Biological mechanisms of disease relapse in childhood medulloblastoma

PhD ThesisOver 30% of patients diagnosed with a medulloblastoma experience disease recurrence. Relapse is almost universally fatal, only infants who receive delayed radiotherapy at disease recurrence typically survive long term. Consequently relapse is the single leading cause of mortality disease-wide. Improved understanding of medulloblastoma at diagnosis has led to the identification of four distinct molecular subgroups with differing biology and outcome. These comprise of medulloblastomas associated with WNT and SHH pathway disruption (MBWNT and MBSHH respectively), and Group 3 and Group 4 tumours (MBGroup3 and MBGroup4). In contrast, very little is understood about the disease at recurrence, and at present there are only two published studies interrogating the biology of relapsed medulloblastoma. However, improved understanding of the biology at relapse is critical to improving treatment. Events at disease relapse could be explored as therapeutic targets or, if predictive of disease recurrence, provide an opportunity to escalate upfront therapy with the aim of preventing relapse. This study compiled a cohort of medulloblastoma tumours sampled at relapse (n=29), paired with their diagnostic counterparts. All clinicopathological and molecular features, with an established relationship to disease prognosis at diagnosis, were interrogated in this paired relapse cohort. With the exception of molecular subgroup, all features investigated displayed evidence of alteration and predominantly acquisition at recurrence. Most strikingly, the emergence of combined p53-MYC defects was commonly observed at relapse and these features were associated with locally aggressive, rapidly progressive disease following relapse. Through collaborative work, this discovery was explored further, with the development of a novel GTML/Trp53 KI/KI mouse model which faithfully recapitulated the clinicopathological and molecular features of the p53-MYC human tumours, and demonstrated the dependency of tumourigenesis and maintenance on this genetic interaction. Moreover, therapeutic inhibition of Aurora A kinase using MLN8237 in these mouse tumours led to degradation of MYCN, tumour reduction and prolonged survival. v A novel genome-wide DNA methylation analysis was next undertaken in the paired relapse cohort, focusing on MBGroup4 tumours, to interrogate maintained and acquired DNA methylation events between diagnosis and relapse, which may play a role in tumour development. Individual CpG sites on the Infinium DNA methylation 450K array were assessed for changes in their DNA methylation status between diagnosis and relapse. Fifteen candidate genes demonstrated tumour-specific methylation states that emerged at relapse and correlated with gene expression. The T-box and Homeobox gene families accounted for 8/15 (53%) candidates identified. Both these families are reportedly important for tumour development in other cancers. In addition, several studies suggest that epigenetic mechanisms, such as DNA methylation, play a regulatory role in their gene expression. Finally, a large cohort of medulloblastoma tumours (n=206), sampled at diagnosis, from patients who are known to go on and recur, was assembled to investigate any subgroup-specific patterns and timings of relapse. MBWNT rarely relapsed, whereas MBSHH frequently relapsed at both local and distant sites, but were the tumour subgroup most readily salvaged by radiotherapy in patients who were not treated with craniospinal irradiation (CSI) at diagnosis (8/12, 67%). Both MBGroup3 and MBGroup4 were widely metastatic at recurrence (34/41 (83%) and 52/61 (85%)) but contrastingly MBGroup3 relapsed quickly (p=0.0022), whereas MBGroup4 relapsed more slowly (p=0.0008). In patients who did not receive upfront CSI, MYC amplification at diagnosis was associated with rapid disease progression after relapse (p=0.0003). No diagnostic feature was significantly associated with time to death following relapse in the cohort of patients who received upfront CSI. This finding was supported by data from the paired relapse cohort where, in patients who received upfront CSI, it was the biological features of the tumour at relapse and not diagnosis, which were associated with disease course. In summary, this study has discovered emergent combined p53-MYC defects at medulloblastoma relapse which are associated with disease behaviour, identified potentially epigenetically regulated candidate genes in relapsed MBGroup4 tumours, and shown that the patterns of disease relapse are associated with radiotherapy and molecular subgroup. Together these findings demonstrate that medulloblastoma tumour biology is significantly different at relapse and that the timings and location of vi disease recurrence should be considered in the context of molecular subgroup and treatment. Biopsy at disease recurrence is now essential to validate and expand on these novel findings, interrogate all molecular subgroups at disease recurrence, and translate these discoveries into improved outcomes for the patients suffering from this devastating diagnosis.Action Medical Researc

Agreement between telehealth and in-person assessment of patients with chronic musculoskeletal conditions presenting to an advanced-practice physiotherapy screening clinic

Objective: To determine the level of agreement between a telehealth and in-person assessment of a representative sample of patients with chronic musculoskeletal conditions referred to an advanced-practice physiotherapy screening clinic. Design: Repeated-measures study design. Participants: 42 patients referred to the Neurosurgical & Orthopaedic Physiotherapy Screening Clinic (Queensland, Australia) for assessment of their chronic lumbar spine, knee or shoulder condition. Intervention: Participants underwent two consecutive assessments by different physiotherapists within a single clinic session. In-person assessments were conducted as per standard clinical practice. Telehealth assessments took place remotely via videoconferencing. Six Musculoskeletal Physiotherapists were paired together to perform both assessment types. Main outcome measures: Clinical management decisions including (i) recommended management pathways, (ii) referral to allied health professions, (iii) clinical diagnostics, and (iv) requirement for further investigations were compared using reliability and agreement statistics. Results: There was substantial agreement (83.3%; 35/42 cases) between in-person and telehealth assessments for recommended management pathways. Moderate to near perfect agreement (AC1 = 0.58–0.9) was reached for referral to individual allied health professionals. Diagnostic agreement was 83.3% between the two delivery mediums, whilst there was substantial agreement (81%; AC1 = 0.74) when requesting further investigations. Overall, participants were satisfied with the telehealth assessment. Conclusion: There is a high level of agreement between telehealth and in-person assessments with respect to clinical management decisions and diagnosis of patients with chronic musculoskeletal conditions managed in an advanced-practice physiotherapy screening clinic. Telehealth can be considered as a viable and effective medium to assess those patients who are unable to attend these services in person

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Rates of diagnostic transition and cognitive change at 18-month follow-up among 1,112 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL)

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing is a prospective study of 1,112 individuals (211 with Alzheimer's disease (AD), 133 with mild cognitive impairment (MCI), and 768 healthy controls (HCs)). Here we report diagnostic and cognitive findings at the first (18-month) follow-up of the cohort. The first aim was to compute rates of transition from HC to MCI, and MCI to AD. The second aim was to characterize the cognitive profiles of individuals who transitioned to a more severe disease stage compared with those who did not. Methods: Eighteen months after baseline, participants underwent comprehensive cognitive testing and diagnostic review, provided an 80 ml blood sample, and completed health and lifestyle questionnaires. A subgroup also underwent amyloid PET and MRI neuroimaging. Results: The diagnostic status of 89.9% of the cohorts was determined (972 were reassessed, 28 had died, and 112 did not return for reassessment). The 18-month cohort comprised 692 HCs, 82 MCI cases, 197 AD patients, and one Parkinson's disease dementia case. The transition rate from HC to MCI was 2.5%, and cognitive decline in HCs who transitioned to MCI was greatest in memory and naming domains compared to HCs who remained stable. The transition rate from MCI to AD was 30.5%. Conclusion: There was a high retention rate after 18 months. Rates of transition from healthy aging to MCI, and MCI to AD, were consistent with established estimates. Follow-up of this cohort over longer periods will elucidate robust predictors of future cognitive decline.12 page(s