Introduction ADVC001 is a patented PSMA-targeting radioligand labelled with 212Pb, an alpha-emitting payload with a short half-life of 10.6 hrs, designed to deliver radiation precisely on a cellular level. Objectives We present results from the Phase 1b part of the TheraPb trial (NCT05720130) evaluating 212Pb-ADVC001 in patients (pts) with metastatic prostate cancer. The feasibility of positron emission tomography (PET) imaging of 212Pb in phantoms and in pts receivin Materials and Methods Open-label, multi-center interval 3+3 dose-escalation and expansion study in pts with progressive PSMA-avid (> liver) mCRPC previously treated with ≥ 1 taxane unless unsuitable/declined and ≥ 1 androgen pathway inhibitor (ARPi). Escalating doses of 60–200 MBq were administered at prespecified intervals every 6, 4, 2 and 1 week(s) for up to 6 cycles in an outpatient setting with minimal restrictions at discharge 3 hours post administration. Primary endpoints were safety and defining the recommended Phase 2 dose and administration schedule.212Pb-ADCV001 point sources in glass capillary tubes in a water phantom were imaged to determine the system spatial resolution, full width at half maximum (FWHM). An IEC phantom was imaged with 98 kBq/mL in the spheres, zero background. Ethics approval for exploratory PET imaging was received and informed consent was obtained by pts.. PET acquisitions were performed using two bed positions, with 15 minutes per bed position, covering the thoracic and abdominal regions including the kidneys, using a Siemens Vision scanner. Results As of the 2 October 2025 data cut-off, dose escalation was completed (n=22). 73% of pts had ≥ 1 prior taxane, 36% had ≥ 2 prior lines of chemotherapy, and all had ≥ 1 prior ARPi. There were no dose-limiting toxicities, dose modifications or treatment discontinuations due to treatment-related adverse events (TRAEs); there were no Gr 4/5 TRAEs, signs of myelosuppression or radiation adverse events of special interest. Xerostomia was predominantly Gr 1, with evidence of reversibility. A PSA50 response was observed in 80% of pts treated at doses ≥ 160 MBq, and a 100% overall response rate (6/6) in pts with RECIST-measurable target lesion(s), including two complete responses.The FWHM of 212Pb-ADVC001 was 4.9 mm and the IEC phantom imaging allowed visualization of the 13 mm spheres, with the recorded count linear with radioactivity. Clinical imaging of 212Pb-ADVC001 PET pair production is feasible. PET maximum intensity projection images (MIP) provide a clear localization of the alpha decay, hence 208Tl and 212Bi, in lesions concordant with diagnostic PSMA PET imaging. Conclusion 212Pb-ADVC001 demonstrated encouraging safety and promising anti-tumor activity in pts with progressive mCRPC. Clinical 212Pb-ADVC001 PET imaging of 208Tl gamma pair production confirmed the alpha emission from 212Pb-ADVC001 within PSMA-avid lesions.Phase 2 expansion will assess 212Pb-ADVC001 with novel dosing strategies to optimize clinical outcomes in 3 indications across mCRPC and metastatic hormone-sensitive prostate cancer. Funding Acknowledgements AdvanCell Pty Ltd

Prostate cancer (PC) is the second leading cause of cancer-related death in men, with metastatic castration-resistant PC (mCRPC) remaining largely incurable. Prostate-specific membrane antigen (PSMA) is a validated target, with PSMA-directed radioligand therapy demonstrating survival benefit in mCRPC. Targeted alpha therapies (TAT) with isotopes Lead-212 (212Pb) and Actinium-225 (225Ac) are in clinical development and deliver high-linear-energy-transfer radiation, inducing potent cytotoxicity and potentially enhancing anti-tumour immunity. Current PSMA-positive preclinical models rely on xenografts or engineered murine cells, limiting evaluation of TAT-induced immune modulation thus far. To investigate the immune-modulatory effects of 212Pb-TAT in metastatic PC, we sought to establish (i) a syngeneic murine model of metastatic PC expressing murine PSMA (mPSMA), and (ii) a PSMA-directed TAT tool compound with high affinity for mPSMA. Murine metastatic PC cells (RM1-BM), which recapitulate late-stage TP53-mutant disease, were engineered to express murine FOLH1 (mPSMA) using a PiggyBac transposon system. Expression of mPSMA was confirmed both in vitro and in vivo by western blotting and immunohistochemistry. The TAT agent 212Pb-PS0001 (AdvanCell) was assessed in biodistribution and efficacy studies in immunocompetent C57Bl/6 mice. RM1-BM-mFolh1 cells expressed mPSMA comparably to human PSMA-positive C4-2 cells. 212Pb-PS0001 showed selective tumour uptake in RM1-BM-mFolh1 models, with minimal off-target accumulation. Therapeutic evaluation demonstrated that a single dose of 212Pb-PS0001 significantly suppressed RM1-BM-mFolh1 tumour growth in immunocompetent mice, while untreated controls exhibited progressive disease. Notably, several animals achieved durable tumour control, suggesting potential activation of an anti-tumour immune response. We established a syngeneic mPSMA-positive metastatic PC model suitable for studying the immune-modulatory effects of PSMA-targeted therapies. This model represents a robust platform for assessing therapeutic efficacy, elucidating immune mechanisms of action, and evaluating rational combination strategies, including integration with immune checkpoint blockade. Preliminary studies with 212Pb-PS0001 demonstrated selective PSMA targeting, rapid clearance, and potent anti-tumour activity, supporting its use as PSMA-TAT tool compound. Melissa Monterosso, Aneesha Jones, Kayden Kwah, Anna Amiss, Abby Sydes, Didier Boucher, Aimee Horsfall, Heather Green, Johannes Koehbach, Ralph Huebner, Yaowu He, Stephen Rose, Gary Li, Feifei Liu, Simon Puttick, Anna Karmann, John Hooper, Thomas Kryza. Development of an immunocompetent murine model of PSMA-positive metastatic prostate cancer to study the impact of PSMA-targeted therapies on the immune response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B040.

Assessing therapeutic response in glioblastoma (GBM) is a major factor limiting the clinical development of effective therapies. The intracranial location limits serial biopsies and only provides an intermittent view of the tumor molecular profile from the initial resection. Liquid biopsy techniques, specifically small extracellular vesicle (sEV) analysis, have the potential to overcome these limitations by providing a window into the brain using peripheral blood. To address the need for monitoring tumor evolution and therapeutic resistance, we developed a GBM biomarker panel (ATPase subunit beta-2, excitatory amino acid transporter 2, CD24, CD44, CD133, and epidermal growth factor receptor) for multiplexed profiling of sEVs using an advanced GBM Extracellular Vesicle Monitoring Phenotypic Analyzer Chip. We successfully tracked patient response to treatment by monitoring changes in glioma stem cell markers on circulating sEVs. We propose that these results provide a strong rationale for using GBM sEVs as a serial monitoring tool in the future clinical management of patients with GBM.

TPS275 Background: Prostate cancer (PC) is the second most common cancer and second leading cause of cancer-related death in men. A recent Lancet Commissionarticle predicts a rise in PC cases from 1.4 million in 2020 to 2.9 million by 2040. Despite ten new therapies being available for metastatic PC in the recent decade, the survival advantage from most agents in the setting of metastatic castration-resistant prostate cancer (mCRPC) is measured in months largely due to cross-resistance, and the 5-year survival is approximately 32%. The radioligand therapy 177 Lu-PSMA-617, which uses a beta-emitting isotope linked to a PSMA-targeting small molecule, has shown a median survival advantage in mCRPC of four months, underpinning the critical need for more effective treatments. Excitement has shifted towards the use of alpha-emitting isotopes that deliver a more lethal payload. Unlike beta particles, alpha particles have a short range of tissue penetration (< 0.1 mm) and high linear energy transfer that induces double-stranded DNA breaks and high levels of cytotoxicity to target expressing cancer cells irrespective of cell cycle or oxygenation state. Herein we describe the ongoing clinical trial of [ 212 Pb]Pb-ADVC001 – a novel PSMA-targeted radioligand labelled with the potent alpha-emitting isotope 212 Pb. Methods: This is a prospective, open-label, non-randomized, dose-escalation, dose optimization and expansion study. The study aims to determine the safety and tolerability of escalating doses of [ 212 Pb]Pb-ADVC001 administered every 6, 4 or 2 weeks during the dose-finding phase (Phase 1b) in participants with PSMA-positive mCRPC who have had exposure to at least one androgen receptor pathway inhibitor (ARPi) and taxane-based chemotherapy at any time in the course of their disease. The dose escalation phase will follow an i3+3 design, with each cohort able to backfill up to 20 participants for further characterization of the safety, tolerability and preliminary efficacy of dose and schedules. The expansion phase (Phase 2a) aims to assess the efficacy, safety and tolerability of [ 212 Pb]Pb-ADVC001 at the recommended Phase 2 dose in three groups of participants with PSMA-positive mCRPC. Group 1: Participants who have had exposure to at least one ARPi and have not received a taxane for the treatment of mCRPC. Group 2: Participants who have had exposure to at least one ARPi and received taxane-based chemotherapy for the treatment of mCRPC. Group 3: Participants who have had exposure to 177 Lu-PSMA. If data from Phase 1b demonstrates multiple dosing regimens are reasonably equivalent in terms of safety, tolerability and anti-tumor activity, the Phase 2a expansion study may include adaptive randomization to identify an optimized dose and schedule. The trial is currently enrolling at two clinical sites in Australia. Clinical trial information: NCT05720130 .

177Lu-PSMA-617 is the first FDA-approved targeted radioligand therapy (RLT), and in clinical trials, significantly prolonged survival and improved quality of life in patients with metastatic castration resistant prostate cancer (mCRPC). However, approximately 30% of the patients do not respond to the treatment and most initial responders ultimately relapse. Compared to the beta-emitter 177Lu, the alpha therapy isotope 212Pb may prove to be advantageous due to its short half-life, high linear energy transfer, and efficient induction of immunogenic cell death. Here we used in vitro and in vivo models to elucidate the intrinsic cellular mechanisms of response to 177Lu-PSMA and 212Pb-PSMA treatment. 177Lu-PSMA-I&T and 212Pb-ADVC001 were used as PSMA-targeted 177Lu- and 212Pb-RLT, respectively. The cytotoxic activity in prostate cancer (PC) cell lines was measured by a cell viability assay. In vivo studies were performed in human PC-bearing mice to compare preclinical efficacy of 177Lu- and 212Pb-PSMA therapy. The kinetic mechanisms associated with 177Lu-PSMA-I&T and 212Pb-ADVC001 mediated cell-death were assessed ex vivo using proteomics, and their impact on the PC cell cycle by flow cytometry. 212Pb-ADVC001 displayed potent cytotoxic activity with an average EC50 of 2.7, 7.2 and 3.3 kBq/mL in PC cell lines PC-3-PIP (PSMAhigh), C4-2 (PSMAint) and LNCaP (PSMAint), respectively, compared to 177Lu-PSMA-I&T (430.7, 434.9 and 814.4 kBq/mL, respectively). In PSMAhigh xenograft models, 212Pb-ADVC001 (0.43 MBq) significantly improved median survival to 84 days compared to 48 days for 177Lu-PSMA I&T (20 MBq). Multidose efficacy studies demonstrated superior tumor response with two cycles of 212Pb-ADVC001 (0.46 MBq) compared to two cycles of 177Lu-PSMA I&T (15 MBq). 212Pb-ADVC001 administration in 177Lu-PSMA I&T-relapsed mice resulted in improved survival. In PSMAint xenograft models, 212Pb-ADVC001 (0.9 MBq) also suppressed tumor progression more effectively than 177Lu-PSMA-I&T (30 MBq), resulting in prolonged survival. Proteomics analysis of RLT-treated tumors revealed a specific impact of 212Pb-ADVC001 on cell cycle checkpoints and DNA replication. In vitro cell cycle experiment further confirmed that 212Pb-ADVC001 caused significant DNA damage, and reduced DNA content in the S-phase of the cell cycle with a concomitant increase in the G1 and G2/M-phase arrest compared to 177Lu-PSMA-I&T (p<0.05). Comparison studies of 177Lu- and 212Pb-PSMA treatment on PC cells showed a higher efficacy of 212Pb-PSMA in vitro and in vivo supporting the clinical application of 212Pb-PSMA for mCRPC. Mechanistic studies furthered the understanding of PC radiobiology and cellular responses to beta- and alpha-RLT with the identification of a cell cycle arrest in PC specifically induced by 212Pb-PSMA. Feifei Liu, Melissa E. Monterosso, Didier Boucher, Stelle Shakti, Kwong Ching Li, Aimee Horsfall, Saawan Kumar, Johannes Koehbach, Kevin Kuan, William Tieu, Stephen Rose, Anna Karmann, Simon Puttick, Gary Li, Thomas Kryza. Uncovering the mechanisms of action of 177Lu- and 212Pb- based PSMA radioligand therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1333.

PSMA-targeted radioligand therapy (RLT) with lutetium-177 (177Lu), a beta-emitter, has been clinically proven to be efficacious for the treatment of prostate cancer (PC). Although emerging clinical data indicate that better efficacy can be achieved by alpha-emitters, the toxicities associated with actinium-225 (225Ac) may limit its broad application especially in early lines of treatment. Lead-212 (212Pb), is a promising isotope for alpha therapy with a high linear energy transfer, a half-life of 10.6 hours, and a simple decay scheme. These properties promote efficient targeting of PSMA+ PC cells while limiting off-target toxicities. Pb-ADVC001 is a novel Pb-based PSMA-targeted RLT currently in Phase Ib/IIa clinical trial (NCT05720130) for patients with metastatic castration-resistant prostate cancer (mCRPC). The affinity of ADVC001 and Pb-ADVC001 to PSMA was determined by SPR and radioligand-binding assays in PSMA+ PC cell lines. Cytotoxic activity was measured by cell viability and clonogenic assays. In vivo biodistribution and anti-tumor efficacy studies were performed in human-derived PC-bearing mice. The intrinsic molecular and cellular mechanisms associated with Pb-ADVC001 mediated cell-death were assessed using transcriptomics and proteomics. ADVC001 binds human, mouse and rat PSMA with comparable nanomolar activities, and efficiently internalizes upon binding to PSMA+ PC cells. In vitro, Pb-ADVC001 showed specific and potent cytotoxic activity against multiple PSMA+ human PC cell lines, while sparing PSMA- cells. In vivo biodistribution of Pb-ADVC001 showed tumor uptake at 19.6, 20.9, 9.4 and 5.4 %ID/g at 1, 3, 24 and 48 h, respectively, with retention out to 72 h. High tumor uptake and fast renal clearance resulted in favorable tumor/kidney ratios. Minimal uptake was observed in other normal tissues. Single administration of Pb-ADVC001 in PSMA+ PC xenografts led to dose-dependent anti-tumor response and significant survival benefit. Transcriptomic analysis of in vitro treated PC cells and proteomic analysis of tumors harvested longitudinally revealed multiple mechanisms of action involving DNA damage, cell cycle arrest and cell death, and immune response modulation. Preclinical data demonstrated the potential of Pb-ADVC001 for the treatment of patients with PSMA+ prostate cancer. Transcriptomic and proteomic analyses indicate multiple mechanisms of action collectively resulting in effective cancer therapy. Melissa E. Monterosso, Feifei Liu, Didier Boucher, Stelle Shakti, Kwong Ching Li, Aimee Horsfall, Saawan Kumar, Johannes Koehbach, Kevin Kuan, William Tieu, Stephen Rose, Anna Karmann, Gary Li, Simon Puttick, Thomas Kryza. Preclinical evaluation of a novel Pb-based, PSMA-targeted radioligand, Pb-ADVC001, for prostate cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 588.

AbstractAssessing therapeutic response in glioblastoma (GBM) is a major factor limiting the clinical development of new and effective therapies. The intracranial location limits serial biopsies, and only provides an intermittent view of the tumor molecular profile from the initial resection. Liquid biopsy techniques, specifically small extracellular vesicle (sEV) analysis, have the potential to overcome these limitations by providing a window into the brain using peripheral blood. To address the need for monitoring tumor evolution and therapeutic resistance, we developed a GBM biomarker panel (ATP1B2, EAAT2, CD24, CD44, CD133 and EGFR) for multiplexed profiling of sEVs using an advanced GBM Extracellular vesicle Monitoring Phenotypic Analyzer Chip (GEMPAC). We successfully tracked patient response to treatment by monitoring changes in glioma stem cell markers on circulating sEVs. We propose that these results provide a strong rationale for using GBM sEVs as a serial monitoring tool in the future clinical management of GBM patients.

There is significant interest in the development of 212Pb-PSMA–based targeted α-therapy for patients with metastatic castration-resistant prostate cancer. A previous phantom study has shown that 212Pb SPECT is feasible by imaging the 238.6 keV and 75 to 91 keV γ-emissions produced after the β-

AbstractPrecision radiotherapy, such as targeted radioligand therapy, accentuates the precise delivery of radiation to tumor cells while limiting radiation damage to surrounding normal cells. Although recent clinical trial data has shown targeted radioligand therapy to have significant patient survival benefit, it is still unavoidable that the cancer cells will eventually adapt and develop radioresistance. Thus, the study of radiotherapy‐induced changes in the tumor microenvironment (TME) is crucial for developing strategies to best overcome radioresistance. To this end, organ‐on‐chip (OOC) systems with integrative sensors represent cutting‐edge pre‐clinical models for miniaturized 3D modelling and profiling of the TME. This Review features OOC systems which have demonstrated feasibility for radiation‐associated studies, as well as showcased the progress of different OOC systems for profiling core components of the TME. Furthermore, this Review discusses the knowledge gap in cancer‐on‐chip systems with integrative TME sensors for precision radiotherapy applications. It is anticipated that this Review can kickstart the propagation of new concepts and approaches to drive a new era of miniaturized sensors on OOC systems for precision radiotherapy.

Background: Acquired Brain Injury (ABI) describes a range of brain injuries occurring after birth, including tumor, traumatic brain injury or stroke. Although MRIs are routinely used for diagnosis, prediction of outcome following brain injury is challenging. Quantitative structural information from brain images may provide an opportunity to predict patient outcomes; how-ever, due to the high prevalence of severe pathology in children with ABI, quantitative ap-proaches must be robust to injury severity.Methods: In this pilot cross-sectional study, automated quantitative measures were extracted from the MRIs of a cohort of children with ABI (n = 30, 8-16 years, follow up MRI taken 1.8-13.4 years after time of injury) as well as 36 typically developing controls with no brain injury (7-17 years) using a pathology-robust technique. Measures of brain volume, lesion volume and cortical morphology were associated with concurrent motor, behavioral, visual and communi-cative function using Least Absolute Shrinkage and Selection Operator (LASSO) regression.Results: These regression models were validated on a separate test set (n = 8 of the ABI cohort), which revealed significant correlations between measures of brain structure with mo-tor, cognitive, visual and communicative function (r = 0.65-0.85, all p < 0.01). Furthermore, comparisons of the structural measures to the typically developing cohort revealed overall reductions in global grey matter volume among the ABI cohort, as well as cortical thinning in several cortical areas.Conclusions: These preliminary associations reveal that motor and behavioral function can be estimated from MRI alone, highlighting the potential utility of the proposed pathology-robust MRI quantification tools to provide estimates of long-term clinical prognosis of children with ABI following injury.Copyright 2022, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Dysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. The association of cortical cholinergic denervation with diverse cognitive profiles in dementia, particularly at early stages, has not yet been fully explored. We assessed the relationship of cholinergic denervation in the cortex measured using 18 F-fluoroethoxybenzovesamicol (FEOBV) with cognitive decline at an early stage of dementia. Participants (8 with mild cognitive impairment (MCI) and 10 cognitively unimpaired (CU) controls, aged 60-86, 55.6% female, MMSE = 28.7±1.5) underwent neuropsychological assessment and FEOBV PET imaging. The neuropsychological battery of tests included measures of memory, executive function, attention and language. Domain-specific composite scores were calculated by averaging z-scores of the related tests or subtasks within a domain. FEOBV images were co-registered to the concurrent structural MRI and normalised to the supratentorial white matter reference region resulting in a standardized uptake value ratio (SUVR). Voxel-wise analysis was performed on normalised FEOBV images to investigate associations with clinical diagnosis and domain-specific cognitive performance. Voxel-based morphometry was also performed to rule out differences in brain morphology. All analyses were corrected for age, sex and total intracranial volume and adjusted for multiple comparisons. The MCI group showed significantly lower global FEOBV SUVR in the cortex although only a focal cluster of reductions near the right middle temporal gyrus was found in the voxel-wise comparisons. When associations with cognitive performance profiles were assessed in the full cohort, regional positive correlations were found between FEOBV SUVR and cognitive scores across different domains (Figure 1), although these did not include memory. For executive functioning, widespread correlation patterns were observed across both cortical and subcortical regions. Moreover, overlapping profiles were identified for all three cognitive domains of executive function, attention and language, which covered the anterior cingulate gyrus, olfactory cortex, calcarine cortex, middle temporal gyrus and caudate nucleus. We have demonstrated that the topographic profile of FEOBV retention correlated with reduced cognitive performance in different domains, suggesting that reduced cortical cholinergic terminal integrity is an important pathological feature of cognitive decline.

The aim of this prospective clinical study was to evaluate the potential of the prostate specific membrane antigen (PSMA) targeting ligand, [68Ga]-PSMA–Glu–NH–CO–NH–Lys-2-naphthyl-L-Ala-cyclohexane-DOTA ([68Ga]Ga-PSMA-617) as a positron emission tomography (PET) imaging biomarker in recurrent glioblastoma patients. Patients underwent [68Ga]Ga-PSMA-617 and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET scans on two separate days. [68Ga]Ga-PSMA-617 tumour selectivity was assessed by comparing tumour volume delineation and by assessing the intra-patient correlation between tumour uptake on [68Ga]Ga-PSMA-617 and [18F]FET PET images. [68Ga]Ga-PSMA-617 tumour specificity was evaluated by comparing its tumour-to-brain ratio (TBR) with [18F]FET TBR and its tumour volume with the magnetic resonance imaging (MRI) contrast-enhancing (CE) tumour volume. Ten patients were recruited in this study. [68Ga]Ga-PSMA-617-avid tumour volume was larger than the [18F]FET tumour volume (p = 0.063). There was a positive intra-patient correlation (median Pearson r = 0.51; p < 0.0001) between [68Ga]Ga-PSMA-617 and [18F]FET in the tumour volume. [68Ga]Ga-PSMA-617 had significantly higher TBR (p = 0.002) than [18F]FET. The [68Ga]Ga-PSMA-617-avid tumour volume was larger than the CE tumour volume (p = 0.0039). Overall, accumulation of [68Ga]-Ga-PSMA-617 beyond [18F]FET-avid tumour regions suggests the presence of neoangiogenesis in tumour regions that are not overly metabolically active yet. Higher tumour specificity suggests that [68Ga]-Ga-PSMA-617 could be a better imaging biomarker for recurrent tumour delineation and secondary treatment planning than [18F]FET and CE MRI.

BACKGROUND:Multiple studies have assessed post-operative readmissions in advanced ovarian cancer.OBJECTIVE:To evaluate all unplanned readmissions during the primary treatment period of advanced epithelial ovarian cancer, and the impact of readmission on progression-free survival.METHODS:This was a single institution retrospective study from January 2008 to October 2018. Χ2/Fisher's exact and t-test, or Kruskal-Wallis test were used. Multivariable Cox proportional hazard models were used to assess the effect of covariates in progression-free survival analysis.RESULTS:A total of 484 patients (279 primary cytoreductive surgery, 205 neoadjuvant chemotherapy) were analyzed. In total, 272 of 484 (56%; 37% primary cytoreductive surgery, 32% neoadjuvant chemotherapy, p=0.29) patients were readmitted during the primary treatment period. Overall, 42.3% of the readmissions were surgery related, 47.8% were chemotherapy related, and 59.6% were cancer related but not related to surgery or chemotherapy, and each readmission could qualify for more than one reason. Readmitted patients had a higher rate of chronic kidney disease (4.1% vs 1.0%, p=0.038). Post-operative, chemotherapy, and cancer-related readmissions were similar between the two groups. However, the percentage of inpatient treatment days due to unplanned readmission was twice as high for primary cytoreductive surgery at 2.2% vs 1.3% for neoadjuvant chemotherapy (p<0.001). Despite longer readmissions in the primary cytoreductive surgery group, Cox regression analysis demonstrated that readmissions did not affect progression-free survival (HR=1.22, 95% CI 0.98 to 1.51; p=0.08). Primary cytoreductive surgery, higher modified Frailty Index, grade 3 disease, and optimal cytoreduction were associated with longer progression-free survival.CONCLUSIONS:In this study, 35% of the women with advanced ovarian cancer had at least one unplanned readmission during the entire treatment time. Patients treated by primary cytoreductive surgery spent more days during readmission than those with neoadjuvant chemotherapy. Readmissions did not affect progression-free survival and may not be valuable as a quality metric.

The APOE- ε 4 allele is the strongest known genetic risk factor for Alzheimer’s disease (AD) and is associated with higher amyloid-β (Aβ) deposition. White matter (WM) microstructural damages are known to occur early at the preclinical stage of AD. Although stable associations between APOE- ε 4 status and WM alternations have been reported in patients with AD and mild cognitive impairment, few studies have described WM differences in cognitively unimpaired (CU) subjects at risk of AD. We aim to investigate associations of APOE- ε 4 status and Aβ load with WM microstructural changes in mid-age CU individuals. 151 CU participants from the Prospective Imaging Study of Ageing (PISA) were included (aged 44-66, 78% female, 77 APOE- ε 4 carriers ( ε 4+) and 74 non-carriers ( ε 4-)) and underwent Aβ PET and 3T MRI scans including multi-shell diffusion-weighted images. Aβ load was quantified in Centiloid (CL) on PET and Aβ+ was defined as CL ≥ 20. Tract based spatial statistics (TBSS) analysis was performed on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) to assess WM alternations associated with APOE- ε 4 status and/or Aβ load. All analyses were corrected for age and for multiple comparisons. A significant effect of gender, but not APOE- ε 4 or Aβ status was observed on WM integrity in the full cohort. When considering females only, APOE- ε 4 carriers showed regional increased MD in several right WM tracts. However, these differences were no longer significant when correcting for Aβ status. In contrast, significant WM alternations associated with Aβ+ status were found when correcting for APOE- ε 4 status. In this female-only subset, widespread WM microstructural damages were observed in Aβ+ ε 4+ subjects (N=10) compared to Aβ- ε 4+ (N=51) and Aβ- ε 4- (N=54) subjects. No significant differences were observed between Aβ- ε 4+ and Aβ- ε 4- subjects. Similar differences were also observed in the global diffusion metrics of WM tracts. These findings suggest that WM alternations associated with Aβ accumulation appear in mid-life CU female subjects. Future studies in larger cohorts enriched for gender, APOE and Aβ status are required to clarify the relative contributions of APOE- ε 4 and Aβ status on WM microstructural damage.

Background Posttraumatic stress disorder (PTSD) has been associated with volumetric and white matter microstructural changes among general and veteran populations. However, regions implicated have greatly varied and often conflict between studies, potentially due to confounding comorbidities within samples. This study compared grey matter volume and white matter microstructure among Australian combat veterans with and without a lifetime diagnosis of PTSD, in a homogenous sample assessed for known confounding comorbidities. Methods Sixty-eight male trauma-exposed veterans (16 PTSD-diagnosed; mean age 69 years) completed a battery of psychometric assessments and underwent magnetic resonance and diffusion tensor imaging. Analyses included tract-based spatial statistics, voxel-wise analyses, diffusion connectome-based group-wise analysis, and volumetric analysis. Results Significantly smaller grey matter volumes were observed in the left prefrontal cortex (P = 0.026), bilateral middle frontal gyrus (P = 0.021), and left anterior insula (P = 0.048) in the PTSD group compared to controls. Significant negative correlations were found between PTSD symptom severity and fractional anisotropy values in the left corticospinal tract (R-2 = 0.34, P = 0.024) and left inferior cerebellar peduncle (R-2 = 0.62, P = 0.016). No connectome-based differences in white matter properties were observed. Conclusions Findings from this study reinforce reports of white matter alterations, as indicated by reduced fractional anisotropy values, in relation to PTSD symptom severity, as well as patterns of reduced volume in the prefrontal cortex. These results contribute to the developing profile of neuroanatomical differences uniquely attributable to veterans who suffer from chronic PTSD.

Differences in individual humor styles (adaptive: affiliative, self-enhancing; maladaptive: aggressive, self-defeating) are associated with various wellness measures. This study examines the association of humor styles with professional fulfillment (PF) and burnout (BO) among Society of Gynecologic Oncology (SGO) members. SGO members were surveyed in 11/2020. The survey included 64 questions (32-item Humor Styles Questionnaire, 16-item Professional Fulfillment Index, and 16-item demographic and practice characteristics). Differences among faculty physicians (FAC), physician trainees (Res/Fel), and advanced practice providers (APP) were compared. Multivariable linear regression adjusted the association of humor styles with BO and PF for possible confounders. Of 1982 members invited to participate, 320 (16.1%) returned completed surveys (69.4% FAC, 23.4% Res/Fel, and 7.2% APP). All provider types scored highest for affiliative and lowest for aggressive humor. Res/Fel were more likely to employ aggressive and self-defeating humor styles than FAC and APP. One-third of respondents met criteria for BO and half experienced PF. FAC were more fulfilled than Res/Fel (p = 0.038). BO was negatively associated with self-enhancing and positively associated with self-defeating humor. Working > 60 h/week was associated with increased BO (p = 0.008) while trainee status (p = 0.010) and age > 55 (p = 0.008) were associated with decreased BO. PF was positively associated with self-enhancing and negatively associated with self-defeating humor. Spending > 10% of work hours on administrative duties led to lower PF (p = 0.008). Beyond advocating for less working hours and administrative duties, humor-based interventions to increase self-enhancing and reducing self-defeating humor use may lead to less BO and greater PF in SGO members, especially among trainees.

Dysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. A validated method to directly quantify cortical cholinergic terminal integrity enables exploration of the involvement of this system in diverse cognitive profiles associated with dementia, particularly at a prodromal stage. In this study, we used the radiotracer [18F]-fluoroethoxybenzovesamicol (FEOBV) as a direct measure of cholinergic terminal integrity and investigated its value for the assessment of cholinergic denervation in the cortex and associated cognitive deficits. Eighteen participants (8 with mild cognitive impairment (MCI) and 10 cognitively unimpaired controls) underwent neuropsychological assessment and brain imaging using FEOBV and [18F]-florbetaben for amyloid-β imaging. The MCI group showed a significant global reduction of FEOBV retention in the cortex and in the parietal and occipital cortices specifically compared to the control group. The global cortical FEOBV retention of all participants positively correlated with the BF, hippocampus and grey matter volumes, but no association was found between the global FEOBV retention and amyloid-β status. Topographic profiles from voxel-wise analysis of FEOBV images revealed significant positive correlations with the cognitive domains associated with the underlying cortical areas. Overlapping profiles of decreased FEOBV were identified in correlation with impairment in executive function, attention and language, which covered the anterior cingulate gyrus, olfactory cortex, calcarine cortex, middle temporal gyrus and caudate nucleus. However, the absence of cortical atrophy in these areas suggested that reduced cholinergic terminal integrity in the cortex is an important factor underlying the observed cognitive decline in early dementia. Our results provide support for the utility and validity of FEOBV PET for quantitative assessment of region-specific cholinergic terminal integrity that could potentially be used for early detection of cholinergic dysfunction in dementia following further validation in larger cohorts.

The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD/MCI pathogenesis is unclear. This study compared the metabolomic and proteomic signature of plasma from cognitively normal (CN) and dementia patients diagnosed with MCI or AD, to identify specific cellular pathways and new biomarkers altered with the progression of the disease. We analysed 80 plasma samples from individuals with MCI or AD, as well as age- and gender-matched CN individuals, by utilising mass spectrometry methods and data analyses that included combined pathway analysis and model predictions. Several proteins clearly identified AD from the MCI and CN groups and included plasma actins, mannan-binding lectin serine protease 1, serum amyloid A2, fibronectin and extracellular matrix protein 1 and Keratin 9. The integrated pathway analysis showed various metabolic pathways were affected in AD, such as the arginine, alanine, aspartate, glutamate and pyruvate metabolism pathways. Therefore, our multi-omics approach identified novel plasma biomarkers for the MCI and AD groups, identified changes in metabolic processes, and may form the basis of a biomarker panel for stratifying dementia participants in future clinical trials.