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Myeloma bone disease (MBD) affects ~90% of multiple myeloma patients, but current treatment options are suboptimal. Therefore, to successfully develop new therapies or optimize current ones, we must improve our fundamental knowledge of how myeloma affects bone microstructure and function. Here, we have investigated the osteocyte lacuno-canalicular network (LCN) in MBD, as bone porosity affects bone quality and resilience. We used the syngeneic 5TGM1-C57BL-Kalwrij and the xenograft U266-NSG models at end stage and compared them to healthy controls (naïve). Micro-computed tomography (μCT) and histomorphometry indicated the 5TGM1 and U266 models developed mild and extensive MBD, respectively, with the U266 model producing large osteolytic lesions. High-resolution synchrotron micro-CT (SR-μCT) revealed significant osteocyte lacunae changes in U266 bones but not 5TGM1, with a reduction in lacunae number and sphericity, and an increase in lacunae volume compared with naïve. Canalicular length, visualized using histological Ploton silver staining, appeared significantly shorter in 5TGM1 and U266 bones compared with naïve. Canalicular area as a proportion of the bone was also decreased by 24.2% in the U266 model. We observed significant upregulation of genes implicated in peri-lacunar remodeling (PLR), but immunohistochemistry confirmed that the osteocyte-specific protein sclerostin, a known driver of PLR, was unchanged between MBD and naïve bones. In summary, we have demonstrated evidence of PLR and altered organization of the osteocyte LCN in MBD mouse models. The next step would be to further understand the drivers and implications of PLR in MBD, and whether treatments to manipulate PLR and the LCN may improve patient outcomes. Lay Summary: Multiple myeloma is a blood cancer that causes bone damage in ~90% of patients. Currently, treatment options for myeloma bone disease (MBD) are suboptimal, leaving patients with chronic pain and increased fracture risk. Therefore, it is important that we improve our fundamental knowledge of how myeloma causes bone damage. With the development of more powerful imaging technologies, this allows us to visualize bone at the submicron level. Here, we assessed bones from two murine models of MBD (termed 5TGM1 and U266) and compared them to bones from healthy control mice (naïve). Using high-resolution imaging (SR-μCT), we found structural changes in the pores where the most abundant bone cells (osteocytes) reside, and that the orientation of their signaling network (lacuno-canalicular network, LCN) is altered in MBD compared with healthy bones. We also found differences in gene expression of key molecules in osteocytes from bones with MBD compared with healthy bones and identified a potential mechanism leading to these changes. The next step would be to use this knowledge to determine how myeloma treatments can affect the osteocyte LCN, as this may allow informed treatment decisions to be made, potentially reducing fracture risk and improving outcomes for patients with MBD. Graphical Abstract [ABSTRACT FROM AUTHOR]

Talking about dying when faced with end-of-life may be important for achieving optimal outcomes for young people and their families. Given the lack of research on young people's communication around end-of-life and death, this analogue study examined the role of attachment theory in conversations about dying. Experiment 1 assessed attachment security of 80 healthy young adults and randomised them to receive either an induction that raised awareness of one's attachment figures or a neutral induction, and then primed them with an imagined scenario where they were diagnosed with an incurable illness. Participants then completed a self-report measure of their willingness to discuss end-of-life topics with family, friends, or a psychologist. The experimental attachment induction did not increase willingness to talk about end-of-life concepts. Experiment 2 extended this design and asked participants to describe these conversations and assessed the content of their imagined end-of-life conversations. Experiment 2 replicated the finding that enhancing individuals' awareness of key attachment figures did not increase participants' willingness to engage in end-of-life conversations. However, heightened attachment awareness led participants to talk more about their relationship with the person they were hypothetically talking with. Across both experiments, avoidant attachment tendencies reduced the likelihood that participants receiving the attachment prime would want to engage in end-of-life conversation. Overall, it seems there are important differences between individuals on willingness to talk about death, and this may be influenced by one's attachment style. These results raise implications for the importance of attachment in the therapeutic relationship for healthcare professionals working with young people with life-limiting illnesses, such as cancer. Further research may shed light on how an individually tailored approach, taking into account attachment security, achieves the best outcomes for individuals who require end-of-life conversations. [ABSTRACT FROM AUTHOR]

Objectives: Hard-to-treat childhood cancers are those where standard treatment options do not exist and the prognosis is poor. Healthcare professionals (HCPs) are responsible for communicating with families about prognosis and complex experimental treatments. We aimed to identify HCPs' key challenges and skills required when communicating with families about hard-to-treat cancers and their perceptions of communication-related training. Methods: We interviewed Australian HCPs who had direct responsibilities in managing children/adolescents with hard-to-treat cancer within the past 24 months. Interviews were analyzed using qualitative content analysis. Results: We interviewed 10 oncologists, 7 nurses, and 3 social workers. HCPs identified several challenges for communication with families including: balancing information provision while maintaining realistic hope; managing their own uncertainty; and nurses and social workers being underutilized during conversations with families, despite widespread preferences for multidisciplinary teamwork. HCPs perceived that making themselves available to families, empowering them to ask questions, and repeating information helped to establish and maintain trusting relationships with families. Half the HCPs reported receiving no formal training for communicating prognosis and treatment options with families of children with hard-to-treat cancers. Nurses, social workers, and less experienced oncologists supported the development of communication training resources, more so than more experienced oncologists. Significance of results: Resources are needed which support HCPs to communicate with families of children with hard-to-treat cancers. Such resources may be particularly beneficial for junior oncologists and other HCPs during their training, and they should aim to prepare them for common challenges and foster greater multidisciplinary collaboration. [ABSTRACT FROM AUTHOR]

This paper investigates the role of caregiver mental health and parenting practices as predictors of attachment in children with intellectual disability/developmental delay, comparing between children with ASD (n = 29) and children with other developmental disabilities (n = 20). Parents reported that children with ASD had high levels of anxiety and stress, and attachment insecurity in children (less closeness and more conflict in attachment relationships, and more inhibited attachment behaviours) compared with children with other developmental disabilities. Children's attachment quality was associated with parenting practices and the presence of an ASD diagnosis. These results highlight the bidirectional nature of the quality of caregiving environments and attachment in children with ASD, and also provide a strong rationale for targeting children's attachment quality in early interventions. [This article represents a collaborative effort on behalf of the Mental Health of Young People with Developmental Disabilities (MHYPeDD) team.]

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia (1). Tumour-secreted proteins play a crucial role in these interactions (2-5) and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable (6). Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality (6,7). The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATcl-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications., Using a primary tumour hypoxic signature (8), retrospective analysis of a cohort of lymph-node-negative breast cancer patients who received no systemic adjuvant therapy (9) revealed a significant association with metastasis [...]