Association of chemotherapy dose intensity and age with outcomes in patients with Ewing's family sarcoma

BACKGROUND: Ewing's family sarcoma (EFS) is an aggressive malignancy with a peak incidence in adolescents. Multimodal treatment involves surgery and/or radiotherapy, and chemotherapy typically with VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide). There is a paucity of data for the treatment of adults, with protocols extrapolated from the pediatric setting. This study aimed to assess patterns of care, chemotherapy tolerability across age groups, and outcomes from four Australian sarcoma centers. METHODS: ANZSA ACCORD sarcoma database and medical records were used to identify and collect data of patients aged ≥ 10 years with EFS who received VDC/IE between 2010 and 2020. Survival outcomes were analyzed based on chemotherapy received dose intensity (RDI). Clinical predictors of RDI were explored using logistic regression. RESULTS: Of 146 patients with EFS, 76 received VDC/IE. The majority had localized disease (65%). Seventy-one percent completed scheduled chemotherapy, with some requiring dose reduction (29%), delay > 7 days (65%), or cycle omission (4%). Hematological toxicity was the main reason for dose reduction/delay. Fifty-seven percent patients achieved an acceptable RDI ≥85%. Compared to those aged 10-19, the odds ratio for acceptable RDI aged 40-59 was 0.20 (95% CI 0.04-0.86, p = 0.04). RDI was an independent prognostic factor for overall survival, after accounting for age, gender, Ewing's type, primary site, and stage (adjusted HR 0.25 [95% CI 0.10-0.63], p = 0.004). CONCLUSION: Survival outcomes in EFS were associated with chemotherapy RDI. Older adults more commonly required dose reduction or early cessation of treatment due to toxicity. VDC/IE chemotherapy should be carefully tailored in adults > 40 years

Systems serology analysis shows IgG1 and IgG3 memory responses six years after one dose of quadrivalent HPV vaccine

The WHO has given a permissive recommendation for an off-label one-dose human papillomavirus (HPV) vaccine schedule to prevent cervical cancer, based on evidence of comparable protection to two or three doses of vaccine. While neutralizing antibodies are thought to be the primary mechanism of protection, the persistence of immunity and whether other antibody-mediated mechanisms of protection are involved is unclear. Using systems serology, we investigated HPV antibody responses in serum from Fijian girls who were unvaccinated or received one, two or three doses of quadrivalent HPV vaccine six years earlier. We also evaluated their HPV antibody responses 28 days following a dose of bivalent HPV vaccine. After six years, one dose induced lower antibody concentrations but similar antibody profiles and phagocytic function as two or three doses. Following bivalent vaccine, antibody concentrations, particularly IgG1/IgG3, antibody profiles and phagocytic function were similar between previously vaccinated girls, indicating immune memory after one dose. Cross-reactive antibody responses against non-vaccine genotypes (HPV31/33/45/52/58) were lower following one dose than two or three doses. These findings provide novel insights into serological immunity and recall responses following one-dose HPV vaccination

Optimised modular anti-FLAG CAR T cells for solid tumor therapy

Objectives: Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of B cell malignancies and show promise in other diseases, including autoimmune disorders and cardiac injury. However, broader application, particularly in solid tumours, is limited by challenges such as antigen escape and tumour heterogeneity. This study aimed to develop an anti-FLAG CAR capable of engaging FLAG-tagged secondary reagents, providing a flexible and adaptable targeting strategy. Methods: We engineered a humanised anti-FLAG CAR to engage FLAG-tagged secondary reagents. The initial construct exhibited tonic signalling, which was addressed through structural optimisation. Therapeutic efficacy was assessed in solid tumour mouse models expressing either FLAG or a FLAG-tagged secondary targeting reagent. Results: The initial anti-FLAG CAR showed functional activity but exhibited tonic signalling and exhaustion, limiting its therapeutic utility. Structural optimisation significantly reduced exhaustion and improved T cell persistence and functionality. The optimised CAR T cells effectively inhibited tumour growth in models using either FLAG- engineered tumour cells or a FLAG-tagged secondary targeting reagent. Conclusion: Our findings underscore the importance of CAR design in minimising exhaustion and enhancing therapeutic efficacy. This work supports a modular CAR T cell platform with the potential to overcome tumour antigen heterogeneity and immune evasion in solid cancers

Right Bundle Branch Block After Transvenous Lead Extraction: An Unreported Complication With Potentially Severe Outcomes

INTRODUCTION: Right bundle branch block (RBBB) following cardiac device extraction has not been previously reported but may have catastrophic consequences. METHODS AND RESULTS: We present two cases of young male patients who developed RBBB following the extraction of single chamber TV ICD systems where the coil was adherent close to the superior tricuspid valve annulus. Both patients had a subcutaneous ICD (SICD) implanted but suffered an inappropriate shock due to T-wave oversensing, requiring very early SICD removal for one patient. CONCLUSION: The development of RBBB following the extraction of a TV ICD is a previously unreported complication and may cause significant sensing problems if an SICD is implanted subsequently. Placement of the ICD lead tip in the right ventricular outflow tract or high on the intraventricular septum may predispose to this complication

Mapping provider and consumer voices using the AACTT framework: a focus group study of advance care planning

BACKGROUND: The provision of healthcare is complex. When evidence-practice gaps are identified, interventions to improve practice across multi-level systems are required. These interventions often consist of multiple interacting components and behaviours. To effectively address these complexities, it is crucial to first identify the specific roles and actions required at each stage of the intervention. This approach enables a thorough examination of what is working well and what needs to be optimised. The action, actor, context, target, time (AACTT) framework provides a consistent approach to identifying key elements such as 'who' (actor) does 'what' (action), 'where' (context), 'to or with whom' (target) and 'when' (time). To our knowledge the AACTT has not yet been applied: 1) to specify complex interventions across patient journeys; and 2) to investigate consumer views, despite the importance of patient-centred care. AIM: Using advance care planning (ACP) as an exemplar complex healthcare process, we describe a method for using the AACTT framework to 1) map a complex model of care across a patient journey 2) capture the consumer perspective; and 3) operationalise these perspectives by comparing across groups and identifying alignments or misalignments. METHODS: Two groups were recruited (healthcare professionals and consumers). Informed by the AACTT framework, four focus groups discussed the process of ACP across existing care pathways. Maps visually representing the perspectives and preferences of healthcare professionals and consumers were co-created iteratively. Qualitative data was deductively coded to the AACTT framework and inductively coded to identify themes within domains. Maps were circulated for critical feedback and refined. RESULTS: Healthcare professional (n-13) and consumer perspectives (n = 11) highlighted what is 'currently occurring' in practice, what is 'not occurring', and what 'should be occurring' to align practice with consumer preferences of care. Comparing participant perspectives identified that most misalignment occurred within the actor, context, and time domains. Misalignment was found predominantly in actions 'occurring sometimes', with no converging perspectives reported for the context and time domains. CONCLUSION: This novel application of the AACTT framework systematically brings in the consumer voice in ways that may influence the delivery of care. This approach to specifying healthcare professional and consumer perspectives across a complex care pathway identifies barriers that are not found with traditional mapping methods or in current applications of the AACTT framework

A generalized epilepsy network derived from brain abnormalities and deep brain stimulation

Idiopathic generalized epilepsy (IGE) is a brain network disease, but the location of this network and its relevance for treatment remain unclear. We combine the locations of brain abnormalities in IGE (131 coordinates from 21 studies) with the human connectome to identify an IGE network. We validate this network by showing alignment with structural brain abnormalities previously identified in IGE and brain areas activated by generalized epileptiform discharges in simultaneous electroencephalogram-functional magnetic resonance imaging. The topography of the IGE network aligns with brain networks involved in motor control and loss of consciousness consistent with generalized seizure semiology. To investigate therapeutic relevance, we analyze data from 21 patients with IGE treated with deep brain stimulation (DBS) for generalized seizures. Seizure frequency reduced a median 90% after DBS and stimulation sites intersect an IGE network peak in the centromedian nucleus of the thalamus. Together, this study helps unify prior findings in IGE and identify a brain network target that can be tested in clinical trials of brain stimulation to control generalized seizures

Step-Wise Assembly of LAT Signaling Clusters Immediately After T Cell Receptor Triggering Contributes to Signal Propagation

Linker for activation of T cells (LAT) is an essential adaptor protein in early T cell receptor (TCR) signaling that propagates multiple signaling pathways. However, how LAT spatial organization facilitates signal initiation and propagation after TCR triggering is not clear. To differentiate de novo assembly in the plasma membrane from pre-existing LAT vesicles and clusters, we developed imaging protocols and analyses to capture the organization and dynamics of single LAT molecules immediately after TCR engagement. We could observe individual LAT molecules in the plasma membrane that assembled into immobile signaling entities requiring LAT phosphorylation. This step-wise assembly process was temporally highly coordinated via the zeta-chain-associated protein kinase 70 (Zap70)-LAT-growth factor receptor-bound protein 2 (Grb2) pathway. While multiple spatial organization co-existed even within the plasma membrane, our data suggest that de novo plasma membrane assemblies facilitated signal propagation

Dietary Patterns and Major Depression: Results from 15,262 Participants (International ALIMENTAL Study)

BACKGROUND: Different patterns of food consumption may be associated with a differential risk of depression. Differences in dietary patterns between men and women and across different age groups have been reported, but their influence on the risk of depression has not been fully explored. OBJECTIVES: To investigate the associations between dietary patterns and risk of depression across sex and age groups to identify vulnerable subpopulations, which may inform targeted prevention and intervention strategies. METHODS: The ALIMENTAL study was a cross-sectional, online international survey conducted between 2021 and 2023. Dietary data were collected using a validated food frequency questionnaire; depression data were collected using a self-reported validated questionnaire. Principal component analysis (PCA) was applied to identify distinct food consumption patterns. Multivariate analyses were then conducted to assess the associations between these patterns and depression, adjusting for multiple potential confounders. RESULTS: Among 15,262 participants without chronic diseases or current psychotropic treatments, 4923 (32.2%) were classified in the depression group. Among those aged 18-34, the PCA-derived factor of ultra-processed foods consumption was significantly associated with increased risk of depression in both sexes with similar odds ratios (women 1.21, 95% confidence interval (CI): (1.15; 1.27), men 1.21, 95% CI: (1.07-1.18)). In women aged 18-34, the PCA factors for sodas (aOR 1.10, 95% CI: (1.06; 1.95) and canned and frozen foods (aOR 1.10, 95% CI: (1.04; 1.15) were associated with an increased risk of depression. In participants aged 35-54 years, the association between ultra-processed foods and depression was only observed in women (35-54 years: aOR 1.30, 95% CI: (1.20; 1.42), ≥55 years: 1.41, 95% CI: (1.11; 1.79)), with a significant association between a higher adherence to the PCA-derived "healthy diet" factor (e.g., fruits, nuts, green vegetables) and a lower risk of depression (35-54 years: aOR 0.82, 95% CI: (0.75; 0.89), ≥55 years: aOR 0.79, 95% CI: (0.64; 0.97)). CONCLUSIONS: These results show significant differences between men and women and between age groups regarding associations between dietary patterns and the risk of depression. These findings can help better target public health interventions