial medical meshes are however either unavailable or unaffordable too expensive for developing countries. Therefore in most resource-poor developing countries a traditional sutured repair is still commonplace although with significantly inferior results. Sterilized mosquito nets have been recently roposed by several authors to replace medical meshes in low-income countries . However in the perspective of their clinical use a better understanding of this mosquito net is obviously requested both in terms of material properties and of in vivo biocompatibility. [less ▲]Detailed reference viewed: 50 (8 ULg)
INFUSION OF THIRD-PARTY MESENCHYMAL STEM CELLS (MSC) AFTER KIDNEY AND LIVER TRANSPLANTATION: A PHASE I-II, OPEN-LABEL, CLINICAL STUDY (EudraCT 2011-001822-81 & NCT01429038)
DETRY, Olivier ; DELBOUILLE, Marie-Hélène ; LECHANTEUR, Chantal et al
Poster (2013, May 30)
MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC ... [more ▼]
MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC infusion after cadaveric kidney and liver transplantation in a prospective phase I-II study, taking advantage of our centre expertise and experience in MSC use in graft-versus-host disease (GVHD) after bone marrow transplantation and using an already functioning GMP-compliant laboratory producing clinical-grade MSC. Secondary end-points will help to evaluate the immunosuppressive potential of MSC after organ transplantation, and the opportunity to develop larger randomised, controlled, phase III trials. After successful transplantation, 10 liver and 10 kidney transplant recipients under standard immunosuppression (tacrolimus, MMF, steroids) will receive an intravenous infusion of 1.5-3x106/kg of third-party MSC on post-operative day 3±2. These patients will be prospectively compared to 10 liver and 10 kidney recipients who meet the inclusion criteria but deny MSC infusion. Safety will be assessed by recording side effects, including opportunistic infections and cancers. Immunosuppressive potential will be evaluated by rejection episode rates, by graft/patient survivals, by immunohistology of 3-months kidney and 6-month liver graft biopsies and by in vitro evaluation of the immunity profile of the recipients. In a second step, reduction (kidney) and progressive weaning (liver) of immunosuppression will be attempted in recipients who received MSC. This ongoing study is supported by research grants from the CHU of Liège, University of Liège, and by the Senior Clinical Research Grant from ESOT. The first patients were included and treated in early 2012, and final results expected in late 2013. [less ▲]Detailed reference viewed: 101 (14 ULg)
The prognostic value of preoperative FDG PET-CT in hepatocellular carcinoma treated by liver transplantation.
; DETRY, Olivier ; BLETARD, Noëlla et al
in PROCEEDINGS OF THE XVIth SYMPOSIUM OF THE BELGIAN SOCIETY OF NUCLEAR MEDICINE (2013, May)Detailed reference viewed: 5 (0 ULg)