Royal Melbourne Hospital

Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen's d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R2 = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R2 = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.

Multiparametric flow cytometry (MFC) enables rapid and sensitive quantification of measurable residual disease (MRD) in patients with acute myeloid leukaemia (AML), providing valuable prognostic information and guiding post-remission therapeutic strategies. Given the clinical utility of MFC AML MRD assessment and its inherent technical and analytical complexity, inter-laboratory standardisation is essential to ensure consistency of practice, diagnostic accuracy and reproducibility of results. However, limited options for external quality assessment exist. Representatives from all diagnostic laboratories in Australia and New Zealand currently performing AML MRD testing were invited to attend an in-person workshop to review site-specific practices and develop harmonisation processes. All six participating laboratories demonstrated a high level of concordance with respect to pre-analytical testing; however, greater variation was observed in post-analytical reporting, and a number of consensus recommendations were formulated for harmonisation. Ongoing meetings have also been established to promote continued sharing of expertise between AML MRD laboratories, align analytical strategies and enhance assay validation in accordance with regulatory requirements. These collaborative efforts provide guidance to existing MRD laboratories and those seeking to establish a new MRD service, facilitating sustainable provision of a high-quality regional MFC AML MRD testing network to meet current and anticipated increases in clinical demand.

To investigate the value of baseline CT imaging for the prediction of functional outcome and benefit of endovascular thrombectomy (EVT) for anterior large vessel occlusion (LVO). We used individual patient data from seven randomized EVT trials and included patients with available baseline CT imaging and outcome data. We developed a model to predict functional outcome and benefit of EVT, including baseline stroke-related and brain frailty CT imaging features alone. We compared the discriminative performance of our model for predicting good functional outcome (modified Rankin Scale [mRS] 0-2) and treatment benefit (difference between the probability of mRS 0-2 with vs without EVT) with MR PREDICTS by calculating the difference in C-statistics (delta C and delta C-for-benefit). We included 1391 patients (median age, 67 years, interquartile range 59-76; 53% male). Discrimination of the model based on CT imaging alone was substantial for the prediction of good functional outcome (C-statistic 0.700, 95% CI: 0.666-0.731) and treatment benefit (C-for-benefit 0.640, 95% CI: 0.586-0.690). After adding the known strongest clinical predictors namely age and National Institutes of Health Stroke Scale score, discrimination improved to slightly lower than MR PREDICTS for prediction of good functional outcome (C-statistic 0.733 vs 0.750; delta C, -0.017 [95% CI: -0.037 to 0.003]) and treatment benefit (C-for-benefit 0.675 vs 0.692; delta C-for-benefit -0.017 [95% CI: -0.084 to 0.050]). Baseline CT imaging holds considerable predictive value with regard to functional outcome and treatment benefit, but a combination of clinical and imaging features offers the best predictive performance. Question The predictive value of baseline CT imaging for the prediction of functional outcome and benefit of EVT for anterior LVO stroke is uncertain. Findings Discrimination of a model based on CT imaging alone is substantial, but can further be improved by the addition of limited clinical characteristics. Clinical relevance Baseline CT imaging holds considerable predictive value with regard to functional outcome and treatment benefit. The addition of limited clinical information is needed to achieve predictive performance similar to an established prediction model.

Today's common practice of empiric activity prescription in radiopharmaceutical therapy is inconsistent with the modern philosophy of personalized medicine. We investigate the radiobiologic relationship between tumor mean absorbed dose (D mean) and progression-free survival (PFS) in 177Lu-PSMA I&T therapy guided by personalized predictive dosimetry in metastatic castration-resistant prostate cancer. Methods: We conducted a single-center retrospective study of the first 20 patients treated with 177Lu-PSMA I&T at our institution. PFS was calculated from the day a patient was assessed by a nuclear medicine physician in the clinic until treatment cessation (due to progression or toxicity) or death. D mean was estimated by predictive dosimetry. Correlation with PFS was performed on the following baseline characteristics: age, Gleason score, Eastern Cooperative Oncology Group performance status, estimated glomerular filtration rate, prostate-specific antigen (PSA) doubling time, injected activity per treatment, D mean and D mean per gigabecquerel. Results: Twenty patients naïve to 177Lu-PSMA were treated over a 2-y period, totaling 65 infusions. The median PSA doubling time was 1.6 mo at baseline. The median follow-up time was 8.4 mo (interquartile range [IQR], 4.6-14.5 mo). Each patient received 3 ± 1 treatments (range, 1-5), with a mean injected activity of 7.74 ± 0.66 GBq per treatment. The mean injected activity for the first treatment was 7.85 ± 0.71 GBq. The median D mean for the first treatment was 23 Gy (IQR, 15-36 Gy). The median PFS was 10.6 mo for a D mean of 23 Gy or greater and was 3.1 mo for a D mean of less than 23 Gy (hazard ratio, 0.39; 95% CI, 0.22-0.68; P < 0.01). There were statistically significant correlations between PFS, PSA doubling time, and D mean (P < 0.05). However, there was no statistically significant correlation between the injected activity per treatment versus PFS or D mean (P > 0.05). Conclusion: We found a strong direct correlation between D mean and PFS in patients with metastatic castration-resistant prostate cancer treated with 177Lu-PSMA in a real-world setting. We identified a D mean of 23 Gy as a possible threshold for significantly better PFS in our cohort with median PSA doubling time of 1.6 mo. Our findings support radiobiologically sound prescription based on the radiation absorbed dose by personalized predictive dosimetry.

The association of idiopathic intracranial hypertension (IIH) with spontaneous skull base CSF leaks is well known; however, its role in spinal CSF leaks is poorly established. CSF-venous fistula (CVFs) are a recognized subtype of spinal CSF leaks, but they rarely recur after successful treatment. Brainstem sagging is a known consequence of spontaneous intracranial hypotension with variable clinical sequelae. Brainstem sagging has not previously been demonstrated to cause obstructive hydrocephalus. The authors describe the case of a female in her early 5th decade with presumed IIH-induced recurrent spinal CVFs. They detail the recurrent nature of her CVFs despite successful transvenous embolization, the advanced imaging techniques required for diagnosis, and the consequences of untreated intracranial hypotension, including bulbar dysfunction and obstructive hydrocephalus requiring external ventricular drainage. The placement of a ventriculoperitoneal shunt to prevent further spinal CVF recurrence is also described. This illustrative case highlights the complexity of treatment in recurrent spinal CVFs and intracranial hypotension. The authors detail the extreme consequences of untreated intracranial hypotension, including obstructive hydrocephalus and progressive bulbar dysfunction. In this context, the necessity of external ventricular drainage in order to equalize transtentorial pressure differentials and restore consciousness is demonstrated. https://thejns.org/doi/10.3171/CASE25680.

Androgen deprivation therapy (ADT) has been pivotal in advanced prostate cancer (PCa) for decades. The introduction of androgen-receptor pathway inhibitors (ARPIs) has transformed treatment paradigms. However, their real-world adoption over time has not been comprehensively characterised. We examined prescribing trends for androgen-directed therapies in Australia over a 29-year period. A retrospective population-based analysis of Pharmaceutical Benefits Scheme (PBS) dispensing data (1996-2024) was performed. PBS-listed anti-androgen therapies-luteinising hormone-releasing hormone (LHRH) agonists (goserelin, leuprorelin, triptorelin), combined androgen blockage (CAB) (LHRH + bicalutamide), ARPIs (enzalutamide, apalutamide, darolutamide, abiraterone)-were included. Annual prescription counts were standardised per 100,000 men. Outcomes included temporal trends, proportional contribution of each drug class, and the effect of ARPI introduction using interrupted time-series (ITS) analysis. Anti-androgen prescriptions rose from 146 to 228,707 between 1996 and 2024, respectively. LHRH monotherapy accounted for > 94% of prescriptions prior to ARPI approval, declining to 51.61% in 2024 despite continued absolute growth (+ 65.16 prescriptions/100,000/year, p < 0.0001). ARPIs expanded following PBS listing, increasing from 2.44% in 2013 to 47.28% in 2024 (+ 131.9 prescriptions/100,000/year, p < 0.0001). ITS modelling demonstrated a significant immediate level increase of + 9.85 percentage points (p < 0.0001) and sustained a post-intervention slope increase of + 3.04 percentage points per year (p < 0.0001) following ARPI introduction, closely mirroring observed proportional and absolute growth 3.44-47.28% between 2013 and 2024, respectively. Australia has transitioned from predominately LHRH-based therapy to widespread use of ARPIs. Health-system structures enabling timely clinical access appears pivotal to the rapid and equitable diffusion of high-value androgen-targeted therapies.

Unplanned return to theater (URTT) following head and neck cancer reconstruction presents significant clinical and economic challenges. Identifying risk factors for URTT can aid in surgical planning and patient risk stratification. This study evaluates preoperative and intraoperative factors associated with URTT in patients undergoing free flap reconstruction after head and neck tumor resection. A retrospective cohort study was conducted on patients undergoing head and neck tumor resection with free flap reconstruction between July 2015 and January 2024. Demographic, clinical, and operative data were analyzed using univariable and multivariable logistic regression. Of 609 patients included, 199 (32.7%) experienced URTT within 90 days postoperatively. Common indications for URTT included infected collections (33.7%), hematoma (24.6%), and flap dehiscence (16.1%). On univariable analysis, preoperative PEG tube use (unadjusted odds ratio (OR) 1.78 [95% confidence interval (CI) 1.03-3.07], p = 0.04), higher frailty index scores (1.27 [1.03-1.58], p = 0.03), longer operative duration (1.15 [1.06-1.24], p < 0.001), use of bony free flaps (2.08 [1.44-3.01], p < 0.001), and tracheostomy (2.09 [1.22-3.56], p = 0.01) were associated with URTT. Yet, on multivariable analysis, only higher frailty index score (adjusted OR 1.32, 95% CI 1.03-1.70, p = 0.03) and use of bony free flaps (adjusted OR 1.92, 95% CI 1.19-3.11, p < 0.01) retained statistical significance. The findings of this study suggest that frailty and the use of bony free flaps are key risk factors for URTT among reconstructive head and neck cancer patients. These findings support patient risk stratification preoperatively and targeted interventions to reduce the risk of URTT and improve resource utilization in head and neck cancer surgery.

Plain Language SummaryPatients with acute stroke due to occlusion of large head blood vessels ideally have the occlusion removed via a surgical procedure (endovascular thrombectomy). They often need transfer between a peripheral and central hospital for this standard of care. Some patients will improve their occlusion while en-route and not need this surgical procedure. Predicting these patients is important in preventing unnecessary surgery. Our last study found that an improvement in National Institute of Health Stroke Scale of one-third or more was an excellent predictor of occlusion resolution. This study assessed this phenomenon in a separate group of patients and again found that a one-third or more improvement in stroke score correlated very well with occlusion resolution before surgical procedure at the central hospital. However, practically using this improvement threshold in a cost model saves only 34 dollars per patient and, for this reason, may be of higher use in areas that have higher logistic, financial, or geographic barriers to access endovascular thrombectomy.

Islet autoantibodies herald early type 1 diabetes. However, less is known of the evolution of autoantibodies to the islet autoantigen ZnT8. Our primary aim was to characterise the development of islet autoantibodies in a pregnancy-birth at-risk cohort and to provide new knowledgeabout ZnT8A. Islet autoantibodies were measured every 3-6 months in 1277/1473 children with a first-degree relative with type 1 diabetes who were followed prospectively from pregnancy in the Environmental Determinants of Islet Autoimmunity (ENDIA) cohort for 7.0 (IQR 5.8-8.3) years. Islet autoantibodies were also measured in the mothers and/or in cord blood in 901 pregnancies with type 1 diabetes. The development of persistent IAA reached a probability of 0.02 by 2 years of age. A combination of IAA- and GADA-first, GADA-first and ZnT8A-first all reached a similar probability by 5 years of age. ZnT8A appeared as the first islet autoantibody, alone or in combination, in 43 (32%) of the 134/1473 children with persistent islet autoantibodies. Persistent single ZnT8A, detected only by ELISA, usually appeared after 4 years of age. ZnT8A that progressed to multiple islet autoantibodies or type 1 diabetes were detected in younger children (p=0.006) and in multiple assay formats. ZnT8A were confirmed in additional assay formats when present with multiple islet autoantibodies, but not when remaining as a single islet autoantibody, unlike IAA and GADA. Maternal islet GADA were detected until 15 months of age and transmission of any islet antibody/autoantibody did not relate to islet autoantibody development in the offspring (χ2=3.32, df=2, p=0.19). Persistent single ZnT8A, which are detected only by ELISA and no other test format, appear not to confer an increased risk of progression to type 1 diabetes.