Emerging Theranostics for Prostate Cancer and a Model of Prostate-specific Membrane Antigen Therapy.

There is increasing demand worldwide to develop diagnostic and therapeutic (theranostic) markers for prostate cancer. One target of interest is prostate-specific membrane antigen (PSMA), a protein which is overexpressed in prostate cancer cells. Over the past decade, a growing body of literature has demonstrated that radiolabeled ligands that target PSMA show favorable clinical response and survival outcomes in patients with advanced prostate cancer. This focused review provides background to the development of PSMA as a target, an overview of key studies informing our current approach to radioligand-based imaging and therapy for prostate cancer, and a model for real-world implementation of PSMA theranostics based on an Australian experience.

Quantitative [68Ga]Ga-PSMA-11 PET biomarkers for the analysis of lesion-level progression in biochemically recurrent prostate cancer: a multicentre study.

[68Ga]Ga-PSMA-11 PET has become the standard imaging modality for biochemically recurrent (BCR) prostate cancer (PCa). However, its prognostic value in assessing response at this stage remains uncertain. The study aimed to assess the prognostic significance of radiographic patient-level patterns of progression derived from lesion-level biomarker quantitation in metastatic disease sites. A total of 138 BCR PCa patients with both baseline and follow-up [68Ga]Ga-PSMA-11 PET scans were included in this analysis. Tumour response was quantified at the lesion level using commonly used quantitative parameters (SUVmean, SUVmax, SUVpeak, volume), and patients were classified as systemic, mixed, or no-progression based on these response classifications. A total of 328 matched lesions between baseline and follow-up scans were analysed. The results showed that systemic progressors had a significantly higher risk of death than patients with no progression with SUVmean demonstrating the highest prognostic value (HR = 5.70, 95% CI = 2.63-12.37, p < 0.001, C-Index = 0.69). Moreover, progressive disease as measured by SUVmean using the radiographic PSMA PET Progression Criteria (rPPP) was found to be significantly prognostic for patient overall survival (HR = 3.67, 95% CI = 1.82-7.39, p < 0.001, C-Index = 0.65). This work provides important evidence supporting the prognostic utility of PSMA response quantitation in the BCR setting.

Prospective inter- and intra-tracer repeatability analysis of radiomics features in [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007 PET scans in metastatic prostate cancer.

OBJECTIVE: This study aimed to quantify both the intra- and intertracer repeatability of lesion-level radiomics features in [68Ga]Ga-prostate-specific membrane antigen (PSMA)-11 and [18F]F-PSMA-1007 positron emission tomography (PET) scans. METHODS: Eighteen patients with metastatic prostate cancer (mPCa) were prospectively recruited for the study and randomised to one of three test-retest groups: (i) intratracer [68Ga]Ga-PSMA-11 PET, (ii) intratracer [18F]F-PSMA-1007 PET or (iii) intertracer between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007 PET. Four conventional PET metrics (standardised uptake value (SUV)max, SUVmean, SUVtotal and volume) and 107 radiomics features were extracted from 75 lesions and assessed using the repeatability coefficient (RC) and the ICC. Radiomic feature repeatability was also quantified after the application of 16 filters to the PET image. RESULTS: Test-retest scans were taken a median of 5 days apart (range: 2-7 days). SUVmean demonstrated the lowest RC limits of the conventional features, with RCs of 7.9%, 14.2% and 24.7% for the [68Ga]Ga-PSMA-11 PET, [18F]F-PSMA-1007 PET, and intertracer groups, respectively. 69%, 66% and 9% of all radiomics features had good or excellent ICC values (ICC ≥ 0.75) for the same groups. Feature repeatability therefore diminished considerably for the intertracer group relative to intratracer groups. CONCLUSION: In this study, robust biomarkers for each tracer group that can be used in subsequent clinical studies were identified. Overall, the repeatability of conventional and radiomic features were found to be substantially lower for the intertracer group relative to both intratracer groups, suggesting that assessing patient response quantitatively should be done using the same radiotracer where possible. ADVANCES IN KNOWLEDGE: Intertracer biomarker repeatability limits are significantly larger than intratracer limits.

Fully automatic prognostic biomarker extraction from metastatic prostate lesion segmentations in whole-body [68Ga]Ga-PSMA-11 PET/CT images.

PURPOSE: This study aimed to develop and assess an automated segmentation framework based on deep learning for metastatic prostate cancer (mPCa) lesions in whole-body [68Ga]Ga-PSMA-11 PET/CT images for the purpose of extracting patient-level prognostic biomarkers. METHODS: Three hundred thirty-seven [68Ga]Ga-PSMA-11 PET/CT images were retrieved from a cohort of biochemically recurrent PCa patients. A fully 3D convolutional neural network (CNN) is proposed which is based on the self-configuring nnU-Net framework, and was trained on a subset of these scans, with an independent test set reserved for model evaluation. Voxel-level segmentation results were assessed using the dice similarity coefficient (DSC), positive predictive value (PPV), and sensitivity. Sensitivity and PPV were calculated to assess lesion level detection; patient-level classification results were assessed by the accuracy, PPV, and sensitivity. Whole-body biomarkers total lesional volume (TLVauto) and total lesional uptake (TLUauto) were calculated from the automated segmentations, and Kaplan-Meier analysis was used to assess biomarker relationship with patient overall survival. RESULTS: At the patient level, the accuracy, sensitivity, and PPV were all > 90%, with the best metric being the PPV (97.2%). PPV and sensitivity at the lesion level were 88.2% and 73.0%, respectively. DSC and PPV measured at the voxel level performed within measured inter-observer variability (DSC, median = 50.7% vs. second observer = 32%, p = 0.012; PPV, median = 64.9% vs. second observer = 25.7%, p < 0.005). Kaplan-Meier analysis of TLVauto and TLUauto showed they were significantly associated with patient overall survival (both p < 0.005). CONCLUSION: The fully automated assessment of whole-body [68Ga]Ga-PSMA-11 PET/CT images using deep learning shows significant promise, yielding accurate scan classification, voxel-level segmentations within inter-observer variability, and potentially clinically useful prognostic biomarkers associated with patient overall survival. TRIAL REGISTRATION: This study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000608561) on 11 June 2015.

Patient satisfaction with Radioguided Occult Lesion Localisation using iodine-125 seeds ('ROLLIS') versus conventional hookwire localisation.

BACKGROUND: Women with impalpable or poorly palpable breast cancer require radiologically guided localisation prior to breast conserving surgery. Radioguided Occult Lesion Localisation using Iodine-125 Seed (ROLLIS) is an emerging alternative to conventional Hookwire Localisation (HWL). We compared ROLLIS with conventional HWL with respect to patient reported stress and discomfort related to the localisation procedure. PATIENTS AND METHODS: From September 2013 to January 2016, women who were eligible for breast conserving surgery with impalpable or poorly palpable histologically confirmed invasive or in-situ carcinoma were recruited to the multi-centre ROLLIS randomised controlled trial and underwent either ROLLIS or HWL. Following surgery, a questionnaire was administered to each participant regarding the stress and discomfort related to the localisation procedure. Multivariate analysis was performed to compare the primary outcome of patient-reported stress and discomfort between localisation groups. RESULTS: 218 participants with 220 lesions were randomised and underwent breast conserving surgery following localisation. 201 (92.2%) and 202 (92.7%) of participants provided responses to the stress and discomfort components of the questionnaire respectively. HWL was associated with a statistically significant increased odds of greater stress and discomfort when compared to ROLLIS (OR = 2.07, p = 0.01 and OR = 1.94, p = 0.01 respectively). Insertion of multiple localisation devices was also associated with increased stress (OR = 5.68, p < 0.01) and discomfort (OR = 2.96, p < 0.01). CONCLUSION: When compared with conventional HWL, ROLLIS is associated with significantly less stress and discomfort for patients prior to breast conserving surgery.

Variability of human upper airway collapsibility during sleep and the influence of body posture and sleep stage.

The critical pressure at which the pharynx collapses (Pcrit) is an objective measurement of upper airway collapsibility, an important pathogenetic factor in obstructive sleep apnoea. This study examined the inherent variability of passive Pcrit measurement during sleep and evaluated the effects of sleep stage and body posture on Pcrit. Repeated measurements of Pcrit were assessed in 23 individuals (15 male) with diagnosed obstructive sleep apnoea throughout a single overnight sleep study. Body posture and sleep stage were unrestricted. Applied upper airway pressure was repetitively reduced to obtain multiple measurements of Pcrit. In 20 subjects multiple measurements of Pcrit were obtained. The overall coefficient of repeatability for Pcrit measurement was 4.1 cm H2O. Considering only the lateral posture, the coefficient was 4.8 cm H2O. It was 3.3 cm H2O in the supine posture. Pcrit decreased from the supine to lateral posture [supine mean 2.5 cm H2O, 95% confidence interval (CI) 1.4-3.6; lateral mean 0.3 cm H2O, 95% CI -0.8-1.4, P = 0.007] but did not vary with sleep stage (P = 0.91). This study has shown that the overall coefficient of repeatability was 4.1 cm H2O, implying that the minimum detectable difference, with 95% probability, between two repeated Pcrit measurements in an individual is 4.1 cm H2O. Such variability in overnight measures of Pcrit indicates that a single unqualified value of Pcrit cannot be used to characterize an individual's overall collapsibility during sleep. When within-subject variability is accounted for, change in body posture from supine to lateral significantly decreases passive pharyngeal collapsibility.

Primary angiosarcoma of the bladder in a young female.

Our case report pertains to a 32-year-old woman initially presenting with left flank pain and gross haematuria throughout her urinary stream. CT of her kidney/ureter/bladder (CT KUB) revealed ureteric dilatation to the level of the bladder without evidence of renal calculus and subsequently a stent was inserted. She represented a month later with contralateral flank pain, and a transuretheral resection of bladder tumour was performed. Histopathological diagnosis was epithelioid angiosarcoma. Further imaging (MRI pelvis) revealed that the tumour arose from the posterior bladder wall with local invasion and regional lymph node metastasis. Ifosfamide and epirubicin chemotherapy with single-fraction radiotherapy induced significant reduction in tumour bulk, although this initial response was followed by the development of symptoms suggestive of disease progression. She died 19 months after initial diagnosis with persistent pulmonary and vertebral metastases although no autopsy was performed.