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Background: Mutation-derived neoantigens are critical targets for tumor rejection in cancer immunotherapy, and better tools for neoepitope identification and prediction are needed to improve neoepitope targeting strategies. Computational tools have enabled the identification of patient-specific neoantigen candidates from sequencing data, but limited data availability has hindered their capacity to predict which of the many neoepitopes will most likely give rise to T cell recognition., Method: To address this, we make use of experimentally validated T cell recognition towards 17,500 neoepitope candidates, with 467 being T cell recognized, across 70 cancer patients undergoing immunotherapy., Results: We evaluated 27 neoepitope characteristics, and created a random forest model, IMPROVE, to predict neoepitope immunogenicity. The presence of hydrophobic and aromatic residues in the peptide binding core were the most important features for predicting neoepitope immunogenicity., Conclusion: Overall, IMPROVE was found to significantly advance the identification of neoepitopes compared to other current methods., Competing Interests: SH is the cofounder of PokeAcell and is the inventor of several licensed patents, however, none of these activities are of relevance to the work presented in this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Borch, Carri, Reynisson, Alvarez, Munk, Montemurro, Kristensen, Tvingsholm, Holm, Heeke, Moss, Hansen, Schaap-Johansen, Bagger, de Lima, Rohrberg, Funt, Donia, Svane, Lassen, Barra, Nielsen and Hadrup.)

Background: Refugee populations have an increased risk for mental disorders, such as depression, anxiety, and posttraumatic stress disorders. Comorbidity is common. At the same time, refugees face multiple barriers to accessing mental health treatment. Only a minority of them receive adequate help. The planned trial evaluates a low-threshold, transdiagnostic Internet-based treatment. The trial aims at establishing its efficacy and cost-effectiveness compared with no treatment., Methods: N = 131 treatment-seeking Arabic- or Farsi-speaking patients, meeting diagnostic criteria for a depressive, anxiety, and/or posttraumatic stress disorder will be randomized to either the intervention or the waitlist control group. The intervention group receives an Internet-based treatment with weekly written guidance provided by Arabic- or Farsi-speaking professionals. The treatment is based on the Common Elements Treatment Approach (CETA), is tailored to the individual patient, and takes 6-16 weeks. The control group will wait for 3 months and then receive the Internet-based treatment., Discussion: The planned trial will result in an estimate of the efficacy of a low-threshold and scalable treatment option for the most common mental disorders in refugees., Trial Registration: German Registry for Clinical Trials DRKS00024154. Registered on February 1, 2021., (© 2023. The Author(s).)

Purpose: Recent studies have demonstrated HLA class II (HLA-II)-dependent killing of melanoma cells by cytotoxic CD4 T cells. We investigated evolution of HLA-II-loss tumors that escape cytotoxic CD4 T-cell activity and contribute to immunotherapy resistance., Experimental Design: Melanoma cells from longitudinal metastases were studied for constitutive and IFN-inducible HLA-II expression, sensitivity towards autologous CD4 T cells, and immune evasion by HLA-II loss. Clinical significance of HLA-II-low tumors was determined by analysis of transcriptomic data sets from patients with immune checkpoint blockade (ICB)., Results: Analysis of longitudinal samples revealed strong intermetastatic heterogeneity in melanoma cell-intrinsic HLA-II expression and subclonal HLA-II loss. Tumor cells from early lesions either constitutively expressed HLA-II, sensitizing to cytotoxic CD4 T cells, or induced HLA-II and gained CD4 T-cell sensitivity in the presence of IFNγ. In contrast, late outgrowing subclones displayed a stable CD4 T-cell-resistant HLA-II-loss phenotype. These cells lacked not only constitutive but also IFNγ-inducible HLA-II due to JAK1/2-STAT1 pathway inactivation. Coevolution of JAK1/2 deficiency and HLA-II loss established melanoma cross-resistance to IFNγ and CD4 T cells, as detected in distinct stage IV metastases. In line with their immune-evasive phenotype, HLA-II-low melanomas showed reduced CD4 T-cell infiltrates and correlated with disease progression under ICB., Conclusions: Our study links melanoma resistance to CD4 T cells, IFNγ, and ICB at the level of HLA-II, highlighting the significance of tumor cell-intrinsic HLA-II antigen presentation in disease control and calling for strategies to overcome its downregulation for improvement of patient outcome., (©2023 American Association for Cancer Research.)

Background: Adoptive cell therapy (ACT) has shown promising results for the treatment of cancer and viral infections. Successful ACT relies on ex vivo expansion of large numbers of desired T-cells with strong cytotoxic capacity and in vivo persistence, which constitutes the greatest challenge to current ACT strategies. Here, in this study, we present a novel technology for ex vivo expansion of antigen-specific T-cells; artificial antigen-presenting scaffolds (Ag-scaffolds) consisting of a dextran-polysaccharide backbone, decorated with combinations of peptide-Major Histocompatibility Complex (pMHC), cytokines and co-stimulatory molecules, enabling coordinated stimulation of antigen-specific T-cells., Methods: The capacity of Ag-scaffolds to expand antigen-specific T-cells was explored in ex vivo cultures with peripheral blood mononuclear cells from healthy donors and patients with metastatic melanoma. The resulting T-cell products were assessed for phenotypic and functional characteristics., Results: We identified an optimal Ag-scaffold for expansion of T-cells for ACT, carrying pMHC and interleukin-2 (IL-2) and IL-21, with which we efficiently expanded both virus-specific and tumor-specific CD8+ T cells from peripheral blood of healthy donors and patients, respectively. The resulting T-cell products were characterized by a high frequency of antigen-specific cells with high self-renewal capacity, low exhaustion, a multifunctional cytokine profile upon antigen-challenge and superior tumor killing capacity. This demonstrates that the coordinated stimuli provided by an optimized stoichiometry of TCR engaging (pMHC) and stimulatory (cytokine) moieties is essential to obtain desired T-cell characteristics. To generate an 'off-the-shelf' multitargeting Ag-scaffold product of relevance to patients with metastatic melanoma, we identified the 30 most frequently recognized shared HLA-A0201-restricted melanoma epitopes in a cohort of 87 patients. By combining these in an Ag-scaffold product, we were able to expand tumor-specific T-cells from 60-70% of patients with melanoma, yielding a multitargeted T-cell product with up to 25% specific and phenotypically and functionally improved T cells., Conclusions: Taken together, the Ag-scaffold represents a promising new technology for selective expansion of antigen-specific CD8+ T cells directly from blood, yielding a highly specific and functionally enhanced T-cell product for ACT., Competing Interests: Competing interests: SRRH is the co-founder of PokeAcell, with license to SRRH co-invented patents (EP2017/083862 and EP3810188A1); further, SRRH is the co-inventor of patents WO2015185067 and WO2015188839 for the barcoded MHC technology that is licensed to Immudex. The remaining authors have no conflicts of interest in the context of the present study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a need for an interview-based measure to assess Prolonged Grief Disorder (PGD) included in the text revision of the fifth Diagnostic and Statistical Manual for Mental Disorder (DSM-5-TR) and 11th edition of the International Classification of Disease (ICD-11). We evaluated the psychometric properties of the Traumatic Grief Inventory-Clinician Administered (TGI-CA); a new interview measuring DSM-5-TR and ICD-11 PGD severity and probable caseness., Methods: In 211 Dutch and 222 German bereaved adults, the: (i) factor structure, (ii) internal consistency, (iii) test-retest reliability, (iv) measurement invariance across subgroups (e.g., differing in language), (v) prevalence of probable caseness, (vi) convergent validity, and (vii) known-groups validity were examined., Results: Confirmatory factor analyses (CFAs) showed acceptable fit for the unidimensional model for DSM-5-TR and ICD-11 PGD. Omega values indicated good internal consistency. Test-retest reliability was high. Multi-group CFAs demonstrated configural and metric invariance for DSM-5-TR and ICD-11 PGD criteria for all group-comparisons; for some we found support for scalar invariance. Rates of probable caseness for DSM-5-TR PGD were lower than ICD-11 PGD. Optimal agreement in probable caseness was reached when increasing the number of accessory symptoms for ICD-11 PGD from 1+ to 3+. Convergent and known-groups validity was demonstrated for both criteria-sets., Limitations: The TGI-CA was developed to assess PGD severity and probable caseness. Clinical diagnostic interviews for PGD are needed., Conclusions: The TGI-CA seems a reliable and valid interview for DSM-5-TR and ICD-11 PGD symptomatology. More research in larger and more diverse samples is needed to further test its psychometric properties., Competing Interests: Conflict of interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Immune checkpoint blockade (ICB) is standard-of-care for patients with metastatic melanoma. It may re-invigorate T cells recognizing tumors, and several tumor antigens have been identified as potential targets. However, little is known about the dynamics of tumor antigen-specific T cells in the circulation, which might provide valuable information on ICB responses in a minimally invasive manner. Here, we investigated individual signatures composed of up to 167 different melanoma-associated epitope (MAE)-specific CD8+ T cells in the blood of stage IV melanoma patients before and during anti-PD-1 treatment, using a peptide-loaded multimer-based high-throughput approach. Additionally, checkpoint receptor expression patterns on T cell subsets and frequencies of myeloid-derived suppressor cells and regulatory T cells were quantified by flow cytometry. Regression analysis using the MAE-specific CD8+ T cell populations was applied to identify those that correlated with overall survival (OS). The abundance of MAE-specific CD8+ T cell populations, as well as their dynamics under therapy, varied between patients. Those with a dominant increase of these T cell populations during PD-1 ICB had a longer OS and progression-free survival than those with decreasing or balanced signatures. Patients with a dominantly increased MAE-specific CD8+ T cell signature also exhibited an increase in TIM-3+ and LAG-3+ T cells. From these results, we created a model predicting improved/reduced OS by combining data on dynamics of the three most informative MAE-specific CD8+ T cell populations. Our results provide insights into the dynamics of circulating MAE-specific CD8+ T cell populations during ICB, and should contribute to a better understanding of biomarkers of response and anti-cancer mechanisms., Competing Interests: CG reports receiving commercial research grants from Bristol-Myers Squibb, Novartis, and Roche, and is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. BW reports receiving commercial research grants from, is a consultant/advisory board member for, and reports receiving travel reimbursement from Bristol-Myers Squibb and Merck Sharp & Dohme. FM reports receiving commercial research grants from Novartis and Roche, and has received travel support or/and speaker´s fees or/and advisor´s honoraria by Novartis, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pierre Fabre. NW reports an advisory role for Pierre-Fabre and Sanofi, consultant’s honoraria from Novartis, and has received travel support from AbbVie and Amgen outside the submitted work. GP has received speaker´s honoraria from Novartis, Roche, Pfizer, GlaxoSmithKline and Astellas. KW-H received commercial research grants from the CatalYm GmbH and travel support from SITC (Society for Immunotherapy of Cancer). SH is the cofounder of Immumap, Tetramer-shop and PokeAcell and is the co-inventor of the patents WO2015185067 and WO2015188839 for the barcoded MHC technology which is licensed to Immudex. The data presented in this study is not directly involved in these activities. TE has received travel support or/and speaker´s fees or/and advisor´s honoraria by Sanofi, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Almiral Hermal, and Pierre Fabre. TA reports institutional grants from SkylineDx, institutional grants and personal fees from Novartis, institutional grants from NeraCare, personal fees from BMS, institutional grants from Sanofi, personal fees from CeCaVa, personal fees from Pierre Fabre, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gaißler, Meldgaard, Heeke, Babaei, Tvingsholm, Bochem, Spreuer, Amaral, Wagner, Klein, Meier, Garbe, Eigentler, Pawelec, Claassen, Weide, Hadrup and Wistuba-Hamprecht.)

Background: The loss of a significant other can lead to variety of responses, including prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and depression. The aim of this study was to replicate and extend previous research that indicated that three subgroups of bereaved individuals can be distinguished based one similar post-loss symptom profiles using latent class analysis (LCA). The second aim was to examine whether sociodemographic and loss-related characteristics as well as the extent of meaning making were related to classes with more pervasive psychopathology., Methods: Telephone-based interviews with 433 Dutch and German speaking persons who had lost a significant other at last 6 months earlier were conducted. Self-rated PGD, PTSD, and depression symptoms were assessed. LCA was conducted and correlates of class-membership were examined using the 3step approach., Results: The LCA resulted in three distinct classes: a no symptoms class (47%), a moderate PGD, low depression/PTSD class (32%), and a high PGD, moderate depression/PTSD class (21%). A multivariate analysis indicated that female gender, a shorter time since loss, an unexpected loss and less meaning made to a loss were significantly associated with membership to the moderate PGD, low depression/PTSD and high PGD, moderate depression/PTSD class compared to membership to the no symptom class. Losing a child or spouse, a shorter time since loss, and having made less meaning to the loss further distinguished between the high PGD, moderate depression/PTSD symptom class and the moderate PGD, low depression/PTSD class., Discussion: We found that the majority of individuals coped well in response to their loss since the no symptom class was the largest class. Post-loss symptoms could be categorized into classes marked by different intensity of symptoms, rather than qualitatively different symptom patterns. The findings indicate that perceiving the loss as more unexpected, finding less meaning in the loss, and loss-related factors, such as the recentness of a loss and the loss of a partner or child, were related to class membership more consistently than sociodemographic factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heeke, Franzen, Hofmann, Knaevelsrud and Lenferink.)

BACKGROUNDNeoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs). Yet how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined.METHODSUsing barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic melanoma patients who received ACT.RESULTSWe identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with increased survival and that neoepitope-specific CD8+ T cells shared with the infusion product in posttreatment blood samples were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product.CONCLUSIONSThese data support previous case studies of neoepitope-specific CD8+ T cells in melanoma and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.FUNDINGNEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.

Background: This study aims to provide a transparent and replicable documentation approach for the cultural adaptation of a cognitive-behavioural transdiagnostic intervention (Common Elements Treatment Approach, CETA) for Arabic-speaking refugees with common mental disorders in Germany., Method: A mixed-methods approach was used, including literature review, interviews, expert decisions and questionnaires, in order to adapt the original CETA as well as an internet-based guided version (eCETA). The process of cultural adaptation was based on a conceptual framework and was facilitated by an adaptation monitoring form as well as guidelines which facilitate the reporting of cultural adaptation in psychological trials (RECAPT)., Results: Consistent with this form and the guidelines, the decision-making process of adaptation proved to be coherent and stringent. All specific CETA treatment components seem to be suitable for the treatment of Arabic-speaking refugees in Germany. Adaptations were made to three different elements: 1) Cultural concepts of distress: a culturally appropriate explanatory model of symptoms was added; socially accepted terms for expressing symptoms (for eCETA only) and assessing suicidal ideation were adapted; 2) Treatment components: no adaptations for theoretically/empirically based components of the intervention, two adaptations for elements used by the therapist to engage the patient or implement the intervention (nonspecific elements), seven adaptations for skills implemented during sessions (therapeutic techniques; two for eCETA only) and 3) Treatment delivery: 21 surface adaptations (10 for eCETA only), two eCETA-only adaptations regarding the format., Conclusion: The conceptual framework and the RECAPT guidelines simplify, standardise and clarify the cultural adaptation process., Competing Interests: Eva Heim is one of the Guest Editors of this CPE Special Issue but played no editorial role in this particular article or intervened in any form in the peer review process.

Background: The Eastern Mediterranean Region (EMR) is the stage of the world's most violent conflicts and the origin of the largest refugee population worldwide. These conflicts can result in symptoms of posttraumatic stress (PTS). To date, no comprehensive meta-analysis on proportions of PTS in civilians from the EMR has been conducted. Sample characteristics, methodological, conflict-related and displacement-related factors might affect rates of PTS., Methods: A systematic literature search for studies investigating PTS in adult civilians from the EMR was conducted until March 2020 and resulted in 118 individual study samples that were suitable for inclusion. A quality assessment was conducted. A random effects meta-analysis on proportions and sensitivity analyses were performed, and a 95% prediction interval was calculated. Subgroup analyses to identify moderators (e.g. diagnostic instruments, displacement) were conducted., Results: The quality of the included study samples varied. The pooled estimate of proportions from all 118 study samples was 0.31 (95% CI: 0.27 - 0.35). Heterogeneity was considerable (Q = 10151.58, p < .0001; I 2  = 98.64%). The prediction interval was 0.01 to 0.76. The results remained unchanged after excluding nine outlier study samples. Heterogeneity remained high in all subgroups (range of I 2 : 87.91 to 99.62)., Limitations: Due to heterogeneity the pooled estimate cannot be interpreted. Moderators contributing to heterogeneity could not be detected., Conclusions: The proportion of symptoms of PTS in civilians from the EMR varies considerably. The prediction interval indicates that the true rate falls between 1% and 76%. Future studies need to identify variables that affect heterogeneity., (Copyright © 2021. Published by Elsevier B.V.)

Background: During the Khmer Rouge regime in Cambodia, about a quarter of the population died, resulting in many individuals losing close relatives. Still today, many individuals are suffering from the psychological consequences of these losses, which might also affect the process of reconciliation within the Cambodian society. The aim of this paper is therefore to investigate the association between symptoms of prolonged grief and attitudes toward reconciliation., Methods: A sample of 775 survivors of the Khmer Rouge regime who lost relatives during the conflict were interviewed about their losses and traumatic events, prolonged grief (PG; Complicated Grief Assessment Self-Report, CGA-SR), posttraumatic stress disorder (PTSD Checklist - Civilian Version) and attitudes toward reconciliation (Readiness to Reconcile Inventory, RRI)., Results: A higher symptom severity of PG was significantly associated with readiness to reconcile even when controlling for other relevant variables (β = -0.22; p <.001). Persons who met caseness criteria for PG were significantly less ready to reconcile, t(773) = 5.47, p <.001, than persons who did not meet caseness for PG., Conclusion: PG seems to be a relevant mental health correlate of attitudes toward reconciliation. The results of the current study underline the importance of also considering PG with regard to the reconciliation process in Cambodia and possibly also in other post-conflict regions., (Copyright © 2020 Stammel, Heinzl, Heeke, Böttche and Knaevelsrud.)

Objective: The recent changes in diagnostic criteria for posttraumatic stress disorder (PTSD) in the 5th edition of the DSM and the 11th edition of the ICD marked a shift towards two perspectives on the same disorder. Previous studies indicate lower prevalence rates for the ICD-11-model as compared to the DSM-5 model. Main purpose of this study is to examine the concordance between ICD-11 and DSM-5 PTSD rates, and to assess the overlap of the two PTSD definitions with anxiety and depression among refugees., Methods: 167 traumatized refugees were assessed with the PCL-5 for the DSM-5 PTSD model. A subset of the items was used as criteria for the ICD-11 model. Depression and anxiety were measured with the HSCL-25., Results: The DSM-5-algorithm for PTSD identified significantly more cases (n = 147; 88%) than the ICD-11 algorithm (80%; n = 134). Level of agreement between the diagnostic systems was substantial (Κ = 0.67, p < .001) and 9% (n = 15) met criteria under one diagnostic system only. Overlap with depression and anxiety was high under both diagnostic systems., Conclusion: PTSD rates indicated a highly distressed sample of survivors of war and trauma. Our data provide further evidence that the DSM-5 diagnoses a larger number of persons than the ICD-11. Although the level of agreement was substantial, the observed discrepancies represent a challenge for research and practice to reliably identify individuals with PTSD. Especially for refugees, this might affect their access to mental health care and appropriate treatment during an asylum procedure., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background : Violent loss (i.e. loss through homicide, suicide, or accident) is associated with high levels of prolonged grief disorder (PGD). Objective : The current meta-analysis aims at identifying correlates of PGD in adults exposed to violent loss. Method : We conducted a systematic literature search in PsycINFO, PsycARTICLES, PubMed, Web of Science, and Scopus. We used the Pearson correlation coefficient r as an effect size measure and a random effects model was applied to calculate effect sizes. Results : Thirty-seven eligible studies published between 2003 and 2017 ( N  = 5911) revealed 29 potential correlates. Most studies used a cross-sectional design. Analyses revealed large significant effect sizes for comorbid psychopathology ( r  = .50-.59), suicidality ( r  = .41, 95% confidence interval [CI] [.30; .52]), and rumination ( r  = .42, 95% CI [.31; .52]), while medium effect sizes were found for exposure to traumatic events and factors concerning the relationship to the deceased. Small effect sizes emerged for sociodemographic characteristics, multiple loss, physical symptoms, and religious beliefs. Ten variables did not show a significant association with PGD. Heterogeneity and a small number of studies assessing certain correlates were observed. Conclusions : The associations with psychological disorders may indicate shared mechanisms of psychopathology. Moreover, we recommend that clinicians carefully assess suicidal ideation among individuals with PGD who have been exposed to violent loss. Further research is warranted using longitudinal study designs with large sample sizes to understand the relevance of these factors for the development of PGD.

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8 + T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.

Background: Exposure to trauma and bereavement is common in conflict-affected regions. Previous research suggests considerable heterogeneity in responses to trauma and loss with varying symptom representations. The purpose of the current study was to (1) identify classes of prolonged grief disorder (PGD) and posttraumatic stress disorder (PTSD) symptom profiles among individuals who were exposed to both trauma and loss due to the Colombian armed conflict and (2) to examine whether sociodemographic, loss and trauma-related characteristics could predict class membership., Methods: Three hundred eight victims of internal displacement who had experienced trauma and loss were assessed through measures of PGD (PG-13), PTSD (PCL-C), and social support (DUKE-UNC). Latent class analysis (LCA) was performed to analyze differential profiles by symptoms of PGD and PTSD and multinomial logistic regression was used to analyze predictors of class membership., Results: LCA revealed a four-class solution: a resilient class (23.6%), a PTSD-class (23.3%), a predominately PGD class (25.3%) and a high distress-class with overall high values of PGD and PTSD (27.8%). Relative to the resilient class, membership to the PGD class was predicted by the loss of a close family member and the exposure to a higher number of assaultive traumatic events, whereas membership to the PTSD class was predicted by the perception of less social support. Compared to the resilient class, participants in the high distress-class were more likely to be female, to have lost a close relative, experienced more accidental and assaultive traumatic events, and perceived less social support., Discussion: Specific symptom profiles emerged following exposure to trauma and loss within the context of the Colombian armed conflict. Profiles were associated with distinct types of traumatic experiences, the degree of closeness to the person lost, the amount of social support perceived, and gender. The results have implications for identifying distressed subgroups and informing interventions in accordance with the patient's symptom profile.

Melanoma often recurs after a latency period of several years, presenting a T cell-edited phenotype that reflects a role for CD8(+) T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen-specific CD8(+) T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8(+) T cell-resistant, HLA class I-negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA class I loss in both metastases originated from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I haplotype-deficient lesion developed in year 3 of stage IV disease that acquired resistance toward dominant CD8(+) T-cell clonotypes targeting stage III tumor cells. At an early stage, melanoma cells showed a dedifferentiated c-Jun(high)/MITF(low) phenotype, possibly associated with immunosuppression, which contrasted with a c-Jun(low)/MITF(high) phenotype of T cell-edited tumor cells derived from late metastases. In summary, our work shows how tumor recurrences after long-term latency evolve toward T-cell resistance by independent genetic events, as a means for immune escape and immunotherapeutic resistance. Cancer Res; 76(15); 4347-58. ©2016 AACR., (©2016 American Association for Cancer Research.)

The impact of war and violence on the mental and physical health of the civilian population is immense. Traumatization is often experienced sequentially, which leads to a higher risk for developing trauma-related disorders (PTSD, depression, chronic pain).Refugees traumatized by war experience specific stressors related to their status of residence (e. g., application hearing, length of the asylum procedure). Together with limited access to health care, these constitute additional risk factors for developing somatic and psychological illnesses.Adequate treatment for this highly vulnerable group requires a multimodal approach facilitated by translators. According to the S3 guidelines (S3-Richtlinien), trauma-adapted psychotherapeutic treatment has to be complemented by the activities of social workers, by medical treatment, and by legal advice.

Background: Disappearances are a frequent phenomenon in the context of violent conflicts. Although it is widely assumed that relatives of missing people face particularly complex adaptation difficulties due to the uncertainty regarding the fate of their loved ones, little is known about the psychological and social consequences for those left behind., Objectives: The aim of this article is to provide an empirical overview on studies addressing ambiguous loss in violent conflicts as well as to highlight potential risk factors for negative mental health outcomes relevant in this group., Results: Due to the limited number of studies, only preliminary conclusions can be drawn. Studies show that the disappearance of a loved one can adversely affect mental health in a substantial number of those left behind. Studies indicate that relatives of missing persons suffer from higher psychological distress than bereaved persons with confirmed losses, particularly in terms of symptom severity of depression and prolonged grief reactions. Research on factors contributing to these mental health outcomes suggests an elevated risk for exposure to traumatic events and lack of social support among relatives of missing persons. The extent of hope regarding the fate of the missing loved one might prevent relatives from achieving closure and facilitate prolonged grief reactions. Lack of grief rituals and complex family dynamics may furthermore exacerbate coping with the loss., Conclusion: Future research should focus on the verification of these findings and evaluate the impact of resilience factors that can protect relatives from maladaptive mental health consequences. Research in this regard can help identify persons at high risk and allow the development of adequate and effective interventions.

Background: The World Health Organization recently proposed significant changes to the posttraumatic stress disorder (PTSD) diagnostic criteria in the 11th edition of the International Classification of Diseases (ICD-11)., Objective: The present study investigated the impact of these changes in two different post-conflict samples., Method: Prevalence and rates of concurrent depression and anxiety, socio-demographic characteristics, and indicators of clinical severity according to ICD-11 in 1,075 Cambodian and 453 Colombian civilians exposed to civil war and genocide were compared to those according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)., Results: Results indicated significantly lower prevalence rates under the ICD-11 proposal (8.1% Cambodian sample and 44.4% Colombian sample) compared to the DSM-IV (11.2% Cambodian sample and 55.0% Colombian sample). Participants meeting a PTSD diagnosis only under the ICD-11 proposal had significantly lower rates of concurrent depression and a lower concurrent total score (depression and anxiety) compared to participants meeting only DSM-IV diagnostic criteria. There were no significant differences in socio-demographic characteristics and indicators of clinical severity between these two groups., Conclusions: The lower prevalence of PTSD according to the ICD-11 proposal in our samples of persons exposed to a high number of traumatic events may counter criticism of previous PTSD classifications to overuse the PTSD diagnosis in populations exposed to extreme stressors. Also another goal, to better distinguish PTSD from comorbid disorders could be supported with our data.

Background: Forced disappearance is a frequent phenomenon in violent conflicts and regimes, yet little is known about unresolved grief processes as a possible outcome of the disappearance of a loved one. This study investigates prolonged grief disorder (PGD) and its risk factors in a sample of persons who lost a significant other to disappearance as compared with a sample of bereaved individuals, both groups having experienced displacement due to the armed conflict in Colombia., Method: In a cross-sectional study conducted in four Colombian provinces, 73 persons who lost a significant other to disappearance and 222 bereaved individuals completed measures of PGD (PG-13), depression (HSCL-25), and PTSD (PCL-C) via face-to-face interviews. Trauma- and loss-related variables, including the extent to which significant others of disappeared persons hoped that their loved one was still alive, were assessed., Results: Results indicated that 23% of participants who lost a significant other to disappearance met criteria for PGD as compared to 31.5% in bereaved participants. No differences were found between the two groups in terms of symptom severity of PGD, depression, posttraumatic stress disorder, or traumatic exposure. Regression analysis indicated that, among relatives and friends of disappeared persons, the extent of hope predicted PGD above and beyond depression severity whereas among bereaved persons, PGD was predicted by time since the loss, the number of traumatic events and symptom severity of PTSD and depression., Limitations: The instruments were not validated for use in Colombia; generalizability of findings is limited., Conclusion: Forced disappearance is related to prolonged grief reactions, particularly when those left behind maintain hope that the disappeared person is still alive., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: CD8(+) T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells., Experimental Design: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell-stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alterations affecting the tumor-T-cell interaction., Results: Metastases Ma-Mel-48a and Ma-Mel-48b, in contrast with Ma-Mel-48c, were infiltrated by T cells. The T-cell-stimulatory capacity was found to be strong for Ma-Mel-48a, lower for Ma-Mel-48b, and completely abrogated for Ma-Mel-48c cells. The latter proved to be HLA class I-negative due to an inactivating mutation in one allele of the beta-2-microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. The same deletion was already present in Ma-Mel-48a and Ma-Mel-48b cells, pointing to an early acquired genetic event predisposing to development of β2m deficiency. Notably, the same chronology of genetic alterations was also observed in a second β2m-deficient melanoma model., Conclusion: Our study reveals a progressive loss in melanoma immunogenicity during the course of metastatic disease. The genetic evolvement of T-cell resistance suggests screening tumors for genetic alterations affecting immunogenicity could be clinically relevant in terms of predicting patient responses to T-cell-based immunotherapy., (©2014 American Association for Cancer Research.)

Background: During the Khmer Rouge (KR) regime from 1975 to 1979 millions of Cambodians were confronted with the death or murder of family members. The long-term psychological consequences of these traumatic losses have not yet been investigated. The purpose of this study was to determine the rate and potential predictors of prolonged grief disorder (PGD) in survivors of the KR regime., Method: The Inventory of Complicated Grief-Revised (ICG-R) was administered in a sample of N=775 Cambodians in face-to-face interviews who had lost at least one family member during the KR regime. Symptoms of PTSD were assessed with the PTSD Checklist-Civilian Version and symptoms of depression and anxiety with the Hopkins Symptom Checklist-25., Results: The prevalence of PGD in the sample was 14.3%. PGD was moderately associated with symptoms of depression, anxiety and PTSD. The loss of a spouse, a child, or a parent was associated with higher symptom severity of PGD than was the loss of a sibling or distant relatives. PGD was predicted by the relationship to the deceased and symptoms of depression and PTSD., Limitations: Limitations of the study include the non-random sampling recruitment. The ICG-R has not been validated for use in Cambodia., Conclusions: The vast majority of Cambodians lost family members during the KR regime. Even three decades later, PGD was prevalent in a substantial proportion of the present sample and related to other psychiatric disorders. The results underline the importance of examining PGD in studies of war-related psychological impairment., (Copyright © 2012 Elsevier B.V. All rights reserved.)