Rodney Hicks - Academia.edu (original) (raw)
Papers by Rodney Hicks
Journal of Nuclear Medicine
For over 40 years, FDG has been the dominant PET tracer in neurology, cardiology, inflammatory di... more For over 40 years, FDG has been the dominant PET tracer in neurology, cardiology, inflammatory diseases and, most particularly, oncology. Combined with the ability to perform whole‐body scanning, FDG has revolutionized the evaluation of cancer and has stifled the adoption of other tracers, except in situations where low avidity or high background activity limits diagnostic performance. The strength of FDG has generally been its ability to detect disease in the absence of structural abnormality, thereby enhancing diagnostic sensitivity, but its simultaneous weakness has been a lack of specificity due to diverse pathologies with enhanced glycolysis. Radiotracers that leverage other hallmarks of cancer or specific cellsurface targets are gradually finding a niche in the diagnostic armamentarium. However, none have had sufficient sensitivity to realistically compete with FDG for evaluation of the broad spectrum of malignancies. Perhaps, this situation is about to change with development of a class of tracers targeting fibroblast activation protein (FAP) that have low uptake in almost all normal tissues but high uptake in most cancer types. In this review, the development and exciting preliminary clinical data relating to various FAP‐specific small‐molecule inhibitor (FAPI) tracers in oncology, will be discussed along with potential non‐oncological application
Cancer Imaging
Almost a decade ago, a French cancer centre, for its 10th anniversary celebratory magazine, asked... more Almost a decade ago, a French cancer centre, for its 10th anniversary celebratory magazine, asked me to write a brief prediction of how oncology might look in 2020. I wrote (loosely translated from the original French version);
Blood
Introduction: Early ASCT improves progression-free survival (PFS) but not overall survival (OS) i... more Introduction: Early ASCT improves progression-free survival (PFS) but not overall survival (OS) in poor prognosis DLBCL treated with R-CHOP immuno-chemotherapy (Stiff P et al., NEJM 2013). Furthermore, indiscriminate ASCT exposes those poor-risk patients destined to remain in CR with R-CHOP alone to unnecessary toxicity. Here, the role of interim PET/CT to risk-stratify is controversial. One confounding factor is that interim PET/CT is typically performed after 2 (or 3) cycles of chemotherapy when FDG-avidity likely reflects a mix of residual cancer cells and inflammation; in contrast, interim PET/CT after cycle 4 may be more representative of resistant lymphoma. We hypothesized that: 1. assessment of DLBCL patients by interim PET/CT after 4 cycles (iPET4) of R-CHOP-14 allows greater specificity of FDG-avidity; and, 2. for patients with iPET4-positivity, early treatment intensification with R-ICE chemotherapy followed by Zevalin-BEAM conditioning and ASCT results in 2-yr PFS that is...
Angewandte Chemie International Edition
Journal of Medical Genetics
BackgroundUntil recently, determining penetrance required large observational cohort studies. Dat... more BackgroundUntil recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA–C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL).MethodsTwo cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA–C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas).ResultsPathogenic SDHA–C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 ...
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2018
The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-l... more The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-ligand 1 (PD-L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression. Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy-naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second-line without brain metastases), or cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg atezolizumab on day 1 (21-day cycles). Primary endpoint was investigator-assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression-free survival, duration of response, and safety. ...
Journal of Nuclear Medicine
The authors declare that no potential conflicts of interest relevant to this article exist view o... more The authors declare that no potential conflicts of interest relevant to this article exist view of pelvic MRI. The detection rate for intrapelvic extra-PF disease was 90% (9/10) for PSMA and 31% (5/16) for MRI compared to FCH. Imaging changed expected management in 46% (42/91) FCH, and 23% (21/88) MRI. PSMA provided additive management change over FCH in a further 23% (7/31). Treatment response to SRT was higher in men with negative or PF confined vs. extra PF disease. FCH 73% (32/44) vs. 33% (3/9) (p< 0.02), pelvic MRI 70% (32/46) vs 50% (2/4), p = ns) and PSMA 88% (7/8) vs. 14% (1/7) (p<0.005). Men with negative imging (MRI, FCH +/-PSMA) had high (78%) response rates to SRT. Conclusion: FCH and PSMA had high detection rates for extra PF disease in men with negative/equivocal conventional imaging and BCR post RP. This impacted management and treatment responses to SRT, suggesting an important role for PET in triaging men being considered for curative SRT.
European Journal of Cancer
Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed ... more Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.
Journal of Nuclear Medicine
European journal of nuclear medicine and molecular imaging, Jan 5, 2018
This paper follows the immunotherapy symposium held during the European Association of Nuclear Me... more This paper follows the immunotherapy symposium held during the European Association of Nuclear Medicine (EANM) 2017 Annual Congress. The biological basis of the immune checkpoint inhibitors and the drugs most frequently used for the treatment of solid tumours are reviewed. The issues of pseudoprogression (frequency, timeline), hyperprogression and immune-related side effects are discussed, as well as their implications for patient management. A review of the recent literature on the use of FDG PET for assessment of immunotherapy is presented, and recommendations are provided for assessing tumour response and reporting immune-related side effects with FDG PET based on published data and experts' experience. Representative clinical cases are also discussed.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 5, 2018
Lu-PSMA-617 enables targeted delivery of beta-particle radiation to prostate cancer. We determine... more Lu-PSMA-617 enables targeted delivery of beta-particle radiation to prostate cancer. We determined its radiation dosimetry and relationships to pre-therapeutic imaging and outcomes. 30 patients with prostate cancer receiving Lu-PSMA-617 within a prospective clinical trial (ACTRN12615000912583) were studied. Screening Ga-PSMA-11 PET-CT demonstrated high PSMA-expression in all patients. Following therapy patients underwent quantitative SPECT-CT at 4, 24 and 96 hours. Pharmacokinetic uptake and clearance at a voxel level was calculated and translated into absorbed dose using voxel S values. Volumes-of-interest were drawn on normal tissues and tumor to assess radiation dose and a 'whole-body' tumor dose was also defined. Correlations between PSMA PET-CT parameters, dosimetry and biochemical and therapeutic response were analyzed to identify relationships between absorbed dose, tumor burden, and patient physiology. Mean absorbed dose to kidneys, submandibular and parotid glands, ...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 30, 2018
Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. The... more Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose. Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375-specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls ( < 0.0005). Moreover, miR-375 serum levels cor...
Journal of Alzheimer's disease : JAD, 2018
The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatom... more The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings suppor...
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, Jan 13, 2018
Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer&#... more Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer's disease (AD) pathophysiology; therefore, oral supplementation may potentially slow neurodegeneration. We examined selenium and selenoproteins in serum and cerebrospinal fluid (CSF) from a dual-dose 24-week randomized controlled trial of sodium selenate in AD patients, to assess tolerability, and efficacy of selenate in modulating selenium concentration in the central nervous system (CNS). A pilot study of 40 AD cases was randomized to placebo, nutritional (0.32 mg sodium selenate, 3 times daily), or supranutritional (10 mg, 3 times daily) groups. We measured total selenium, selenoproteins, and inorganic selenium levels, in serum and CSF, and compared against cognitive outcomes. Supranutritional selenium supplementation was well tolerated and yielded a significant (p < 0.001) but variable (95% CI = 13.4-24.8 μg/L) increase in CSF selenium, distributed across selenoproteins and ino...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 20, 2018
The optimal methodology for defining response with F-fluorodeoxyglucose positron emission tomogra... more The optimal methodology for defining response with F-fluorodeoxyglucose positron emission tomography (FDG-PET) after curative-intent chemoradiation for non-small cell lung cancer (NSCLC) is unknown. We compared survival outcomes according to European Organization for Research and Treatment of Cancer (EORTC), Positron Emission tomography Response Criteria In Solid Tumors 1.0 (PERCIST), Peter Mac Metabolic Visual and Deauville criteria respectively. Three prospective trials of chemoradiation for NSCLC, involving baseline and post-treatment FDG-PET/Computer Tomography (CT) imaging, were conducted between 2004 and 2016. Responses were categorized as complete metabolic response (CMR), partial metabolic response, stable metabolic disease or progressive metabolic disease. Cox proportional hazard models and logrank tests assessed the impact of each response on overall survival (OS). Eighty-seven patients underwent FDG-PET/CT before and after radical chemoradiation for NSCLC. Follow-up FDG-P...
European journal of nuclear medicine and molecular imaging, Jan 7, 2018
To evaluate the impact of positron emission tomography (PET) staging on overall survival (OS) and... more To evaluate the impact of positron emission tomography (PET) staging on overall survival (OS) and progression-free survival (PFS) in patients with early-stage (stages I and II) follicular lymphoma (ESFL) treated with radiation therapy alone. Eighty-five patients with ESFL treated with curative-intent radiation therapy (RT) between December 2000 and May 2011 were identified. Of those, 13 who had no PET staging and 25 who received additional systemic therapy were excluded from the analysis. Thus, we analyzed 47 patients with PET-staged ESFL treated with definitive radiation therapy alone (dose > 23Gy). Tumour features, pre-treatment computed tomography (CT) and PET stage, dose fractionation, and radiation therapy field extent were recorded. The Kaplan-Meier method was used to estimate the OS and PFS. Patterns of failure were assessed as cumulative incidences assuming competing risks. Median age was 57 years (range 24-83); 43% were females. Most were PET stage 1 (76.6%). Median maxi...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 4, 2018
To assess feasibility, safety and utility of a novel Ga-nanocolloid radio-tracer with PET-CT lymp... more To assess feasibility, safety and utility of a novel Ga-nanocolloid radio-tracer with PET-CT lymphoscintigraphy for identification of sentinel lymph nodes (SLN). Pilot study of patients from a tertiary cancer hospital who required insertion of gold fiducials for prostate cancer radiation therapy. Participation did not affect cancer management. Ultrasound-guided transperineal intra-prostatic injection of PET tracer (iron oxide nanocolloid labelled with gallium-68) after placement of fiducials. PET-CT lymphoscintigraphy imaging at approximately 45 and 100 minutes after in-jection of tracer. The study was monitored using Bayesian trial design with the as-sumption that at least one sentinel lymph node (SLN) could be identified in at least two-thirds of cases with >80% confidence. SLN identification was successful in all 5 participants, allowing completion of the pilot study as per protocol. No adverse effects were observed. Unexpected po-tential pathways for transit of malignant cell...
BJU international, Jan 3, 2018
Accurate staging of patients with prostate cancer (PCa) is important for therapeutic decision-mak... more Accurate staging of patients with prostate cancer (PCa) is important for therapeutic decision-making. Relapse after surgery or radiotherapy of curative intent is not uncommon and, in part, represents a failure of staging with current diagnostic imaging techniques to detect disease spread. Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) is a new whole-body scanning technique that enables visualization of PCa with high contrast. The hypotheses of this study are that: (i) PSMA-PET/CT has improved diagnostic performance compared with conventional imaging; (ii) PSMA-PET/CT should be used as a first-line diagnostic test for staging; (iii) the improved diagnostic performance of PSMA-PET/CT will result in significant management impact; and (iv) there are economic benefits if PSMA-PET/CT is incorporated into the management algorithm. The proPSMA trial is a prospective, multicentre study in which patients with untreated high-risk PCa will ...
The Lancet. Oncology, May 7, 2018
Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new e... more Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments. In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high...
The New England journal of medicine, Mar 29, 2018
Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in t... more Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. The study included 24 patients with relapsed or refractory mantle-cell lymphoma (2...
Journal of Nuclear Medicine
For over 40 years, FDG has been the dominant PET tracer in neurology, cardiology, inflammatory di... more For over 40 years, FDG has been the dominant PET tracer in neurology, cardiology, inflammatory diseases and, most particularly, oncology. Combined with the ability to perform whole‐body scanning, FDG has revolutionized the evaluation of cancer and has stifled the adoption of other tracers, except in situations where low avidity or high background activity limits diagnostic performance. The strength of FDG has generally been its ability to detect disease in the absence of structural abnormality, thereby enhancing diagnostic sensitivity, but its simultaneous weakness has been a lack of specificity due to diverse pathologies with enhanced glycolysis. Radiotracers that leverage other hallmarks of cancer or specific cellsurface targets are gradually finding a niche in the diagnostic armamentarium. However, none have had sufficient sensitivity to realistically compete with FDG for evaluation of the broad spectrum of malignancies. Perhaps, this situation is about to change with development of a class of tracers targeting fibroblast activation protein (FAP) that have low uptake in almost all normal tissues but high uptake in most cancer types. In this review, the development and exciting preliminary clinical data relating to various FAP‐specific small‐molecule inhibitor (FAPI) tracers in oncology, will be discussed along with potential non‐oncological application
Cancer Imaging
Almost a decade ago, a French cancer centre, for its 10th anniversary celebratory magazine, asked... more Almost a decade ago, a French cancer centre, for its 10th anniversary celebratory magazine, asked me to write a brief prediction of how oncology might look in 2020. I wrote (loosely translated from the original French version);
Blood
Introduction: Early ASCT improves progression-free survival (PFS) but not overall survival (OS) i... more Introduction: Early ASCT improves progression-free survival (PFS) but not overall survival (OS) in poor prognosis DLBCL treated with R-CHOP immuno-chemotherapy (Stiff P et al., NEJM 2013). Furthermore, indiscriminate ASCT exposes those poor-risk patients destined to remain in CR with R-CHOP alone to unnecessary toxicity. Here, the role of interim PET/CT to risk-stratify is controversial. One confounding factor is that interim PET/CT is typically performed after 2 (or 3) cycles of chemotherapy when FDG-avidity likely reflects a mix of residual cancer cells and inflammation; in contrast, interim PET/CT after cycle 4 may be more representative of resistant lymphoma. We hypothesized that: 1. assessment of DLBCL patients by interim PET/CT after 4 cycles (iPET4) of R-CHOP-14 allows greater specificity of FDG-avidity; and, 2. for patients with iPET4-positivity, early treatment intensification with R-ICE chemotherapy followed by Zevalin-BEAM conditioning and ASCT results in 2-yr PFS that is...
Angewandte Chemie International Edition
Journal of Medical Genetics
BackgroundUntil recently, determining penetrance required large observational cohort studies. Dat... more BackgroundUntil recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA–C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL).MethodsTwo cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA–C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas).ResultsPathogenic SDHA–C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 ...
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2018
The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-l... more The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-ligand 1 (PD-L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression. Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy-naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second-line without brain metastases), or cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg atezolizumab on day 1 (21-day cycles). Primary endpoint was investigator-assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression-free survival, duration of response, and safety. ...
Journal of Nuclear Medicine
The authors declare that no potential conflicts of interest relevant to this article exist view o... more The authors declare that no potential conflicts of interest relevant to this article exist view of pelvic MRI. The detection rate for intrapelvic extra-PF disease was 90% (9/10) for PSMA and 31% (5/16) for MRI compared to FCH. Imaging changed expected management in 46% (42/91) FCH, and 23% (21/88) MRI. PSMA provided additive management change over FCH in a further 23% (7/31). Treatment response to SRT was higher in men with negative or PF confined vs. extra PF disease. FCH 73% (32/44) vs. 33% (3/9) (p< 0.02), pelvic MRI 70% (32/46) vs 50% (2/4), p = ns) and PSMA 88% (7/8) vs. 14% (1/7) (p<0.005). Men with negative imging (MRI, FCH +/-PSMA) had high (78%) response rates to SRT. Conclusion: FCH and PSMA had high detection rates for extra PF disease in men with negative/equivocal conventional imaging and BCR post RP. This impacted management and treatment responses to SRT, suggesting an important role for PET in triaging men being considered for curative SRT.
European Journal of Cancer
Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed ... more Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.
Journal of Nuclear Medicine
European journal of nuclear medicine and molecular imaging, Jan 5, 2018
This paper follows the immunotherapy symposium held during the European Association of Nuclear Me... more This paper follows the immunotherapy symposium held during the European Association of Nuclear Medicine (EANM) 2017 Annual Congress. The biological basis of the immune checkpoint inhibitors and the drugs most frequently used for the treatment of solid tumours are reviewed. The issues of pseudoprogression (frequency, timeline), hyperprogression and immune-related side effects are discussed, as well as their implications for patient management. A review of the recent literature on the use of FDG PET for assessment of immunotherapy is presented, and recommendations are provided for assessing tumour response and reporting immune-related side effects with FDG PET based on published data and experts' experience. Representative clinical cases are also discussed.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 5, 2018
Lu-PSMA-617 enables targeted delivery of beta-particle radiation to prostate cancer. We determine... more Lu-PSMA-617 enables targeted delivery of beta-particle radiation to prostate cancer. We determined its radiation dosimetry and relationships to pre-therapeutic imaging and outcomes. 30 patients with prostate cancer receiving Lu-PSMA-617 within a prospective clinical trial (ACTRN12615000912583) were studied. Screening Ga-PSMA-11 PET-CT demonstrated high PSMA-expression in all patients. Following therapy patients underwent quantitative SPECT-CT at 4, 24 and 96 hours. Pharmacokinetic uptake and clearance at a voxel level was calculated and translated into absorbed dose using voxel S values. Volumes-of-interest were drawn on normal tissues and tumor to assess radiation dose and a 'whole-body' tumor dose was also defined. Correlations between PSMA PET-CT parameters, dosimetry and biochemical and therapeutic response were analyzed to identify relationships between absorbed dose, tumor burden, and patient physiology. Mean absorbed dose to kidneys, submandibular and parotid glands, ...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 30, 2018
Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. The... more Merkel cell carcinoma (MCC) is an aggressive skin cancer with neuroendocrine differentiation. There is an unmet need for MCC-specific blood-based surrogate biomarkers of tumor burden; circulating cell-free miRNA may serve this purpose. Expression of miR-375 was quantified in 24 MCC and 23 non-MCC cell lines, 67 MCC and 58 non-MCC tumor tissues, sera of 2 preclinical MCC models, and sera of 109 patients with MCC and 30 healthy controls by nCounter human-v2-miRNA expression or miR-375-specific real-time PCR assays. The patients' sera consisted of two retrospective (discovery and training) and two prospective (validation) cohorts. miR-375 expression was high in MCC cell lines and tissues compared with non-MCCs. It was readily detected in MCC-conditioned medium and sera of preclinical models bearing MCC xenografts. miR-375 levels were higher in sera from tumor-bearing patients with MCC than in tumor-free patients or healthy controls ( < 0.0005). Moreover, miR-375 serum levels cor...
Journal of Alzheimer's disease : JAD, 2018
The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatom... more The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings suppor...
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, Jan 13, 2018
Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer&#... more Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer's disease (AD) pathophysiology; therefore, oral supplementation may potentially slow neurodegeneration. We examined selenium and selenoproteins in serum and cerebrospinal fluid (CSF) from a dual-dose 24-week randomized controlled trial of sodium selenate in AD patients, to assess tolerability, and efficacy of selenate in modulating selenium concentration in the central nervous system (CNS). A pilot study of 40 AD cases was randomized to placebo, nutritional (0.32 mg sodium selenate, 3 times daily), or supranutritional (10 mg, 3 times daily) groups. We measured total selenium, selenoproteins, and inorganic selenium levels, in serum and CSF, and compared against cognitive outcomes. Supranutritional selenium supplementation was well tolerated and yielded a significant (p < 0.001) but variable (95% CI = 13.4-24.8 μg/L) increase in CSF selenium, distributed across selenoproteins and ino...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 20, 2018
The optimal methodology for defining response with F-fluorodeoxyglucose positron emission tomogra... more The optimal methodology for defining response with F-fluorodeoxyglucose positron emission tomography (FDG-PET) after curative-intent chemoradiation for non-small cell lung cancer (NSCLC) is unknown. We compared survival outcomes according to European Organization for Research and Treatment of Cancer (EORTC), Positron Emission tomography Response Criteria In Solid Tumors 1.0 (PERCIST), Peter Mac Metabolic Visual and Deauville criteria respectively. Three prospective trials of chemoradiation for NSCLC, involving baseline and post-treatment FDG-PET/Computer Tomography (CT) imaging, were conducted between 2004 and 2016. Responses were categorized as complete metabolic response (CMR), partial metabolic response, stable metabolic disease or progressive metabolic disease. Cox proportional hazard models and logrank tests assessed the impact of each response on overall survival (OS). Eighty-seven patients underwent FDG-PET/CT before and after radical chemoradiation for NSCLC. Follow-up FDG-P...
European journal of nuclear medicine and molecular imaging, Jan 7, 2018
To evaluate the impact of positron emission tomography (PET) staging on overall survival (OS) and... more To evaluate the impact of positron emission tomography (PET) staging on overall survival (OS) and progression-free survival (PFS) in patients with early-stage (stages I and II) follicular lymphoma (ESFL) treated with radiation therapy alone. Eighty-five patients with ESFL treated with curative-intent radiation therapy (RT) between December 2000 and May 2011 were identified. Of those, 13 who had no PET staging and 25 who received additional systemic therapy were excluded from the analysis. Thus, we analyzed 47 patients with PET-staged ESFL treated with definitive radiation therapy alone (dose > 23Gy). Tumour features, pre-treatment computed tomography (CT) and PET stage, dose fractionation, and radiation therapy field extent were recorded. The Kaplan-Meier method was used to estimate the OS and PFS. Patterns of failure were assessed as cumulative incidences assuming competing risks. Median age was 57 years (range 24-83); 43% were females. Most were PET stage 1 (76.6%). Median maxi...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 4, 2018
To assess feasibility, safety and utility of a novel Ga-nanocolloid radio-tracer with PET-CT lymp... more To assess feasibility, safety and utility of a novel Ga-nanocolloid radio-tracer with PET-CT lymphoscintigraphy for identification of sentinel lymph nodes (SLN). Pilot study of patients from a tertiary cancer hospital who required insertion of gold fiducials for prostate cancer radiation therapy. Participation did not affect cancer management. Ultrasound-guided transperineal intra-prostatic injection of PET tracer (iron oxide nanocolloid labelled with gallium-68) after placement of fiducials. PET-CT lymphoscintigraphy imaging at approximately 45 and 100 minutes after in-jection of tracer. The study was monitored using Bayesian trial design with the as-sumption that at least one sentinel lymph node (SLN) could be identified in at least two-thirds of cases with >80% confidence. SLN identification was successful in all 5 participants, allowing completion of the pilot study as per protocol. No adverse effects were observed. Unexpected po-tential pathways for transit of malignant cell...
BJU international, Jan 3, 2018
Accurate staging of patients with prostate cancer (PCa) is important for therapeutic decision-mak... more Accurate staging of patients with prostate cancer (PCa) is important for therapeutic decision-making. Relapse after surgery or radiotherapy of curative intent is not uncommon and, in part, represents a failure of staging with current diagnostic imaging techniques to detect disease spread. Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) is a new whole-body scanning technique that enables visualization of PCa with high contrast. The hypotheses of this study are that: (i) PSMA-PET/CT has improved diagnostic performance compared with conventional imaging; (ii) PSMA-PET/CT should be used as a first-line diagnostic test for staging; (iii) the improved diagnostic performance of PSMA-PET/CT will result in significant management impact; and (iv) there are economic benefits if PSMA-PET/CT is incorporated into the management algorithm. The proPSMA trial is a prospective, multicentre study in which patients with untreated high-risk PCa will ...
The Lancet. Oncology, May 7, 2018
Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new e... more Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments. In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high...
The New England journal of medicine, Mar 29, 2018
Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in t... more Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood. The study included 24 patients with relapsed or refractory mantle-cell lymphoma (2...