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Biomedical subjects

Philippe Morel

Publications and source records attributed to Philippe Morel.

At least 55 records · Page 3Linked to original sources
PubMed2005

Xenotransplantation: an update on recent progress and future perspectives.

Currently, the number of patients awaiting transplantation is continuously increasing, and shortage of available deceased organ donors is the major limitation for organ and cell allotransplantation. Research to develop alternative sources of tissues is ongoing and xenogeneic organs or cells represent an attractive solution. This review focuses on recent progress achieved in this field, including the development of newly genetically modified animal donors and new immunosuppressive approaches. As xenotransplantation is moving closer to clinical application, future perspectives must establish guidelines to ensure that future clinical trials are carried out ethically and safely.

Animals↗
PubMed2005

Impairment of renal function after islet transplant alone or islet-after-kidney transplantation using a sirolimus/tacrolimus-based immunosuppressive regimen.

The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.

Adult↗
PubMed2005

Anti-CD154 mAb treatment but not recipient CD154 deficiency leads to long-term survival of xenogeneic islet grafts.

The aim of the study was to evaluate the role of recipient CD40 and CD154 in the rejection process of concordant and discordant islets xenotransplantation (Tx). Diabetic C57BL/6 mice, CD40- or CD154-knockout (KO) and complement C3-deficient (C3-/-) mice were transplanted with either rat or human islets. Group 1, C57BL/6 Tx without therapy; Group 2, C57BL/6 Tx with anti-CD154 monoclonal antibody (mAb) (MR1) therapy; Group 3, CD40-KO; and Group 4, CD154-KO Tx without therapy; Group 5, C3-/- Tx without therapy and Group 6, C3-/-Tx with MR1 therapy. Mixed lymphocyte reactions (MLR) were performed. Compared to Group 1, MR1 induced long-term survival of xenografts in Group 2, but not in Group 6, survival of islets was not prolonged significantly in Groups 3 and 4. MLR responses in Group 2 were reduced approximately 50% compared to Group 1. In Groups 3, 4 and 6, MLR responses were not modified by the absence of CD40 or CD154 molecules, or MR1 and were similar to Group 1. Improved graft survival and reduced MLR responses in Group 2, but not in Group 6, could be explained by specific targeting of activated T cells with inactivation by complement- or cellular-mediated mechanisms. Rejection of xenografts and strong MLR responses in Groups 3 and 4 are possible through efficient activation of alternate pathways of costimulation.

Animals↗
PubMed2005

A simple and highly effective method for the stable transduction of uncultured porcine hepatocytes using lentiviral vector.

Gene therapy is an attractive approach for the treatment of a wide spectrum of liver diseases. Lentiviral vectors allow the stable integration of transgenes into the genome of nondividing differentiated cells including hepatocytes and could provide long-lasting expression of a therapeutic gene. To develop such approaches, preclinical studies in large animal models such as pigs are necessary to evaluate the feasibility and safety of stable lentiviral integration and long-term vector expression. In addition, effective lentivector-mediated gene transfer onto porcine hepatocytes could advance in cell-based therapies for acute liver failure. To investigate this issue, porcine hepatocytes were transduced in suspension immediately after their isolation in University of Wisconsin (UW) solution containing vitamin E. Up to 80% of hepatocytes stably expressed a GFP transgene after a single exposure to lentiviral vector coding for GFP under the control of either liver-specific or ubiquitous promoters. Moreover, porcine hepatocytes cryopreserved in UW solution containing fetal bovine serum, dimethyl sulfoxide, and vitamin E remained highly transducible with lentiviral vector after thawing. When thawed, transduced in suspension, and immediately transplanted into the spleen of immunodeficient mice, ex vivo lentivirally transgene marked xenogeneic hepatocytes were detected in murine liver. We demonstrated that porcine hepatocytes are highly susceptible to lentiviral vector and describe an easy methodology to efficiently, rapidly, and stably introduce transgenes into uncultured porcine hepatocytes.

Animals↗
PubMed2005

Effect of microcapsule composition and short-term immunosuppression on intraportal biocompatibility.

With higher nutrient and oxygen supply and close contact to blood, the portal vein is a possible alternative to the peritoneal cavity for transplantation of encapsulated cells. Data regarding intraportal biocompatibility of microcapsules are lacking. Microcapsules were built from five alginate types differing in their molar mass and mannuronic/guluronic acid ratios by complex formation with divalent cations (barium or calcium) or mixtures of divalent cations and polycations. They were injected in the portal vein of rats, and cellular and fibrotic pericapsular infiltration thickness was measured 3 and 7 days after implantation. Overgrowth was characterized using various stainings or immunohistochemistry (hematoxylin and eosin, Giemsa, ED-1 for monocyte/macrophage, alpha-actin for myofibroblasts, CD31 for endothelial cells). The impact of short-term immunosuppression (gadolinium-chloride IV 20 mg/kg/day on days--1 and 4 as well as 10 days of rapamycin PO 1 mg/kg/day, tacrolimus PO 3 mg/kg/day, or combinations of rapamycin/tacrolimus or gadolinium/tacrolimus) was further assessed 3, 7, and 42 days after implantation. Overall, overgrowth increased from day 3 to day 7 (p < 0.05). Three and 7 days after implantation, polycation-containing microcapsules induced more reaction than microbeads (p < 0.0001 and p < 0.01). Considering polycation-free beads, barium-alginate induced the weakest reaction. Biocompatibility of microbeads was independent of mannuronic/guluronic acid ratio and molar mass of the alginate. Infiltration was mainly a monocyte/macrophage-rich foreign body reaction, but an eosinophil-containing immunoallergic reaction was also observed. Short-term immunosuppression significantly reduced infiltration in all conditions and up to 42 days after implantation. Biocompatibility after intraportal infusion was best for barium-alginate microbeads and poorest for polycation-containing microcapsules. Short- and long-term overgrowth could be significantly reduced by short-term immunosuppression.

Alginates↗
PubMed2004

Two colons-two cancers: paradigm shift and clinical implications.

Embryological and physiological data suggest that proximal (in relation to the splenic flexure) and distal parts of the colon represent distinct anatomical and functional entities. Since 1990, molecular biologists have identified two distinct pathways, microsatellite instability (MSI) and chromosomal instability (CIN), which are involved in the pathogenesis of colon cancer (CC). Thus, a new paradigm has emerged with the discovery that CC is a heterogeneous disease; furthermore recent data have demonstrated that these two distinct pathways in colorectal carcinogenesis are characterized by a different clinical outcome. The implications for the clinicians are twofold; (1) tumors originating from the proximal colon have a better prognosis due to a high percentage of MSI-positive lesions; and (2) location of the neoplasm in reference to the splenic flexure should be documented before group stratification in ongoing trials of adjuvant chemotherapy for CC. In the future, clinical decision-making regarding adjuvant chemotherapy might be stratified according to the MSI status of cancers located proximally to the splenic flexure.

Chemotherapy, Adjuvant↗
PubMed2004

Lymphatic vessel density and vascular endothelial growth factor-C expression correlate with malignant behavior in human pancreatic endocrine tumors.

Metastatic dissemination of tumor cells to regional lymph nodes is a common early feature of many human cancers including pancreatic adenocarcinoma. In contrast, lymph node metastasis is more variably observed in pancreatic endocrine tumors. The objective of this study was to assess the lymphatic system of human pancreatic endocrine tumors and correlate this to clinical behavior. Immunohistochemistry was performed using antibodies to two recently identified markers of lymphatic endothelium, namely, LYVE-1 and podoplanin, and to the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. As has been reported previously, we observed that in the normal pancreas, islets of Langerhans are devoid of intra-islet lymphatics, but that lymphatics are present in connective tissue in association with ducts and blood vessels. We found that both benign and malignant pancreatic endocrine tumors contain intratumoral lymphatic vessels. Lymphatic vessel density was related to the size of the tumor in benign tumors and to the presence of liver metastasis but not to lymph node metastasis in malignant tumors. VEGF-C was expressed in tumor cells: 4 of 19 (21%) benign tumors were positive, whereas 6 of 9 (67%) borderline tumors and 9 of 11 (82%) carcinomas were positive. These findings strongly suggest that lymphangiogenesis occurs in pancreatic endocrine tumors and that lymphatic invasion and the development of metastases are associated with VEGF-C expression.

Adolescent↗
PubMed2004

[New results in allotransplantation of pancreatic islet cells].

An up-to-date synthesis of pancreatic islet allotransplantation is included in this summary, with emphasis on new developments and clinical results of the field. Rationale for islet transplantation in type 1 diabetes mellitus, current patient selection criteria, clinical data, technical aspects of organ procurement, islet isolation and transplantation are highlighted. The current challenges are also presented and analysed. Significant advances in clinical islet transplantation have been achieved recently. New immunosuppressive strategies were introduced, there were considerable changes in the patient selection criteria. International collaborations were established in order to standardize islet isolation and transplantation procedures. The spectacular results, recently reported by the Edmonton-group, represent a major breakthrough of the field and the outcomes are comparable with the results of whole pancreas transplantation. Islet transplantation became one of the most promising fields of tolerance induction research. Although still considered experimental, within the frameworks of expanding international collaborations, pancreatic islet allotransplantation gains more and more recognition in the clinical practice. These elements give hope that diabetes might be in the near future treated by islet cell transplantation.

Animals↗
PubMed2004

Influence of islet transportation on pancreatic islet allotransplantation in type 1 diabetic patients within the Swiss-French GRAGIL network.

BACKGROUND: The influence of islet transportation on pancreatic islet allotransplantation in type 1 diabetic patients was evaluated within the GRAGIL network. PATIENTS AND METHODS: From December 2001 to April 2003, 16 human pancreatic islet transplants were performed in 9 type 1 diabetic patients with an established kidney graft (functioning for at least 6 months) in four centers of the GRAGIL network. Islet isolation was performed in a core laboratory in Geneva, and the islet preparations were shipped by ambulance to each center for transplantation. One month after transplantation, the efficiency of the graft was assessed according to islet transportation time (ITT): ITT less than 2 hours (group 1, n=5), and ITT greater than 4.5 hours (group 2, n=4, mediant 5 hours). RESULTS: Primary graft dysfunction was observed in one patient in group 1 after one month. Two patients became insulin independent in groups 1 and 2. All other patients in both groups had a plasma C-peptide level greater than 0.5 ng/ml. The HbA1c level and the exogenous insulin needs decreased in both groups. CONCLUSIONS: ITT does not seem to influence the efficiency of pancreatic islet allotransplantation in type 1 diabetic patients. These results emphasize the scope for multicenter networks such as the GRAGIL group.

Adult↗
PubMed2004

Ribavirin/interferon-alpha sequential treatment of recurrent hepatitis C after liver transplantation.

Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), and sequels of chronic hepatitis of the graft are a significant cause of morbidity and mortality. In an uncontrolled trial, 31 patients with histologically confirmed hepatitis C after LT received, sequentially, ribavirin (10 mg/kg body weight q.d.) for 12 weeks, followed by ribavirin at the same dose q.d. plus interferon-alpha (IFN-alpha) [3 million units three times a week (3 MU TIW)] for another 48 weeks. Based on an intent-to-treat analysis, the percentages of patients with undetectable HCV RNA in their serum were 0%, 38.7% and 45.2% after 12, 36 and 60 weeks of therapy, respectively. A sustained virological response, as defined by undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/31 patients (29%). Sustained responders had a significant improvement of their liver inflammatory activity score (P=0.025), but not of their liver fibrosis score. The chances of sustained virological response correlated with the length of treatment, but not with the HCV genotype or baseline HCV RNA level. In conclusion, patients with recurrent hepatitis C after LT might benefit from ribavirin/IFN-alpha therapy, provided that the treatment is tolerated for a sufficient duration of time.

Adult↗
PubMed2004

Management of gastrointestinal stromal tumors: from diagnosis to treatment.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the digestive tract. Most gastrointestinal soft tissue neoplasms, previously classified as leiomyomas, schwannomas, leiomyoblastomas or leiomyosarcomas, are today classified as GIST on the basis of molecular and immunohistological features. They originate from gastrointestinal pacemaker cells and are characterised by over-expression of the tyrosine kinase receptor KIT. Overall 5-year survival after surgical resection of GIST is approximately 60%. However, these tumours span a wide clinical spectrum from benign to highly malignant. Prognostic factors have recently been identified for GIST and include tumour size, mitotic rate and other minor factors. At present, surgery is the standard treatment for primary resectable GIST. Benign GIST have an excellent prognosis after primary surgical treatment, with over 90% 5-year survival. While recurrent or malignant GIST, which are resistant to radiotherapy and chemotherapy, had until recently an extremely poor prognosis even after surgical resection, with median survival of 12 months. The development of a tyrosine kinase inhibitor has changed the management of unresectable malignant cases. This new tyrosine kinase inhibitor, imatinib mesylate, which inhibits the c-kit receptor, has proved highly effective against GIST and has improved survival in metastatic GIST. This paper reviews the literature and our experience of GIST, including: diagnosis, pathology, treatment and prognosis.

Algorithms↗
PubMed2004

Does mechanical bowel preparation have a role in preventing postoperative complications in elective colorectal surgery?

BACKGROUND: mechanical bowel preparation (MBP) consists of orthograde fluid preparation to clean the bowel. MBP is considered to prevent postoperative complications. METHODS: meta-analysis of prospective randomised clinical trials (RCT) evaluating MBP versus no MBP. RESULTS: following a medline search we retrieved 15 prospective trials of which only 5 where RCT comparing MBP versus no MBP in elective colorectal surgery. For the randomised studies, there were respectively 186, 179, 149, 267 and 380 patients, including all type of resections. The total number of patients in these 5 studies was 1144 (565 with MBP and 579 with no preparation). All patients received perioperative antibiotic prophylaxis. Only one of these RCT show a significant decrease in anastomotic leak (AL), but among all the patients enrolled, AL is significantly more frequent in the group with MBP (Odds Ratio 1.8). Wound infection, re-operation and intra-abdominal abscess rates were more frequent in the MBP group but the difference did not reach statistical significance and the odds ratios for a 95% confidence interval were extremely large. CONCLUSION: there is limited evidence in the literature to support the use of MBP in patient undergoing elective colorectal surgery. Available data tend to suggest that MBP could be harmful with respect to the incidence of anastomotic leak. Moreover, MBP does not reduce the incidence of other infectious complications. Further RCTs are needed to establish an evidence-based rationale for the use of MBP in elective colorectal surgery.

Anastomosis, Surgical↗
PubMed2004

Mechanical bowel preparation for elective colorectal surgery: a meta-analysis.

HYPOTHESIS: There is little scientific evidence to support the routine practice of mechanical bowel preparation (MBP) before elective colorectal surgery in order to minimize the risk of postoperative septic complications. DATA SOURCES: Trials were retrieved using a MEDLINE search followed by a manual search of the bibliographic information in select articles. Languages were restricted to English, French, Spanish, Italian, and German. There was no date restriction. STUDY SELECTION: Only prospective randomized clinical trials (RCTs) evaluating MBP vs no MBP before elective colorectal surgery were included. DATA EXTRACTION: Outcomes evaluated were anastomotic leakage, intra-abdominal infection, wound infection, reoperation, and general and extra-abdominal morbidity and mortality rates. Data were extracted by 2 independent observers. DATA SYNTHESIS: Seven RCTs were retrieved. The total number of patients in these RCTs was 1297 (642 who had received MBP and 655 who had not). Among all the RCTs reviewed, anastomotic leak was significantly more frequent in the MBP group, 5.6% (36/642), compared with the no-MBP group, 2.8% (18/655) (odds ratio, 1.84; P = .03). Intra-abdominal infection (3.7% for the MBP group vs 2.0% for the no-MBP group), wound infection (7.5% for the MBP group vs 5.5% for the no-MBP group), and reoperation (5.2% for the MBP group vs 2.2% for the no-MBP group) rates were nonstatistically significantly higher in the MBP group. General morbidity and mortality rates were slightly higher in the MBP group. CONCLUSIONS: There is no evidence to support the use of MBP in patients undergoing elective colorectal surgery. Available data tend to suggest that MBP could be harmful with respect to the incidence of anastomotic leak and does not reduce the incidence of septic complications.

Cathartics↗
PubMed2004

Are there any prognostic factors for small intestinal stromal tumors?

BACKGROUND: Stromal tumors of the digestive tract, or gastrointestinal stromal tumors (GIST), originate from an intestinal mesenchymal precursor cell. Criteria that predict the outcome of small intestinal stromal tumors (SIST) after surgical resection are not clearly established. The aim of the study was to define prognostic criteria for SIST. METHODS: All c-kit positive SIST treated in our center over a 10-year period were reviewed. RESULTS: Eighteen patients with SIST treated by surgical resection were included. Overall actuarial 5-year survival was 74% (median follow-up of 69 months). We developed a panel of five criteria (tumor size, mitotic rate, proliferation index, presence of necrosis, and invasion of mucosa or adjacent structures) that permitted distinction between low and high malignant potential SIST. Presence of any four of these five criteria defined a high malignant potential SIST, and was associated with disease recurrence and poor prognosis after surgical resection (P <0.01). Patients with low malignant potential SIST had a 5-year survival of 92%, compared with 0% for high malignant potential SIST (P <0.01). CONCLUSIONS: This study demonstrates that a panel of morphologic factors can reliably distinguish between low and high malignant potential SIST. Although patients with low malignant potential SIST have an excellent prognosis after surgical resection, the role of adjuvant treatment for high malignant potential SIST remains to be defined.

Actuarial Analysis↗
PubMed2004

Are criteria for islet and pancreas donors sufficiently different to minimize competition?

Islet and pancreas transplantation may compete for a limited number of organs. We analyzed records from the national Swiss transplant registry during a 4-year period to investigate the proportion of donors that are suitable for islet and pancreas transplantation. Suitability for pancreas transplantation was mainly defined as: age 10-45 years; weight <or= 80 kg; BMI <or= 25 kg/m(2); amylasemia <or= 150 U/l; ICU stay <or= 3 days and absence of severe hypotension (MAP <or= 60 mmHG). Between 1.1.1997 and 31.12.2000, data of 407 donors were collected, from which 321 donors were included in the study. Thirty-three (10%), 143 (45%), and 23 (7%) donors fulfilled the criteria for pancreas, islet transplantation, and both procedures, respectively. Giving priority to pancreas transplantation and accepting the absence of one selection criterion, 90 (28%) pancreas and 100 (31%) islet donors were identified. We conclude that with current allocation policies prioritizing pancreas transplantation, pancreas and islet transplantation may coexist with little competition.

Adult↗
PubMed2004

Chemotherapeutic options in the management of anal cancer.

During the past two decades, anal cancer has served as a paradigm for the successful application of chemoradiation to solid tumours; so far, it remains one of the few carcinomas of the gastrointestinal tract which are curable without the need for definitive surgery. Since the original contribution by Nigro in 1974, surprisingly few changes have been made to the standard of care in chemotherapy, which still consists of a combination of 5-fluorouracil and mitomycin C. However, many issues have yet to be clarified, such as the potential role of cisplatin as a substitute to mitomycin, as well as treatment-induced toxicity in HIV-positive patients. In this paper, the management of patients with anal cancer is presented, and new chemotherapeutic options are critically reviewed. Finally, the authors' opinion regarding currently unresolved issues in the treatment of these rare neoplasms is expressed.

Anus Neoplasms↗