Manuel Pascual
University of Lausanne
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Featured researches published by Manuel Pascual.
Transplantation | 2001
Marta Crespo; Manuel Pascual; Nina Tolkoff-Rubin; Shamila Mauiyyedi; A. Bernard Collins; Donna M. Fitzpatrick; Mary Lin Farrell; Winfred W. Williams; Francis L. Delmonico; A. Benedict Cosimi; Robert B. Colvin; Susan L. Saidman
Background. Acute rejection (AR) associated with de novo production of donor-specific antibodies (DSA) is a clinicopathological entity that carries a poor prognosis (acute humoral rejection, AHR). The aim of this study was to determine the incidence and clinical characteristics of AHR in renal allograft recipients, and to further analyze the antibodies involved. Methods. During a 4-year period, 232 renal transplants (Tx) were performed at our institution. Assays for DSA included T and B cell cytotoxic and/or flow cytometric cross-matches and cytotoxic antibody screens (PRA). C4d complement staining was performed on frozen biopsy tissue. Results. A total of 81 patients (35%) suffered at least one episode of AR within the first 3 months: 51 had steroid-insensitive AR whereas the remaining 30 had steroid-sensitive AR. No DSA were found in patients with steroid-sensitive AR. In contrast, circulating DSA were found in 19/51 patients (37%) with steroid-insensitive AR, and widespread C4d deposits in peritubular capillaries were present in 18 of these 19 (95%). In at least three cases, antibodies were against donor HLA class II antigens. DSA were not found in the remaining 32 patients but C4d staining was positive in 2 of 32. The DSA/C4d positive (n=18) and DSA/C4d negative (n=30) groups differed in pre-Tx PRA levels, percentage of re-Tx patients, refractoriness to antilymphocyte therapy, and outcome. Plasmapheresis and tacrolimus-mycophenolate mofetil rescue reversed rejection in 9 of 10 recipients with refractory AHR. Conclusion. More than one-third of the patients with steroid-insensitive AR had evidence of AHR, often resistant to antilymphocyte therapy. Most cases (95%) with DSA at the time of rejection had widespread C4d deposits in peritubular capillaries, suggesting a pathogenic role of the circulating alloantibody. Combined DSA testing and C4d staining provides a useful approach for the early diagnosis of AHR, a condition that often necessitates a more intensive therapeutic rescue regimen.
Transplantation | 2001
Seema Baid; A. Benedict Cosimi; Mary Lin Farrell; David A. Schoenfeld; Sandy Feng; Raymond T. Chung; Nina Tolkoff-Rubin; Manuel Pascual
Background. Recent studies suggest an association between diabetes mellitus and hepatitis C virus (HCV) infection. Our aim was to determine (1) the prevalence and determinants of new onset posttransplant diabetes mellitus (PTDM) in HCV (+) liver transplant (OLT) recipients, (2) the temporal relationship between recurrent allograft hepatitis and the onset of PTDM, and (3) the effects of antiviral therapy on glycemic control. Methods. Between January of 1991 and December of 1998, of 185 OLTs performed in 176 adult patients, 47 HCV (+) cases and 111 HCV (-) controls were analyzed. We reviewed and analyzed the demographics, etiology of liver failure, pretransplant alcohol abuse, prevalence of diabetes mellitus, and clinical characteristics of both groups. In HCV (+) patients, the development of recurrent allograft hepatitis and its therapy were also studied in detail. Results. The prevalence of pretransplant diabetes was similar in the two groups, whereas the prevalence of PTDM was significantly higher in HCV (+) than in HCV (-) patients (64% vs. 28%, P =0.0001). By multivariate analysis, HCV infection (hazard ratio 2.5, P =0.001) and methylprednisolone boluses (hazard ratio 1.09 per bolus, P =0.02) were found to be independent risk factors for the development of PTDM. Development of PTDM was found to be an independent risk factor for mortality (hazard ratio 3.67, P <0.0001). The cumulative mortality in HCV (+) PTDM (+) versus HCV (+) PTDM (-) patients was 56% vs. 14% (P =0.001). In HCV (+) patients with PTDM, we could identify two groups based on the temporal relationship between the allograft hepatitis and the onset of PTDM: 13 patients developed PTDM either before or in the absence of hepatitis (group A), and 12 concurrently with the diagnosis of hepatitis (group B). In gr. B, 11 of 12 patients received antiviral therapy. Normalization of liver function tests with improvement in viremia was achieved in 4 of 11 patients, who also demonstrated a marked improvement in their glycemic control. Conclusion. We found a high prevalence of PTDM in HCV (+) recipients. PTDM after OLT was associated with significantly increased mortality. HCV infection and methylprednisolone boluses were found to be independent risk factors for the development of PTDM. In approximately half of the HCV (+) patients with PTDM, the onset of PTDM was related to the recurrence of allograft hepatitis. Improvement in glycemic control was achieved in the patients who responded to antiviral therapy.
Clinical Transplantation | 2007
Jay A. Fishman; Vincent C. Emery; Richard B. Freeman; Manuel Pascual; Lionel Rostaing; Hans J. Schlitt; Dino Sgarabotto; Julián Torre-Cisneros; Marc E. Uknis
Abstract: Background: Cytomegalovirus (CMV) infection of solid organ transplant (SOT) recipients causes both ‘‘direct’’ and ‘‘indirect’’ effects including allograft rejection, decreased graft and patient survival, and predisposition to opportunistic infections and malignancies. Options for CMV prevention include pre‐emptive therapy, whereby anti‐CMV agents are administered based on sensitive viral assays, or universal prophylaxis of all at‐risk patients. Each approach has advantages and disadvantages in terms of efficacy, costs, and side effects. Standards of care for prophylaxis have not been established.
Transplantation | 1998
Manuel Pascual; Susan L. Saidman; Nina Tolkoff-Rubin; Winfred W. Williams; Shamila Mauiyyedi; Ji Ming Duan; Mary Lin Farrell; Robert B. Colvin; A. Benedict Cosimi; Francis L. Delmonico
BACKGROUND Acute renal allograft rejection associated with the development of donor-specific alloantibody (acute humoral rejection, AHR) typically carries a poor prognosis. The best treatment of this condition remains undefined. METHODS During a 14-month period, 73 renal transplants were performed. During the first postoperative month, five recipients (6.8%) with AHR were identified. The diagnosis was based on: (1) evidence of severe rejection, resistant to steroid and antilymphocyte therapy; (2) typical pathologic features; and (3) demonstration of donor-specific alloantibody (DSA) in recipients serum at the time of rejection. Pretransplant donor-specific T- and B-cell cross-matches were negative. RESULTS Plasma exchange (PE, four to seven treatments per patient) significantly decreased circulating DSA to almost pretransplant levels in four of five patients, and improvement in renal function occurred in all patients. One patient had recurrent renal dysfunction in the setting of an increase in circulating DSA. A second series of five PE treatments decreased DSA and reversed the rejection episode. Rescue therapy with tacrolimus (initial mean dose: 0.14+/-0.32 mg/kg/day) and mycophenolate mofetil (2 g/day) was used in five of five and four of five patients, respectively. With a mean follow-up of 19.6+/-5.6 months, patient and allograft survival are 100%. Renal function remains excellent with a mean current serum creatinine of 1.2+/-0.3 mg/dl. (range: 0.9-1.8 mg/dl). CONCLUSIONS Our findings suggest that a therapeutic approach combining PE and tacrolimus-mycophenolate mofetil rescue has the potential to improve the outcome of AHR.
Transplantation | 2003
William C. Goggins; Manuel Pascual; John A. Powelson; Colm Magee; Nina Tolkoff-Rubin; Mary Lin Farrell; Dicken S.C. Ko; Winfred W. Williams; Anil Chandraker; Francis L. Delmonico; Hugh Auchincloss; A. Benedict Cosimi
Background. Delayed graft function (DGF) is frequently observed in recipients of cadaveric renal transplants. Previous retrospective or nonrandomized studies have suggested that intraoperative administration of polyclonal antithymocyte preparations may reduce the incidence of DGF, possibly by decreasing ischemia-reperfusion injury. Methods. We performed a prospective randomized study of Thymoglobulin induction therapy in adult cadaveric renal transplant recipients. Between January 2001 and January 2002, 58 adult cadaveric renal transplant recipients were randomized to receive intraoperative or postoperative Thymoglobulin induction therapy. Three to six doses of Thymoglobulin (1 mg/kg/dose) were administered during the first week posttransplant. Baseline immunosuppression consisted of tacrolimus (54 of 58) or cyclosporine A (4 of 58), steroids, and mycophenolate mofetil. DGF was defined by the requirement for hemodialysis within the first week posttransplant. Results. There were no significant differences between the two groups in recipient demographics, donor age, cold ischemia time, or total number of doses of Thymoglobulin administered. Intraoperative Thymoglobulin administration was associated with significantly less DGF and a lower mean serum creatinine on postoperative days 10 and 14 (P <0.05). Posttransplant length of stay was also significantly shorter for the intraoperative Thymoglobulin patient group. The acute rejection rate was also lower in the intraoperative treatment group but this did not achieve statistical significance. There was no difference in the incidence of cytomegalovirus disease between the two groups. Conclusions. The results of this study indicate that intraoperative Thymoglobulin administration, in adult cadaveric renal transplant recipients, is associated with a significant decrease in DGF, better early allograft function in the first month posttransplant, and a decreased posttransplant hospital length of stay.
Journal of Hepatology | 2011
Christian Lange; Darius Moradpour; Alexandra Doehring; Hans-Anton Lehr; Beat Müllhaupt; Stéphanie Bibert; Pierre-Yves Bochud; Antonino A; Manuel Pascual; Harald Farnik; Ying Shi; Wolf Otto Bechstein; Christian Moench; Martin-Leo Hansmann; Christoph Sarrazin; Jörn Lötsch; Stefan Zeuzem; W.P. Hofmann
BACKGROUND & AIMS Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. METHODS Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. RESULTS Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively). CONCLUSIONS We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.
American Journal of Transplantation | 2003
Seema Baid; Nina Tolkoff-Rubin; Susan L. Saidman; Raymond T. Chung; Winfred W. Williams; Hugh Auchincloss; Robert B. Colvin; Francis L. Delmonico; A. Benedict Cosimi; Manuel Pascual
The use of interferon‐alpha (IFN) in hepatitis C (HCV)‐infected renal recipients has been associated with acute rejection and graft loss. We reviewed our recent experience in HCV (+) renal recipients treated with antiviral therapy for biopsy proven chronic hepatitis C. Twelve HCV (+) recipients who recently received antiviral therapy were analyzed. Post‐treatment sera were tested for donor‐specific human leukocyte antigen (HLA) antibodies (DSA). Within 6 months of initiating antiviral therapy, two of 12 patients (17%) developed acute rejection, which was characterized as acute humoral rejection (de novo DSA in serum and C4d deposits in peritubular capillaries). Both progressed to graft failure. Nine of the remaining 10 patients tested did not have DSA. The use of IFN was associated with severe acute humoral rejection (C4d +, DSA +). The recognition of IFN‐associated acute humoral rejection in this series may explain the high rate of graft loss reported previously in renal recipients receiving IFN.
American Journal of Transplantation | 2005
Solange Moll; Manuel Pascual
In recent years, the deleterious clinical consequences of recipient de novo alloantibody production against HLA antigens from human organ allografts have been extensively investigated. In kidney transplantation, the identification of the complement C4d fragment in peritubular capillaries as a specific marker for humoral rejection has helped to define and characterize distinct clinical alloantibody‐mediated syndromes. This knowledge is relevant for patient management as new therapeutic strategies to remove and control anti‐donor antibody production, particularly in the setting of acute humoral rejection, have been reported. For recipients of nonrenal organ allografts such as heart transplant recipients, de novo anti‐HLA alloantibody may also be important, although more studies are needed before clear guidelines can be proposed.
European Journal of Immunology | 2008
Donatella Ciuffreda; Denis Comte; Matthias Cavassini; Emiliano Giostra; Leo H. Buhler; Monika Perruchoud; Markus H. Heim; Manuel Battegay; Daniel Genné; Beat Mulhaupt; Raffaele Malinverni; Carl Oneta; Enos Bernasconi; Martine Monnat; Andreas Cerny; Christian Chuard; Jan Borovicka; Gilles Mentha; Manuel Pascual; Jean-Jacques Gonvers; Giuseppe Pantaleo; Valérie Dutoit
HCV infection has a severe course of disease in HIV/HCV co‐infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV‐specific T‐cell responses in 86 HCV mono‐infected patients, 48 HIV/HCV co‐infected patients and 42 liver transplant recipients. IFN‐γ and IL‐2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCV‐derived peptides. We observed that HCV‐specific T‐cell responses were polyfunctional in HCV mono‐infected patients, with presence of proliferating single IL‐2‐, dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD4+ and dual IL‐2/IFN‐γ and single IFN‐γ‐producing CD8+ cells. In contrast, HCV‐specific T‐cell responses had an effector profile in HIV/HCV co‐infected individuals and liver transplant recipients with absence of single IL‐2‐producing HCV‐specific CD4+ and dual IL‐2/IFN‐γ‐producing CD8+ T cells. In addition, HCV‐specific proliferation of CD4+ and CD8+ T cells was severely impaired in HIV/HCV co‐infected patients and liver transplant recipients. Importantly, “only effector” T‐cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores. Therefore, the present results suggest that immune‐based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV‐1 co‐infection and liver transplantation.
Annals of Surgery | 2013
Yves Patrice Le Treut; Emilie Gregoire; Jürgen Klempnauer; Jacques Belghiti; Elisabeth Jouve; Jan Lerut; Denis Castaing; Olivier Soubrane; O. Boillot; Georges Mantion; Kia Homayounfar; Manuel Bustamante; Daniel Azoulay; P. Wolf; Marek Krawczyk; Andreas Pascher; Bertrand Suc; Laurence Chiche; Jorge Ortiz De Urbina; Vladimir Mejzlik; Manuel Pascual; J. Peter A. Lodge; Salvatore Gruttadauria; François Paye; François-René Pruvot; Stefan Thorban; Aksel Foss; René Adam
Objective:The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. Background:LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. Methods:This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1–149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. Results:Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. Conclusions:LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.