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Introduction: Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. Methods: We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. Results: cGVHD incidence among patients surviving >= 6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving >= 6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. Conclusion: cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT.

Predictive modeling has the potential to improve risk stratification of cancer patients and thereby contribute to optimized treatment strategies and better outcomes for patients in clinical practice. To develop robust predictive models for decision-making in healthcare, sensitive patient-level data is often required when developing the training models. Consequently, data privacy is an important aspect to consider when building these predictive models and in subsequent communication of the results. In this study we have used Graph Neural Networks for survival prediction, and compared the accuracy to state-of-the-art prediction models after applying Differential Privacy and k-Anonymity, i.e. two privacy-preservation solutions. By using two different data sources we demonstrated that Graph Neural Networks and Survival Forests are the two most well-performing survival prediction methods when used in combination with privacy preservation solutions. Furthermore, when the predictive model was built using clinical expertise in the specific area of interest, the prediction accuracy of the proposed knowledge based graph model drops by at most 10% when used with privacy preservation solutions. Our proposed knowledge based graph is therefore more suitable to be used in combination with privacy preservation solutions as compared to other graph models., Part of proceedings: ISBN 978-1-6654-3902-2QC 20220707

Outcomes for patients with multiple myeloma (MM) have improved with the advent of novel therapies, however, real-world evidence of outcomes in clinical practice is scarce. We conducted a multi-center registry study to build a reliable picture of treatment and patient outcomes in Finland. The aim of this study was also to understand any methodological challenges in assessing treatment outcomes using disease registry data. Methods: We carried out a retrospective, observational study using data from the national Finnish Hematology Registry (FHR) to provide real-world evidence of outcomes for all adult patients diagnosed with and treated for MM between 2009-2013 at one of the six regional hospitals, with at least six months of recorded follow-up. Patients were identified within the FHR by applying eligibility criteria of a diagnosis of MM and verifiable records of medical treatment and lines of treatment during the study period. Patients receiving allogenic stem cell transplantation were excluded from the cohort, as were individuals who only had monoclonal gammopathy of undetermined significance diagnosis and patients who had not initiated treatment during this period. Kaplan Meier curves were used to calculate overall survival and time to next treatment. Stratification was carried out by drug status (conventional/novel) and by autologous stem cell transplant (ASCT) status. Results: A total of 321 patients met the inclusion criteria and were included in this study. Overall survival (OS) was longest in patients who received first-line novel therapy and ASCT (median not reached during 60-month follow-up) versus 46.2 months for novel first-line therapy without ASCT and 25.6 months for first-line conventional therapy without ASCT. Similarly, median time to next treatment were 33.9 months, 12.6 months and 7.8 months, respectively. Conclusions: The adoption of novel treatments in MM in Finland has had substantial impact on patient outcomes. Given the reality of complex treatm

Dendritic cells (DCs) involved in proinflammatory immune responses derive mainly from peripheral monocytes, and the cells subsequently mature and migrate into the inflammatory micromilieu. Here we report that suppressing of 15-lipoxygenase-1 led to a substantial reduction in DC spreading and podosome formation in vitro. The surface expression of CD83 was significantly lower in both sh-15-lipoxygenase-1 (15-LOX-1)-transduced cells and DCs cultivated in the presence of a novel specific 15-LOX-1 inhibitor. The T-cell response against tetanus-pulsed DCs was only affected to a minor extent on inhibition of 15-LOX-1. In contrast, endocytosis and migration ability of DCs were significantly suppressed on 15-LOX-1 inhibition. The expression of 15-LOX-1 in DCs was also demonstrated in affected human skin in atopic and contact dermatitis, showing that the enzyme is indeed expressed in inflammatory diseases in vivo. This study demonstrated that inhibiting 15-LOX-1 led to an impaired podosome formation in DCs, and consequently suppressed antigen uptake and migration capacity. These results indicated that 15-LOX-1 is a potential target for inhibiting the trafficking of DCs to lymphoid organs and inflamed tissues and decreasing the inflammatory response attenuating symptoms of certain immunologic and inflammatory disorders such as dermatitis.-Han, H., Liang, X., Ekberg, M., Kritikou, J. S., Brunnstro " m, angstrom., Pelcman, B., Matl, M., Miao, X., Andersson, M., Yuan, X., Schain, F., Parvin, S., Melin, E., Sjoberg, J., Xu, D., Westerberg, L. S., Bjorkholm, M., Claesson, H.- E. Human 15-lipoxygenase- 1 is a regulator of dendritic-cell spreading and podosome formation.

Classical Hodgkin lymphoma (cHL) is a malignant disorder with striking inflammatory features. Since cysteinyl leukotrienes (cysLTs) are potent inflammatory mediators it was of interest to study their potential role in the pathogenesis of cHL. We have shown that certain HL cell lines express functional CysLT1 receptors, responding with a robust calcium signal upon leukotriene (LT) D4 challenge. Stimulation of these cells with LTD4 induced a CysLT1 receptor-dependent release of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha. The malignant Hodgkin Reed-Sternberg (H-RS) cells in the majority of the primary cHL biopsies under study also expressed the CysLT1 receptor. Since these cells are surrounded by cysLT-producing eosinophils, macrophages and mast cells, our results suggest that the cysLTs might be of importance for the pathogenesis of cHL (paper I). The cHL cell line L1236 has high expression of 15-lipoxygenase-1 (15-LO-1) and these cells were able to convert arachidonic acid to eoxin (EX) C4, EXD4 and EXE4, pro-inflammatory metabolites recently discovered in human eosinophils and mast cells. Immunohistochemical studies of cHL tumor tissue demonstrated that 15-LO-1 was expressed in primary H-RS cells in the majority of the investigated biopsies. Thus, the expression of 15-LO-1 and the formation of eoxins by H-RS cells are likely to contribute to the inflammatory features of cHL. These findings may have important diagnostic and therapeutic implications (paper II). The expression of the CysLT1 receptor and 15-LO-1 was also elucidated in non-Hodgkin lymphomas (NHLs). The majority of the primary mediastinal B cell lymphomas under study, in contrast to other NHLs, expressed the CysLT1 receptor. Furthermore, T cell-derived anaplastic large cell lymphoma was the only NHL entity shown to express 15-LO-1. Thus, the CysLT1 receptor and 15-LO-1 are potential targets in lymphoma diagnostics and sub-classification (paper III). Finally, we have studied the post-tr

Classical Hodgkin Lymphoma (cHL) is histologically characterized by a minority of malignant cells, the so-called Hodgkin-Reed Sternberg (H-RS) cells, surrounded by inflammatory cells such as T lymphocytes, eosinophils, macrophages and mast cells. It is generally believed that various molecules released by the H-RS cells are of major importance in the pathophysiology of cHL. In paper I, we report a link between inflammatory cell-derived arachidonic acid metabolites, the cysteinyl leukotrienes (CysLT), to tumor cell growth and function in this disease entity. Two HL cell lines, L 1236 and KMH2, were shown to express functional CysLT, receptors, responding with a robust calcium signal upon challenge with LTD4. Incubation of L1236 cells with LTD4 not only stimulated DNA synthesis but also the transcription and protein release of tumor necrosis factor-á, interleukin-6 and -8. Importantly, all these LTD4-induced effects were blocked by the CysLT1, receptor-specific antagonist zafirlukast. Immunohistochemical studies of classical HL biopsies and microarray analysis of laser captured cells revealed that the CysLT1, receptor is expressed also by the Hodgkin Reed-Stemberg cells ex vivo. Since these cells are surrounded by CysLT-producing eosinophils, macrophages and mast cells, our results suggest the CysLTs as novel mediators in the pathogenesis of classical HL by contributing to the growth and the cytokine features of this tumor. Lipoxygenases are highly regulated enzymes that catalyze the introduction of molecular oxygen in polyunsaturated fatty acids. The lipoxygenases are classified with respect to their positional selectivity of the substrate arachidonic acid. 15-lipoxygenase- 1 (15-LO-1), an enzyme implicated in several pathophysiological conditions, possesses the ability to oxygenate free fatty acids and fatty acids bound to membrane phospholipids. The regulation of the enzymatic activity of membrane associated 15- LO-1 is poorly understood. In paper II we demonstrate