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1.
J Robot Surg ; 16(1): 169-178, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33723791

ABSTRACT

Robotic-assisted surgery (RAS) involves training processes and challenges that differ from open or laparoscopic surgery, particularly regarding the possibilities of observation and embodied guidance. The video recording and the dual-console system creates a potential opportunity for participation. Our research, conducted within the department of visceral surgery of a big Swiss, public, academic hospital, uses a methodology based on the co-analysis of video recordings with surgeons in self-confrontation interviews, to investigate the teaching activity of the lead surgeon supervising a surgeon in training at the dual console. Three short sequences have been selected for the paper. Our analysis highlights the skills-in-construction of the surgeon in training regarding communication with the operating team, fluency of working with three hands, and awareness of the whole operating site. It also shows the divergent necessities of enabling verbalization for professional training, while ensuring a quiet and efficient environment for medical performance. To balance these requirements, we argue that dedicated briefing and debriefing sessions may be particularly effective; we also suggest that the self-confrontation video technique may be valuable to support the verbalization on both the mentor's and the trainee's side during such debriefing, and to enhance the mentor's reflexivity regarding didactic choices.


Subject(s)
Laparoscopy , Robotic Surgical Procedures , Surgeons , Clinical Competence , Humans , Learning , Robotic Surgical Procedures/methods , Surgeons/education , Video Recording
2.
Cancers (Basel) ; 13(22)2021 Nov 12.
Article in English | MEDLINE | ID: mdl-34830815

ABSTRACT

Overall survival of gastric cancer remains low, as patients are often diagnosed with advanced stage disease. In this review, we give an overview of current research on biomarkers in gastric cancer and their implementation in treatment strategies. The HER2-targeting trastuzumab is the first molecular targeted agent approved for gastric cancer treatment. Other promising biomarkers for targeted therapies that have shown relevance in clinical trials are VEGF and Claudin 18.2. Expression of MET has been shown to be a negative prognostic factor in gastric cancer. Targeting the PD-1/PD-L1 pathway with immune checkpoint inhibitors has proven efficacy in advanced gastric cancer. Recent technology advances allow the detection of circulating tumor cells that may be used as diagnostic and prognostic indicators and for therapy monitoring in gastric cancer patients. Prognostic molecular subtypes of gastric cancer have been identified using genomic data. In addition, transcriptome profiling has allowed a comprehensive characterization of the immune and stromal microenvironment in gastric cancer and development of novel risk scores. These prognostic and predictive markers highlight the rapidly evolving field of research in gastric cancer, promising improved treatment stratification and identification of molecular targets for individualized treatment in gastric cancer.

3.
Rev Med Suisse ; 16(699): 1292-1299, 2020 Jul 01.
Article in French | MEDLINE | ID: mdl-32608586

ABSTRACT

Esophageal cancer remains an oncological burden with a low survival rate. Multidisciplinary management is essential to offer an adjusted treatment to the patient general condition and the tumor stage. New minimally invasive surgical treatments help to reduce the surgical trauma and improve post-operative patient recovery. Oncological treatments have also evolved and definitive treatment by radio-chemotherapy can be proposed in specific cases.


Le cancer de l'œsophage reste un fardeau oncologique avec un taux de survie bas. Une prise en charge multidisciplinaire est primordiale afin d'offrir un traitement adapté à l'état général du patient et au stade de la tumeur. De nouvelles prises en charge minimalement invasives chirurgicales permettent de diminuer le traumatisme d'une chirurgie majeure et améliorent la récupération des patients en postopératoire. Les traitements oncologiques ont également évolué et un traitement définitif par radiochimiothérapie peut être proposé dans des cas précis.


Subject(s)
Esophageal Neoplasms/therapy , Combined Modality Therapy , Esophageal Neoplasms/surgery , Esophagectomy , Humans , Stomach Neoplasms/surgery , Stomach Neoplasms/therapy
5.
Langenbecks Arch Surg ; 404(5): 615-620, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31300891

ABSTRACT

PURPOSE: The da Vinci Surgical System family remains the most widely used surgical robotic system for laparoscopy. Data about gastric bypass surgery with the Xi Surgical System are not available yet. We compared Roux-en-Y gastric bypass surgery performed at our institution with the da Vinci Xi and the da Vinci Si Surgical System. METHODS: All robotic gastric bypass procedures performed between January 2013 and September 2016 were analyzed retrospectively. Patient demographics and operative and postoperative outcomes up to 30 days were compared for the da Vinci Xi and Si Surgical System. Robotic costs per procedure were modeled including posts for a standard set of robotic instruments, capital investment, and yearly maintenance. RESULTS: One-hundred forty-four Xi Surgical System and 195 Si Surgical System procedures were identified. Mean age (p = 0.9), gender distribution (p = 0.8), BMI (p = 0.6), and ASA scores (p > 0.5) were similar in both cohorts. Operating room times were similar in both groups (219.4 ± 58.8 vs. 227.4 ± 60.5 min for Xi vs. Si, p = 0.22). Docking times were significantly longer with the Xi compared with the Si Surgical System (9 ± 4.8 vs. 5.8 ± 4 min, p < 0.0001). There was no difference in incidence of minor (13.9 vs. 10.3%, p = 0.3) and major complications (5.6 vs. 5.1%, p = 1 for Xi vs. Si). Costs were higher for the Xi Surgical System caused by higher capital investment and yearly maintenance. CONCLUSIONS: Roux-en-Y gastric bypass surgery can be safely performed with the Xi Surgical System, while drawbacks include longer docking times and higher costs.


Subject(s)
Gastric Bypass/instrumentation , Laparoscopy/instrumentation , Obesity, Morbid/surgery , Postoperative Complications/epidemiology , Robotic Surgical Procedures/instrumentation , Adult , Female , Gastric Bypass/adverse effects , Gastric Bypass/economics , Humans , Laparoscopy/adverse effects , Laparoscopy/economics , Length of Stay , Male , Middle Aged , Obesity, Morbid/complications , Operative Time , Retrospective Studies , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/economics , Treatment Outcome
6.
Updates Surg ; 71(3): 401-409, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31243725

ABSTRACT

The minimal length of proximal margin (PM) in esophagogastric junction cancer has not been established yet and its impact on patient survival remains unclear. Pubmed, Embase and Scopus databases were searched for "adenocarcinoma of the esophagogastric junction", "adenocarcinoma of the gastroesophageal junction" and "cardia cancer", each combined with "proximal margin". English written studies that specified PM length in AEG were included. Survival data in relation to PM were extracted. 13 studies, that were all retrospective case series, with a total number of 2648 patients met inclusion criteria and were analyzed. While 93% of 230 patients with Siewert type I had esophagectomy, 69% of 1270 patients with Siewert type II and 93% of 872 patients with Siewert type III had transhiatal extended gastrectomy. Minimal PM length was treated by five studies and ranged between 2 and 6 cm. While three studies defined minimal PM by the necessary length to obtain R0 resection, two studies found minimal PM length significantly associated with survival. Multivariate analyses revealed in two studies an independent impact of PM on survival, whereas one study did not found any significant relation between PM and survival. One study showed that PM length was significantly associated with survival in T2-4N0-2 tumors, but not in T1 or N3 tumors. In conclusion, available retrospective studies did not allow a conclusion for a minimal length of PM and showed no clear evidence for an impact of PM length on survival. Taking into consideration available data and the shrinkage phenomen, a PM > 2 cm might be necessary to obtain a sufficient PM.


Subject(s)
Adenocarcinoma/surgery , Esophageal Neoplasms/surgery , Esophagogastric Junction/surgery , Margins of Excision , Stomach Neoplasms/surgery , Humans
7.
Ann N Y Acad Sci ; 1434(1): 115-123, 2018 12.
Article in English | MEDLINE | ID: mdl-30138532

ABSTRACT

Early carcinomas of the esophagus are histologically classified as adenocarcinoma or squamous cell carcinoma and microscopically subdivided into mucosal and submucosal carcinomas depending on infiltration depth. The prevalence of lymph node metastasis in mucosal carcinoma remains low. However, lymph node metastases arise frequently from tumors with submucosal infiltration, with increasing prevalence in the deeper submucosal sublayers. According to current German guidelines, endoscopic resection is the recommended treatment in mucosal adenocarcinoma without histologic risk factors (lymphatic invasion 1, vascular invasion 1, >grade 2, R1-margin). In superficial submucosal infiltration without histologic risk factors, endoscopic resection can be considered. In squamous cell carcinoma, endoscopic resection is indicated up to middle layer mucosal carcinoma. Beyond these criteria, surgical resection should be considered. The gold standard is a subtotal transthoracic esophagectomy with two-field lymphadenectomy. Total esophagectomy is performed in cervical esophageal carcinoma and transhiatal extended gastrectomy in carcinoma of the cardia. Minimally invasive procedures show good oncologic results and reduce the morbidity of radical esophagectomy. Reduced morbidity might be an argument for surgical resection in borderline cases between endoscopic and surgical resection. In early squamous cell cancer, the combination of endoscopic resection and adjuvant chemoradiotherapy is a therapeutic option with promising results.


Subject(s)
Carcinoma, Squamous Cell , Chemoradiotherapy/methods , Esophageal Neoplasms , Esophagectomy/methods , Esophagoscopy/methods , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Esophagus/pathology , Esophagus/surgery , Humans , Lymph Node Excision , Lymphatic Metastasis , Neoplasm Staging
8.
Transpl Int ; 31(8): 917-929, 2018 08.
Article in English | MEDLINE | ID: mdl-29603452

ABSTRACT

The microbiological safety of islet preparations is paramount. Preservation medium contamination is frequent, and its impact on islet yield and function remains unclear. Microbiological samples collected during islet isolations from 2006 to 2016 were analyzed and correlated to isolation and allo- and autotransplantation outcomes. Microbial contamination of preservation medium was found in 64.4% of processed donor pancreases (291/452). We identified 464 microorganisms including Staphylococcus (253/464, 54.5%), Streptococcus (31/464, 6.7%), and Candida species (25/464, 5.4%). Microbial contamination was associated with longer warm and cold ischemia times and lower numbers of postpurification islet equivalents, purity, transplant rate, and stimulation index (all P < 0.05). Six percent of the preparations accepted for transplantation showed microbial contamination after isolation (12/200); 9 of 12 were Candida species. Six patients were transplanted with a sample with late microbial growth discovered after the infusion. Insulin independence rate was not affected. This risk of transplanting a contaminated islets preparation was reduced by half following the implementation of an additional sampling after 24 h of islet culture. Pancreas preservation fluid microbial contamination is associated with lower transplant rate and poorer in vitro function, but not with changes in graft survival. Culture medium testing 1 day after isolation reduces the risk of incidental transplantation with contaminated islets.


Subject(s)
Drug Contamination/statistics & numerical data , Islets of Langerhans Transplantation/statistics & numerical data , Organ Preservation Solutions , Adolescent , Adult , Aged , Child , Cohort Studies , Female , Humans , Islets of Langerhans/microbiology , Male , Middle Aged , Young Adult
9.
Rev Med Suisse ; 13(567): 1236-1239, 2017 Jun 14.
Article in French | MEDLINE | ID: mdl-28643978

ABSTRACT

At the border between the esophagus and the stomach, gastro-esophageal junction tumors require a specific management that cannot be simplified to either of these two organs. Staging work-up with endoscopy, CT-Scan and PET-Scan, is essential because it will condition the choice of neo-adjuvant treatment. Surgery remains the only curative treatment and should be undergone in specialized center.


A la frontière entre l'œsophage et l'estomac, les tumeurs de la jonction œsogastrique nécessitent une prise en charge spécifique ne pouvant être simplifiée à l'un ou l'autre de ces deux organes. Le bilan complémentaire par endoscopie, CT-scan et PET-scan, est capital car il va conditionner le traitement néoadjuvant. La chirurgie reste le seul traitement curatif et doit être effectuée dans un centre spécialisé.


Subject(s)
Esophageal Neoplasms/therapy , Esophagogastric Junction/pathology , Stomach Neoplasms/therapy , Endoscopy, Gastrointestinal/methods , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/pathology , Humans , Neoadjuvant Therapy/methods , Neoplasm Staging , Positron-Emission Tomography/methods , Stomach Neoplasms/diagnosis , Stomach Neoplasms/pathology , Tomography, X-Ray Computed/methods
10.
Transpl Int ; 29(5): 627-35, 2016 May.
Article in English | MEDLINE | ID: mdl-26987785

ABSTRACT

The optimal order of revascularization for pancreas and kidney grafts in simultaneous pancreas-kidney transplantation has not been established. In this study, we investigate the influence of graft implantation order on graft survival in SPK. 12 700 transplantations from the Scientific Registry of Transplant Recipients were analyzed retrospectively. Graft implantation order was determined based on the reported ischemia times of pancreas and kidney grafts. Pancreas and kidney graft survivals were analyzed depending on graft implantation order at 3 months and 5 years using Kaplan-Meier plots. Significance was tested with log-rank test and Cox regression model. In 8454 transplantations, the pancreas was implanted first (PBK), and in 4246 transplantations, the kidney was implanted first (KBP). The proportion of lost pancreas grafts at 3 months was significantly lower in PBK (9.4% vs. 10.8%, P = 0.011). Increasing time lag (>2 h) between kidney and pancreas graft implantation in KBP accentuated the detrimental impact on pancreas graft survival (12.5% graft loss at 3 months, P = 0.001). Technical failure rates were reduced in PBK (5.6 vs. 6.9%, P = 0.005). Graft implantation order had no impact on kidney graft survival. In summary, although observed differences are small, pancreas graft implantation first increases short-term pancreas graft survival and reduces rates of technical failure.


Subject(s)
Diabetes Mellitus, Type 1/surgery , Kidney Transplantation/methods , Pancreas Transplantation/methods , Pancreatic Diseases/surgery , Renal Insufficiency/surgery , Adult , Diabetes Mellitus, Type 1/complications , Diabetic Nephropathies/complications , Diabetic Nephropathies/surgery , Female , Graft Rejection , Graft Survival , Humans , Kaplan-Meier Estimate , Kidney Transplantation/mortality , Male , Pancreas Transplantation/mortality , Pancreatic Diseases/complications , Proportional Hazards Models , Regression Analysis , Renal Insufficiency/complications , Retrospective Studies , Time Factors , Treatment Outcome , Young Adult
11.
Endocr Dev ; 31: 146-62, 2016.
Article in English | MEDLINE | ID: mdl-26824893

ABSTRACT

Pancreas and islet transplantation are 2 types of beta-cell replacement therapies for type 1 diabetes mellitus. Since 1966, when pancreas transplantation was first performed, it has evolved to become a highly efficient procedure with high success rates, thanks to advances in surgical technique and immunosuppression. Pancreas transplantation is mostly performed as simultaneous pancreas-kidney transplantation in patients with end-stage nephropathy secondary to diabetes. In spite of its efficiency, pancreas transplantation is still a major surgical procedure burdened by high morbidity, which called for the development of less invasive and hazardous ways of replacing beta-cell function in the past. Islet transplantation was developed in the 1970s as a minimally invasive procedure with initially poor outcomes. However, since the report of the 'Edmonton protocol' in 2000, the functional results of islet transplantation have substantially and constantly improved and are about to match those of whole pancreas transplantation. Islet transplantation is primarily performed alone in nonuremic patients with severe hypoglycemia. Both pancreas transplantation and islet transplantation are able to abolish hypoglycemia and to prevent or slow down the development of secondary complications of diabetes. Pancreas transplantation and islet transplantation should be seen as two complementary, rather than competing, therapeutic approaches for beta-cell replacement that are able to optimize organ donor use and patient care.


Subject(s)
Insulin-Secreting Cells/transplantation , Islets of Langerhans Transplantation/methods , Pancreas Transplantation/methods , Diabetes Mellitus, Type 1/surgery , Diabetes Mellitus, Type 1/therapy , Humans , Islets of Langerhans Transplantation/trends , Pancreas Transplantation/trends , Treatment Outcome
12.
Transplantation ; 99(1): 94-9, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24914570

ABSTRACT

BACKGROUND: The impact of recipient body mass index on graft and patient survival after pancreas transplantation is not well known. METHODS: We have analyzed data from all pancreas transplant recipients reported in the Scientific Registry of Transplant Recipients between 1987 and 2011. Recipients were categorized into BMI classes, as defined by the World Health Organization. Short-term (90 days) and long-term (90 days to 5 years) patient and graft survivals were analyzed according to recipient BMI class using Kaplan-Meier estimates. Hazard ratios were estimated using Cox proportional hazard models. RESULTS: A total of 21,075 adult recipients were included in the analysis. Mean follow-up was 5 ± 1.1 years. Subjects were overweight or obese in 39%. Increasing recipient BMI was an independent predictor of pancreatic graft loss and patient death in the short term (P<0.001), especially for obese class II patient survival (hazard ratio, 2.07; P=0.009). In the long term, obesity, but not overweight, was associated with higher risk of graft failure (P=0.01). Underweight was associated with a higher risk of long-term death (P<0.001). CONCLUSION: These results question the safety of pancreas transplantation in obese patients and suggest that they may be directed to alternate therapies, such as behavioral modifications or bariatric surgery, before pancreas transplantation is considered.


Subject(s)
Body Mass Index , Graft Survival , Obesity/complications , Pancreas Transplantation , Thinness/complications , Transplant Recipients , Adult , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Obesity/diagnosis , Obesity/mortality , Pancreas Transplantation/adverse effects , Pancreas Transplantation/mortality , Patient Selection , Proportional Hazards Models , Registries , Risk Assessment , Risk Factors , Thinness/diagnosis , Thinness/mortality , Time Factors , Treatment Outcome , United States
13.
Transplantation ; 98(12): 1301-9, 2014 Dec 27.
Article in English | MEDLINE | ID: mdl-25286053

ABSTRACT

BACKGROUND: Our final objective is to develop an adoptive therapy with tolerogenic donor-specific type 1 T regulatory cells for patients with type 1 diabetes undergoing islet transplantation. The achievement of this objective depends on the availability of an immunosuppressive treatment compatible with the survival, function, and expansion of type 1 T regulatory cells. METHODS: For this purpose, we designed a single-group, phase 1 to 2 trial with an immunosuppression protocol including: (i) rapamycin treatment before the first islet infusion (starting ≥ 30 days before transplantation); (ii) induction therapy with anti-thymocyte globulin (ATG) instead of anti-interleukin-2Ra monoclonal antibody (after the first islet infusion only); (iii) short-term treatment with steroids and interleukin-1Ra (right before and for 2 weeks after each infusion); rapamycin+mycophenolate mofetil treatment as maintenance therapy. The target enrollment was 10 patients. RESULTS: Ten of 15 patients who started the pretransplant rapamycin treatment completed it. Nine of 10 patients did not complete the induction therapy with ATG, and three of 10 required adaptation of maintenance immunosuppression caused by side effects. Four of 10 patients acquired insulin independence which can be maintained up to year 3 after last infusion. All six other patients have lost their graft, and the early graft loss was associated with lower dose of ATG during induction. CONCLUSION: This protocol resulted feasible, safe but less efficient in maintaining graft survival during the time than other T-cell depletion-based protocols. An adequate induction at the first infusion should be considered to improve the overall clinical outcome.


Subject(s)
Diabetes Mellitus, Type 1/therapy , Immunosuppressive Agents/therapeutic use , Islets of Langerhans Transplantation , Adult , Antilymphocyte Serum/chemistry , Antilymphocyte Serum/therapeutic use , Calcineurin Inhibitors/chemistry , Female , Glomerular Filtration Rate , Graft Survival , Humans , Immunosuppression Therapy/methods , Immunosuppressive Agents/chemistry , Insulin/metabolism , Interleukin 1 Receptor Antagonist Protein/chemistry , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Male , Middle Aged , Sirolimus/chemistry , Sirolimus/therapeutic use , Steroids/chemistry , Steroids/therapeutic use , T-Lymphocytes, Regulatory/cytology , Treatment Outcome
14.
Transplantation ; 98(6): 593-9, 2014 Sep 27.
Article in English | MEDLINE | ID: mdl-25029387

ABSTRACT

Both pancreas and islet transplantations are therapeutic options for complicated type 1 diabetes. Until recent years, outcomes of islet transplantation have been significantly inferior to those of whole pancreas. Islet transplantation is primarily performed alone in patients with severe hypoglycemia, and recent registry reports have suggested that results of islet transplantation alone in this indication may be about to match those of pancreas transplant alone in insulin independence. Figures of 50% insulin independence at 5 years for either procedure have been cited. In this article, we address the question whether islet transplantation has indeed bridged the gap with whole pancreas. Looking at the evidence to answer this question, we propose that although pancreas may still be more efficient in taking recipients off insulin than islets, there are in fact numerous "gaps" separating both procedures that must be taken into the equation. These "gaps" relate to organ utilization, organ allocation, indication for transplantation, and morbidity. In-depth analysis reveals that islet transplantation, in fact, has an edge on whole pancreas in some of these aspects. Accordingly, attempts should be made to bridge these gaps from both sides to achieve the same level of success with either procedure. More realistically, it is likely that some of these gaps will remain and that both procedures will coexist and complement each other, to ensure that ß cell replacement can be successfully implemented in the greatest possible number of patients with type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/therapy , Islets of Langerhans Transplantation/methods , Pancreas Transplantation/methods , Health Care Costs , Humans , Hypoglycemia/physiopathology , Insulin/chemistry , Insulin-Secreting Cells/cytology , Islets of Langerhans Transplantation/economics , Islets of Langerhans Transplantation/statistics & numerical data , Pancreas/surgery , Pancreas Transplantation/economics , Pancreas Transplantation/statistics & numerical data , Registries , Risk , Tissue and Organ Procurement , Treatment Outcome
15.
Transplantation ; 93(7): 703-8, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22343333

ABSTRACT

BACKGROUND: Institut Georges Lopez-1 (IGL-1) is a preservation solution similar to University of Wisconsin (UW) with reversed Na/K contents. In this study, we assessed the impact of IGL-1, UW, and Celsior (CS) solutions on islet isolation and transplant outcome. METHODS: We retrospectively analyzed 376 islet isolations from pancreases flushed and transported with IGL-1 (n=95), UW (n=204), or CS (n=77). We determined isolation outcome and ß-cell function in vitro. Transplanted patients were divided into three groups depending on preservation solution of pancreas, and islet graft function was assessed by decrease in daily insulin needs, C-peptide/glucose ratios, ß-scores, and transplant estimated function at 1- and 6-month follow-up. RESULTS: IGL-1, UW, and CS groups were similar according to donor age, body mass index, and pancreas weight. There was no difference in islet yields between the three groups. Success rates, transplant rates, ß-cell secretory function, and viability were similar for all three groups. We observed no difference in decreased insulin needs, C-peptide glucose ratios, ß-scores, and transplant estimated function at 1- and 6-month follow-up between IGL-1, UW, and CS groups. CONCLUSIONS: Our study shows that IGL-1 is equivalent to UW or CS solutions for pancreas perfusion and cold storage before islet isolation and transplantation.


Subject(s)
Diabetes Mellitus/surgery , Islets of Langerhans Transplantation , Islets of Langerhans/drug effects , Organ Preservation Solutions/therapeutic use , Organ Preservation/methods , Tissue and Organ Harvesting/methods , Adenosine/therapeutic use , Adult , Allopurinol/therapeutic use , Analysis of Variance , Biomarkers/blood , Blood Glucose/metabolism , C-Peptide/blood , Chi-Square Distribution , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Disaccharides/therapeutic use , Electrolytes/therapeutic use , Female , Glutamates/therapeutic use , Glutathione/therapeutic use , Glycated Hemoglobin/metabolism , Histidine/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Islets of Langerhans/metabolism , Male , Mannitol/therapeutic use , Middle Aged , Raffinose/therapeutic use , Retrospective Studies , Time Factors , Tissue Culture Techniques , Treatment Outcome
16.
PLoS One ; 6(9): e25442, 2011.
Article in English | MEDLINE | ID: mdl-21980458

ABSTRACT

BACKGROUND: Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra) during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration. METHODS: We performed 70%-hepatectomy in wild type (WT) mice, IL-1ra knock-out (KO) mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes. RESULTS: At 24h and at 48 h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1ß and MCP-1) and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPß expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment. CONCLUSION: IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.


Subject(s)
Hepatectomy , Interleukin 1 Receptor Antagonist Protein/pharmacology , Liver Regeneration/drug effects , Alanine Transaminase/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Proliferation/drug effects , Gene Expression Regulation/drug effects , Gene Knockout Techniques , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Interleukin 1 Receptor Antagonist Protein/deficiency , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/metabolism , Liver Regeneration/genetics , Male , Mice , Time Factors
17.
Transplantation ; 92(9): 1031-8, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21926944

ABSTRACT

BACKGROUND: Insulin independence after islet transplantation is generally achieved after multiple infusions. However, single infusion would increase the number of recipients. Our aim was to evaluate the results of islet-after-kidney transplantation according to the number of infusions. METHODS: Islets were isolated at the Geneva University, shipped, and transplanted into French patients from the Swiss-French GRAGIL network, on the "Edmonton" immunosuppression protocol between 2004 and 2010. RESULTS: Nineteen patients were transplanted with 33 preparations. Fifteen patients reached 24 months follow-up; eight subjects were single-graft recipients and seven were double-graft recipients. Finally, single-graft recipients received a median of 5312 islet equivalents/kg (5186-6388) vs. 10,564 (10,054-11,375) for double-graft recipients (P=0.0003) with similar islet mass at first infusion. Insulin independence was achieved in five of eight single-graft subjects (62.5%) versus five of seven in double-graft subjects (71.4%), not significant. Median insulin independence duration was 4.7 (3.1-15.2) months after one infusion vs. 19 (9.6-20.8) months after two infusions (not significant). At 24 months posttransplant, comparing single- with double-graft patients, insulin doses were 0.23 (0.11-0.34) U/kg vs. 0.02 (0.0-0.23) U/kg, P=0.11; HbA1c was 6.5% (5.9%-6.8%) vs. 6.2% (5.9%-6.3%), P=0.16; and basal C-peptide was 302 (143-480) pmol/L vs. 599 (393-806) pmol/L, P=0.05. Only 37.5% of single-graft patients had a ß-score ≥4 compared with 100% of double-graft patients (P=0.03). Two recipients experienced postinfusion bleeding, and two patients (13%) showed renal dysfunction in the absence of biopsy-proven rejection. CONCLUSIONS: One infusion achieves good glycemic control and sometimes insulin independence. However, double-graft patients remain insulin-free longer, tend to have lower HbA1c, and show better graft function 24 months after transplant.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 1/surgery , Glycated Hemoglobin/metabolism , Islets of Langerhans Transplantation/methods , Kidney Transplantation , Adult , C-Peptide/blood , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Female , France , Humans , Insulin/therapeutic use , Islets of Langerhans Transplantation/physiology , Kidney Transplantation/physiology , Longitudinal Studies , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment Outcome
18.
Transplantation ; 91(8): 895-901, 2011 Apr 27.
Article in English | MEDLINE | ID: mdl-21372755

ABSTRACT

BACKGROUND: Extended pancreatectomy is associated with the risk of surgical diabetes. Islet autotransplantation is successful in the prevention of diabetes after pancreas resection for chronic pancreatitis (CP), with insulin independence rates of 50% at 1 year. The aim of the present study is to demonstrate the safety and efficiency of islet autotransplantation after extended left pancreatectomy for benign disease. METHODS: Between 1992 and 2009, 25 patients underwent extended pancreatectomy and islet autotransplantation for benign disease. Of these, 15 patients were operated for focal lesions located at the neck of the pancreas (14 benign tumors and 1 traumatic pancreatic section), the remainder being CP cases. After unequivocal diagnosis of benignity, the rest of the pancreas was processed and infused into the portal vein. Metabolic results were analyzed and isolation results were compared with those obtained from patients with CP or donors with brain death (DBD). RESULTS: There was no mortality and a low morbidity (Streptococcus mitis bacteremia in 1 patient), no portal thrombosis or pancreatic fistula occurred. Median follow-up was 90 months. Actuarial patient survival was 100% at 10 years. Actuarial insulin independence was 94% at 10 years. All patients had positive basal and stimulated C-peptide levels and normal HbA1c. Mean islet yields were 5455 IEQ/gram vs. 1457 in CP (P=0.001) and 3738 in DBD (P=0.003). CONCLUSIONS: Islet autotransplantation after extensive pancreatic resection for benign disease is a safe and successful procedure. Islet yields after isolation, which are equivalent to the live donor situation, are significantly better than those from DBD donors.


Subject(s)
Islets of Langerhans Transplantation , Pancreatectomy , Pancreatic Diseases/surgery , Adult , Aged , Aged, 80 and over , Case-Control Studies , Chi-Square Distribution , Diabetes Mellitus/etiology , Diabetes Mellitus/prevention & control , Female , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Islets of Langerhans Transplantation/adverse effects , Kaplan-Meier Estimate , Male , Middle Aged , Pancreatectomy/adverse effects , Pancreatic Diseases/diagnostic imaging , Pancreatitis, Chronic/surgery , Switzerland , Time Factors , Tomography, X-Ray Computed , Transplantation, Autologous , Treatment Outcome
19.
Transplantation ; 91(7): 714-22, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21297554

ABSTRACT

BACKGROUND: The cause for a progressive attrition of islet graft function observed over the years after islet transplantation is not well defined but may be in part the result of adverse effects of immunosuppressive agents. In this study, we examined the effect of rapamycin, a key component of the immunosuppressive regimen, on ß-cell replication of transplanted islets. METHODS: Mice transplanted with rat islets under kidney capsule received bromodeoxyuridine for 7 days. Mice were treated with rapamycin or appropriate vehicle. ß-cell replication was determined by double immunofluorescence staining for insulin and bromodeoxyuridine. For in vitro studies, apoptosis, glucose-stimulated insulin secretion, and proliferation were determined in islet cells incubated with EdU in the presence or absence of rapamycin. RESULTS: In our islet transplant model, rapamycin impaired glucose tolerance and ß-cell proliferation of transplanted and host islets. In vitro, rapamycin reduced glucose-stimulated insulin secretion and reversibly decreased ß-cell replication. The inhibitory effect of rapamycin on ß-cell proliferation was not due to the decrease in insulin release. Additionally, in islet cells, expression of cell cycle proteins was significantly modified by rapamycin, suggesting a blockade of cell cycle progression. Inhibition of p38MAPK partially reverted rapamycin effect on ß-cell proliferation. CONCLUSION: Rapamycin, at concentration usually used to prevent islet graft rejection, is able to reduce the rate of ß-cell proliferation in transplanted rat islets but also in host murine islets. These data suggest that the progressive islet graft dysfunction observed under immunosuppressive therapy may result in part from an impairment of ß-cell regeneration.


Subject(s)
Cell Proliferation/drug effects , Immunosuppressive Agents/pharmacology , Insulin-Secreting Cells/drug effects , Islets of Langerhans Transplantation , Sirolimus/pharmacology , Animals , Cells, Cultured , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/physiology , Male , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects
20.
Transplantation ; 91(3): 360-6, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21344706

ABSTRACT

BACKGROUND: It has been suggested that the age of human organ donors might influence islet isolation and transplantation outcome in a negative way due to a decrease of in vivo function in islets isolated from older donors. METHODS: We retrospectively analyzed 332 islet isolations according to donor age. We determined isolation outcome by islet yields, transplantation rates, and [beta]-cell function in vitro. Transplanted patients were divided into two groups depending on donor age (n=25 and n=31 patients for <=45- and >45-year-old donors, respectively). We assessed islet graft function by C-peptide/glucose ratio, [beta] score, secretory units of islets in transplantation index, and insulin independence rate at 1, 6, and 12 months after transplantation. RESULTS: There was no difference in islet yields between the two groups (251,900+/-14,100 and 244,600+/-8400 islet equivalent for <=45- and >45-year-old donors, respectively). Transplantation rates and stimulation indices were similar in both groups as well. All islet graft function parameters were significantly higher at 1-month follow-up in patients who had received islets from younger donors. At 6-month follow-up after second or third injection and at 12-month follow-up, secretory units of islets in transplantation indices and C-peptide/glucose ratios were significantly higher in patients with donors aged 45 years or younger. CONCLUSIONS: These data suggest that, despite similar outcomes of the isolation procedure, islet graft function is significantly influenced by donor age. These results may have important consequences in the definition of pancreas allocation criteria.


Subject(s)
Diabetes Mellitus, Type 1/surgery , Islets of Langerhans Transplantation/physiology , Islets of Langerhans/physiology , Islets of Langerhans/surgery , Tissue Donors , Adult , Age Factors , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/drug therapy , Female , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Male , Middle Aged , Retrospective Studies , Treatment Outcome
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