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2. Identification of novel genetic loci for risk of multiple myeloma by functional annotation

Author

Macauda, Angelica, Briem, Klara, Clay-Gilmour, Alyssa, Cozen, Wendy, Försti, Asta, Giaccherini, Matteo, Corradi, Chiara, Sainz, Juan, Niazi, Yasmeen, ter Horst, Rob, Li, Yang, Netea, Mihai G., Vogel, Ulla, Hemminki, Kari, Slager, Susan L., Varkonyi, Judit, Andersen, Vibeke, Iskierka-Jazdzewska, Elzbieta, Mártinez-Lopez, Joaquin, Zaucha, Jan, Camp, Nicola J., Rajkumar, S. Vincent, Druzd-Sitek, Agnieszka, Bhatti, Parveen, Chanock, Stephen J., Kumar, Shaji K., Subocz, Edyta, Mazur, Grzegorz, Landi, Stefano, Machiela, Mitchell J., Jerez, Andrés, Norman, Aaron D., Hildebrandt, Michelle A. T., Kadar, Katalin, Berndt, Sonja I., Ziv, Elad, Buda, Gabriele, Nagler, Arnon, Dumontet, Charles, Raźny, Malgorzata, Watek, Marzena, Butrym, Aleksandra, Grzasko, Norbert, Dudzinski, Marek, Rybicka-Ramos, Malwina, Matera, Eva-Laure, García-Sanz, Ramón, Goldschmidt, Hartmut, Jamroziak, Krzysztof, Jurczyszyn, Artur, Clavero, Esther, Giles, Graham G., Pelosini, Matteo, Zawirska, Daria, Kruszewski, Marcin, Marques, Herlander, Haastrup, Eva, Sánchez-Maldonado, José Manuel, Bertsch, Uta, Rymko, Marcin, Raab, Marc-Steffen, Brown, Elizabeth E., Hofmann, Jonathan N., Vachon, Celine, Campa, Daniele, and Canzian, Federico

Published
2023
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3. Level of unique T cell clonotypes is associated with clonal hematopoiesis and survival in patients with lymphoma undergoing ASCT

Author

Husby, Simon, Jørgensen, Gustav Ø., Favero, Francesco, Jespersen, Jakob Schmidt, Rodriguez-Gonzalez, Francisco G., Nielsen, Christian, Sorensen, Betina, Ebbesen, Lene H., Bæch, John, Haastrup, Eva K., Josefsson, Pär, Thorsgaard, Michael, Brown, Peter, El-Galaly, Tarec C., Larsen, Thomas Stauffer, Weischenfeldt, Joachim, and Grønbæk, Kirsten

Published
2022
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4. Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation.

Author

Minculescu, Lia, Reekie, Joanne, Petersen, Soeren Lykke, Kornblit, Brian Thomas, Schjoedt, Ida, Andersen, Niels Smedegaard, Andersen, Lisbeth Pernille, Fischer-Nielsen, Anne, Haastrup, Eva Kannik, Friis, Lone Smidstrup, and Sengelov, Henrik

Subjects
STEM cell transplantation, ACUTE myeloid leukemia, MYELODYSPLASTIC syndromes, OVERALL survival, LYMPHOCYTES
Abstract

Introduction: Donor lymphocyte infusion (DLI) is used to induce remission in patients who relapse after allogeneic stem cell transplantation (allo-HSCT). During the last decade, the hypomethylating agent Azacitidine has been used together with DLI for a synergistic graft-versus-leukemia (GVL) effect. Here, we report results of DLI/Azacitidine treatment from a retrospective single-center study. Methods: Fifty AML/MDS patients treated for relapse after allo-HSCT between 2001 and 2020 with DLI at the Department of Hematology, at Rigshospitalet, Copenhagen University Hospital were included for analyses. A subgroup of patients who obtained complete remission (CR) after reinduction chemotherapy, received DLI in combination with low-dose (32 mg/m2) Azacitidine. Results: Overall survival in all patients after DLI treatment was 59% at 2 years and 20% at 5 years. Relapse-free survival in patients in CR prior to DLI was 32% after 2 years and 7% after 5 years. In the DLI + low-dose-Azacitidine group, 5-year relapse-free survival was 40%. Conclusion: DLI remains an effective treatment in post-transplant relapse leaving one-fifth of patients' long-term survivors. Our results support the concomitant use of low-dose Azacitidine in the future use of DLI in order to enhance the GVL effect of donor lymphocytes. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation

Author

Minculescu, Lia, primary, Reekie, Joanne, additional, Petersen, Soeren Lykke, additional, Kornblit, Brian Thomas, additional, Schjoedt, Ida, additional, Andersen, Niels Smedegaard, additional, Andersen, Lisbeth Pernille, additional, Fischer-Nielsen, Anne, additional, Haastrup, Eva Kannik, additional, Friis, Lone Smidstrup, additional, and Sengelov, Henrik, additional

Published
2023
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6. A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

Author

Dicanio, Marco, Giaccherini, Matteo, Clay-Gilmour, Alyssa, Macauda, Angelica, Sainz, Juan, Machiela, Mitchell J., Rybicka-Ramos, Malwina, Norman, Aaron D., Tyczyńska, Agata, Chanock, Stephen J., Barington, Torben, Kumar, Shaji K., Bhatti, Parveen, Cozen, Wendy, Brown, Elizabeth E., Suska, Anna, Haastrup, Eva K., Orlowski, Robert Z., Dudziński, Marek, Garcia-Sanz, Ramon, Kruszewski, Marcin, Martinez-Lopez, Joaquin, Beider, Katia, Iskierka-Jazdzewska, Elżbieta, Pelosini, Matteo, Berndt, Sonja I., Raźny, Małgorzata, Jamroziak, Krzysztof, Rajkumar, S. Vincent, Jurczyszyn, Artur, Vangsted, Annette Juul, Collado, Pilar Garrido, Vogel, Ulla, Hofmann, Jonathan N., Petrini, Mario, Butrym, Aleksandra, Slager, Susan L., Ziv, Elad, Subocz, Edyta, Giles, Graham G., Andersen, Niels Frost, Mazur, Grzegorz, Watek, Marzena, Lesueur, Fabienne, Hildebrandt, Michelle A.T., Zawirska, Daria, Ebbesen, Lene Hyldahl, Marques, Herlander, Gemignani, Federica, Dumontet, Charles, Várkonyi, Judit, Buda, Gabriele, Nagler, Arnon, Druzd-Sitek, Agnieszka, Wu, Xifeng, Kadar, Katalin, Camp, Nicola J., Grzasko, Norbert, Waller, Rosalie G., Vachon, Celine, Canzian, Federico, Campa, Daniele, Dicanio, Marco, Giaccherini, Matteo, Clay-Gilmour, Alyssa, Macauda, Angelica, Sainz, Juan, Machiela, Mitchell J., Rybicka-Ramos, Malwina, Norman, Aaron D., Tyczyńska, Agata, Chanock, Stephen J., Barington, Torben, Kumar, Shaji K., Bhatti, Parveen, Cozen, Wendy, Brown, Elizabeth E., Suska, Anna, Haastrup, Eva K., Orlowski, Robert Z., Dudziński, Marek, Garcia-Sanz, Ramon, Kruszewski, Marcin, Martinez-Lopez, Joaquin, Beider, Katia, Iskierka-Jazdzewska, Elżbieta, Pelosini, Matteo, Berndt, Sonja I., Raźny, Małgorzata, Jamroziak, Krzysztof, Rajkumar, S. Vincent, Jurczyszyn, Artur, Vangsted, Annette Juul, Collado, Pilar Garrido, Vogel, Ulla, Hofmann, Jonathan N., Petrini, Mario, Butrym, Aleksandra, Slager, Susan L., Ziv, Elad, Subocz, Edyta, Giles, Graham G., Andersen, Niels Frost, Mazur, Grzegorz, Watek, Marzena, Lesueur, Fabienne, Hildebrandt, Michelle A.T., Zawirska, Daria, Ebbesen, Lene Hyldahl, Marques, Herlander, Gemignani, Federica, Dumontet, Charles, Várkonyi, Judit, Buda, Gabriele, Nagler, Arnon, Druzd-Sitek, Agnieszka, Wu, Xifeng, Kadar, Katalin, Camp, Nicola J., Grzasko, Norbert, Waller, Rosalie G., Vachon, Celine, Canzian, Federico, and Campa, Daniele

Abstract

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Published
2023

7. Identification of novel genetic loci for risk of multiple myeloma by functional annotation

Author

European Commission, National Cancer Institute (US), National Institutes of Health (US), Projekt DEAL, Macauda, Angelica, Briem, Klara, Clay-Gilmour, Alyssa, Cozen, Wendy, Försti, Asta, Giaccherini, Matteo, Corradi, Chiara, Sainz, Juan, Niazi, Yasmeen, Ter Horst, Rob, Li, Yang, Netea, Mihai G., Vogel, Ulla, Hemminki, Kari, Slager, Susan L., Varkonyi, Judit, Andersen, Vibeke, Iskierka-Jazdzewska, Elżbieta, Martínez-López, Joaquín, Zaucha, Jan, Camp, Nicola J., Rajkumar, S. Vincent, Druzd-Sitek, Agnieszka, Bhatti, Parveen, Chanock, Stephen J., Kumar, Shaji K., Subocz, Edyta, Mazur, Grzegorz, Landi, Stefano, Machiela, Mitchell J., Jerez, Andrés, Norman, Aaron D., Hildebrandt, Michelle A. T., Kadar, Katalin, Berndt, Sonja I., Ziv, Elad, Buda, Gabriele, Nagler, Arnon, Dumontet, Charles, Raźny, Malgorzata, Watek, Marzena, Butrym, Aleksandra, Grzasko, Norbert, Dudzinski, Marek, Rybicka-Ramos, Malwina, Matera, Eva-Laure, García-Sanz, Ramón, Goldschmidt, Hartmut, Jamroziak, Krzysztof, Jurczyszyn, Artur, Clavero, Esther, Giles, Graham G., Pelosini, Matteo, Zawirska, Daria, Kruszewski, Marcin, Marques, Herlander, Haastrup, Eva, Sánchez Maldonado, José Manuel, Bertsch, Uta, Rymko, Marcin, Raab, Marc-Steffen, Brown, Elizabeth E., Hofmann, Jonathan N., Vachon, Celine, Campa, Daniele, Canzian, Federico, European Commission, National Cancer Institute (US), National Institutes of Health (US), Projekt DEAL, Macauda, Angelica, Briem, Klara, Clay-Gilmour, Alyssa, Cozen, Wendy, Försti, Asta, Giaccherini, Matteo, Corradi, Chiara, Sainz, Juan, Niazi, Yasmeen, Ter Horst, Rob, Li, Yang, Netea, Mihai G., Vogel, Ulla, Hemminki, Kari, Slager, Susan L., Varkonyi, Judit, Andersen, Vibeke, Iskierka-Jazdzewska, Elżbieta, Martínez-López, Joaquín, Zaucha, Jan, Camp, Nicola J., Rajkumar, S. Vincent, Druzd-Sitek, Agnieszka, Bhatti, Parveen, Chanock, Stephen J., Kumar, Shaji K., Subocz, Edyta, Mazur, Grzegorz, Landi, Stefano, Machiela, Mitchell J., Jerez, Andrés, Norman, Aaron D., Hildebrandt, Michelle A. T., Kadar, Katalin, Berndt, Sonja I., Ziv, Elad, Buda, Gabriele, Nagler, Arnon, Dumontet, Charles, Raźny, Malgorzata, Watek, Marzena, Butrym, Aleksandra, Grzasko, Norbert, Dudzinski, Marek, Rybicka-Ramos, Malwina, Matera, Eva-Laure, García-Sanz, Ramón, Goldschmidt, Hartmut, Jamroziak, Krzysztof, Jurczyszyn, Artur, Clavero, Esther, Giles, Graham G., Pelosini, Matteo, Zawirska, Daria, Kruszewski, Marcin, Marques, Herlander, Haastrup, Eva, Sánchez Maldonado, José Manuel, Bertsch, Uta, Rymko, Marcin, Raab, Marc-Steffen, Brown, Elizabeth E., Hofmann, Jonathan N., Vachon, Celine, Campa, Daniele, and Canzian, Federico

Abstract

Multiple myeloma (MM) is one of the most common hematological malignancies, accounting for 20% of all newly diagnosed hematological cancers [1]. The most recent data from Cancer Today show that in 2020 the number of new MM cases was 176,404 worldwide

Published
2023

8. A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

Author

Università di Pisa, German Cancer Research Center, Dicanio, Marco, Giaccherini, Matteo, Clay-Gilmour, Alyssa, Macauda, Angelica, Sainz, Juan, Machiela, Mitchell J., Rybicka-Ramos, Malwina, Norman, Aaron D., Tyczyńska, Agata, Chanock, Stephen J., Barington, Torben, Kumar, Shaji K., Bhatti, Parveen, Cozen, Wendy, Brown, Elizabeth E., Suska, Anna, Haastrup, Eva K., Orlowski, R. Z., Dudziński, Marek, García-Sanz, Ramón, Kruszewski, Marcin, Martínez-López, Joaquín, Beider, Katia, Iskierka-Jazdzewska, Elżbieta, Pelosini, Matteo, Berndt, Sonja, Raźny, Małgorzata, Jamroziak, Krzysztof, Rajkumar, S. Vincent, Jurczyszyn, Artur, Vangsted, Annette Juul, Garrido, Pilar, Vogel, Ulla, Hofmann, Jonathan N., Petrini, Mario, Butrym, Aleksandra, Slager, Susan L., Ziv, Elad, Subocz, Edyta, Giles, Graham G., Frost Andersen, Niels, Mazur, Grzegorz, Watek, Marzena, Lesueur, Fabienne, Hildebrandt, Michelle A. T., Zawirska, Daria, Hyldahl Ebbesen, Lene, Marques, Herlander, Gemignani, Federica, Dumontet, Charles, Várkonyi, Judit, Buda, Gabriele, Nagler, Arnon, Druzd-Sitek, Agnieszka, Wu, Xifeng, Kadar, Katalin, Camp, Nicola J., Grzasko, Norbert, Waller, Rosalie G., Vachon, Celine, Canzian, Federico, Campa, Daniele, Università di Pisa, German Cancer Research Center, Dicanio, Marco, Giaccherini, Matteo, Clay-Gilmour, Alyssa, Macauda, Angelica, Sainz, Juan, Machiela, Mitchell J., Rybicka-Ramos, Malwina, Norman, Aaron D., Tyczyńska, Agata, Chanock, Stephen J., Barington, Torben, Kumar, Shaji K., Bhatti, Parveen, Cozen, Wendy, Brown, Elizabeth E., Suska, Anna, Haastrup, Eva K., Orlowski, R. Z., Dudziński, Marek, García-Sanz, Ramón, Kruszewski, Marcin, Martínez-López, Joaquín, Beider, Katia, Iskierka-Jazdzewska, Elżbieta, Pelosini, Matteo, Berndt, Sonja, Raźny, Małgorzata, Jamroziak, Krzysztof, Rajkumar, S. Vincent, Jurczyszyn, Artur, Vangsted, Annette Juul, Garrido, Pilar, Vogel, Ulla, Hofmann, Jonathan N., Petrini, Mario, Butrym, Aleksandra, Slager, Susan L., Ziv, Elad, Subocz, Edyta, Giles, Graham G., Frost Andersen, Niels, Mazur, Grzegorz, Watek, Marzena, Lesueur, Fabienne, Hildebrandt, Michelle A. T., Zawirska, Daria, Hyldahl Ebbesen, Lene, Marques, Herlander, Gemignani, Federica, Dumontet, Charles, Várkonyi, Judit, Buda, Gabriele, Nagler, Arnon, Druzd-Sitek, Agnieszka, Wu, Xifeng, Kadar, Katalin, Camp, Nicola J., Grzasko, Norbert, Waller, Rosalie G., Vachon, Celine, Canzian, Federico, and Campa, Daniele

Abstract

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Published
2023

9. Efficacy of mesenchymal stem cell-delivery using perpendicular multi-needle injections to the skin:Evaluation of post-ejection cellular health and dermal delivery

Author

Rangatchew, Filip, Rasmussen, Bo Sonnich, Svalgaard, Jesper Dyrendom, Haastrup, Eva, Talman, Maj Lis M., Bonde, Christian, Fischer-Nielsen, Anne, Drzewiecki, Krzysztof T., Holmgaard, Rikke, Munthe-Fog, Lea, Rangatchew, Filip, Rasmussen, Bo Sonnich, Svalgaard, Jesper Dyrendom, Haastrup, Eva, Talman, Maj Lis M., Bonde, Christian, Fischer-Nielsen, Anne, Drzewiecki, Krzysztof T., Holmgaard, Rikke, and Munthe-Fog, Lea

Abstract

Aim: Mesenchymal stem cell (MSC)-therapy is increasingly being evaluated in clinical trials. Dermal delivery is not only time consuming but also unreliable, potentially hampering the therapeutic result. Therefore, qualification of cell delivery protocols is essential. This study evaluated a clinically relevant automated multi-needle injection method for cutaneous MSC-therapy, allowing the skin to be readily and timely treated, by assessing both the cellular health post-ejection and dermal delivery. Methods: Following dispensation through the injector (31 G needles: 9- or 5-pin) the cellular health and potency (perceived- and long-term (12 h) viability, recovery, metabolism, adherence, proliferation and IDO1-expression) of adipose-derived stem cells (10–20–50 ×106 cells/ml) were assessed in vitro in addition to dermal delivery of solution in human skin. Results: No significant detrimental effect on the perceived cell viability, recovery, metabolism, adherence or IDO1-expression of either cell concentration was observed. However, the overall long-term viability and proliferation decreased significantly regardless of cell concentration, nonetheless marginally. An injection depth above 1.0 mm resulted in all needles piercing the skin with dermal delivery from up to 89% needles and minimal reflux to the skin surface, and the results were confirmed by ultrasound and histology. Conclusion: The automated injector is capable of delivering dermal cell-doses with an acceptable cell quality.

Published
2023

10. A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

Author

Dicanio, Marco, primary, Giaccherini, Matteo, additional, Clay‐Gilmour, Alyssa, additional, Macauda, Angelica, additional, Sainz, Juan, additional, Machiela, Mitchell J., additional, Rybicka‐Ramos, Malwina, additional, Norman, Aaron D., additional, Tyczyńska, Agata, additional, Chanock, Stephen J., additional, Barington, Torben, additional, Kumar, Shaji K., additional, Bhatti, Parveen, additional, Cozen, Wendy, additional, Brown, Elizabeth E., additional, Suska, Anna, additional, Haastrup, Eva K., additional, Orlowski, Robert Z., additional, Dudziński, Marek, additional, Garcia‐Sanz, Ramon, additional, Kruszewski, Marcin, additional, Martinez‐Lopez, Joaquin, additional, Beider, Katia, additional, Iskierka‐Jazdzewska, Elżbieta, additional, Pelosini, Matteo, additional, Berndt, Sonja I., additional, Raźny, Małgorzata, additional, Jamroziak, Krzysztof, additional, Rajkumar, S. Vincent, additional, Jurczyszyn, Artur, additional, Vangsted, Annette Juul, additional, Collado, Pilar Garrido, additional, Vogel, Ulla, additional, Hofmann, Jonathan N., additional, Petrini, Mario, additional, Butrym, Aleksandra, additional, Slager, Susan L., additional, Ziv, Elad, additional, Subocz, Edyta, additional, Giles, Graham G., additional, Andersen, Niels Frost, additional, Mazur, Grzegorz, additional, Watek, Marzena, additional, Lesueur, Fabienne, additional, Hildebrandt, Michelle A. T., additional, Zawirska, Daria, additional, Ebbesen, Lene Hyldahl, additional, Marques, Herlander, additional, Gemignani, Federica, additional, Dumontet, Charles, additional, Várkonyi, Judit, additional, Buda, Gabriele, additional, Nagler, Arnon, additional, Druzd‐Sitek, Agnieszka, additional, Wu, Xifeng, additional, Kadar, Katalin, additional, Camp, Nicola J., additional, Grzasko, Norbert, additional, Waller, Rosalie G., additional, Vachon, Celine, additional, Canzian, Federico, additional, and Campa, Daniele, additional

Published
2022
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12. Intraglandular Off-the-Shelf Allogeneic Mesenchymal Stem Cell Treatment in Patients with Radiation-Induced Xerostomia:A Safety Study (MESRIX-II)

Author

Lynggaard, Charlotte Duch, Grønhøj, Christian, Christensen, Robin, Fischer-Nielsen, Anne, Melchiors, Jacob, Specht, Lena, Andersen, Elo, Mortensen, Jann, Oturai, Peter, Barfod, Gry Hoffmann, Haastrup, Eva Kannik, Møller-Hansen, Michael, Haack-Sørensen, Mandana, Ekblond, Annette, Kastrup, Jens, Jensen, Siri Beier, von Buchwald, Christian, Lynggaard, Charlotte Duch, Grønhøj, Christian, Christensen, Robin, Fischer-Nielsen, Anne, Melchiors, Jacob, Specht, Lena, Andersen, Elo, Mortensen, Jann, Oturai, Peter, Barfod, Gry Hoffmann, Haastrup, Eva Kannik, Møller-Hansen, Michael, Haack-Sørensen, Mandana, Ekblond, Annette, Kastrup, Jens, Jensen, Siri Beier, and von Buchwald, Christian

Abstract

No effective therapy exists for the most common long-term side effect of radiation therapy for head and neck cancer (HNC)-xerostomia. The objective was to evaluate safety and provide proof of concept for efficacy of allogeneic adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs) injected into the major salivary glands of irradiated patients. This open-label, first-in-human, phase 1b, and single-center trial was conducted with repeated measurements days 0, 1, 5, and 30 and 4 months. Eligible patients with objective and subjective signs of radiation-induced salivary gland damage after treatment of oropharyngeal squamous cell carcinoma stages I-II (UICC 8) were enrolled. Twenty-five million cryopreserved AT-MSCs were injected into each submandibular and 50 million AT-MSCs into each parotid gland. Data were collected on adverse events, unstimulated and stimulated whole saliva (UWS and SWS) flow rates and saliva composition, patient-reported outcomes (EORTC QLQ-H&N35 and Xerostomia Questionnaire [XQ]), blood samples and salivary gland scintigraphy. Data were analyzed using repeated measures linear mixed models. Ten patients (7 men, 3 women, 59.5 years [range: 45-70]) were treated in 4 glands. No treatment-related serious adverse events occurred. During 4 months, UWS flow rate increased from 0.13 mL/minute at baseline to 0.18 mL/minute with a change of 0.06 (P = .0009) mL/minute. SWS flow rate increased from 0.66 mL/minute at baseline to 0.75 mL/minute with a change of 0.09 (P = .017) mL/minute. XQ summary score decreased by 22.6 units (P = .0004), EORTC QLQ-H&N35 dry mouth domains decreased by 26.7 (P = .0013), sticky saliva 23.3 (P = .0015), and swallowing 10.0 (P = .0016). Our trial suggests treatment of the major salivary glands with allogenic AT-MSCs is safe, warranting confirmation in larger trials.

Published
2022

13. Intraglandular Off-the-Shelf Allogeneic Mesenchymal Stem Cell Treatment in Patients with Radiation-Induced Xerostomia: A Safety Study (MESRIX-II)

Author

Lynggaard, Charlotte Duch, primary, Grønhøj, Christian, additional, Christensen, Robin, additional, Fischer-Nielsen, Anne, additional, Melchiors, Jacob, additional, Specht, Lena, additional, Andersen, Elo, additional, Mortensen, Jann, additional, Oturai, Peter, additional, Barfod, Gry Hoffmann, additional, Haastrup, Eva Kannik, additional, Møller-Hansen, Michael, additional, Haack-Sørensen, Mandana, additional, Ekblond, Annette, additional, Kastrup, Jens, additional, Jensen, Siri Beier, additional, and von Buchwald, Christian, additional

Published
2022
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14. Efficacy of mesenchymal stem cell-delivery using perpendicular multi-needle injections to the skin: evaluation of post-ejection cellular health and dermal delivery

Author

Rangatchew, Filip, primary, Rasmussen, Bo Sonnich, additional, Svalgaard, Jesper Dyrendom, additional, Haastrup, Eva, additional, Talman, Maj-Lis M., additional, Bonde, Christian, additional, Fischer-Nielsen, Anne, additional, Drzewiecki, Krzysztof T., additional, Holmgaard, Rikke, additional, and Munthe-Fog, Lea, additional

Published
2022
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15. Efficacy of mesenchymal stem cell-delivery using perpendicular multi-needle injections to the skin: Evaluation of post-ejection cellular health and dermal delivery.

Author

Rangatchew, Filip, Rasmussen, Bo Sonnich, Svalgaard, Jesper Dyrendom, Haastrup, Eva, Talman, Maj-Lis M., Bonde, Christian, Fischer-Nielsen, Anne, Drzewiecki, Krzysztof T., Holmgaard, Rikke, and Munthe-Fog, Lea

Subjects
*SKIN regeneration, *MESENCHYMAL stem cells, *INJECTIONS, *CELL survival, *STEM cells
Abstract

Mesenchymal stem cell (MSC)-therapy is increasingly being evaluated in clinical trials. Dermal delivery is not only time consuming but also unreliable, potentially hampering the therapeutic result. Therefore, qualification of cell delivery protocols is essential. This study evaluated a clinically relevant automated multi-needle injection method for cutaneous MSC-therapy, allowing the skin to be readily and timely treated, by assessing both the cellular health post-ejection and dermal delivery. Following dispensation through the injector (31 G needles: 9- or 5-pin) the cellular health and potency (perceived- and long-term (12 h) viability, recovery, metabolism, adherence, proliferation and IDO1-expression) of adipose-derived stem cells (10–20–50 ×106 cells/ml) were assessed in vitro in addition to dermal delivery of solution in human skin. No significant detrimental effect on the perceived cell viability, recovery, metabolism, adherence or IDO1-expression of either cell concentration was observed. However, the overall long-term viability and proliferation decreased significantly regardless of cell concentration, nonetheless marginally. An injection depth above 1.0 mm resulted in all needles piercing the skin with dermal delivery from up to 89% needles and minimal reflux to the skin surface, and the results were confirmed by ultrasound and histology. The automated injector is capable of delivering dermal cell-doses with an acceptable cell quality. • Qualification of cell delivery protocols is crucial to ensure reproducible therapies. • The study validates a clinically relevant injection method for cutaneous MSC-therapy. • The method reliably delivers dermal doses with an acceptable cell viability. • The method allows for the skin to be readily treated with MSC in a timely manner. [ABSTRACT FROM AUTHOR]

Published
2023
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16. A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

Author

Dicanio M, Giaccherini M, Clay-Gilmour A, Macauda A, Sainz J, Machiela MJ, Rybicka-Ramos M, Norman AD, Tyczyńska A, Chanock SJ, Barington T, Kumar SK, Bhatti P, Cozen W, Brown EE, Suska A, Haastrup EK, Orlowski RZ, Dudziński M, Garcia-Sanz R, Kruszewski M, Martinez-Lopez J, Beider K, Iskierka-Jazdzewska E, Pelosini M, Berndt SI, Raźny M, Jamroziak K, Rajkumar SV, Jurczyszyn A, Vangsted AJ, Collado PG, Vogel U, Hofmann JN, Petrini M, Butrym A, Slager SL, Ziv E, Subocz E, Giles GG, Andersen NF, Mazur G, Watek M, Lesueur F, Hildebrandt MAT, Zawirska D, Ebbesen LH, Marques H, Gemignani F, Dumontet C, Várkonyi J, Buda G, Nagler A, Druzd-Sitek A, Wu X, Kadar K, Camp NJ, Grzasko N, Waller RG, Vachon C, Canzian F, and Campa D

Subjects
Humans, Oncogenes, Alleles, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Predisposition to Disease, HSP40 Heat-Shock Proteins genetics, DNA-Binding Proteins genetics, RNA-Binding Proteins, Multiple Myeloma epidemiology, Multiple Myeloma genetics
Abstract

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10 -8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10 -7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Published
2023
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