Comparing fluorodeoxyglucose positron emission tomography with computed tomography in staging for nodal and distant metastasis in urothelial/bladder cancer.

Objectives: We aim to assess the clinical value of 18F-fluorodeoxyglucose positron (18F-FDG-PET) scan in detecting nodal and distant metastasis compared with computed tomography (CT) scan in patients with urothelial carcinoma or bladder cancer, aiming to improve staging accuracy and thereby better prognosticate and determine therapy. Methods: A retrospective review of 75 patients with invasive bladder cancer (≥T1) who were staged with both CT and 18F-FDG-PET within an 8-week interval was performed for the period between 2015 and 2020. Seventy-two per cent (54/75) had formal pelvic lymph node (LN) dissection or biopsy of lesions suspicious for metastases. FDG-PET definitions for positive sites were assessed depending on SUV Max (nodes with SUVmax >4 at any size, SUV > 2 for lymph nodes >8 mm, or any SUV if the lymph node was >10 mm on axial images). For CT scanning, enlarged LN by RECIST 1.1 criteria (>10 mm) as well as qualitative findings suggesting metastasis were considered positive. The analysis was based on the comparison of CT and 18F-FDG-PET findings to histopathology results from LN dissection or biopsies. Results: Sensitivity, specificity, positive predictive values (PPV) and negative predictive value (NPV) of CT versus FDG-PET for detecting metastasis, in patients who underwent pelvic LN dissection or biopsy of lesions suspicious of metastases, were 46.6% (95% CI: 21%-70%) versus 60% (95% CI: 32%-84%), 100% (95% CI: 91%-100%) versus 83.78% (95% CI: 69%-94%), 100% (95% CI: 63%-100%) versus 60% (95% CI: 32%-84%), and 82.2% (95% CI: 68%-92%) versus 83.78% (95% CI: 69%-94%), respectively. 7/75 (9.3%) patients avoided cystectomy due to 18F-FDG-PET features of metastases that were not detected by CT. Conclusion: FDG-PET may be more sensitive than CT for metastases in the staging of bladder cancer, which resulted in significant avoidance of aggressive local management in cases with occult metastasis.

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.

Prognostic utility of RECIP 1.0 with manual and AI-based segmentations in biochemically recurrent prostate cancer from [68Ga]Ga-PSMA-11 PET images.

PURPOSE: This study aimed to (i) validate the Response Evaluation Criteria in PSMA (RECIP 1.0) criteria in a cohort of biochemically recurrent (BCR) prostate cancer (PCa) patients and (ii) determine if this classification could be performed fully automatically using a trained artificial intelligence (AI) model. METHODS: One hundred ninety-nine patients were imaged with [68Ga]Ga-PSMA-11 PET/CT once at the time of biochemical recurrence and then a second time a median of 6.0 months later to assess disease progression. Standard-of-care treatments were administered to patients in the interim. Whole-body tumour volume was quantified semi-automatically (TTVman) in all patients and using a novel AI method (TTVAI) in a subset (n = 74, the remainder were used in the training process of the model). Patients were classified as having progressive disease (RECIP-PD), or non-progressive disease (non RECIP-PD). Association of RECIP classifications with patient overall survival (OS) was assessed using the Kaplan-Meier method with the log rank test and univariate Cox regression analysis with derivation of hazard ratios (HRs). Concordance of manual and AI response classifications was evaluated using the Cohen's kappa statistic. RESULTS: Twenty-six patients (26/199 = 13.1%) presented with RECIP-PD according to semi-automated delineations, which was associated with a significantly lower survival probability (log rank p < 0.005) and higher risk of death (HR = 3.78 (1.96-7.28), p < 0.005). Twelve patients (12/74 = 16.2%) presented with RECIP-PD according to AI-based segmentations, which was also associated with a significantly lower survival (log rank p = 0.013) and higher risk of death (HR = 3.75 (1.23-11.47), p = 0.02). Overall, semi-automated and AI-based RECIP classifications were in fair agreement (Cohen's k = 0.31). CONCLUSION: RECIP 1.0 was demonstrated to be prognostic in a BCR PCa population and is robust to two different segmentation methods, including a novel AI-based method. RECIP 1.0 can be used to assess disease progression in PCa patients with less advanced disease. This study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000608561) on 11 June 2015.

A review of laboratory considerations in thrombophilia testing.

Venous thromboembolism is a multifactorial disease with interacting genetic and acquired predisposing factors. Thrombophilia screening is utilised in specific individuals when the test result is likely to influence management decisions, rather than universal screening in all patients with thrombosis. When thrombophilia testing is undertaken, the results must be considered in the context of pre-analytical, analytical and post-analytical variables to minimise misinterpretation. Clinical indications for thrombophilia testing have been covered elsewhere, and the focus of this review will be the laboratory considerations in thrombophilia testing, highlighting potential interferences when investigating for factor V Leiden, prothrombin gene mutation, protein C deficiency, protein S deficiency, antithrombin deficiency and antiphospholipid antibodies.

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.

Low rates of venous thromboembolism in hospitalised COVID-19 patients: an Australian experience.

BACKGROUND: Venous thromboembolic (VTE) complications appear common in hospitalised COVID-19 patients, particularly among critically ill patients in intensive care units. However, there is significant heterogeneity in the reported use of thromboprophylaxis. AIMS: The primary objective was to determine rates of symptomatic VTE in hospitalised COVID-19 patients. Secondary objectives were to assess adherence to an institutional risk-adapted thromboprophylaxis guideline, and rates of bleeding complications. METHODS: A retrospective, single-centre, cohort study was performed in consecutive hospitalised COVID-19 patients over a 6-month period (March to August 2020). Enoxaparin was used as thromboprophylaxis in all patients without a contraindication, with dose adjusted according to disease severity, weight and renal function. RESULTS: Among 86 hospitalised COVID-19 patients, no VTE were identified. Eighty-one (94%) patients received anticoagulation, with 90% adherence to institutional thromboprophylaxis guidelines. Four bleeding events occurred, with one clinically relevant non-major bleeding event and three minor bleeding events. CONCLUSION: Low rates of VTE were identified in hospitalised COVID-19 patients using a risk-adapted thromboprophylaxis protocol.

Purtscher-like retinopathy in a patient with COVID-19 and disseminated intravascular coagulation.

PURPOSE: To describe a unique case of Purtscher-like retinopathy after a severe, complicated COVID-19 course which included development of disseminated intravascular coagulation (DIC). OBSERVATIONS: A 58-year-old male developed blurry vision in the left eye one week after being discharged from the hospital for severe COVID-19 pneumonia and DIC. He had been intubated and ventilated for 5 days. Fundus examination revealed optic nerve hyperemia in the right eye, optic nerve pallor in the left eye, arteriolar attenuation, multiple cotton wool spots and ill-defined areas of retinal whitening in the posterior pole in both eyes. His exam findings were most consistent with Purtscher-like retinopathy in both eyes. CONCLUSIONS AND IMPORTANCE: While several cases of central retinal artery and vein occlusion have been described in COVID-19 patients thus far, there has not been any reported cases of Purtscher-like retinopathy. To the best of our knowledge, this is the first case of Purtscher-like retinopathy in a patient who developed DIC during a severe COVID-19 infection.

Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas.

The treatment landscape of B-cell lymphomas is evolving with the advent of novel agents including immune and cellular therapies. Bispecific antibodies (bsAbs) are molecules that recognise two different antigens and are used to engage effector cells, such as T-cells, to kill malignant B-cells. Several bispecific antibodies have entered early phase clinical development since the approval of the CD19/CD3 bispecific antibody, blinatumomab, for relapsed/refractory acute lymphoblastic leukaemia. Novel bsAbs include CD20/CD3 antibodies that are being investigated in both aggressive and indolent non-Hodgkin lymphoma with encouraging overall response rates including complete remissions. These results are seen even in heavily pre-treated patient populations such as those who have relapsed after chimeric antigen receptor T-cell therapy. Potential toxicities include cytokine release syndrome, neurotoxicity and tumour flare, with a number of strategies existing to mitigate these risks. Here, we review the development of bsAbs, their mechanism of action and the different types of bsAbs and how they differ in structure. We will present the currently available data from clinical trials regarding response rates, progression free survival and outcomes across a range of non-Hodgkin lymphoma subtypes. Finally, we will discuss the key toxicities of bsAbs, their rates and management of these adverse events.

An immunosuppressed 37-year-old woman with right atrial necrotising myocarditis.

A 37-year-old immunocompromised woman was admitted with palpitations, fevers and myalgias. An echocardiogram demonstrated a mass in the right atrial walls and interatrial septum. Endovascular biopsy of the myocardium revealed neutrophilic necrotising myocarditis isolated to the right atrium. Multiple blood, urine and stool cultures were negative but a high anti-streptolysin O antibody titre was detected. The combination of these findings led to the working diagnosis of necrotising myocarditis. Without a positive culture, it was not possible to definitively state the cause of this condition. She was treated with intravenous antibiotics and continued to improve physically and biochemically on discharge.

Positive molecular breast imaging: challenges and problem solving with contrast-enhanced spectral mammography.

Molecular breast imaging (MBI) is a relatively new technique with high sensitivity for breast cancer detection. However, because it only provides limited anatomical information, cross-correlation of MBI findings with conventional breast imaging modalities such as full field digital mammography can be challenging. We report a case of a positive MBI study in a supplemental screening setting, where cross-correlation of MBI, ultrasound, mammogram and biopsy findings was difficult. Contrast-enhanced spectral mammography (CESM) demonstrated a hypervascular lesion at the biopsy clip, helping to prove imaging/histopathological concordance. This case highlights the challenges of incorporating MBI into conventional imaging workup, as well as the use of CESM in problem solving.

The value of peer mentoring for the psychosocial wellbeing of junior doctors: a randomised controlled study.

OBJECTIVE: To explore the value of a peer mentoring program for first year medical interns and to assess the demand for and benefits of such a program in an Australian hospital. DESIGN, SETTING AND PARTICIPANTS: Randomised controlled study of the impact on first year interns of peer-led mentoring by second and third year interns, undertaken during 2015 at the Royal Perth Hospital, a tertiary teaching hospital. Methods and main outcome measure: Interns were recruited and randomised 1:1 to being assigned or not assigned a mentor. Qualitative outcome data were collected in semi-structured interviews and focus groups at 12 months to assess psychosocial wellbeing and job satisfaction. RESULTS: Fifty-three of 79 interns (67%) applied to participate in the program. Twenty-six mentor-mentee pairs matched by sex and career preferences were established; 27 interns were allocated to the control group. Iterative data analysis identified two major themes related to the value of the mentorship program: aiding navigation through the complex health care system, and enhancing a sense of community. Participants with mentors reported high satisfaction with the program and a positive impact on stress levels, morale, sense of support, job satisfaction, and psychosocial wellbeing compared with participants without mentors. CONCLUSION: An optional peer mentoring program enhances junior doctor support structures, builds a sense of community, and helps participating interns navigate their new professional environment. Our trial provides a feasibility model that could be adapted to local conditions, regionally or nationally. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12618000455268; 29 March 2018 (retrospective).

Hot melt extrusion of ion-exchange resin for taste masking.

Taste masking is important for some unpleasant tasting bioactives in oral dosage forms. Among many methods available for taste-masking, use of ion-exchange resin (IER) holds promise. IER combined with hot melt extrusion (HME) may offer additional advantages over solvent methods. IER provides taste masking by complexing with the drug ions and preventing drug dissolution in the mouth. Drug-IER complexation approaches described in literatures are mainly based either on batch processing or column eluting. These methods of drug-IER complexation have obvious limitations such as high solvent volume requirements, multiprocessing steps and extended processing time. Thus, the objective of this study was to develop a single-step, solvent-free, continuous HME process for complexation of drug-IER. The screening study evaluated drug to IER ratio, types of IER and drug complexation methods. In the screening study, a potassium salt of a weakly acidic carboxylate-based cationic IER was found suitable for the HME method. Thereafter, optimization study was conducted by varying HME process parameters such as screw speed, extrusion temperature and drug to IER ratio. It was observed that extrusion temperature and drug to IER ratio are imperative in drug-IER complexation through HME. In summary, this study has established the feasibility of a continuous complexation method for drug to IER using HME for taste masking.

Peripheral blood stem cell mobilisation with G-CSF alone versus G-CSF and cyclophosphamide after bortezomib, cyclophosphamide and dexamethasone induction in multiple myeloma.

Bortezomib-based induction is often used in transplant-eligible patients with myeloma. The optimal peripheral blood stem cell (PBSC) mobilisation strategy in this context is unclear. We reviewed the efficacy of G-CSF alone (G-alone) vs. G-CSF and cyclophosphamide (G-cyclo: standard dose: 1.5-2 g/m2; high dose: 3-4 g/m2) PBSC mobilisation strategies in 288 patients who only received bortezomib, cyclophosphamide and dexamethasone (VCD) induction prior to autograft across six apheresis centres from November 2012 to June 2017. 'Uncomplicated successful mobilisation' was defined as achieving a PBSC yield of ≥4 × 106/kg within two aphereses, without plerixafor or mobilisation-associated toxicity (predominantly febrile neutropenia, FN). Success rates were 84% in G-cyclo standard dose (6% FN), 64% in G-cyclo high dose (18% FN) and 69% in G-alone (plerixafor successfully salvaged 8/9 patients). Median total stem cell yield was significantly higher with G-cyclo, but not different between the two cyclophosphamide doses. Age greater than the median of 61 years was associated with higher failure rates (22 vs. 11%, p = 0.01) and lower PBSC yield, especially in the G-alone group. Prior radiotherapy exposure did not impact on collection success. Our observations suggest that both G-cyclo standard dose and G-alone are reasonable mobilisation strategies. The former may be preferred if salvage plerixafor is unavailable.