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3. The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjects: an interventional, randomized, double-blind, parallel-group, placebo-controlled study

Author

Nadja Bredo Rasmussen, Christina Deligianni, Casper Emil Christensen, William Kristian Karlsson, Haidar Muhsen Al-Khazali, Tom Van de Casteele, Charlotte Granhall, Faisal Mohammad Amin, and Messoud Ashina

Subjects
Migraine, Pituitary adenylate cyclase-activating polypeptide, Migraine disorders, Monoclonal antibody, Migraine treatment, Medicine
Abstract

Abstract Background Pituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222—an investigational humanized monoclonal antibody directed against PACAP ligand—would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities. Methods In a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18–45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days’ interval: placebo + saline + saline (n = 5), placebo + PACAP38 + VIP (n = 10), and Lu AG09222 + PACAP38 + VIP (n = 10). The primary outcome measure was area under the curve (AUC) of the change in superficial temporal artery (STA) diameter from 0 to 120 min after start of infusion of PACAP38. The study was conducted at the Danish Headache Center in Copenhagen, Denmark. Results In participants who received Lu AG09222 + PACAP38 infusion, there was a significantly lower STA diameter (mean (SE) [95% CI] AUC ‒35.4 (4.32) [‒44.6, ‒26.3] mm × min; P

Published
2023
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7. Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV

Author

Uffe Klausen, Jacob Handlos Grauslund, Nicolai Grønne Dahlager Jørgensen, Shamaila Munir Ahmad, Merete Jonassen, Stine Emilie Weis-Banke, Evelina Martinenaite, Lone Bredo Pedersen, Thomas Landkildehus Lisle, Anne Ortved Gang, Lisbeth Enggaard, Morten Hansen, Morten Orebo Holmström, Özcan Met, Inge Marie Svane, Carsten Utoft Niemann, Lars Møller Pedersen, and Mads Hald Andersen

Subjects
PD-L1, PD-L2, chronic lymphocytic leukemia (CLL), immunotherapy, cancer vaccine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain (IgHV) are at risk of early disease progression compared to patients with mutated IgHV. As a preventive strategy, we treated 19 previously untreated CLL patients with unmutated IgHV in a phase 1/2 trial (clinicaltrials.gov, NCT03939234) exploring the efficacy and toxicity of a therapeutic cancer vaccine containing peptides derived from programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2), hoping to restore immunological control of the disease. According to the International Workshop on Chronic lymphocytic Leukemia (iwCLL) response criteria, no patients obtained a response; however, during follow-up, one patient had complete normalization of the peripheral lymphocyte count and remained in biochemical remission after a follow-up time of 15 months. At the end of treatment, one patient had progressed, and 17 patients had stable disease. During follow-up with a median time of 23.5 months since inclusion, seven patients had progressed, and eight patients had stable disease. The median time to first treatment (TTFT) from diagnosis was 90.3 months with a median follow-up time of 50.1 months. This apparent favorable outcome in TTFT needs to be investigated in a randomized setting, as our population may have been biased. More than 80% of patients obtained vaccine-specific immune responses, confirming the immunogenicity of the vaccine. The vaccine was generally well tolerated with only grade I–II adverse events. Although there were some signs of clinical effects, the vaccine seems to be insufficient as monotherapy in CLL, possibly due to a high tumor burden. The efficacy of the vaccine should preferably be tested in combination with novel targeted therapies or as a consolidating treatment.

Published
2022
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8. Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Author

Agathangelidis, Andreas, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee C., Sutton, Lesley-Ann, Baliakas, Panagiotis, Scarfò, Lydia, van Gastel, Ellen J., Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, Langlois de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Brazdilova, Kamila, Ritgen, Matthias, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova Francova, Hana, Moysiadis, Theodoros, Veronese, Silvio, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon, Panovska, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagiotis, Costeas, Paul, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, Niemann, Carsten, Campo, Elias, Anagnostopoulos, Achilles, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane, Chiorazzi, Nicholas, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W., Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2021
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9. Searching for Truth, Beauty, and Goodness in Educational Research

Author

Bredo, Eric

Abstract

In this article, the author considers some issues in the educational research community that relate to ethical conduct. The author will not be concerned with surface issues in research ethics, however important, such as whether one has informed consent, but with deeper ways in which educational research can end up reinforcing unethical conduct. [Paper presented at the Values and Leadership Conference (12th, State College, PA, Sept. 27-29, 2007).]

Published
2008

10. Detailed Long-Term Follow-Up of Patients Who Relapsed After the Nordic Mantle Cell Lymphoma Trials: MCL2 and MCL3

Author

Christian Winther Eskelund, Kostas Dimopoulos, Arne Kolstad, Ingrid Glimelius, Riikka Räty, Lise Mette Rahbek Gjerdrum, Kristina Sonnevi, Pär Josefsson, Herman Nilsson-Ehle, Hans H. N. Bentzen, Unn Merete Fagerli, Outi Kuittinen, Jacob Haaber, Carsten Utoft Niemann, Lone Bredo Pedersen, Maria Torp Larsen, Christian Hartmann Geisler, Martin Hutchings, Mats Jerkeman, and Kirsten Grønbæk

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD.

Published
2021
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11. An immunogenic first-in-human immune modulatory vaccine with PD-L1 and PD-L2 peptides is feasible and shows early signs of efficacy in follicular lymphoma

Author

Uffe Klausen, Nicolai Grønne Dahlager Jørgensen, Jacob Handlos Grauslund, Shamaila Munir Ahmad, Anne Ortved Gang, Evelina Martinenaite, Stine Emilie Weis-Banke, Marie Fredslund Breinholt, Guy Wayne Novotny, Julie Westerlin Kjeldsen, Morten Orebo Holmström, Lone Bredo Pedersen, Christian Bjørn Poulsen, Per Boye Hansen, Özcan Met, Inge Marie Svane, Carsten Utoft Niemann, Lars Møller Pedersen, and Mads Hald Andersen

Subjects
pd-l1, pd-l2, immune modulatory vaccine, anti-regulatory t cells, anti-tregs, follicular lymphoma, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Cells in the tumor microenvironment of Follicular lymphoma (FL) express checkpoint molecules such as programmed death ligands 1 and 2 (PD-L1 and PD-L2) and are suppressing anti-tumor immune activity. Stimulation of peripheral blood mononuclear cells (PBMC) with PD-L1 (IO103) or PD-L2 (IO120) peptides can activate specific T cells inducing anti-regulatory functions including cytotoxicity against PD-L1/PD-L2-expressing cells. In this study, we vaccinated eight FL patients with PD-L1 and PD-L2 peptides following treatment with standard chemotherapy. Patients experienced grade 1–2 injection site reaction (5/8) and mild flu-like symptoms (6/8). One patient experienced neutropenia and thrombocytopenia during pseudo-progression. Enzyme-linked immunospot detected vaccine-specific immune responses in PBMC from all patients, predominately toward PD-L1. The circulating immune composition was stable during treatment; however, we observed a reduction regulatory T cells, however, not significant. One patient achieved a complete remission during vaccination and two patients had pseudo-progression followed by long-term disease regression. Further examination of these early signs of clinical efficacy of the dual-epitope vaccine in a larger study is warranted.

Published
2021
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13. The Darwinian Center to the Vision of William James.

Author

Bredo, Eric

Abstract

The essence of William James's vision can sometimes be hard to discover due to emotional volatility and exploratory impulsiveness. On the other hand, beneath James's apparent inconsistency was a constancy of purpose that can be easily underestimated. This paper argues that the center of James's vision lay in an interpretation of Darwinism. By drawing specific connections between James and Darwin, the paper seeks to make James's overall approach clearer and to relate a variety of seemingly disparate themes within it. First the paper explores James's emotional concerns. Next the paper considers Charles Darwin's influence on James' thinking. The paper questions what it means to be "Darwinian," especially when considered philosophically, examining Darwin's accomplishments. According to the paper, Darwin introduced and legitimized a number of intellectual innovations that have become so familiar today that their radical character often goes unrecognized. Contending that pragmatism can be viewed as the generalization of Darwinian philosophy to human social and moral affairs, to see how James used Darwin's ideas, the paper first considers James's work in psychology and then in philosophy. The paper concludes that James tackled the problems facing him by adopting a version of an evolutionary philosophy. (Contains 20 notes and 33 references.) (BT)

Published
1998

14. Passivity and Powerlessness in Educational Thought.

Author

Bredo, Eric

Abstract

Educational thinking in America was once strongly activist. Schools had a part to play in social evolution and were an important factor in social progress. This paper shows how passivity and powerlessness is built into the deepest assumptions of current educational thinking. It provides an overview of modernist theory and postmodern accounts, and asserts that both share pre-Darwinian assumptions. The paper suggests that reform will require a different attitude and way of thinking, one that is more in tune with the post-Darwinian evolutionary assumptions of pragmatist philosophers such as William James. If one adopted a more Darwinian kind of view, as William James did, then one might see humans as busily engaged in trying to create better lives in an uncertain and changing world. Rather than taking things as given, as defined by a set of rules, or assuming that one must rebel against all such rules, people then can use different sets of rules to aid their own adaptation. In short, if theorizing is viewed as a tool for change, people may not be so prone to modern passivity or postmodern powerlessness. (Contains 15 references.) (LMI)

Published
1997

16. Correction: The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjects: an interventional, randomized, double-blind, parallel-group, placebo-controlled study

Author

Rasmussen, Nadja Bredo, primary, Deligianni, Christina, additional, Christensen, Casper Emil, additional, Karlsson, William Kristian, additional, Al-Khazali, Haidar Muhsen, additional, Van de Casteele, Tom, additional, Granhall, Charlotte, additional, Amin, Faisal Mohammad, additional, and Ashina, Messoud, additional

Published
2023
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18. Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years

Author

Kolstad, Arne, Pedersen, Lone Bredo, Eskelund, Christian W., Husby, Simon, Grønbæk, Kirsten, Jerkeman, Mats, Laurell, Anna, Räty, Riikka, Elonen, Erkki, Andersen, Niels Smedegaard, Brown, Peter deNully, Kimby, Eva, Bentzen, Hans, Sundström, Christer, Ehinger, Mats, Karjalainen-Lindsberg, Marja-Liisa, Delabie, Jan, Ralfkiær, Elisabeth, Fagerli, Unn-Merete, Nilsson-Ehle, Herman, Lauritzsen, Grete Fossum, Kuittinen, Outi, Niemann, Carsten, and Geisler, Christian Hartman

Published
2017
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24. Figure S2B from Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes

Author

Xochelli, Aliki, primary, Baliakas, Panagiotis, primary, Kavakiotis, Ioannis, primary, Agathangelidis, Andreas, primary, Sutton, Lesley-Ann, primary, Minga, Eva, primary, Ntoufa, Stavroula, primary, Tausch, Eugen, primary, Yan, Xiao-Jie, primary, Shanafelt, Tait, primary, Plevova, Karla, primary, Boudjogra, Myriam, primary, Rossi, Davide, primary, Davis, Zadie, primary, Navarro, Alba, primary, Sandberg, Yorick, primary, Vojdeman, Fie Juhl, primary, Scarfo, Lydia, primary, Stavroyianni, Niki, primary, Sudarikov, Andrey, primary, Veronese, Silvio, primary, Tzenou, Tatiana, primary, Karan-Djurasevic, Teodora, primary, Catherwood, Mark, primary, Kienle, Dirk, primary, Chatzouli, Maria, primary, Facco, Monica, primary, Bahlo, Jasmin, primary, Pott, Christiane, primary, Pedersen, Lone Bredo, primary, Mansouri, Larry, primary, Smedby, Karin E., primary, Chu, Charles C., primary, Giudicelli, Véronique, primary, Lefranc, Marie-Paule, primary, Panagiotidis, Panagiotis, primary, Juliusson, Gunnar, primary, Anagnostopoulos, Achilles, primary, Vlahavas, Ioannis, primary, Antic, Darko, primary, Trentin, Livio, primary, Montillo, Marco, primary, Niemann, Carsten, primary, Döhner, Hartmut, primary, Langerak, Anton W., primary, Pospisilova, Sarka, primary, Hallek, Michael, primary, Campo, Elias, primary, Chiorazzi, Nicholas, primary, Maglaveras, Nikos, primary, Oscier, David, primary, Gaidano, Gianluca, primary, Jelinek, Diane F., primary, Stilgenbauer, Stephan, primary, Chouvarda, Ioanna, primary, Darzentas, Nikos, primary, Belessi, Chrysoula, primary, Davi, Frederic, primary, Hadzidimitriou, Anastasia, primary, Rosenquist, Richard, primary, Ghia, Paolo, primary, and Stamatopoulos, Kostas, primary

Published
2023
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25. Table S1 from Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes

Author

Xochelli, Aliki, primary, Baliakas, Panagiotis, primary, Kavakiotis, Ioannis, primary, Agathangelidis, Andreas, primary, Sutton, Lesley-Ann, primary, Minga, Eva, primary, Ntoufa, Stavroula, primary, Tausch, Eugen, primary, Yan, Xiao-Jie, primary, Shanafelt, Tait, primary, Plevova, Karla, primary, Boudjogra, Myriam, primary, Rossi, Davide, primary, Davis, Zadie, primary, Navarro, Alba, primary, Sandberg, Yorick, primary, Vojdeman, Fie Juhl, primary, Scarfo, Lydia, primary, Stavroyianni, Niki, primary, Sudarikov, Andrey, primary, Veronese, Silvio, primary, Tzenou, Tatiana, primary, Karan-Djurasevic, Teodora, primary, Catherwood, Mark, primary, Kienle, Dirk, primary, Chatzouli, Maria, primary, Facco, Monica, primary, Bahlo, Jasmin, primary, Pott, Christiane, primary, Pedersen, Lone Bredo, primary, Mansouri, Larry, primary, Smedby, Karin E., primary, Chu, Charles C., primary, Giudicelli, Véronique, primary, Lefranc, Marie-Paule, primary, Panagiotidis, Panagiotis, primary, Juliusson, Gunnar, primary, Anagnostopoulos, Achilles, primary, Vlahavas, Ioannis, primary, Antic, Darko, primary, Trentin, Livio, primary, Montillo, Marco, primary, Niemann, Carsten, primary, Döhner, Hartmut, primary, Langerak, Anton W., primary, Pospisilova, Sarka, primary, Hallek, Michael, primary, Campo, Elias, primary, Chiorazzi, Nicholas, primary, Maglaveras, Nikos, primary, Oscier, David, primary, Gaidano, Gianluca, primary, Jelinek, Diane F., primary, Stilgenbauer, Stephan, primary, Chouvarda, Ioanna, primary, Darzentas, Nikos, primary, Belessi, Chrysoula, primary, Davi, Frederic, primary, Hadzidimitriou, Anastasia, primary, Rosenquist, Richard, primary, Ghia, Paolo, primary, and Stamatopoulos, Kostas, primary

Published
2023
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26. The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjects:an interventional, randomized, double-blind, parallel-group, placebo-controlled study

Author

Rasmussen, Nadja Bredo, Deligianni, Christina, Christensen, Casper Emil, Karlsson, William Kristian, Al-Khazali, Haidar Muhsen, Van de Casteele, Tom, Granhall, Charlotte, Amin, Faisal Mohammad, Ashina, Messoud, Rasmussen, Nadja Bredo, Deligianni, Christina, Christensen, Casper Emil, Karlsson, William Kristian, Al-Khazali, Haidar Muhsen, Van de Casteele, Tom, Granhall, Charlotte, Amin, Faisal Mohammad, and Ashina, Messoud

Abstract

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222—an investigational humanized monoclonal antibody directed against PACAP ligand—would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities. Methods: In a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18–45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days’ interval: placebo + saline + saline (n = 5), placebo + PACAP38 + VIP (n = 10), and Lu AG09222 + PACAP38 + VIP (n = 10). The primary outcome measure was area under the curve (AUC) of the change in superficial temporal artery (STA) diameter from 0 to 120 min after start of infusion of PACAP38. The study was conducted at the Danish Headache Center in Copenhagen, Denmark. Results: In participants who received Lu AG09222 + PACAP38 infusion, there was a significantly lower STA diameter (mean (SE) [95% CI] AUC ‒35.4 (4.32) [‒44.6, ‒26.3] mm × min; P < 0.0001) compared to participants who received placebo + PACAP38 infusion. Secondary and explorative analysis revealed that PACAP38 infusion induced an increase in facial blood flow, heart rate and mild headache, and indicated that these PACAP38-induced responses were inhibited by Lu AG09222. Conclusions: This proof-of-mechanism study demonstrated that Lu AG09222 inhibited PACAP38-induced cephalic vasodilation and increases in heart rate, and reduced concomitant headache. Lu AG09222 may be a potential therapy against migraine and other PACAP-mediated diseases. Trial registration: ClinicalTrials.gov: NCT04976309. Registration date

Published
2023

28. Figure S1 from Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes

Author

Kostas Stamatopoulos, Paolo Ghia, Richard Rosenquist, Anastasia Hadzidimitriou, Frederic Davi, Chrysoula Belessi, Nikos Darzentas, Ioanna Chouvarda, Stephan Stilgenbauer, Diane F. Jelinek, Gianluca Gaidano, David Oscier, Nikos Maglaveras, Nicholas Chiorazzi, Elias Campo, Michael Hallek, Sarka Pospisilova, Anton W. Langerak, Hartmut Döhner, Carsten Niemann, Marco Montillo, Livio Trentin, Darko Antic, Ioannis Vlahavas, Achilles Anagnostopoulos, Gunnar Juliusson, Panagiotis Panagiotidis, Marie-Paule Lefranc, Véronique Giudicelli, Charles C. Chu, Karin E. Smedby, Larry Mansouri, Lone Bredo Pedersen, Christiane Pott, Jasmin Bahlo, Monica Facco, Maria Chatzouli, Dirk Kienle, Mark Catherwood, Teodora Karan-Djurasevic, Tatiana Tzenou, Silvio Veronese, Andrey Sudarikov, Niki Stavroyianni, Lydia Scarfo, Fie Juhl Vojdeman, Yorick Sandberg, Alba Navarro, Zadie Davis, Davide Rossi, Myriam Boudjogra, Karla Plevova, Tait Shanafelt, Xiao-Jie Yan, Eugen Tausch, Stavroula Ntoufa, Eva Minga, Lesley-Ann Sutton, Andreas Agathangelidis, Ioannis Kavakiotis, Panagiotis Baliakas, and Aliki Xochelli

Abstract

Distribution of IGHV4-34 CLL according to IGHV mutational status and subset membership.

Published
2023

29. Data from Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes

Author

Kostas Stamatopoulos, Paolo Ghia, Richard Rosenquist, Anastasia Hadzidimitriou, Frederic Davi, Chrysoula Belessi, Nikos Darzentas, Ioanna Chouvarda, Stephan Stilgenbauer, Diane F. Jelinek, Gianluca Gaidano, David Oscier, Nikos Maglaveras, Nicholas Chiorazzi, Elias Campo, Michael Hallek, Sarka Pospisilova, Anton W. Langerak, Hartmut Döhner, Carsten Niemann, Marco Montillo, Livio Trentin, Darko Antic, Ioannis Vlahavas, Achilles Anagnostopoulos, Gunnar Juliusson, Panagiotis Panagiotidis, Marie-Paule Lefranc, Véronique Giudicelli, Charles C. Chu, Karin E. Smedby, Larry Mansouri, Lone Bredo Pedersen, Christiane Pott, Jasmin Bahlo, Monica Facco, Maria Chatzouli, Dirk Kienle, Mark Catherwood, Teodora Karan-Djurasevic, Tatiana Tzenou, Silvio Veronese, Andrey Sudarikov, Niki Stavroyianni, Lydia Scarfo, Fie Juhl Vojdeman, Yorick Sandberg, Alba Navarro, Zadie Davis, Davide Rossi, Myriam Boudjogra, Karla Plevova, Tait Shanafelt, Xiao-Jie Yan, Eugen Tausch, Stavroula Ntoufa, Eva Minga, Lesley-Ann Sutton, Andreas Agathangelidis, Ioannis Kavakiotis, Panagiotis Baliakas, and Aliki Xochelli

Abstract

Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication.Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34–expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes.Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively).Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Clin Cancer Res; 23(17); 5292–301. ©2017 AACR.

Published
2023

30. Table S1 from Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes

Author

Kostas Stamatopoulos, Paolo Ghia, Richard Rosenquist, Anastasia Hadzidimitriou, Frederic Davi, Chrysoula Belessi, Nikos Darzentas, Ioanna Chouvarda, Stephan Stilgenbauer, Diane F. Jelinek, Gianluca Gaidano, David Oscier, Nikos Maglaveras, Nicholas Chiorazzi, Elias Campo, Michael Hallek, Sarka Pospisilova, Anton W. Langerak, Hartmut Döhner, Carsten Niemann, Marco Montillo, Livio Trentin, Darko Antic, Ioannis Vlahavas, Achilles Anagnostopoulos, Gunnar Juliusson, Panagiotis Panagiotidis, Marie-Paule Lefranc, Véronique Giudicelli, Charles C. Chu, Karin E. Smedby, Larry Mansouri, Lone Bredo Pedersen, Christiane Pott, Jasmin Bahlo, Monica Facco, Maria Chatzouli, Dirk Kienle, Mark Catherwood, Teodora Karan-Djurasevic, Tatiana Tzenou, Silvio Veronese, Andrey Sudarikov, Niki Stavroyianni, Lydia Scarfo, Fie Juhl Vojdeman, Yorick Sandberg, Alba Navarro, Zadie Davis, Davide Rossi, Myriam Boudjogra, Karla Plevova, Tait Shanafelt, Xiao-Jie Yan, Eugen Tausch, Stavroula Ntoufa, Eva Minga, Lesley-Ann Sutton, Andreas Agathangelidis, Ioannis Kavakiotis, Panagiotis Baliakas, and Aliki Xochelli

Abstract

Univariable and multivariable analysis for TTFT within M-CLL.

Published
2023

32. The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjects:an interventional, randomized, double-blind, parallel-group, placebo-controlled study

Author

Nadja Bredo Rasmussen, Christina Deligianni, Casper Emil Christensen, William Kristian Karlsson, Haidar Muhsen Al-Khazali, Tom Van de Casteele, Charlotte Granhall, Faisal Mohammad Amin, and Messoud Ashina

Subjects
Monoclonal antibody, Anesthesiology and Pain Medicine, Migraine disorders, Neurology (clinical), General Medicine, Pituitary adenylate cyclase-activating polypeptide, Migraine treatment, Migraine
Abstract

Background Pituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222—an investigational humanized monoclonal antibody directed against PACAP ligand—would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities. Methods In a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18–45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days’ interval: placebo + saline + saline (n = 5), placebo + PACAP38 + VIP (n = 10), and Lu AG09222 + PACAP38 + VIP (n = 10). The primary outcome measure was area under the curve (AUC) of the change in superficial temporal artery (STA) diameter from 0 to 120 min after start of infusion of PACAP38. The study was conducted at the Danish Headache Center in Copenhagen, Denmark. Results In participants who received Lu AG09222 + PACAP38 infusion, there was a significantly lower STA diameter (mean (SE) [95% CI] AUC ‒35.4 (4.32) [‒44.6, ‒26.3] mm × min; P Conclusions This proof-of-mechanism study demonstrated that Lu AG09222 inhibited PACAP38-induced cephalic vasodilation and increases in heart rate, and reduced concomitant headache. Lu AG09222 may be a potential therapy against migraine and other PACAP-mediated diseases. Trial registration ClinicalTrials.gov: NCT04976309. Registration date: July 19, 2021.

Published
2023

33. Higher-order connections between stereotyped subsets

Author

Andrea Patriarca, Marco Montillo, Niki Stavroyianni, Claudia Haferlach, Lesley-Ann Sutton, Livio Trentin, Franco Fais, Raphael Sandaltzopoulos, Arnon P. Kater, Anton W. Langerak, Marine Armand, Davide Rossi, Diane F. Jelinek, Davide Bagnara, Lydia Scarfò, Andreas Agathangelidis, Krzysztof Giannopoulos, Eugen Tausch, Andrey Sudarikov, Silvio Veronese, Salem H. Alshemmari, B V Biderman, Zadie Davis, Chrysoula Belessi, Lisa Bonello, Achilles Anagnostopoulos, Gerlinde Mitterbauer-Hohendanner, David Oscier, Sofia Kossida, Lone Bredo Pedersen, Paolo Ghia, Csaba Bödör, Christian Brieghel, Andrea Visentin, Véronique Giudicelli, Matthias Ritgen, Panagiotis Panagiotidis, Panagiotis Baliakas, Stephan Stilgenbauer, Ellen J van Gastel, Renee C. Tschumper, Christiane Pott, Frederic Davi, Katerina Gemenetzi, Valentina Guido, Elias Campo, Gianluca Gaidano, Irina Panovska, Sabine Jeromin, Karla Plevová, Kostas Stamatopoulos, Kamila Brázdilová, Maria Karypidou, Alba Navarro, Christof W. Schneider, Theodoros Moysiadis, Larry Mansouri, Darko Antic, Cristina Tresoldi, Constance Baer, Šárka Pospíšilová, Maria Roumelioti, Katrina Vanura, Xiao-Jie Yan, Hana Skuhrová Francová, Richard Rosenquist, Blanca Espinet, Paola Francia di Celle, Monica Facco, Paul Costeas, Michael Hallek, Carsten Utoft Niemann, Teodora Karan-Djurasevic, Manja Meggendorfer, Kirsten Fischer, Aleksandar Dimovski, Letizia Foroni, Marie-Paule Lefranc, Mark Catherwood, Anne de Septenville, Anastasia Chatzidimitriou, Sarah Lawless, Nicholas Chiorazzi, Agathangelidis, Andrea, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie A, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee, Sutton, Lesley A, Baliakas, Panagioti, Scarfò, Lydia, van Gastel, Ellen J, Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Stranska, Kamila, Ritgen, Matthia, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova Francova, Hana, Moysiadis, Theodoro, Veronese, Silvio M, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon P, Panovska-Stavridis, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagioti, Costeas, Paul A, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, Niemann, Carsten Utoft, Campo, Elía, Anagnostopoulos, Achille, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David Graham, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane F, Chiorazzi, Nichola, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, Stamatopoulos, Kostas, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, and Immunology

Subjects
Chronic lymphocytic leukemia, Immunology, B-cell receptor, Immunoglobulin Variable Region, Disease, Computational biology, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, Immunoglobulin, medicine, Humans, Chronic, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Leukemia, Lymphoid Neoplasia, Repertoire, B-Cell, breakpoint cluster region, Cell Biology, Hematology, Gene rearrangement, Somatic Hypermutation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Stereotypy (non-human), Immunoglobulin Heavy Chains, Somatic Hypermutation, Immunoglobulin, 030220 oncology & carcinogenesis, IGHV@
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified.

Published
2021

36. Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV

Author

Klausen, Uffe, primary, Grauslund, Jacob Handlos, additional, Jørgensen, Nicolai Grønne Dahlager, additional, Ahmad, Shamaila Munir, additional, Jonassen, Merete, additional, Weis-Banke, Stine Emilie, additional, Martinenaite, Evelina, additional, Pedersen, Lone Bredo, additional, Lisle, Thomas Landkildehus, additional, Gang, Anne Ortved, additional, Enggaard, Lisbeth, additional, Hansen, Morten, additional, Holmström, Morten Orebo, additional, Met, Özcan, additional, Svane, Inge Marie, additional, Niemann, Carsten Utoft, additional, Pedersen, Lars Møller, additional, and Andersen, Mads Hald, additional

Published
2022
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37. Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study

Author

Baliakas, Panagiotis, Hadzidimitriou, Anastasia, Sutton, Lesley-Ann, Minga, Eva, Agathangelidis, Andreas, Nichelatti, Michele, Tsanousa, Athina, Scarfò, Lydia, Davis, Zadie, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie Juhl, Boudjogra, Myriam, Tzenou, Tatiana, Chatzouli, Maria, Chu, Charles C, Veronese, Silvio, Gardiner, Anne, Mansouri, Larry, Smedby, Karin E, Pedersen, Lone Bredo, van Lom, Kirsten, Giudicelli, Véronique, Francova, Hana Skuhrova, Nguyen-Khac, Florence, Panagiotidis, Panagiotis, Juliusson, Gunnar, Angelis, Lefteris, Anagnostopoulos, Achilles, Lefranc, Marie-Paule, Facco, Monica, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Geisler, Christian H, Langerak, Anton W, Pospisilova, Sarka, Chiorazzi, Nicholas, Oscier, David, Jelinek, Diane F, Darzentas, Nikos, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas

Published
2014
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38. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma

Author

Kolstad, Arne, Laurell, Anna, Jerkeman, Mats, Grønbæk, Kirsten, Elonen, Erkki, Räty, Riikka, Pedersen, Lone Bredo, Loft, Annika, Bogsrud, Trond Velde, Kimby, Eva, Hansen, Per Boye, Fagerli, Unn-Merete, Nilsson-Ehle, Herman, Lauritzsen, Grete Fossum, Lehmann, Anne Kristine, Sundstrom, Christer, Karjalainen-Lindsberg, Marja-Liisa, Ralfkiaer, Elisabeth, Ehinger, Mats, Delabie, Jan, Bentzen, Hans, Schildt, Jukka, Kostova-Aherdan, Kamelia, Frederiksen, Henrik, Brown, Peter de Nully, and Geisler, Christian H.

Published
2014
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