Search

Your search keyword '"Gunnar Söderdahl"' showing total 11 results
Start Over Author "Gunnar Söderdahl" Language english
11 results on '"Gunnar Söderdahl"'

1. Real-world assessment of immunogenicity in immunocompromised individuals following SARS-CoV-2 mRNA vaccination: a two-year follow-up of the prospective clinical trial COVAXIDResearch in context

Author

Puran Chen, Peter Bergman, Ola Blennow, Lotta Hansson, Stephan Mielke, Piotr Nowak, Yu Gao, Gunnar Söderdahl, Anders Österborg, C.I.Edvard Smith, Jan Vesterbacka, David Wullimann, Angelica Cuapio, Mira Akber, Gordana Bogdanovic, Sandra Muschiol, Mikael Åberg, Karin Loré, Margaret Sällberg Chen, Per Ljungman, Marcus Buggert, Soo Aleman, and Hans-Gustaf Ljunggren

Subjects
SARS-CoV-2, COVID-19, mRNA vaccine, Clinical study, Primary immunodeficiency disease, HIV, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Immunocompromised patients with primary and secondary immunodeficiencies have shown impaired responses to SARS-CoV-2 mRNA vaccines, necessitating recommendations for additional booster doses. However, longitudinal data reflecting the real-world impact of such recommendations remains limited. Methods: This study represents a two-year follow-up of the COVAXID clinical trial, where 364 of the original 539 subjects consented to participate. 355 individuals provided blood samples for evaluation of binding antibody (Ab) titers and pseudo-neutralisation capacity against both the ancestral SARS-CoV-2 strain and prevalent Omicron variants. T cell responses were assessed in a subset of these individuals. A multivariate analysis determined the correlation between Ab responses and the number of vaccine doses received, documented infection events, immunoglobulin replacement therapy (IGRT), and specific immunosuppressive drugs. The original COVAXID clinical trial was registered in EudraCT (2021-000175-37) and clinicaltrials.gov (NCT04780659). Findings: Several of the patient groups that responded poorly to the initial primary vaccine schedule and early booster doses presented with stronger immunogenicity-related responses including binding Ab titres and pseudo-neutralisation at the 18- and 24-month sampling time point. Responses correlated positively with the number of vaccine doses and infection. The vaccine response was blunted by an immunosuppressive state due to the underlying specific disease and/or to specific immunosuppressive treatment. Interpretation: The study results highlight the importance of continuous SARS-CoV-2 vaccine booster doses in building up and sustaining Ab responses in specific immunocompromised patient populations. Funding: The present studies were supported by the European Research Council, Karolinska Institutet, Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and the Swedish Research Council.

Published
2024
Full Text
View/download PDF

2. Real-world assessment of immunogenicity in immunocompromised individuals following SARS-CoV-2 mRNA vaccination: a one-year follow-up of the prospective clinical trial COVAXIDResearch in context

Author

Puran Chen, Peter Bergman, Ola Blennow, Lotta Hansson, Stephan Mielke, Piotr Nowak, Gunnar Söderdahl, Anders Österborg, C.I. Edvard Smith, Jan Vesterbacka, David Wullimann, Angelica Cuapio, Mira Akber, Gordana Bogdanovic, Sandra Muschiol, Mikael Åberg, Karin Loré, Margaret Sällberg Chen, Marcus Buggert, Per Ljungman, Soo Aleman, and Hans-Gustaf Ljunggren

Subjects
SARS-CoV-2, COVID-19, mRNA vaccine, Clinical study, Primary immunodeficiency disease, HIV, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Immunocompromised patients have varying responses to SARS-CoV-2 mRNA vaccination. However, there is limited information available from prospective clinical trial cohorts with respect to long-term immunogenicity-related responses in these patient groups following three or four vaccine doses, and in applicable cases infection. Methods: In a real-world setting, we assessed the long-term immunogenicity-related responses in patients with primary and secondary immunodeficiencies from the prospective open-label clinical trial COVAXID. The original clinical trial protocol included two vaccine doses given on days 0 and 21, with antibody titres measured at six different timepoints over six months. The study cohort has subsequently been followed for one year with antibody responses evaluated in relation to the third and fourth vaccine dose, and in applicable cases SARS-CoV-2 infection. In total 356/539 patients were included in the extended cohort. Blood samples were analysed for binding antibody titres and neutralisation against the Spike protein for all SARS-CoV-2 variants prevailing during the study period, including Omicron subvariants. SARS-CoV-2 infections that did not require hospital care were recorded through quarterly in-person, or phone-, interviews and assessment of IgG antibody titres against SARS-CoV-2 Nucleocapsid. The original clinical trial was registered in EudraCT (2021-000175-37) and clinicaltrials.gov (NCT04780659). Findings: The third vaccine dose significantly increased Spike IgG titres against all the SARS-CoV-2 variants analysed in all immunocompromised patient groups. Similarly, neutralisation also increased against all variants studied, except for Omicron. Omicron-specific neutralisation, however, increased after a fourth dose as well as after three doses and infection in many of the patient subgroups. Noteworthy, however, while many patient groups mounted strong serological responses after three and four vaccine doses, comparably weak responders were found among patient subgroups with specific primary immunodeficiencies and subgroups with immunosuppressive medication. Interpretation: The study identifies particularly affected patient groups in terms of development of long-term immunity among a larger group of immunocompromised patients. In particular, the results highlight poor vaccine-elicited neutralising responses towards Omicron subvariants in specific subgroups. The results provide additional knowledge of relevance for future vaccination strategies. Funding: The present studies were supported by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and Karolinska Institutet.

Published
2023
Full Text
View/download PDF

3. NK cell frequencies, function and correlates to vaccine outcome in BNT162b2 mRNA anti-SARS-CoV-2 vaccinated healthy and immunocompromised individuals

Author

Angelica Cuapio, Caroline Boulouis, Iva Filipovic, David Wullimann, Tobias Kammann, Tiphaine Parrot, Puran Chen, Mira Akber, Yu Gao, Quirin Hammer, Benedikt Strunz, André Pérez Potti, Olga Rivera Ballesteros, Joshua Lange, Jagadeeswara Rao Muvva, Peter Bergman, Ola Blennow, Lotta Hansson, Stephan Mielke, Piotr Nowak, Gunnar Söderdahl, Anders Österborg, C. I. Edvard Smith, Gordana Bogdanovic, Sandra Muschiol, Fredrika Hellgren, Karin Loré, Michal J. Sobkowiak, Giorgio Gabarrini, Katie Healy, Margaret Sällberg Chen, Evren Alici, Niklas K. Björkström, Marcus Buggert, Per Ljungman, Johan K. Sandberg, Soo Aleman, and Hans-Gustaf Ljunggren

Subjects
Anti-SARS-CoV-2 antibodies, BNT162b2 mRNA vaccine, Clinical trial, COVID-19, NK cells, Innate immunity, Therapeutics. Pharmacology, RM1-950, Biochemistry, QD415-436
Abstract

Abstract Adaptive immune responses have been studied extensively in the course of mRNA vaccination against COVID-19. Considerably fewer studies have assessed the effects on innate immune cells. Here, we characterized NK cells in healthy individuals and immunocompromised patients in the course of an anti-SARS-CoV-2 BNT162b2 mRNA prospective, open-label clinical vaccine trial. See trial registration description in notes. Results revealed preserved NK cell numbers, frequencies, subsets, phenotypes, and function as assessed through consecutive peripheral blood samplings at 0, 10, 21, and 35 days following vaccination. A positive correlation was observed between the frequency of NKG2C+ NK cells at baseline (Day 0) and anti-SARS-CoV-2 Ab titers following BNT162b2 mRNA vaccination at Day 35. The present results provide basic insights in regards to NK cells in the context of mRNA vaccination, and have relevance for future mRNA-based vaccinations against COVID-19, other viral infections, and cancer. Trial registration: The current study is based on clinical material from the COVAXID open-label, non-randomized prospective clinical trial registered at EudraCT and clinicaltrials.gov (no. 2021–000175-37). Description: https://clinicaltrials.gov/ct2/show/NCT04780659?term=2021-000175-37&draw=2&rank=1 .

Published
2022
Full Text
View/download PDF

4. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial

Author

Peter Bergman, MD, Ola Blennow, MD, Lotta Hansson, MD, Stephan Mielke, MD, Piotr Nowak, MD, Puran Chen, MD, Gunnar Söderdahl, MD, Anders Österborg, MD, C. I. Edvard Smith, MD, David Wullimann, MSc, Jan Vesterbacka, MD, Gustaf Lindgren, MD, Lisa Blixt, MD, Gustav Friman, MD, Emilie Wahren-Borgström, MD, Anna Nordlander, MD, Angelica Cuapio Gomez, MD, Mira Akber, MSc, Davide Valentini, MD, Anna-Carin Norlin, MD, Anders Thalme, MD, Gordana Bogdanovic, MD, Sandra Muschiol, PhD, Peter Nilsson, PhD, Sophia Hober, PhD, Karin Loré, PhD, Margaret Sällberg Chen, PhD, Marcus Buggert, PhD, Hans-Gustaf Ljunggren, MD, Per Ljungman, MD, and Soo Aleman, MD

Subjects
mRNA BNT162b2 vaccine, Immunocompromised patients, Primary Immunodeficiency, HIV, human stem-cell transplantation, CAR-T, Medicine, Medicine (General), R5-920
Abstract

Background: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. Methods: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. Findings: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. Interpretation: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity. Funding: Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.

Published
2021
Full Text
View/download PDF

5. Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination

Author

Yu Gao, Curtis Cai, David Wullimann, Julia Niessl, Olga Rivera-Ballesteros, Puran Chen, Joshua Lange, Angelica Cuapio, Ola Blennow, Lotta Hansson, Stephan Mielke, Piotr Nowak, Jan Vesterbacka, Mira Akber, Andre Perez-Potti, Takuya Sekine, Thomas R. Müller, Caroline Boulouis, Tobias Kammann, Tiphaine Parrot, Jagadeeswara Rao Muvva, Michal Sobkowiak, Katie Healy, Gordana Bogdanovic, Sandra Muschiol, Gunnar Söderdahl, Anders Österborg, Fredrika Hellgren, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Karin Loré, Margaret Sällberg Chen, Per Ljungman, Johan K. Sandberg, C.I. Edvard Smith, Peter Bergman, Hans-Gustaf Ljunggren, Soo Aleman, and Marcus Buggert

Subjects
SARS-CoV-2, Vaccination, Immunology, T cells, COVID-19, Immunology in the medical area, Syndrome, CD8-Positive T-Lymphocytes, Antibodies, Viral, Immunity, Humoral, Infectious Diseases, mRNA vaccine, Viral Envelope Proteins, Immunologi inom det medicinska området, Humans, Immunology and Allergy, RNA, Messenger
Abstract

Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4+ and CD8+ T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4+ T cells and robust expansions of oligoclonal effector-memory CD45RA+ CD8+ T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.

Published
2022

6. Salivary IgG to SARS-CoV-2 indicates seroconversion and correlates to serum neutralization in mRNA-vaccinated immunocompromised individuals

Author

Katie Healy, Elisa Pin, Puran Chen, Gunnar Söderdahl, Piotr Nowak, Stephan Mielke, Lotta Hansson, Peter Bergman, C.I. Edvard Smith, Per Ljungman, Davide Valentini, Ola Blennow, Anders Österborg, Giorgio Gabarrini, Khaled Al-Manei, Hassan Alkharaan, Michał Jacek Sobkowiak, Jamil Yousef, Sara Mravinacova, Angelica Cuapio, Xinling Xu, Mira Akber, Karin Loré, Cecilia Hellström, Sandra Muschiol, Gordana Bogdanovic, Marcus Buggert, Hans-Gustaf Ljunggren, Sophia Hober, Peter Nilsson, Soo Aleman, and Margaret Sällberg Chen

Subjects
Infectious Medicine, Translation to patients, Infektionsmedicin, Antibodies, Viral, Immunocompromised Host, antibody, cancer, Humans, Prospective Studies, RNA, Messenger, BNT162 Vaccine, saliva, SARS-CoV-2, COVID-19, HIV, General Medicine, vaccination, Leukemia, Lymphocytic, Chronic, B-Cell, Seroconversion, Immunoglobulin G, Immunoglobulin A, Secretory, Spike Glycoprotein, Coronavirus, Clinical and Translational Article, immunodeficiency, serum, transplantation
Abstract

Background Immunocompromised individuals are highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Whether vaccine-induced immunity in these individuals involves oral cavity, a primary site of infection, is presently unknown. Methods Immunocompromised patients (n = 404) and healthy controls (n = 82) participated in a prospective clinical trial (NCT04780659) encompassing two doses of the mRNA BNT162b2 vaccine. Primary immunodeficiency (PID), secondary immunodeficiencies caused by human immunodeficiency virus (HIV) infection, allogeneic hematopoietic stem cell transplantation (HSCT)/chimeric antigen receptor T cell therapy (CAR-T), solid organ transplantation (SOT), and chronic lymphocytic leukemia (CLL) patients were included. Salivary and serum immunoglobulin G (IgG) reactivities to SARS-CoV-2 spike were measured by multiplex bead-based assays and Elecsys anti-SARS-CoV-2 S assay. Findings IgG responses to SARS-CoV-2 spike antigens in saliva in HIV and HSCT/CAR-T groups were comparable to those of healthy controls after vaccination. The PID, SOT, and CLL patients had weaker responses, influenced mainly by disease parameters or immunosuppressants. Salivary responses correlated remarkably well with specific IgG titers and the neutralizing capacity in serum. Receiver operating characteristic curve analysis for the predictive power of salivary IgG yielded area under the curve (AUC) = 0.95 and positive predictive value (PPV) = 90.7% for the entire cohort after vaccination. Conclusions Saliva conveys vaccine responses induced by mRNA BNT162b2. The predictive power of salivary spike IgG makes it highly suitable for screening vulnerable groups for revaccination. Funding Knut and Alice Wallenberg Foundation, Erling Perssons family foundation, Region Stockholm, Swedish Research Council, Karolinska Institutet, Swedish Blood Cancer Foundation, PID patient organization of Sweden, Nordstjernan AB, Center for Medical Innovation (CIMED), Swedish Medical Research Council, and Stockholm County Council (ALF)., Graphical abstract, Context and significance People with a weakened immune system may respond less well to vaccination and are more vulnerable to infections. This work investigates the predictive value of saliva antibodies in immunocompromised patients. We report that IgG to SARS-CoV-2 spike in saliva correlated remarkably well to that detected in blood after Pfizer mRNA vaccination. Among the immunosuppressive conditions studied, low spike-IgG responses were mainly associated with genetic immune disorders, organ transplantation, chronic lymphatic leukemia, and immunosuppressants, while people living with human immunodeficiency virus or stem cell transplant responded comparably to healthy participants. The clear correlation between anti-spike-IgG in saliva and blood extends to the neutralizing capacity in serum. In conclusion, saliva is suitable and efficient for monitoring vaccine immunity and revaccination., Healy et al. report a clear correlation between salivary and blood IgG to SARS-CoV-2 spike in immunocompromised patients after mRNA vaccination. The specific IgG also correlates to the serum-neutralizing capacity. Their findings indicate that saliva is highly suitable for monitoring vaccine immunity in these extremely vulnerable patients.

Published
2022

7. mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors

Author

Antonio Daniele Pinna, Natalie Filmann, Lionel Rostaing, Jens Brockmann, Michael Heise, Andreas A. Schnitzbauer, Simone I. Strasser, Giorgio Rossi, Silvio Nadalin, Jean Gugenheim, Tom M. Ganten, Umberto Cillo, Norman M. Kneteman, Koert P. de Jong, André Roy, Víctor Sánchez Turrión, Thomas Becker, Christoph Duvoux, Markus Rentsch, Jürgen Klempnauer, Utz Settmacher, George Philippe Pageaux, Christian Klein, Roberto Troisi, Edward K. Geissler, Darius F. Mirza, Gunnar Söderdahl, Peter Neuhaus, Jan Lerut, Hans J. Schlitt, Patrizia Burra, Vincenzo Mazzaferro, Johann Pratschke, T. Scholz, Neville V. Jamieson, Wolf O. Bechstein, James Powel, Thomas Soliman, Heikki Mäkisalo, Magnus Rizell, René Adam, Bart van Hoek, Michele Colledan, Itxarone Bilbao, Philippe Bachellier, Olivier Chazoullières, Sherrie Bhoori, Jaques Pirenne, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, Schnitzbauer, A, Filmann, N, Adam, R, Bachellier, P, Bechstein, W, Becker, T, Bhoori, S, Bilbao, I, Brockmann, J, Burra, P, Chazoullieres, O, Cillo, U, Colledan, M, Duvoux, C, Ganten, T, Gugenheim, J, Heise, M, van Hoek, B, Jamieson, N, de Jong, K, Klein, C, Klempnauer, J, Kneteman, N, Lerut, J, Makisalo, H, Mazzaferro, V, Mirza, D, Nadalin, S, Neuhaus, P, Pageaux, G, Pinna, A, Pirenne, J, Pratschke, J, Powel, J, Rentsch, M, Rizell, M, Rossi, G, Rostaing, L, Roy, A, Scholz, T, Settmacher, U, Soliman, T, Strasser, S, Soderdahl, G, Troisi, R, Turrion, V, Schlitt, H, Geissler, E, Universitätsklinikum Frankfurt, Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Les Hôpitaux Universitaires de Strasbourg (HUS), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, IRCCS Istituto Nazionale dei Tumori [Milano], Vall d'Hebron University Hospital [Barcelona], Universitätsklinikum Münster, Universita degli Studi di Padova, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Azienda Ospedaliera di Padova, Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), UniversitätsKlinikum Heidelberg, Centre Hospitalier Universitaire de Nice (CHU Nice), Leiden University Medical Center (LUMC), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Addenbrooke's Hospital, Cambridge University NHS Trust, University Medical Center Groningen [Groningen] (UMCG), University of Groningen [Groningen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Medizinische Hochschule Hannover (MHH), University of Alberta, Université Catholique de Louvain = Catholic University of Louvain (UCL), Helsinki University Hospital, University Hospitals Birmingham [Birmingham, Royaume-Uni], Queens Elizabeth Hospital [Birmingham], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Policlinico S. Orsola-malpighi, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)-Servizio sanitario regionale Emilia-Romagna, UZLeuven, Royal Infirmary of Edinburgh, Ludwig-Maximilians-Universität München (LMU), Sahlgrenska University Hospital [Gothenburg], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, CHU Grenoble, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Uppsala University Hospital, Universitätsklinikum Jena [Jena], Medizinische Universität Wien = Medical University of Vienna, Royal Prince Alfred Hospital, Karolinska University Hospital [Stockholm], Ghent University Hospital, Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], University Hospital Regensburg, Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Publica, Schnitzbauer, A. A., Filmann, N., Adam, R., Bachellier, P., Bechstein, W. O., Becker, T., Bhoori, S., Bilbao, I., Brockmann, J., Burra, P., Chazoullieres, O., Cillo, U., Colledan, M., Duvoux, C., Ganten, T. M., Gugenheim, J., Heise, M., van Hoek, B., Jamieson, N., de Jong, K. P., Klein, C. G., Klempnauer, J., Kneteman, N., Lerut, J., Makisalo, H., Mazzaferro, V., Mirza, D. F., Nadalin, S., Neuhaus, P., Pageaux, G. -P., Pinna, A. D., Pirenne, J., Pratschke, J., Powel, J., Rentsch, M., Rizell, M., Rossi, G., Rostaing, L., Roy, A., Scholz, T., Settmacher, U., Soliman, T., Strasser, S., Soderdahl, G., Troisi, R., Turrion, V. S., Schlitt, H. J., Geissler, E. K., Università degli Studi di Padova = University of Padua (Unipd), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Herrada, Anthony, Groningen Institute for Organ Transplantation (GIOT), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Male, Oncology, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, medicine.medical_treatment, Medizin, Liver transplantation, MESH: Intention to Treat Analysis, mTOR-inhibition, 0302 clinical medicine, MESH: Liver Neoplasms, Clinical endpoint, MESH: Carcinoma, Hepatocellular, Milan criteria, MESH: Aged, MESH: Middle Aged, Liver Neoplasms, Hazard ratio, Middle Aged, Intention to Treat Analysis, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, multivariate COX regression, Female, 030211 gastroenterology & hepatology, MESH: Immunosuppressive Agents, MESH: Neoplasm Recurrence, Local, Immunosuppressive Agents, medicine.drug, medicine.medical_specialty, MESH: Liver Transplantation, Carcinoma, Hepatocellular, MESH: Survival Rate, AFP, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 03 medical and health sciences, Internal medicine, medicine, Carcinoma, Humans, Survival rate, Aged, Sirolimus, MESH: Humans, business.industry, medicine.disease, digestive system diseases, MESH: Male, Liver Transplantation, Surgery, MESH: Sirolimus, Neoplasm Recurrence, Local, business, MESH: Female
Abstract

OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862. ispartof: ANNALS OF SURGERY vol:272 issue:5 pages:855-862 ispartof: location:United States status: published

Published
2020
Full Text
View/download PDF

8. Liver transplantation in the Nordic countries – An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982–2013

Author

Helena Isoniemi, Styrbjörn Friman, Erik Schrumpf, Marie Larsson, Bjarte Fosby, Bo-Göran Ericzon, Christina Wibeck, Heikki Mäkisalo, Arno Nordin, Tom H. Karlsen, Kristian Bjøro, Susanne Keiding, Pål-Dag Line, Aksel Foss, Allan Rasmussen, Michael Olausson, Stein Foss, Leena Toivonen, Annika Bergquist, Espen Melum, Ina Marie Andersen, Truls Sanengen, Krister Höckerstedt, Greg Nowak, Kirsten Muri Boberg, Gunnar Söderdahl, Mette Gotlieb, Maria Castedal, Henrik Gjertsen, and William Bennet

Subjects
Adult, Male, Reoperation, Alcoholic liver disease, medicine.medical_specialty, organ allocation, Tissue and Organ Procurement, Waiting Lists, end-stage liver disease, medicine.medical_treatment, indication, Milan criteria, Liver transplantation, registry, Scandinavian and Nordic Countries, Primary sclerosing cholangitis, Liver disease, Primary biliary cirrhosis, Biliary atresia, Internal medicine, Medicine, Humans, Registries, Survival rate, Aged, Retrospective Studies, liver transplantation, business.industry, Gastroenterology, Middle Aged, medicine.disease, Liver Transplantation, 3. Good health, Surgery, Intention to Treat Analysis, Survival Rate, outcome, Kidney Failure, Chronic, Original Article, Female, business
Abstract

AIM AND BACKGROUND: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013.MATERIALS AND METHODS: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report.RESULTS: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively.CONCLUSION: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Published
2015
Full Text
View/download PDF

9. Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

Author

Christian Klein, Christophe Duvoux, James J. Powell, Andreas A. Schnitzbauer, Bart van Hoek, Roberto Troisi, Carl Zülke, Johann Hauss, Lionel Rostaing, Itxarone Bilbao, René Adam, J. Gugenheim, Tom M. Ganten, Heiner Wolters, Victor Sanchez Turrion, Fred Fändrich, Koert P. de Jong, Simone I. Strasser, Peter Neuhaus, Silvio Nadalin, Olivier Chazouillères, Christian Graeb, Giorgio Rossi, Michael Heise, Jan Lerut, P. Lamby, André Roy, Karl-Walter Jauch, Gerd Otto, Angela Schlitt, Jens Brockmann, Thomas Becker, Darius F. Mirza, Hans J. Schlitt, Jan Schmidt, Patrizia Burra, Stefan Schreiber, Jürgen Klempnauer, Jacques Pirenne, Ernest Hidalgo, Andrea Proneth, Umberto Cillo, Norman M. Kneteman, Ingrid Mutzbauer, Philippe Wolf, Neville V. Jamieson, Umberto Valente, Philippe Bachellier, Edward K. Geissler, Gunnar Söderdahl, Thomas Soliman, Antonio Daniele Pinna, Sherrie Bhoori, Johann Pratschke, Susanne Beckebaum, Wolf O. Bechstein, Magnus Rizell, T. Scholz, Vincenzo Mazzaferro, Raimund Margreiter, Heikki Mäkisalo, Michele Colledan, Utz Settmacher, Rudolf Steininger, Alfred Königsrainer, Georges-Philippe Pageaux, Markus Rentsch, IV kirurgian klinikka, Clinicum, Department of Surgery, Geissler, E, Schnitzbauer, A, Zulke, C, Lamby, P, Proneth, A, Duvoux, C, Burra, P, Jauch, K, Rentsch, M, Ganten, T, Schmidt, J, Settmacher, U, Heise, M, Rossi, G, Cillo, U, Kneteman, N, Adam, R, van Hoek, B, Bachellier, P, Wolf, P, Rostaing, L, Bechstein, W, Rizell, M, Powell, J, Hidalgo, E, Gugenheim, J, Wolters, H, Brockmann, J, Roy, A, Mutzbauer, I, Schlitt, A, Beckebaum, S, Graeb, C, Nadalin, S, Valente, U, Turrion, V, Jamieson, N, Scholz, T, Colledan, M, Fandrich, F, Becker, T, Soderdahl, G, Chazouilleres, O, Makisalo, H, Pageaux, G, Steininger, R, Soliman, T, de Jong, K, Pirenne, J, Margreiter, R, Pratschke, J, Pinna, A, Hauss, J, Schreiber, S, Strasser, S, Klempnauer, J, Troisi, R, Bhoori, S, Lerut, J, Bilbao, I, Klein, C, Konigsrainer, A, Mirza, D, Otto, G, Mazzaferro, V, Neuhaus, P, Schlitt, H, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Hautepierre [Strasbourg], Service de Néphrologie - Hypertension Artérielle Dialyse - Transplantation, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'hépatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département d'Hépato-Gastroentérologie et de Transplantation Hépatique [CHU Saint-Eloi], Université de Montpellier (UM)-CHU Saint-Eloi, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Groningen Institute for Organ Transplantation (GIOT), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hépato-gastro-entérologie [CHU Saint-Antoine], Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Male, Time Factors, Intention to Treat Analysi, medicine.medical_treatment, Medizin, PROGRESSION, Kaplan-Meier Estimate, Liver transplantation, Gastroenterology, Immunosuppressive Agent, 0302 clinical medicine, EVEROLIMUS, RENAL-CELL CARCINOMA, Risk Factors, Medicine and Health Sciences, Clinical endpoint, Age Factor, Sirolimu, Prospective Studies, IMMUNOSUPPRESSION, TOR Serine-Threonine Kinase, TOR Serine-Threonine Kinases, Hazard ratio, Liver Neoplasms, Age Factors, Immunosuppression, Middle Aged, CANCER, 3. Good health, Intention to Treat Analysis, Europe, RAPAMYCIN INHIBITORS, Treatment Outcome, TARGET, Local, Liver Neoplasm, 030220 oncology & carcinogenesis, Combination, Disease Progression, SURVIVAL, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, Immunosuppressive Agents, medicine.drug, Human, Adult, medicine.medical_specialty, Canada, Carcinoma, Hepatocellular, Time Factor, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Risk Assessment, Disease-Free Survival, 03 medical and health sciences, Young Adult, Drug Therapy, Internal medicine, medicine, Humans, Aged, Australia, Neoplasm Recurrence, Local, Sirolimus, Liver Transplantation, Transplantation, RECURRENCE, METAANALYSIS, Everolimus, Intention-to-treat analysis, business.industry, Risk Factor, Carcinoma, Hepatocellular, 3126 Surgery, anesthesiology, intensive care, radiology, Surgery, Prospective Studie, Neoplasm Recurrence, business
Abstract

International audience; BACKGROUND:We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).METHODS:In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint.RESULTS:Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874).CONCLUSIONS:Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.TRIAL REGISTRATION:ClinicalTrials.gov NCT00355862.

Published
2016
Full Text
View/download PDF

10. A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Author

Johann Hauss, Peter Neuhaus, Gerd Otto, Koert P. de Jong, Jan Schmidt, Jean Gugenheim, Hans J. Schlitt, Justine Rochon, Simone I. Strasser, Victor Sanchez Turrion, Giorgio Rossi, Michele Colledan, Ernest Hidalgo, Itxarone Bilbao, Thomas Becker, Darius F. Mirza, Ingrid Mutzbauer, Jan Lerut, Michael Heise, Karl-Walter Jauch, Edward K Geissler, Neville V. Jamieson, Umberto Valente, Christophe Duvoux, Susanne Beckebaum, Bart van Hoek, Magnus Rizell, Philippe Wolf, Olivier Chazouillères, Christian Graeb, Gunnar Söderdahl, Rudolf Steininger, Andreas A. Schnitzbauer, Wolf O. Bechstein, Jacques Pirenne, Lionel Rostaing, Umberto Cillo, Norman M. Kneteman, T. Scholz, Vincenzo Mazzaferro, Raimund Margreiter, André Roy, P. Lamby, Roberto Troisi, Heikki Mäkisalo, Antonio Daniele Pinna, Georges-Philippe Pageaux, Patrizia Burra, René Adam, Carl Zuelke, Heiner Wolters, Alfred Königsrainer, Fred Fändrich, Schnitzbauer A.A., Zuelke C., Graeb C., Rochon J., Bilbao I., Burra P., de Jong K.P., Duvoux C., Kneteman N.M., Adam R., Bechstein W.O., Becker T., Beckebaum S., Chazouillères O., Cillo U., Colledan M., Fändrich F., Gugenheim J., Hauss J.P., Heise M., Hidalgo E., Jamieson N., Königsrainer A., Lamby P.E., Lerut J.P., Mäkisalo H., Margreiter R., Mazzaferro V., Mutzbauer I., Otto G., Pageaux G.P., Pinna A.D., Pirenne J., Rizell M., Rossi G., Rostaing L., Roy A., Turrion V.S., Schmidt J., Troisi R.I., van Hoek B., Valente U., Wolf P., Wolters H., Mirza D.F., Scholz T., Steininger R., Soderdahl G., Strasser S.I., Jauch K.W., Neuhaus P., Schlitt H.J., Geissler E.K., Schnitzbauer, A, Zuelke, C, Graeb, C, Rochon, J, Bilbao, I, Burra, P, de Jong, K, Duvoux, C, Kneteman, N, Adam, R, Bechstein, W, Becker, T, Beckebaum, S, Chazouilleres, O, Cillo, U, Colledan, M, Fandrich, F, Gugenheim, J, Hauss, J, Heise, M, Hidalgo, E, Jamieson, N, Konigsrainer, A, Lamby, P, Lerut, J, Makisalo, H, Margreiter, R, Mazzaferro, V, Mutzbauer, I, Otto, G, Pageaux, G, Pinna, A, Pirenne, J, Rizell, M, Rossi, G, Rostaing, L, Roy, A, Turrion, V, Schmidt, J, Troisi, R, van Hoek, B, Valente, U, Wolf, P, Wolters, H, Mirza, D, Scholz, T, Steininger, R, Soderdahl, G, Strasser, S, Jauch, K, Neuhaus, P, Schlitt, H, Geissler, E, IV kirurgian klinikka, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service de chirurgie et transplantation abdominale

Subjects
Oncology, Cancer Research, Time Factors, medicine.medical_treatment, Medizin, Intracellular Signaling Peptides and Proteins - antagonists & inhibitors, metabolism, Kaplan-Meier Estimate, 312 Clinical medicine, Protein-Serine-Threonine Kinase, Liver transplantation, THERAPY, Study Protocol, Immunosuppressive Agent, endothelial growth-factor renal-cell carcinoma tumor progression rapamycin cancer cyclosporine efficacy therapy target model, 0302 clinical medicine, RENAL-CELL CARCINOMA, Risk Factors, Recurrence, Surgical oncology, Medicine and Health Sciences, Liver Neoplasms - drug therapy, enzymology, mortality, surgery, Sirolimu, Prospective Studies, TUMOR PROGRESSION, Transplantation, Homologou, education.field_of_study, liver transplantation, TOR Serine-Threonine Kinases, Liver Neoplasms, Intracellular Signaling Peptides and Proteins, Immunosuppression, hepatocellular carcinoma, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, CANCER, 3. Good health, Europe, Multicenter Study, Treatment Outcome, TARGET, sirolimus, Liver Neoplasm, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Randomized Controlled Trial, mTOR, Carcinoma, Hepatocellular - drug therapy, enzymology, mortality, surgery, 030211 gastroenterology & hepatology, Immunosuppressive Agents, RCT, Human, medicine.drug, Canada, medicine.medical_specialty, Carcinoma, Hepatocellular, Time Factor, education, Population, Liver Transplantation - adverse effects, mortality, Protein Serine-Threonine Kinases, lcsh:RC254-282, Disease-Free Survival, 03 medical and health sciences, Internal medicine, Genetics, medicine, Transplantation, Homologous, Humans, Comparative Study, Rapamycin, ddc:610, Protein-Serine-Threonine Kinases - antagonists & inhibitors, metabolism, Kaplan-Meiers Estimate, business.industry, Risk Factor, Australia, Immunosuppressive Agents - therapeutic use, Sirolimus - therapeutic use, EFFICACY, Liver Transplantation, Hepatocellular Carcinoma, Sirolimus, medicine.disease, Surgery, MODEL, Transplantation, Clinical trial, Prospective Studie, Intracellular Signaling Peptides and Protein, ENDOTHELIAL GROWTH-FACTOR, CYCLOSPORINE, RAPAMYCIN, business
Abstract

Background The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods/Design The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. Trial Register Trial registered at http://www.clinicaltrials.gov: NCT00355862 (EudraCT Number: 2005-005362-36)

Published
2010

Catalog

Books, media, physical & digital resources
See catalog results