Prädiktive Relevanz regulatorischer T-Zellsubpopulationen nach Stimulation mit dendritischen Zellen leukämischer Abstammung für die antileukämische T-Zellantwort

Regulatory T-cells (Treg) are important regulators of immune responses. In AML patients before/after immunotherapy (stem-cell-transplantation (SZT) or donor-lymphocyte-infusion (DLI)) their suppressive role can contribute to suppress severe graft-versus-host-reactions (GVHD), but also to impair antileukemic reactions. Aim: Since leukemia-derived dendritic-cells (DCleu) are known to improve antileukemic functionality of T-cells we evaluated the composition and development of distinct Treg-subtypes in AML-pts (n=12) compared to healthy probands (n=5) under unstimulated conditions and during stimulation with DCleu-containing DC (‘DC’) or blast-containing mononuclear cells (‘MNC’) in 0-7 days mixed lymphocyte cultures (MLC) by flowcytometry. T-cell-subgroups in AML pts were correlated with antileukemic functionality before and after ‘DC’ or ’MNC’ stimulation by functional fluorolysis-assays. Results: 1. AML-pts’ T-cells presented with significantly higher frequencies of Treg-subgroups in unstimulated T-cells compared to healthy probands. 2. After 7 days of ‘DC’ or ‘MNC’-stimulation all Treg-subtypes generally increased; significantly higher frequencies of Treg-subtypes were still found in AML-pts. 3. Antileukemic cytotoxicity was achieved in 36% of T-cells after ‘MNC’- compared to 64% after ‘DC’-stimulation. Antileukemic activity after ‘DC’ but not after ‘MNC’-stimulation correlated with significantly lower frequencies of Treg-subtypes (CD8+ Treg/Teff/em reg). Furthermore, cut-off-values for Treg subpopulations could be defined allowing a prediction of antileukemic response. Conclusion: We demonstrate a crucial role of special Treg-subtypes in the mediation of antileukemic functionality. High CD8+Treg, Teff/em reg and CD39+T-Zellen clearly correlated with reduced antileukemic activity of T-cells. ‘DC’ stimulation of T-cells contributes to overcome impaired antileukemic T-cell-reactivity. Refined analyses in the context of clinical responses to immunotherapy and GVHD reactions are required.Regulatorische T-Zellen (Treg) sind wichtige Regulatoren von Immunantworten. Bei Patienten mit akuter myeloischer Leukämie (AML), welche vor oder nach einer Stammzelltransplantation (SZT) oder Erhalt von Donor-Lymphozyten-Infusionen (DLI) stehen, können Treg einerseits dazu beitragen schwere Graft-versus-Host- Reaktionen (GVHD) zu unterdrücken, andererseits können sie jedoch die gewünschte antileukämische Antwort mindern. Dendritische Zellen sind als antigenpräsentierende Zellen in der Lage, T-Zellen und somit Immunantworten zu stimulieren. Es ist bekannt, dass dendritische Zellen aus leukämischen Blasten (DCleu) generiert werden können und diese DCleu die antileukämische T-Zellantwort verbessern [1]. Unklar in diesem Zusammenhang, und somit Ziel dieser Arbeit, ist die genaue Zusammensetzung und kinetische Entwicklung von verschiedenen Treg Untergruppen bei AML Patienten unter Stimulation mit DCleu. Hierzu wurden die Treg Untergruppen von 12 AML Patienten mit 5 gesunden Probanden unter unstimulierten Bedingungen und während der siebentägigen Stimulation verglichen. Die T-Zell-Stimulation wurde einerseits mit dendritischen Zellen, welche DCleu enthielten, andererseits mit mononukleären Zellen, welche bei den AML Patienten auch leukämischen Blasten enthielten, in einer gemischten Lymphozyten Kultur (MLC) durchgeführt. Die T-Zell-Analysen erfolgten mittels Durchflusszytometrie. Zuletzt wurde bei den AML Patienten die antileukämische T-Zell-Funktionalität mit unstimulierten sowie ‚DC‘- oder ‚MNC‘- stimulierten Bedingungen anhand eines funktionellen Fluorolyse Zytotoxizitätsassay korreliert. Die Ergebnisse dieser Arbeit zeigten, dass AML Patienten unter unstimulierten Bedingungen signifikant höhere Anteile von Treg Untergruppen aufwiesen als die gesunden Probanden. Nach der siebentägigen Stimulation mit ‚DC‘ oder ‚MNC‘ konnte ein genereller Anstieg der verschiedenen Treg Untergruppen nachgewiesen werden. AML Patienten zeigten auch nach Zusammenfassung 3 Stimulation weiterhin signifikant höhere Anteile an Treg als die gesunden Probanden. Eine antileukämische, zytotoxische T-Zell-Antwort wurde bei 36% der Patienten nach ‚MNC‘ Stimulation sowie bei 64% nach ‚DC‘ Stimulation erreicht. Die antileukämische Aktivität korrelierte nach ‚DC‘ Stimulation, jedoch nicht nach ‚MNC‘ Stimulation mit signifikant niedrigeren Anteile an Treg Untergruppen, insbesondere der CD8+ Treg und der Teff/em reg. Des Weiteren konnten erstmalig Cut-off-Werte für die Treg Untergruppen definiert werden, welche eine prädiktive Aussage über die antileukämische T-Zellantwort zulassen. Zusammenfassend zeigt diese Arbeit die wichtige Rolle einzelner Treg Untergruppen bei der Vermittlung spezifischer antileukämischer T-Zell-Antworten. Hohe Anteile an CD8+ Treg oder Teff/em reg oder CD39+ T-Zellen korrelieren mit einer verminderten antileukämischen T-Zell-Aktivität. Die T-Zell-Stimulation mit DCleu kann bei AML Patienten dazu beitragen, die verminderte antileukämische T-Zell-Aktivität zu verbessern

Mental health assessments in refugees and asylum seekers

Background Mental health problems resulting from persecution and forced migration are very common among refugees and asylum seekers and evolve into a major public health challenge in hosting societies. Language barriers often prevent timely access to appropriate health care, leading to chronic trajectories and abortive social integration. Tools for multilingual screening and assessment could be of great benefit for this particularly vulnerable population as well as for policy makers. This study aimed at testing the reliability, feasibility and usability of the Multi-Adaptive Psychological Screening Software (MAPSS), a newly developed Audio Computer-Assisted Self- Interview Software (ACASI) for touchscreen devices, for screening purposes in a clinical setting. Methods In a randomized cross-over design including both MAPSS and paper-pencil clinician-administered interviews, 30 treatment-seeking refugees completed clinical measures and a feasibility questionnaire to rate the user interface of MAPSS. Five professionals performed given tasks in MAPSS and completed usability questionnaires for the administration interface. Results Results showed no differences between the two assessment modalities with regard to symptom scores. The findings suggest good feasibility and usability of MAPSS in traumatized refugees. The administration via MAPSS was significantly shorter than the paper-pencil interview. Conclusion MAPSS may be a cost-effective, flexible and valid alternative to interpreter-based psychometric screening and assessment

Mental health assessments in refugees and asylum seekers: evaluation of a tablet-assisted screening software

BACKGROUND: Mental health problems resulting from persecution and forced migration are very common among refugees and asylum seekers and evolve into a major public health challenge in hosting societies. Language barriers often prevent timely access to appropriate health care, leading to chronic trajectories and abortive social integration. Tools for multilingual screening and assessment could be of great benefit for this particularly vulnerable population as well as for policy makers. This study aimed at testing the reliability, feasibility and usability of the Multi-Adaptive Psychological Screening Software (MAPSS), a newly developed Audio Computer-Assisted Self-Interview Software (ACASI) for touchscreen devices, for screening purposes in a clinical setting. METHODS: In a randomized cross-over design including both MAPSS and paper-pencil clinician-administered interviews, 30 treatment-seeking refugees completed clinical measures and a feasibility questionnaire to rate the user interface of MAPSS. Five professionals performed given tasks in MAPSS and completed usability questionnaires for the administration interface. RESULTS: Results showed no differences between the two assessment modalities with regard to symptom scores. The findings suggest good feasibility and usability of MAPSS in traumatized refugees. The administration via MAPSS was significantly shorter than the paper-pencil interview. CONCLUSION: MAPSS may be a cost-effective, flexible and valid alternative to interpreter-based psychometric screening and assessment

Diaphragmatic Breathing during Virtual Reality Exposure Therapy for Aviophobia: Functional Coping Strategy or Avoidance Behavior?

Background: Although there is solid evidence for the efficacy of in vivo and virtual reality (VR) exposure therapy for a specific phobia, there is a significant debate over whether techniques promoting distraction or relaxation have impairing or enhancing effects on treatment outcome. In the present pilot study, we investigated the effect of diaphragmatic breathing (DB) as a relaxation technique during VR exposure treatment. Method: Twenty-nine patients with aviophobia were randomly assigned to VR exposure treatment either with or without diaphragmatic breathing (six cycles per minute). Subjective fear ratings, heart rate and skin conductance were assessed as indicators of fear during both the exposure and the test session one week later. Results: The group that experienced VR exposure combined with diaphragmatic breathing showed a higher tendency to effectively overcome the fear of flying. Psychophysiological measures of fear decreased and self-efficacy increased in both groups with no significant difference between the groups. Conclusions: Our findings indicate that diaphragmatic breathing during VR exposure does not interfere with the treatment outcome and may even enhance treatment effects of VR exposure therapy for aviophobic patients

Augmented reality-enhanced navigation in endoscopic sinus surgery: A prospective, randomized, controlled clinical trial

Objective: Endoscopic sinus surgery represents the gold standard for surgical treatment of chronic sinus diseases. Thereby, navigation systems can be of distinct use. In our study, we tested the recently developed KARL STORZ NAV1 SinusTracker navigation software that incorporates elements of augmented reality (AR) to provide a better preoperative planning and guidance during the surgical procedure. Methods: One hundred patients with chronic sinus disease were operated on using either a conventional navigation software (n = 52, non‐AR, control group) or a navigation software incorporating AR elements (n = 48, AR, intervention group). Incidence of postoperative complications, duration of surgery, surgeon‐reported benefit from the navigation system and patient‐reported postoperative rehabilitation were assessed. Results: The surgeons reported a higher benefit during surgery, used the navigation system for more surgical steps and spent longer time with preoperative image analysis when using the AR system as compared with the non‐AR system. No significant differences were seen in terms of postoperative complications, target registration error, operation time and postoperative rehabilitation. Conclusion: The AR enhanced navigation software shows a high acceptance by sinus surgeons in different stages of surgical training and offers potential benefits during surgery without affecting the duration of the operation or the incidence of postoperative complications

HPV Status as Prognostic Biomarker in Head and Neck Cancer—Which Method Fits the Best for Outcome Prediction?

The incidence of human papillomavirus (HPV)-related head and neck cancer (HNSCC) is rising globally, presenting challenges for optimized clinical management. To date, it remains unclear which biomarker best reflects HPV-driven carcinogenesis, a process that is associated with better therapeutic response and outcome compared to tobacco/alcohol-induced cancers. Six potential HPV surrogate biomarkers were analyzed using FFPE tissue samples from 153 HNSCC patients (n = 78 oropharyngeal cancer (OPSCC), n = 35 laryngeal cancer, n = 23 hypopharyngeal cancer, n = 17 oral cavity cancer): p16, CyclinD1, pRb, dual immunohistochemical staining of p16 and Ki67, HPV-DNA-PCR, and HPV-DNA-in situ hybridization (ISH). Biomarkers were analyzed for correlation with one another, tumor subsite, and patient survival. P16-IHC alone showed the best performance for discriminating between good (high expression) vs poor outcome (low expression; p = 0.0030) in OPSCC patients. Additionally, HPV-DNA-ISH (p = 0.0039), HPV-DNA-PCR (p = 0.0113), and p16-Ki67 dual stain (p = 0.0047) were significantly associated with prognosis in uniand multivariable analysis for oropharyngeal cancer. In the non-OPSCC group, however, none of the aforementioned surrogate markers was prognostic. Taken together, P16-IHC as a single biomarker displays the best diagnostic accuracy for prognosis stratification in OPSCC patients with a direct detection of HPV-DNA by PCR or ISH as well as p16-Ki67 dual stain as potential alternatives

Landscape of 4D Cell Interaction in Hodgkin and Non-Hodgkin Lymphomas

Profound knowledge exists about the clinical, morphologic, genomic, and transcriptomic characteristics of most lymphoma entities. However, information is currently lacking on the dynamic behavior of malignant lymphomas. This pilot study aimed to gain insight into the motility of malignant lymphomas and bystander cells in 20 human lymph nodes. Generally, B cells were faster under reactive conditions compared with B cells in malignant lymphomas. In contrast, PD1-positive T cells did not show systematic differences in velocity between reactive and neoplastic conditions in general. However, lymphomas could be divided into two groups: one with fast PD1-positive T cells (e.g., Hodgkin lymphoma and mantle cell lymphoma; means 8.4 and 7.8 µm/min) and another with slower PD1-positive T cells (e.g., mediastinal grey zone lymphoma; mean 3.5 µm/min). Although the number of contacts between lymphoma cells and PD1-positive T cells was similar in different lymphoma types, important differences were observed in the duration of these contacts. Among the lymphomas with fast PD1-positive T cells, contacts were particularly short in mantle cell lymphoma (mean 54 s), whereas nodular lymphocyte-predominant Hodgkin lymphoma presented prolonged contact times (mean 6.1 min). Short contact times in mantle cell lymphoma were associated with the largest spatial displacement of PD1-positive cells (mean 12.3 µm). Although PD1-positive T cells in nodular lymphocyte-predominant Hodgkin lymphoma were fast, they remained in close contact with the lymphoma cells, in line with a dynamic immunological synapse. This pilot study shows for the first time systematic differences in the dynamic behavior of lymphoma and bystander cells between different lymphoma types

Feasibility and acceptability of Problem Management Plus (PM+) among Syrian refugees and asylum seekers in Switzerland: a mixed-method pilot randomized controlled trial

Background: Syrian refugees in Switzerland face several barriers in accessing mental health care. Cost-effective psychological interventions are urgently needed to meet the mental health needs of refugees. Problem Management Plus (PM+) is an evidence-based, psychological intervention delivered by trained non-specialist ‘helpers’. Objective: To assess the feasibility and acceptability of PM+ among Syrian refugees in Switzerland. Methods: We conducted a single-blind pilot randomized controlled trial (RCT) with Syrian refugees impaired by psychological distress (K10 > 15 and WHODAS 2.0 > 16). Participants were randomized to PM+ or Enhanced Treatment As Usual (ETAU). Participants were assessed at baseline, and 1 week and 3 months after the intervention, and completed measures indexing mental health problems and health care usage. Semi-structured interviews were conducted with different stakeholders. Results: N = 59 individuals were randomized into PM+ (n = 31) or ETAU (n = 28). N = 18 stakeholders were interviewed about facilitators and barriers for the implementation of PM+. Retention rates in the trial (67.8%) and mean intervention attendance (M = 3.94 sessions, SD = 1.97) were high. No severe events related to the study were reported. These findings indicate that the trial procedures and PM+ were feasible, acceptable and safe. Conclusions: The findings support the conduct of a definitive RCT and show that PM+ might have the potential to be scaled-up in Switzerland. The importance, as well as the challenges, of implementing and scaling-up PM+ in high-income countries, such as Switzerland, are discussed