Implementing the EffTox dose-finding design in the Matchpoint trial

Background: The Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial. Methods: EffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes. We describe a nomenclature for succinctly describing outcomes in phase I/II dose-finding trials. We use dose-transition pathways, where doses are calculated for each feasible set of outcomes in future cohorts. We introduce the phenomenon of dose ambivalence, where EffTox can recommend different doses after observing the same outcomes. We also describe our experiences with outcome ambiguity, where the categorical evaluation of some primary outcomes is temporarily delayed. Results: We arrived at an EffTox parameterisation that is simulated to perform well over a range of scenarios. In scenarios where dose ambivalence manifested, we were guided by the dose-transition pathways. This technique facilitates planning, and also helped us overcome short-term outcome ambiguity. Conclusions: EffTox is an efficient and powerful design, but not without its challenges. Joint phase I/II clinical trial designs will likely become increasingly important in coming years as we further investigate non-cytotoxic treatments and streamline the drug approval process. We hope this account of the problems we faced and the solutions we used will help others implement this dose-finding clinical trial design. Trial registration: Matchpoint was added to the European Clinical Trials Database (2012-005629-65) on 2013-12-30

Proceedings from the 8th and 9th Scientific Conference Methodology and Archaeometry

Methodology and Archaeometry (MetArh) is an annual scientific conference organized since 2013 by the Department of Archaeology of the Faculty of Humanities and Social Sciences of the University of Zagreb, and the Croatian Archaeological Society.The goal of the conference is to entice interdisciplinarity, critical thinking, new insights and approaches as well as new theoretical frameworks in contemporary archaeological science. It offers a wider perspective in observing methodology and methodological practices, also challenging traditional approaches in archaeological research, and following the creative adaptation of methods from other disciplines into archaeology. Also, it enables scholars to present their work, engage in discussion and motivate young scholars and archaeology students to pursue contemporary topics and present their research.This edition of the conference Proceedings contains twelve papers from the 8th and 9th MetArh conference which was held at the Faculty of Humanities and Social Sciences of the University of Zagreb. The 8th MetArh conference was held from 3rd – 4th of December 2020, and the 9th from 2nd – 3rd of December 2021 (https://metarh.ffzg.unizg.hr/).Due to COVID-19, both conferences were held on the online platform Hopin.to. It was very challenging to organize and realize the conference in a virtual format but, most importantly, it produced high-quality works some of which are published in this publication. Papers in this volume are focused on different aspects of archaeological methodology and archaeometry, including case studies from Croatia, Slovenia, Serbia and Ukraine.Methodology and Archaeometry (MetArh) is an annual scientific conference organized since 2013 by the Department of Archaeology of the Faculty of Humanities and Social Sciences of the University of Zagreb, and the Croatian Archaeological Society.The goal of the conference is to entice interdisciplinarity, critical thinking, new insights and approaches as well as new theoretical frameworks in contemporary archaeological science. It offers a wider perspective in observing methodology and methodological practices, also challenging traditional approaches in archaeological research, and following the creative adaptation of methods from other disciplines into archaeology. Also, it enables scholars to present their work, engage in discussion and motivate young scholars and archaeology students to pursue contemporary topics and present their research.This edition of the conference Proceedings contains twelve papers from the 8th and 9th MetArh conference which was held at the Faculty of Humanities and Social Sciences of the University of Zagreb. The 8th MetArh conference was held from 3rd – 4th of December 2020, and the 9th from 2nd – 3rd of December 2021 (https://metarh.ffzg.unizg.hr/).Due to COVID-19, both conferences were held on the online platform Hopin.to. It was very challenging to organize and realize the conference in a virtual format but, most importantly, it produced high-quality works some of which are published in this publication. Papers in this volume are focused on different aspects of archaeological methodology and archaeometry, including case studies from Croatia, Slovenia, Serbia and Ukraine

Unique features and clinical importance of acute alloreactive immune responses

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation