Fusion transcriptome profiling defines the monoclonal origin of multifocal epithelioid haemangioma of bone.

AIMS: Epithelioid haemangioma (EH) of bone remains a highly controversial entity. Indeed, the WHO classifies EHs of soft tissues as benign tumours, whereas bone EHs are considered intermediate-locally aggressive tumours due to common multifocal presentation and local destructive growth. To gain insights into the clinical behaviour and biology of EH of bone we retrospectively analysed 42 patients treated in a single institution from 1978 to 2021. METHODS AND RESULTS: Multifocal presentation was detected in 17 of 42 patients (40%) primarily as synchronous lesions. Patients were treated with curettage (57%), resection (29%) or biopsy, followed by radiotherapy or embolisation (14%). Follow-up (minimum 24 months) was available for 38 patients, with only five local recurrences (13%) and no death of disease. To clarify whether the synchronous bone lesions in multifocal EH represent multicentric disease or clonal dissemination, four cases were profiled by RNA-sequencing. Separate lesions from the same patient, which showed a similar transcriptional profile, expressed the same fusion transcript (involving FOS or FOSB) with identical gene breakpoints. CONCLUSIONS: These results indicate that, in EH of bone, multifocal lesions are clonally related and therefore represent the spread of a same neoplastic clone rather than simultaneous independent tumours. This finding is in apparent contradiction with the benign clinical course of the disease, and suggests that tumour dissemination in bone EH probably reflects a phenomenon of passive spreading, with tumour cells colonising distal sites while maintaining their benign biological nature.

Beyond SMARCB1 Loss: Recent Insights into the Pathobiology of Epithelioid Sarcoma.

Epithelioid sarcoma (ES) is a very rare and aggressive mesenchymal tumor of unclear origin and uncertain lineage characterized by a prevalent epithelioid morphology. The only recurrent genetic alteration reported in ES as yet is the functional inactivation of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), a key component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes. How SMARCB1 deficiency dictates the clinicopathological characteristics of ES and what other molecular defects concur to its malignant progression is still poorly understood. This review summarizes the recent findings about ES pathobiology, including defects in chromatin remodeling and other signaling pathways and their role as therapeutic vulnerabilities.

The impact of maternal depressive symptoms and traumatic events on early childhood mental health in conflict-affected Timor-Leste.

BACKGROUND: Longitudinal studies are needed to examine the association between maternal depression, trauma and childhood mental health in conflict-affected settings. AIMS: To examine maternal depressive symptoms, trauma-related adversities and child mental health by using a longitudinal path model in conflict-affected Timor-Leste. METHOD: Women were recruited in pregnancy. At wave 1, 1672 of 1740 eligible women were interviewed (96% response rate). The final sample comprised 1118 women with complete data at all three time points. Women were followed up when the index child was aged 18 months (wave 2) and 36 months (wave 3). Measures included the Edinburgh Postnatal Depression Scale, lifetime traumatic events and the Child Behaviour Checklist. A longitudinal path analysis examined associations cross-sectionally and in a cross-lagged manner across time. RESULTS: Maternal depressive symptom score was associated with child mental health (cross-sectional association at wave 2, ß = 0.35, P < 0.001; cross-sectional association at wave 3, ß = 0.33, P < 0.001). The maternal depressive symptom score at wave 1 was associated with child mental health at wave 2 (ß = 0.12, P < 0.001), and the maternal depressive symptom score at wave 2 showed an indirect association with child mental health at wave 3 (indirect standardised coefficient 0.23, P < 0.001). There was a time-lagged relationship between child mental health at wave 2 and maternal depression at wave 3 (ß = 0.08, P = 0.02). CONCLUSIONS: Maternal depressive symptoms are longitudinally associated with child mental health, and traumatic events play a role. Maternal depression symptoms are also affected by child mental health. Findings suggest the need for skilled assessment for depression, trauma-informed maternity care and parenting support in a post-conflict country such as Timor-Leste.

A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs.

Longitudinal path analysis of depressive symptoms and functioning among women of child-rearing age in postconflict Timor-Leste.

This longitudinal study indicates that exposure to the traumas of mass conflict and subsequent depressive symptoms play an important role in pathways leading to functional impairment in the postconflict period among women of child-rearing age. Our study, conducted in Timor-Leste, involved an analytic sample of 1292 women recruited at antenatal clinics in the capital and its surrounding districts. Women were re-interviewed at home 2 years later (77.3% retention). We applied the Edinburgh Postnatal Depression Scale, the Harvard Trauma Questionnaire for conflict-related traumatic events, the WHO Violence Against Women Instrument covering the past year for intimate partner violence and the WHO Disability Assessment Schedule (WHODAS V.2.0) to assess functional impairment. A longitudinal path analysis tested direct and indirect relationships involving past conflict-related trauma exposure, depressive symptoms measured over the two time points and functional impairment at follow-up. The prevalence of predefined clinically significant depressive symptoms diminished from 19.3% to 12.8%. Nevertheless, there was a tendency for depressive symptoms to persist over time (ß=0.20; p<0.001). Follow-up depressive symptoms were associated with functional impairment (ß=0.35; p<0.001). Reported conflict-related trauma occurring a minimum of 6 years earlier (ß=0.23; p<0.001) and past-year physical intimate partner violence (ß=0.26; p<0.001) were each associated with depressive symptoms at baseline and at follow-up. A measure of poverty specific to the context and reported health problems in the mother and infant also contributed to depressive symptoms. The findings highlight the association between ongoing trauma-related depressive symptoms and the capacity of women in the childbearing age to function in multiple areas of their lives in a postconflict country. Recognition of these relationships is important in the formulation and implementation of contemporary international recovery and development policies applied to postconflict countries.

Six-year longitudinal study of pathways leading to explosive anger involving the traumas of recurrent conflict and the cumulative sense of injustice in Timor-Leste.

PURPOSE: Cumulative evidence suggests that explosive anger may be a common reaction among survivors of mass conflict. However, little is known about the course of explosive anger in the years following mass conflict, or the psychosocial factors that influence the trajectory of that reaction pattern. We examined these issues in a 6-year longitudinal study (2004-2010) conducted among adult residents of a rural and an urban village in Timor-Leste (n = 1022). METHODS: We derived a brief, context-specific index of explosive anger using qualitative methods. Widely used measures of post-traumatic stress disorder (PTSD) and severe psychological distress were calibrated to the Timor context. We developed an index of the cumulative sense of injustice related to consecutive historical periods associated with conflict in Timor-Leste. We applied partial structural equation modeling (SEM) to examine pathways from baseline explosive anger, socio-demographic factors, recurrent trauma, mental health indices (PTSD, severe psychological distress) and the sense of injustice, to explosive anger. RESULTS: Half of the sample with explosive anger at baseline continued to report that reaction pattern after 6 years; and a third of those who did not report explosive anger at baseline developed the response by follow-up. A symmetrical pattern of younger age, female gender and the trauma count for the preceding historical period predicted explosive anger at each assessment point. The sense of injustice was related to explosive anger at follow-up. Explosive anger was associated with impairment in functioning and conflict with the intimate partner and wider family. CONCLUSIONS: Sampling constraints caution against generalizing our findings to other populations. Nevertheless, our data suggest that explosive anger may persist for a prolonged period of time following mass conflict and that the response pattern is initiated and maintained by recurrent trauma exposure associated with a sense of injustice. Averting recurrence of mass violence and addressing persisting feelings of injustice may assist in reducing anger in conflict-affected societies. Whether explosive anger at the individual level increases risk of collective violence under conditions of social and political instability requires further inquiry.

Identifying a combined construct of grief and explosive anger as a response to injustice amongst survivors of mass conflict: A latent class analysis of data from Timor-Leste.

Previous studies have identified high rates of explosive anger amongst post-conflict populations including Timor-Leste. We sought to test whether explosive anger was integrally associated with symptoms of grief amongst the Timorese, a society that has experienced extensive conflict-related losses. In 2010 and 2011 we recruited adults (n = 2964), 18-years and older, living in an urban and a rural village in Timor-Leste. We applied latent class analysis to identify subpopulations based on symptoms of explosive anger and grief. The best fitting model comprised three classes: grief (24%), grief-anger (25%), and a low symptom group (51%). There were more women and urban dwellers in the grief and grief-anger classes compared to the reference class. Persons in the grief and grief-anger classes experienced higher rates of witnessing murder and atrocities and traumatic losses, ongoing poverty, and preoccupations with injustice for the two historical periods of conflict (the Indonesian occupation and the later internal conflict). Compared to the reference class, only the grief-anger class reported greater exposure to extreme deprivations during the conflict, ongoing family conflict, and preoccupations with injustice for contemporary times; and compared to the grief class, greater exposure to traumatic losses, poverty, family conflict and preoccupations with injustice for both the internal conflict and contemporary times. A substantial number of adults in this post-conflict country experienced a combined constellation of grief and explosive anger associated with extensive traumatic losses, deprivations, and preoccupations with injustice. Importantly, grief-anger may be linked to family conflict in this post-conflict environment.

Associations between bride price obligations and women's anger, symptoms of mental distress, poverty, spouse and family conflict and preoccupations with injustice in conflict-affected Timor-Leste.

OBJECTIVES: Bride price is a widespread custom in many parts of the world, including in most countries in sub-Saharan Africa and parts of Asia. We hypothesised that problems relating to the obligatory ongoing remittances made by the husband and his family to the bride's family may be a source of mental disturbance (in the form of explosive anger and severe mental distress) among women. In addition, we postulated that problems arising with bride price would be associated with conflict with the spouse and family, poverty and women's preoccupations with injustice. DESIGN: A mixed-methods study comprising a total community household survey and semistructured qualitative interviews. SETTING: Two villages, one urban, the other rural, in Timor-Leste. PARTICIPANTS: 1193 married women participated in the household survey and a structured subsample of 77 women participated in qualitative interviews. RESULTS: Problems with bride price showed a consistent dose-effect relationship with sudden episodes of explosive anger, excessive anger and severe psychological distress. Women with the most severe problems with bride price had twice the poverty scores as those with no problems with the custom. Women with the most severe problems with bride price also reported a threefold increase in conflict with their spouse and a fivefold increase in conflict with family. They also reported heightened preoccupations with injustice. CONCLUSIONS: Our study is the first to show consistent associations between problems with bride price obligations and mental distress, poverty, conflict with spouse and family and preoccupations with injustice among women in a low-income, postconflict country.

Pathways to perinatal depressive symptoms after mass conflict in Timor-Leste: a modelling analysis using cross-sectional data.

BACKGROUND: The contributions of potentially traumatic events (PTEs) of mass conflict and post-traumatic stress disorder (PTSD) symptoms to perinatal depression in women living in low-income, post-conflict countries are unclear. We tested a model including these factors, intimate partner violence (IPV), and continuing adversity in women in Timor-Leste. METHODS: Our modelling study used cross-sectional data from a sample of women living in two districts in Timor-Leste, identified through service registers, clinic records, village chiefs, and a door-to-door survey between June, 2012, and June, 2013. Eligible women were 3-6 months pregnant or 3-6 months postpartum. We assessed conflict-related PTEs, IPV, continuing adversity (poverty and insecurity), PTSD symptoms (the Harvard Trauma Questionnaire), and maternal depressive symptoms (the Edinburgh Postnatal Depression Scale [EPDS]) to develop a theoretical model to examine pathways leading directly and indirectly to depressive symptoms. FINDINGS: We assessed 427 eligible women, of whom 258 (60%) were pregnant and 169 (40%) were postnatal. 87 (22%) of 387 women who were given the EPDS to complete were above the threshold used to define depression, and 40 (9%) of 427 were regarded as having PTSD. Our most comprehensive model showed that IPV and conflict-related deprivations led directly to depressive symptoms as well as to continuing adversity. Human rights-related trauma, witnessing murder, and a further path from IPV led to PTSD symptoms. Human rights-related trauma also led to continuing adversity. Paths from continuing adversity led to depressive symptoms, and PTSD symptoms, which was the predominant path. We noted a strong and unidirectional path from PTSD symptoms to depressive symptoms. INTERPRETATION: Protection of women from human rights abuses, prevention of IPV, reduction in insecurity and poverty in the post-conflict period, and identification of and treatment for PTSD symptoms might reduce the risk of perinatal depression in post-conflict, low-income countries. Longitudinal studies are needed to confirm these findings. FUNDING: Australian National Health and Medical Research Council.

Intermittent explosive disorder amongst women in conflict affected Timor-Leste: associations with human rights trauma, ongoing violence, poverty, and injustice.

INTRODUCTION: Women in conflict-affected countries are at risk of mental disorders such as posttraumatic stress disorder and depression. No studies have investigated the association between experiences of abuse and injustice and explosive anger amongst women in these settings, and the impact of anger on women's health, family relationships and ability to participate in development. METHODS: A mixed methods study including an epidemiological survey (n = 1513, 92.6% response) and qualitative interviews (n = 77) was conducted in Timor-Leste. The indices measured included Intermittent Explosive Disorder, posttraumatic stress disorder; severe distress; days out of role (the number of days that the person was unable to undertake normal activities); gender-specific trauma; conflict/violence; poverty; and preoccupations with injustice. RESULTS: Women with Intermittent Explosive Disorder (n = 184, 12.2%) were more disabled than those without the disorder (for >5 days out of role, 40.8% versus 31.5%, X(2) (2) = 12.93 p = 0.0016). Multivariable associations with Intermittent Explosive Disorder, controlling for the presence of PTSD, psychological distress and other predictors in the model, included the sense of being sick (OR 1.73; 95% CI 1.08-2.77); victimization as a result of helping the resistance movement (OR 2.33, 95% CI 1.48-3.68); war-related trauma specific to being a woman (OR 1.95, 95%, CI 1.09-3.50); ongoing family violence and community conflict (OR 1.88, 95% CI 1.27-2.77); extreme poverty (OR 1.23, 95%, CI 1.08-1.39); and distressing preoccupations with injustice (relating to 2/3 historical periods, OR 2.10, 95% CI 1.35-3.28). In the qualitative study, women elaborated on the determinants of anger and its impact on their health, family and community functioning, child-rearing, and capacity to engage in development. Women reflected on the strategies that might help them overcome their anger. CONCLUSIONS: Intermittent Explosive Disorder is prevalent and disabling amongst women in conflict-affected Timor-Leste, impacting on their health, child-rearing and ability to participate fully in socio-economic development.