Publications by authors named "Rodney J Hicks"

389 Publications

Intra-patient comparison of physiologic Ga-PSMA-11 and F-DCFPyL PET/CT uptake in ganglia in prostate cancer patients: a pictorial essay.

Cancer Imaging 2021 Apr 16;21(1):35. Epub 2021 Apr 16.

Centre for Molecular Imaging, Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Background: Recent studies reported metabolic uptake in at least one of the evaluated ganglia in 98.5% of patients undergoing Ga -PSMA-11 and in 96.9% of patients undergoing F-DCFPyL PET/CT examination. We have observed different patterns of ganglion visualization with F-DCFPyL compared to Ga-PSMA-11. This includes more frequent visualization of cervical and sacral ganglia, which may be attributable to better imaging characteristics with F PET imaging.

Case Presentation: This pictorial essay is to illustrate and compare, in the same patient, various representative cases of Ga-PSMA-11 and F-DCFPyL PET/CT uptake in ganglia at different anatomic locations, with different patterns and distribution of metabolic activity.

Conclusion: Reading physicians should be aware of the frequently encountered and occasionally different physiologic uptake of Ga-PSMA-11 and F DCFPyL in different ganglia.
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http://dx.doi.org/10.1186/s40644-021-00404-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052677PMC
April 2021

A New Turn in Peptide-Based Imaging Agents: Foldamers Afford Improved Theranostics Targeting Cholecystokinin-2 Receptor-Positive Cancer.

J Med Chem 2021 Apr 7;64(8):4841-4856. Epub 2021 Apr 7.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3010, Australia.

Proteins adopt unique folded secondary and tertiary structures that are responsible for their remarkable biological properties. This structural complexity is key in designing efficacious peptides that can mimic the three-dimensional structure needed for biological function. In this study, we employ different chemical strategies to induce and stabilize a β-hairpin fold of peptides targeting cholecystokinin-2 receptors for theranostic application (combination of a targeted therapeutic and a diagnostic companion). The newly developed peptides exhibited enhanced folding capacity as demonstrated by circular dichroism (CD) spectroscopy, ion-mobility spectrometry-mass spectrometry, and two-dimensional (2D) NMR experiments. Enhanced folding characteristics of the peptides led to increased biological potency, affording four optimal Ga-68 labeled radiotracers ([Ga]Ga-, [Ga]Ga-) targeting CCK-2R. In particular, [Ga]Ga- and [Ga]Ga- presented improved metabolic stability, enhanced cell internalization, and up to 6 fold increase in tumor uptake. These peptides hold great promise as next-generation theranostic radiopharmaceuticals.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02213DOI Listing
April 2021

Imaging Somatostatin Positive Tumors with Tyr-Octreotate/Octreotide Conjugated to Desferrioxamine B Squaramide Radiolabeled with either Zirconium-89 or Gallium-68.

Bioconjug Chem 2021 Mar 31. Epub 2021 Mar 31.

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.

Radiolabeled derivatives of Tyr-octreotide and Tyr-octreotate, synthetic analogues of the peptide hormone somatostatin, can be used for positron emission tomography (PET) imaging of somatostatin receptor expression in neuroendocrine tumors. In this work, a squaramide ester derivative of desferrioxamine B (HDFOSq) was used attach either Tyr-octreotide or Tyr-octreotate to the metal binding ligand to give HDFOSq-TIDE and HDFOSq-TATE. These new peptide-HDFOSq conjugates form stable complexes with either of the positron-emitting radionuclides gallium-68 ( = 68 min) or zirconium-89 ( = 3.3 days). The new complexes were evaluated in an AR42J xenograft model that has endogenous expression of SSTR2. All four agents displayed good tumor uptake and produced high-quality PET images. For both radionuclides, the complexes formed with HDFOSq-TATE performed better, with higher tumor uptake and retention than the complexes formed with HDFOSq-TIDE. The versatile ligands presented here can be radiolabeled with either gallium-68 or zirconium-89 at room temperature. The long radioactive half-life of zirconium-89 makes distribution of pre-synthesized tracers produced to certified standards feasible and could increase the number of clinical centers that can perform diagnostic PET imaging of neuroendocrine tumors.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00109DOI Listing
March 2021

High-Specific-Activity-I-MIBG versus Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Clin Cancer Res 2021 Mar 8. Epub 2021 Mar 8.

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland.

Targeted radionuclide therapies (TRT) using I-metaiodobenzylguanidine (I-MIBG) and peptide receptor radionuclide therapy (Lu or Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-I-MIBG therapy was approved by the FDA and both Lu-DOTATATE and I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3703DOI Listing
March 2021

Molecular Imaging of Neuroendocrine Differentiation of Prostate Cancer: A Case Series.

Clin Genitourin Cancer 2021 Feb 9. Epub 2021 Feb 9.

Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1016/j.clgc.2021.01.008DOI Listing
February 2021

γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival.

Cancer Immunol Res 2021 Mar 5. Epub 2021 Mar 5.

Department of Clinical Pathology and Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-IHC/immunofluorescence (m-IHC/IF). CD4 or CD8 T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double-negative (DN) T-cell infiltrates (>20% DN T cells), and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2 γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD-1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes, and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. On the basis of a 13-gene γδ T-cell signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores, and complete responses to anti-PD-1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0817DOI Listing
March 2021

Gallium-68 Ventilation/Perfusion PET-CT and CT Pulmonary Angiography for Pulmonary Embolism Diagnosis: An Interobserver Agreement Study.

Front Med (Lausanne) 2020 16;7:599901. Epub 2021 Feb 16.

Nuclear Medicine, Brest University Hospital, EA3878 (GETBO) IFR 148, Brest, France.

Ga Ventilation/Perfusion V/Q PET-CT is a promising imaging tool for pulmonary embolism diagnosis. However, no study has verified whether the interpretation is reproducible between different observers. The aim of this study was to assess the interobserver agreement in the interpretation of V/Q PET-CT for the diagnosis of acute PE, and to compare it to the interobserver agreement of CTPA interpretation. Twenty-four cancer patients with suspected acute PE underwent V/Q PET-CT and CTPA within 24 h as part of a prospective pilot study evaluating V/Q PET-CT for the management of patients with suspected PE. V/Q PET-CT and CTPA scans were reassessed independently by four nuclear medicine physicians and four radiologists, respectively. Physicians had different levels of expertise in reading V/Q scintigraphy and CTPA. Interpretation was blinded to the initial interpretation and any clinical information or imaging test result. For each modality, results were reported on a binary fashion. V/Q PET/CT scans were read as positive if there was at least one segmental or two subsegmental mismatched perfusion defects. CTPA scans were interpreted as positive if there was a constant intraluminal filling defect. Interobserver agreement was assessed by calculating kappa (κ) coefficients. Out of the 24 V/Q PET-CT scans, the diagnostic conclusion was concordantly negative in 22 patients and concordantly positive in one patient. The remaining scan was interpreted as positive by one reader and negative by three readers. Out of the 24 CTPA scans, the diagnostic conclusion was concordantly negative in 16 and concordantly positive in one. Out of the seven remaining scans, PE was reported by one reader in four cases, by two readers in two cases, by three readers in one case. Most of discordant results on CTPA were related to clots reported on subsegmental arteries. Mean kappa coefficient was 0.79 for V/Q PET-CT interpretation and 0.39 for CTPA interpretation. Interobserver agreement in the interpretation of V/Q PET-CT for PE diagnosis was substantial (kappa 0.79) in a population with a low prevalence of significant PE. Agreement was lower with CTPA, mainly as a result of discrepancies at the level of the subsegmental arteries.
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http://dx.doi.org/10.3389/fmed.2020.599901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921798PMC
February 2021

Consensus on molecular imaging and theranostics in neuroendocrine neoplasms.

Eur J Cancer 2021 Mar 12;146:56-73. Epub 2021 Feb 12.

Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing gallium-labelled somatostatin analogue ([Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing fluorine-fluoro-2-deoxyglucose ([F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [F]FDG and [Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.
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http://dx.doi.org/10.1016/j.ejca.2021.01.008DOI Listing
March 2021

Utility of Ga-DOTA-Exendin-4 PET/CT imaging in distinguishing between insulinoma and nesidioblastosis in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia.

Intern Med J 2020 Dec 14. Epub 2020 Dec 14.

Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: Because management is very different, it is important to differentiate between small focal insulinomas and diffuse pancreatic dysplasia (nesidioblastosis) in patients with confirmed endogenous hyperinsulinaemic hypoglycaemia (EHH). Most insulinomas highly express Glucagon Like Peptide-1 receptors enabling PET/CT imaging with its radiolabelled analogue; Ga-DOTA-exendin-4 (Exendin).

Aim: To determine (a) the utility of Exendin in EHH patients in a clinical setting; (b) whether degree of Exendin uptake differentiates non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) from post gastric bypass hypoglycaemia (PGBH).

Methods: This retrospective study reviewed the clinical, biochemistry and prior imaging findings in confirmed EHH patients referred for Exendin. Accuracy of Exendin was based on surgical findings and treatment outcomes. Finally, average Exendin uptake (SUVmax) of 5 PGBH studies was compared with the SUVmax of a key NIPHS case report. RESULTS: 20/25 consecutive patients had confirmed EHH. Exendin located insulinomas in 8/9 patients enabling successful surgical excision with rapid and durable cure. Exendin correctly identified diffuse nesidioblastosis in 2/3 cases requiring partial pancreatectomy for hypoglycaemia control. All 3 relapsed within 1.7 years with 1 needing completion pancreatectomy. Establishing the cause in the remainder relied on other investigations, clinical correlation and response to empirical treatment. Finally, Exendin SUVmax could not distinguish between NIPHS and PGBH.

Conclusion: In EHH patients, Exendin accurately identifies the site of insulinoma and thereby differentiates it from nesidioblastosis but negative findings should not be ignored. Exendin is unlikely to differentiate between normal pancreatic uptake, NIPHS and PGBH. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15141DOI Listing
December 2020

PERCISTence: Strength or Stubbornness?

J Nucl Med 2020 12;61(Suppl 2):199S-200S

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Radiology & Nuclear Medicine, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.

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http://dx.doi.org/10.2967/jnumed.120.250563DOI Listing
December 2020

FAPI PET/CT: Will It End the Hegemony of F-FDG in Oncology?

J Nucl Med 2021 03 4;62(3):296-302. Epub 2020 Dec 4.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

For over 40 years, F-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, F-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 F-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 cell-surface targets are gradually finding a niche in the diagnostic armamentarium. However, none have had sufficient sensitivity to realistically compete with F-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 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 fibroblast activation protein-specific small-molecule inhibitor tracers in oncology will be discussed along with potential nononcologic applications.
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http://dx.doi.org/10.2967/jnumed.120.256271DOI Listing
March 2021

Therapeutic Efficacy of a Bivalent Inhibitor of Prostate-Specific Membrane Antigen Labeled with Copper-67.

J Nucl Med 2020 Oct 16. Epub 2020 Oct 16.

School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, Australia.

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising treatment for prostate cancer. We reported a ligand featuring two lysine-ureido-glutamate groups, Cu-CuSarbisPSMA previously. Here, we report the therapeutic potential of Cu-CuSarbisPSMA. Growth of PSMA-positive xenografts was evaluated following treatment with Cu-CuSarbisPSMA or Lu-LuPSMA I&T. At 13 days post-injection, tumor growth was similarly inhibited by the two tracers in a dose-dependent manner. Survival was comparable after single (30 MBq) or fractionated administrations (2 x 15MBq, two weeks apart). Cu-CuSarbisPSMA is efficacious in a PSMA-expressing model of prostate cancer.
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http://dx.doi.org/10.2967/jnumed.120.251579DOI Listing
October 2020

Clinical, FDG-PET and molecular markers of immune checkpoint inhibitor response in patients with metastatic Merkel cell carcinoma.

J Immunother Cancer 2020 10;8(2)

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Background: Metastatic Merkel cell carcinoma (mMCC) is an aggressive neuroendocrine malignancy of the skin with a poor prognosis. Immune checkpoint inhibitors (ICIs) have shown substantial efficacy and favorable safety in clinical trials.

Methods: Medical records of patients (pts) with mMCC treated with ICIs from August 2015 to December 2018 at Peter MacCallum Cancer Centre in Australia were analyzed. Response was assessed with serial imaging, the majority with FDG-PET/CT scans. RNA sequencing and immunohistochemistry for PD-L1, CD3 and Merkel cell polyomavirus (MCPyV) on tumor samples was performed.

Results: 23 pts with mMCC were treated with ICIs. A median of 8 cycles (range 1 to 47) were administered, with treatment ongoing in 6 pts. Objective responses (OR) were observed in 14 pts (61%): 10 (44%) complete responses (CR) and 4 (17%) partial responses (PR). Median time to response was 8 weeks (range 6 to 12) and 12-month progression-free survival rate was 39%. Increased OR were seen in pts aged less than 75 (OR 80% vs 46%), no prior history of chemotherapy (OR 64% vs 50%), patients with an immune-related adverse event (OR 100% vs 43%) and in MCPyV-negative tumors (OR 69% vs 43%). Pts with a CR had lower mean metabolic tumor volume on baseline FDG-PET/CT scan (CR: 35.7 mL, no CR: 187.8 mL, p=0.05). There was no correlation between PD-L1 positivity and MCPyV status (p=0.764) or OR (p=0.245). 10 pts received radiation therapy (RT) during ICI: 4 pts started RT concurrently (OR 75%, CR 50%), 3 pts had isolated ICI-resistant lesions successfully treated with RT and 3 pts with multisite progression continued to progress despite RT. Overall, 6 pts (26%) had grade 1-2 immune-related adverse events.

Conclusion: ICIs showed efficacy and safety in mMCC consistent with trial data. Clinical and imaging predictors of response were identified.
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http://dx.doi.org/10.1136/jitc-2020-000700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566424PMC
October 2020

First clinical study of a pegylated diabody I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers.

Theranostics 2020 15;10(25):11404-11415. Epub 2020 Sep 15.

Avipep Pty Ltd and the Victorian Cancer Biologics Consortium, Parkville, Victoria 3052, Australia.

Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 (I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/mI-PEG-AVP0458 in patients with TAG-72 positive relapsed/ metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. PEG-AVP0458 was radiolabeled with I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients.
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http://dx.doi.org/10.7150/thno.49422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545991PMC
September 2020

The utility of pharmacological and radiological interventions to optimize diagnostic information from PET/CT.

Cancer Imaging 2020 Sep 22;20(1):68. Epub 2020 Sep 22.

The Department of Nuclear Medicine, University Hospital, Caen, France.

Background: Positron Emission Tomography with Computed Tomography (PET/CT) is widely used in the assessment of many diseases, particularly including cancer. However, many factors can affect image quality and diagnostic performance of PET scans using FDG or other PET probes.

Main Body: The aim of this pictorial essay is to review PET/CT protocols that can be useful to overcome these confounding factors in routine clinical situations, with a particular focus on pharmacological interventions and problem-oriented CT acquisition protocols.

Conclusion: Imaging protocols and representative cases will be discussed, in addition to potential contraindications and precautions to be taken.
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http://dx.doi.org/10.1186/s40644-020-00344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510123PMC
September 2020

Octreotide for resuscitation of cardiac arrest due to carcinoid crisis precipitated by novel peptide receptor radionuclide therapy (PRRT): A case report.

J Crit Care 2020 12 17;60:319-322. Epub 2020 Aug 17.

Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia; Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Australia; Joint Health Command, Australian Defence Force, Canberra, Australia.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic carcinoid tumours but can precipitate a carcinoid crisis through release of stored bioamines. Cardiac arrest is an uncommon manifestation of carcinoid crisis and has never been reported as a complication of PRRT. We report a case of a 58-year old female who suffered from cardiac arrest following PRRT for metastatic carcinoid tumour. She was successfully resuscitated using intravenous octreotide following 22 min of failure to resuscitate with a standard advanced cardiac life support protocol. Following resuscitation, severe carcinoid heart disease was diagnosed, and the patient subsequently underwent successful surgical valve replacement. Although there is no trial evidence, considering pharmacological rationale and successful outcome in this case, we suggest early administration of intravenous octreotide during resuscitation of patients suffering cardiac arrest post PRRT for carcinoid disease and recommend preventive strategies.
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http://dx.doi.org/10.1016/j.jcrc.2020.08.011DOI Listing
December 2020

Imaging the Cancer Immune Environment and Its Response to Pharmacologic Intervention, Part 2: The Role of Novel PET Agents.

J Nucl Med 2020 11 4;61(11):1553-1559. Epub 2020 Sep 4.

Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Although F-FDG PET/CT is widely available and is increasingly being used to monitor response to immunotherapy and simultaneously identify immune-related adverse events, there are several challenges in interpreting the results of this investigation, especially early in the course of treatment. It also has limited utility in selecting the optimal type of immunotherapy. As knowledge about immune contexture increases, new targets that may be amenable to imaging are being defined. These exciting advances, coupled with increasingly sophisticated methods for generating radiopharmaceuticals, provide the potential for either replacing or complementing F-FDG PET/CT in the selection and monitoring of immunotherapy. Approaches include imaging specific characteristics of immune cell infiltrates or aspects of the tumor microenvironment that are known to be associated with suppression of the innate and adaptive immune response. Following a large body of preclinical work, promising agents that are entering into early clinical evaluation are discussed. We suggest a speculative algorithm as to how these might be used in routine practice, subject to validation in clinical trials.
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http://dx.doi.org/10.2967/jnumed.120.248823DOI Listing
November 2020

Bivalent Inhibitors of Prostate-Specific Membrane Antigen Conjugated to Desferrioxamine B Squaramide Labeled with Zirconium-89 or Gallium-68 for Diagnostic Imaging of Prostate Cancer.

J Med Chem 2020 09 13;63(17):9258-9270. Epub 2020 Aug 13.

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.

Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (HDFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The HDFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 ( = 68 min) or zirconium-89 ( = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00291DOI Listing
September 2020

Enhancing the anti-tumour activity of Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP.

Sci Rep 2020 06 23;10(1):10196. Epub 2020 Jun 23.

Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Peptide receptor radionuclide therapy (PRRT) is an important treatment option for patients with somatostatin receptor-2 (SSTR2)-expressing neuroendocrine tumour (NET) though tumour regression occurs in only a minority of patients. Therefore, novel PRRT regimens with improved therapeutic activity are needed. Radiation induced DNA damage repair is an attractive therapeutic target to increase PRRT efficacy and consequently, we have characterised a panel of preclinical models for their SSTR2 expression, in vivo growth properties and response to Lu-DOTA-octreotate (LuTate) PRRT to identify models with features suitable for evaluating novel therapeutic combinations. In vitro studies using the SSTR2 expressing AR42J model demonstrate that the combination of LuTate and the small molecule Poly(ADP-ribose) polymerase-1 (PARP) inhibitor, talazoparib led to increased DNA double strand breaks, as assessed by γ-H2AX foci formation, as compared to LuTate alone. Furthermore, using the AR42J tumour model in vivo we demonstrate that the combination of LuTate and talazoparib significantly improved the anti-tumour efficacy of LuTate alone. These findings support the clinical evaluation of the combination of LuTate and PARP inhibition in SSTR2-expressing NET.
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http://dx.doi.org/10.1038/s41598-020-67199-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311440PMC
June 2020

Peptide Receptor Radionuclide Therapy During the COVID-19 Pandemic: Are There Any Concerns?

J Nucl Med 2020 Aug 23;61(8):1094-1095. Epub 2020 Jun 23.

Department of Nuclear Medicine, University Hospital Essen, Essen, Germany, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.

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http://dx.doi.org/10.2967/jnumed.120.249136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413236PMC
August 2020

Theranostic implications of molecular imaging phenotype of well-differentiated pulmonary carcinoid based on Ga-DOTATATE PET/CT and F-FDG PET/CT.

Eur J Nucl Med Mol Imaging 2021 Jan 22;48(1):204-216. Epub 2020 Jun 22.

Cancer imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Purpose: This study aimed to analyse the molecular imaging (MI) phenotype of typical carcinoid (TC) and atypical carcinoid (AC) by Ga-DOTATATE (GaTATE) and F-FDG (FDG) PET/CT with the emphasis on its potential theranostic implications for peptide receptor radionuclide therapy (PRRT).

Methods: Retrospective review of patients with biopsy-proven TC or AC undergoing both GaTATE and FDG PET/CT at presentation. Based on correlative CT or MRI, positive lesions on either scan were defined by uptake above liver parenchyma. Per patient MI phenotypic pattern was classified as score 1, if all lesions were negative on both scans; score 2, if all were GaTATE positive/FDG negative; score 3, if all lesions were GaTATE positive but some or all were also FDG positive and score 4, if there were any GaTATE negative/FDG positive lesions. Scores 1 and 4 were deemed unsuitable for PRRT.

Results: Of 56 patients (median age 66.5 years, 32 female), 22 had TC, and 34 had AC. Distant metastases were seen in 32% of TC and 94% of AC. At a median follow-up of 37 months for TC and 38 months for AC, 100% and 63% were alive, respectively. Median OS for AC was 56 months (95% CI 43, not reached [NR]), and TC was NR. On inter-patient dual-tracer analysis, scores 1, 2, 3 and 4 were 23%, 18%, 36% and 23% in TC and 3%, 15%, 32% and 50% in AC, respectively. In 16 patients (score 2, N = 3; score 3, N = 12; score 4, N = 1) who were treated with PRRT, disease control rate at 3 months and OS were, 85% and 54.6 months (95% CI 44-70), respectively.

Conclusions: TC and AC showed a wide inter-patient phenotypic heterogeneity on GaTATE and FDG with around half of patients (46% TC and 53% AC) having an unsuitable phenotype for PRRT. Dual-tracer MI phenotype can be used to select the most suitable patients for PRRT.
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http://dx.doi.org/10.1007/s00259-020-04915-7DOI Listing
January 2021

Imaging the Cancer Immune Environment and Its Response to Pharmacologic Intervention, Part 1: The Role of F-FDG PET/CT.

J Nucl Med 2020 07 22;61(7):943-950. Epub 2020 May 22.

Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Immunotherapy agents are now entering the clinic in a wide array of malignancies and have provided a valuable addition to the therapeutic armamentarium. These agents enhance the global immune response by modulating the tumor microenvironment but can lead to unconventional patterns of response, challenging the conceptual framework that imaging is a robust surrogate for therapeutic efficacy. There is also increasing evidence that an effective antitumor response requires a systemic immune response in primary and secondary lymphoid tissues. However, an enhanced systemic immune response can lead to disruption of immunologic hemostasis in healthy tissues, causing adverse events. Better understanding of the complex interplay between tumoral and systemic immune response has been provided through tissue and liquid biopsy. However, the applicability of these methods is constrained by the biologic, spatial, and temporal heterogeneity of the processes involved. There is a growing interest in molecular imaging of cell-specific lineage markers of the immune system using biomolecules. However, the ongoing role of the more widely available F-FDG PET/CT for response assessment is being recognized through ongoing refinement of interpretative guidelines and emerging evidence. These noninvasive methods provide insights into the biologic basis of the global immune response to maximize potential therapeutic benefit. In this review, we aim to provide an overview of the current status of F-FDG PET/CT in the monitoring of tumoral and systemic immune response. In a companion review, the role of other imaging probes that might complement F-FDG PET/CT will be discussed.
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http://dx.doi.org/10.2967/jnumed.119.234278DOI Listing
July 2020

Technical Note: Rapid multiexponential curve fitting algorithm for voxel-based targeted radionuclide dosimetry.

Med Phys 2020 Sep 12;47(9):4332-4339. Epub 2020 Jun 12.

Department of Molecular Imaging & Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, 3000, Australia.

Background: Dosimetry in nuclear medicine often relies on estimating pharmacokinetics based on sparse temporal data. As analysis methods move toward image-based three-dimensional computation, it becomes important to interpolate and extrapolate these data without requiring manual intervention; that is, in a manner that is highly efficient and reproducible. Iterative least-squares solvers are poorly suited to this task because of the computational overhead and potential to optimize to local minima without applying tight constraints at the outset.

Methodology: This work describes a fully analytical method for solving three-phase exponential time-activity curves based on three measured time points in a manner that may be readily employed by image-based dosimetry tools. The methodology uses a series of conditional statements and a piecewise approach for solving exponential slope directly through measured values in most instances. The proposed algorithm is tested against a purpose-designed iterative fitting technique and linear piecewise method followed by single exponential in a cohort of ten patients receiving Lu-DOTA-Octreotate therapy.

Results: Tri-exponential time-integrated values are shown to be comparable to previously published methods with an average difference between organs when computed at the voxel level of 9.8 ± 14.2% and -3.6 ± 10.4% compared to iterative and interpolated methods, respectively. Of the three methods, the proposed tri-exponential algorithm was most consistent when regional time-integrated activity was evaluated at both voxel- and whole-organ levels. For whole-body SPECT imaging, it is possible to compute 3D time-integrated activity maps in <5 min processing time. Furthermore, the technique is able to predictably and reproducibly handle artefactual measurements due to noise or spatial misalignment over multiple image times.

Conclusions: An efficient, analytical algorithm for solving multiphase exponential pharmacokinetics is reported. The method may be readily incorporated into voxel-dose routines by combining with widely available image registration and radiation transport tools.
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http://dx.doi.org/10.1002/mp.14243DOI Listing
September 2020

Peptide Receptor Radionuclide Therapy with Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model.

J Nucl Med 2020 12 15;61(12):1800-1805. Epub 2020 May 15.

School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia

Peptide receptor radionuclide therapy (PRRT) using radiolabeled octreotate is an effective treatment for somatostatin receptor 2-expressing neuroendocrine tumors. The diagnostic and therapeutic potential of Cu and Cu, respectively, offers the possibility of using a single somatostatin receptor-targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCOSar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid), conjugated to (Tyr)-octreotate, called Cu-CuSarTATE, was demonstrated to be an imaging agent and potential prospective dosimetry tool in 10 patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, Lu-LuDOTA-Tyr-octreotate (Lu-LuTATE). The antitumor efficacy of various doses of Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor-bearing mice was compared with Lu-LuTATE. Seven days after a single administration of Cu-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of Lu-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival was extended from 12 d in the control group to 21 d after treatment with both Cu-CuSarTATE and Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of Cu-CuSarTATE or Lu-LuTATE, either as a single intravenous injection or as two 15-MBq fractions 2 wk apart. Treatment of tumors with 2 fractions significantly improved survival over delivery as a single fraction (Cu-CuSarTATE: 47 vs. 36 d [ = 0.036]; Lu-LuTATE: 46 vs. 29 d [ = 0.040]). This study demonstrates that Cu-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of Cu-CuSarTATE and Lu-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of Cu-CuSarTATE in the AR42J tumor model demonstrated the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2-expressing neuroendocrine tumors.
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http://dx.doi.org/10.2967/jnumed.120.243543DOI Listing
December 2020

F-FDG PET/CT based spleen to liver ratio associates with clinical outcome to ipilimumab in patients with metastatic melanoma.

Cancer Imaging 2020 May 14;20(1):36. Epub 2020 May 14.

Research Division, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia.

Background: Immune checkpoint blockade such as ipilimumab and anti-PD1 monoclonal antibodies have significantly improved survival in advanced melanoma. Biomarkers are urgently needed as a majority of patients do not respond, despite treatment-related toxicities. We analysed pre-treatment F-fluorodeoxyglucose positron emission tomography/computerised tomography (FDG PET/CT) parameters to assess its correlation with patient outcome.

Methods: This retrospective study evaluated pre-treatment FDG PET/CT scans in a discovery cohort of patients with advanced melanoma treated with ipilimumab or anti-PD1. Pre-treatment scans were assessed for maximum tumoral standardised uptake value (SUVmax), metabolic tumour volume (MTV) and spleen to liver ratio (SLR). Progression-free survival (PFS) and overall survival (OS) were characterised and modelled using univariable and multivariable analyses. Correlation of SLR and OS was validated in an independent cohort. Blood parameters and stored sera of patients from the discovery cohort was analysed to investigate biological correlates with SLR.

Results: Of the 90 evaluable patients in the discovery cohort: 50 received ipilimumab monotherapy, 20 received anti-PD1 monotherapy, and 20 patients received ipilimumab followed by anti-PD1 upon disease progression. High SLR > 1.1 was associated with poor PFS (median 1 vs 3 months; HR 3.14, p = 0.008) for patients treated with ipilimumab. High SLR was associated with poor OS after ipilimumab (median 1 vs 21 months; HR 5.83, p = 0.0001); as well as poor OS after first line immunotherapy of either ipilimumab or anti-PD1 (median 1 vs 14 months; HR 3.92, p = 0.003). The association of high SLR and poor OS after ipilimumab was validated in an independent cohort of 110 patients (median 2.3 months versus 11.9 months, HR 3.74). SLR was associated with poor OS in a multi-variable model independent of stage, LDH, absolute lymphocyte count and MTV.

Conclusions: Pre-treatment Spleen to liver ratio (SLR) > 1.1 was associated with poor outcome after ipilimumab in advanced melanoma. This parameter warrants prospective evaluation.
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http://dx.doi.org/10.1186/s40644-020-00313-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227105PMC
May 2020

FDG PET/CT for tumoral and systemic immune response monitoring of advanced melanoma during first-line combination ipilimumab and nivolumab treatment.

Eur J Nucl Med Mol Imaging 2020 11 21;47(12):2776-2786. Epub 2020 Apr 21.

Cancer Imaging, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.

Purpose: We aimed to investigate the role of FDG-PET/CT in monitoring of response and immune-related adverse events (irAEs) following first-line combination-immune checkpoint inhibitor (combination-ICI) therapy for advanced melanoma.

Methods: We retrospectively reviewed outcomes in patients who had (1) first-line nivolumab plus ipilimumab; (2) pre- and post-treatment FDG-PET/CT scans (pre-FDG-PET/CT and post-FDG-PET/CT) within 2 and 4 months of starting ICI, respectively; and (3) at least one lesion assessable by PET response criteria in solid tumors (PERCIST). Extracranial response was monitored by 3 monthly FDG-PET/CT. Whole-body metabolic tumor volume (wbMTV) was measured pre- and post-treatment and correlated with outcome. FDG-PET/CT manifestations of irAE were defined as new increased non-tumoral uptake on post-FDG-PET/CT and were correlated with clinical presentation.

Results: Thirty-one consecutive patients, median age 60 years (range, 30-78), were identified from 2016 to 2018. The median number of combination-ICI cycles to the first post-FDG-PET/CT response assessment was 3 (interquartile range (IQR), 2-4). The best-overall responses were complete metabolic response (CMR) in 25 (80%), partial metabolic response (PMR) in 3 (10%), and progressive metabolic disease (PMD) in 3 (10%) patients. Patients with PMD had significantly higher pre-treatment wbMTV (p = 0.009). At a median follow-up of 21.5 months, 26 (84%) patients were alive with median progression-free and overall survival not reached. Secondary progression occurred in 9/31 (29%) patients at a median of 8.2 months (IQR, 6.9-15.5), of those majority (78%) was detected by FDG-PET/CT. Of 36 findings on post-FDG-PET/CT suggestive of irAE, 29 (80%) had clinical confirmation. In 3 (7%), the FDG-PET/CT findings preceded clinical presentation. The most common FDG-PET/CT detectable irAEs were endocrinopathies (36%) and enterocolitis (35%).

Conclusion: FDG-PET/CT response evaluation predicts the long-term outcome of patients treated with first-line combination-ICIs. Long-term treatment response monitoring for detection of extracranial secondary progression is feasible by FDG-PET/CT. Beyond response assessment, FDG-PET/CT frequently detects clinically relevant irAEs, which may involve multiple systems contemporaneously or at various time-points and may precede clinical diagnosis.
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http://dx.doi.org/10.1007/s00259-020-04815-wDOI Listing
November 2020

Durable Complete Remission and Long-Term Survival in FDG-PET Staged Patients with Stage III Follicular Lymphoma, Treated with Wide-Field Radiation Therapy.

Cancers (Basel) 2020 Apr 17;12(4). Epub 2020 Apr 17.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.

Advanced-stage follicular lymphoma (FL) is generally considered incurable with conventional systemic therapies, but historic series describe long-term disease-free survival in stage III disease treated with wide-field radiation therapy (WFRT), encompassing all known disease sites. We report outcomes for patients staged with F-fluorodeoxyglucose positron emission tomography (FDG-PET) and treated with CT-planned WFRT, given as either comprehensive lymphatic irradiation (CLI) or total nodal irradiation (TNI). This analysis of a prospective cohort includes PET-staged patients given curative-intent WFRT as a component of initial therapy, or as sole treatment for stage III FL. Thirty-three PET-staged patients with stage III FL received WFRT to 24-30Gy between 1999 and 2017. Fifteen patients also received planned systemic therapy (containing rituximab in 11 cases) as part of their primary treatment. At 10 years, overall survival and freedom from progression (FFP) were 100% and 75%, respectively. None of the 11 rituximab-treated patients have relapsed. Nine relapses occurred; seven patients required treatment, and all responded to salvage therapies. A single death occurred at 16 years. The principal acute toxicity was transient hematologic; one patient had residual grade two toxicity at one year. With FDG-PET staging, most patients with stage III FL experience prolonged FFP after WFRT, especially when combined with rituximab.
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http://dx.doi.org/10.3390/cancers12040991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226391PMC
April 2020

Applied Systems Biology-embracing molecular imaging for systemic medicine.

Eur J Nucl Med Mol Imaging 2020 11;47(12):2721-2725

QIMP Team, Center for Medical Physics and Biomedical Engineering, Medical University Vienna, Lazarettgasse 14, 1090, Vienna, Austria.

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http://dx.doi.org/10.1007/s00259-020-04798-8DOI Listing
November 2020

Carboplatin dosing in the era of IDMS-creatinine; the Cockroft-Gault formula no longer provides a sufficiently accurate estimate of glomerular filtration rate for routine use in clinical care.

Gynecol Oncol 2020 06 24;157(3):793-798. Epub 2020 Mar 24.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 3000; Royal Womens Hospital, Parkville, Victoria, Australia 3052; Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address:

Background: Glomerular filtration rate (GFR) measured by Chromium-51-EDTA excretion (Cr-GFR) is considered the gold standard of renal function assessment, but serum creatinine in the Cockcroft-Gault (CG) formula is routinely used to estimate GFR for carboplatin dosing. Serum creatinine measured by isotope-dilution-mass-spectrometry (IDMS) can generate spuriously high GFR estimates when used in the CG formula. We hypothesized that GFR calculated using IDMS-creatinine in the CG formula (CG-GFR) exposes patients to inaccurate carboplatin dosing.

Methods: This is a multicenter retrospective study of patients who had a Cr-GFR assessment for malignant or non-malignant indications, with a matched CG-GFR. Carboplatin dose based on Cr-GFR at AUC5 was used as the reference.

Results: 550 patients were analyzed, median age 62 (19-90), 64% female. Indication for GFR evaluation: malignancy (85%), assessment for live kidney donation (12%), other (3%). Median ratio of CG-GFR: Cr-GFR 1.04 (0.43-3.38); <0.8 in 72 patients (13%), >1.2 in 180 patients (33%). Despite capping of CG-GFR at 125 mL/min, dosing according to AUC6 would have resulted in 18% of patients being underdosed and 23% overdosed by >100 mg compared to Cr-GFR. Subgroup analysis identified BMI (>35, MPE 39%), gender (female MPE 15%), GFR indication (malignancy MPE 11%) as risk factors for overestimate of CG-GFR, and BMI < 20 for underestimate (MPE -3.5%).

Conclusions: The convention of considering AUC5 carboplatin based on Cr-GFR, and AUC6 carboplatin based on CG-GFR as equivalent is invalid and should be abandoned. When Cr-GFR is unavailable, capping CG-GFR at 125 mL/min is recommended.
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http://dx.doi.org/10.1016/j.ygyno.2020.03.017DOI Listing
June 2020

Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.

Lancet 2020 04 22;395(10231):1208-1216. Epub 2020 Mar 22.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Background: Conventional imaging using CT and bone scan has insufficient sensitivity when staging men with high-risk localised prostate cancer. We aimed to investigate whether novel imaging using prostate-specific membrane antigen (PSMA) PET-CT might improve accuracy and affect management.

Methods: In this multicentre, two-arm, randomised study, we recruited men with biopsy-proven prostate cancer and high-risk features at ten hospitals in Australia. Patients were randomly assigned to conventional imaging with CT and bone scanning or gallium-68 PSMA-11 PET-CT. First-line imaging was done within 21 days following randomisation. Patients crossed over unless three or more distant metastases were identified. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358.

Findings: From March 22, 2017 to Nov 02, 2018, 339 men were assessed for eligibility and 302 men were randomly assigned. 152 (50%) men were randomly assigned to conventional imaging and 150 (50%) to PSMA PET-CT. Of 295 (98%) men with follow-up, 87 (30%) had pelvic nodal or distant metastatic disease. PSMA PET-CT had a 27% (95% CI 23-31) greater accuracy than that of conventional imaging (92% [88-95] vs 65% [60-69]; p<0·0001). We found a lower sensitivity (38% [24-52] vs 85% [74-96]) and specificity (91% [85-97] vs 98% [95-100]) for conventional imaging compared with PSMA PET-CT. Subgroup analyses also showed the superiority of PSMA PET-CT (area under the curve of the receiver operating characteristic curve 91% vs 59% [32% absolute difference; 28-35] for patients with pelvic nodal metastases, and 95% vs 74% [22% absolute difference; 18-26] for patients with distant metastases). First-line conventional imaging conferred management change less frequently (23 [15%] men [10-22] vs 41 [28%] men [21-36]; p=0·008) and had more equivocal findings (23% [17-31] vs 7% [4-13]) than PSMA PET-CT did. Radiation exposure was 10·9 mSv (95% CI 9·8-12·0) higher for conventional imaging than for PSMA PET-CT (19·2 mSv vs 8·4 mSv; p<0·001). We found high reporter agreement for PSMA PET-CT (κ=0·87 for nodal and κ=0·88 for distant metastases). In patients who underwent second-line image, management change occurred in seven (5%) of 136 patients following conventional imaging, and in 39 (27%) of 146 following PSMA PET-CT.

Interpretation: PSMA PET-CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning.

Funding: Movember and Prostate Cancer Foundation of Australia. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/S0140-6736(20)30314-7DOI Listing
April 2020