[18F]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: protocol for a prospective, multicentre PET/CT trial.

INTRODUCTION: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. METHODS AND ANALYSIS: The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. ETHICS AND DISSEMINATION: The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12619001735145.

Prospective intra-individual blinded comparison of [18F]PSMA-1007 and [68 Ga]Ga-PSMA-11 PET/CT imaging in patients with confirmed prostate cancer.

INTRODUCTION: [18F]PSMA-1007 has potential advantages over [68 Ga]Ga-PSMA-11, although limited prospective data evaluating diagnostic performance exist. The aims of this study are to describe the concordance of [18FPSMA-1007 and [68 Ga]Ga-PSMA-11 for TNM with the American Joint Committee on Cancer (AJCC) prognostic stage and assess differences in tracer uptake. METHODS: Fifty men (mean age 71.8) were imaged with [68 Ga]Ga-PSMA-11 and [18F]PSMA-1007 < 4 weeks apart. Images were independently reported according to TNM by two experienced nuclear medicine specialists blinded to the other scan and prior imaging. Discordant results were resolved by a third independent nuclear medicine specialist. Quantitative analysis of lesion uptake and physiologic tissue for each tracer was performed by one experienced reader. RESULTS: Scan indications were initial staging (n = 12), biochemical recurrence (n = 27) and metastatic disease evaluation (n = 11). Most patients had ISUP grade group 3 or higher. Median PSA value was 2.7 ng/ml (IQR 0.7-12.0), and a minority of patients (28%) were currently treated with androgen deprivation therapy. [18F]PSMA-1007 uptake was significantly higher than [68Ga]Ga-PSMA-11 in local recurrence, nodal and distant metastases and most physiologic sites (including bone) except for urinary bladder which was significantly lower. [18F]PSMA-1007 upstaged local prostate staging in 5/17 patients, local recurrence in 3/33 patients, regional nodal disease in 3/50 patients and 1 distant metastasis (bladder). [68Ga]Ga-PSMA-11 upstaged regional nodal disease in 1/50 patients and distant metastasis in one patient (right adrenal). Overall AJCC prognostic stage was concordant in 46/50 (92%) patients, with two patients upstaged for both [18F]PSMA-1007 and [68Ga]Ga-PSMA-11. [18F]PSMA-1007 had more equivocal results (one regional node; six equivocal bone lesions, one of which was subsequently confirmed metastatic) than [68Ga]Ga-PSMA-11 (one equivocal local recurrence). CONCLUSION: Overall AJCC prognostic stage was similar (92%) between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11. [18F]PSMA-1007 demonstrates higher uptake within involved nodes and distant metastases and most physiologic sites except urinary bladder which aided [18F]PSMA-1007 local staging of the prostate primary/local recurrence and regional nodal disease adjacent ureters. However, [18F]PSMA-1007 liver uptake obscured a solitary right adrenal metastasis, and more equivocal bone lesions were identified. Trial registration The study was registered with Australia New Zealand Clinical Trials Registry (ACTRN12618000665235) on 24 April 2018.

Risk of metastatic disease using [18F]PSMA-1007 PET/CT for primary prostate cancer staging.

BACKGROUND: Accurate prostate cancer imaging is critical for patient management. Multiple studies have demonstrated superior diagnostic accuracy of [68Ga]-PSMA-11 PET/CT over conventional imaging for disease detection, with validated clinical and biochemical predictors of disease detection. More recently [18F]PSMA-1007 offers theoretical imaging advantages, but there is limited evidence of clinical and biochemical predictors of scan findings in the staging population. This study investigates the association of clinical variables with imaging characteristics among patients who underwent [18F]PSMA-1007 PET/CT for primary staging of men with histopathologically confirmed prostate carcinoma. A retrospective review of 194 consecutive patients imaged between May 2019 to May 2020 was performed. Association between imaging variables (presence and distribution of metastatic disease, primary tumour SUVmax) and clinical variables (EAU risk criteria) were assessed using descriptive statistics, logistic regression model and ROC analysis. RESULTS: The median age, PSA level and ISUP grade were 70 years, 10 ng/mL and ISUP grade 3, respectively. There were 36.6% of patients with intermediate-risk and 60.8% of patients with high-risk disease. ISUP grade was associated with the presence of metastasis overall (p = 0.008) as well as regional nodal (p = 0.003), non-regional nodal (p = 0.041) and bone (p = 0.006) metastases. PSA level was associated with metastatic disease overall (p = 0.001), regional (p = 0.001) and non-regional nodal metastases (p = 0.004), but not with bone metastases (p = 0.087). There were too few visceral metastases for meaningful analysis. SUVmax of the primary prostatic tumour was associated with ISUP grade (p = 0.004), PSA level (p < 0.001) and AJCC stage (p = 0.034). PSA > 20 ng/mL and ISUP grade > 3 had a specificity of 85% (95% CI 78-91%) and 60% (95% CI 50-68%) and a sensitivity of 36% (95% CI 25-49%) and 62% (95% CI 49-74%), respectively, for detection of metastatic disease. CONCLUSION: Metastatic disease according to [18F]PSMA-1007 PET/CT was associated with ISUP grade and PSA level. This is the largest study using [18F]PSMA-1007 PET/CT to confirm a positive correlation of PSA level, ISUP grade and stage with primary prostate tumour SUVmax.

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy in the world, with 22% of patients presenting with metastatic disease and a further 50% destined to develop metastasis. Molecular imaging uses antigen-specific ligands conjugated to radionuclides to detect and characterise primary cancer and metastases. Expression of the cell surface protein CDCP1 is increased in CRC, and here we sought to assess whether it is a suitable molecular imaging target for the detection of this cancer. CDCP1 expression was assessed in CRC cell lines and a patient-derived xenograft to identify models suitable for evaluation of radio-labelled 10D7, a CDCP1-targeted, high-affinity monoclonal antibody, for preclinical molecular imaging. Positron emission tomography-computed tomography was used to compare zirconium-89 (89Zr)-10D7 avidity to a nonspecific, isotype control 89Zr-labelled IgGκ1 antibody. The specificity of CDCP1-avidity was further confirmed using CDCP1 silencing and blocking models. Our data indicate high avidity and specificity for of 89Zr-10D7 in CDCP1 expressing tumors at. Significantly higher levels than normal organs and blood, with greatest tumor avidity observed at late imaging time points. Furthermore, relatively high avidity is detected in high CDCP1 expressing tumors, with reduced avidity where CDCP1 expression was knocked down or blocked. The study supports CDCP1 as a molecular imaging target for CRC in preclinical PET-CT models using the radioligand 89Zr-10D7.

Dual-Tracer Positron-Emission Tomography Using Prostate-Specific Membrane Antigen and Fluorodeoxyglucose for Staging of Prostate Cancer: A Systematic Review.

PSMA PET is more accurate than conventional imaging (CT/bone scan) for staging of intermediate- or high-risk prostate cancer (PCa), but 5-10% of primary tumours have low PSMA ligand uptake. FDG PET has been used to further define disease extent in end-stage castrate-resistant PCa and may be beneficial earlier in the disease course for more accurate staging. The objective of this study was to review the available evidence for patients undergoing both FDG and PSMA PET for PCa staging at initial diagnosis and in recurrent disease. A systematic literature review was performed for studies with direct, intraindividual comparison of PSMA and FDG PET for staging of PCa. Assessment for radioligand therapy eligibility was not considered. Risk of bias was assessed. 543 citations were screened and assessed. 13 case reports, three retrospective studies, and one prospective study were included. FDG after PSMA PET improved the detection of metastases from 65% to 73% in high-risk early castration-resistant PCa with negative conventional imaging (M0). Positive FDG PET was found in 17% of men with negative PSMA PET for postprostatectomy biochemical recurrence. Gleason score ≥8 and higher PSA levels predicted FDG-avid metastases in BCR and primary staging. Variant histology (ductal and neuroendocrine) was common in case reports, resulting in PSMA-negative FDG-positive imaging for 3 patients. Dual-tracer PET for PCa may assist in characterising high-risk disease during primary staging and restaging. Further studies are required to determine the additive benefit of FDG PET and if the FDG-positive phenotype may indicate a poorer prognosis.

Clinical insignificance of [18F]PSMA-1007 avid non-specific bone lesions: a retrospective evaluation.

PURPOSE: [18F]PSMA-1007 offers advantages of low urinary tracer excretion and theoretical improved spatial resolution for imaging prostate cancer. However, non-specific bone lesions (NSBLs), defined as mild to moderate focal bone uptake without a typical morphological correlate on CT, are a common finding on [18F]PSMA-1007 PET/CT. The purpose of this study was to investigate the clinical outcomes of patients with [18F]PSMA-1007 avid NSBLs, to determine whether patients with NSBLs represent a higher risk clinical cohort, and to determine whether SUVmax can be used as a classifier of bone metastasis. METHODS: A retrospective audit of 214 men with prostate cancer was performed to investigate the clinical outcomes of [18F]PSMA-1007 avid NSBLs according to defined criteria. We also compared the serum PSA, Gleason score, and uptake time of patients with [18F]PSMA-1007 avid NSBLs to patients without [18F]PSMA-1007 avid bone lesions. Finally, we analysed an SUVmax threshold to identify bone metastases using ROC curve analysis. RESULTS: Ninety-four of 214 patients (43.9%) demonstrated at least one NSBL. No [18F]PSMA-1007 avid NSBLs met criteria for a likely malignant or definitely malignant lesion after a median 15.8-month follow-up interval (11.9% definitely benign, 50.3% likely benign, and 37.7% equivocal). There were no statistically significant differences in serum PSA, Gleason score, and uptake time between patients with [18F]PSMA-1007 avid NSBLs and those without [18F]PSMA-1007 avid bone lesions. All NSBLs with adequate follow-up had SUVmax ≤ 11.1. The value of the highest SUVmax distinguished between NSBLs and definite prostate cancer bone metastases, whereby an SUVmax threshold of ≥ 7.2 maximized the Youden's index. CONCLUSION: [18F]PSMA-1007 avid NSBLs rarely represent prostate cancer bone metastases. When identified in the absence of definite metastatic disease elsewhere, it is appropriate to classify those with SUVmax < 7.2 as likely benign. NSBLs with SUVmax 7.2-11.1 may be classified as equivocal or metastatic, with patient clinical risk factors, scan appearance, and potential management implications used to guide interpretation.

PET Imaging Quantifying 68Ga-PSMA-11 Uptake in Metastatic Colorectal Cancer.

At diagnosis, 22% of colorectal cancer (CRC) patients have metastases, and 50% later develop metastasis. Peptide receptor radionuclide therapy (PRRT), such as 177Lu-PSMA-617, is used to treat metastatic prostate cancer. 177Lu-PSMA-617 targets prostate-specific membrane antigen (PSMA), a cell-surface protein enriched in prostate cancer and the neovasculature of other solid tumors, including CRC. We performed 68Ga-PSMA-11 PET/CT imaging of 10 patients with metastatic CRC to assess metastasis avidity. Eight patients had lesions lacking avidity, and 2 had solitary metastases exhibiting very low avidity. Despite expression of PSMA in CRC neovasculature, none of the patients exhibited tumor avidity sufficient to be considered for 177Lu-PSMA-617 PRRT.

Effective targeting of intact and proteolysed CDCP1 for imaging and treatment of pancreatic ductal adenocarcinoma.

Background: CUB domain-containing protein 1 (CDCP1) is a cell surface receptor regulating key signalling pathways in malignant cells. CDCP1 has been proposed as a molecular target to abrogate oncogenic signalling pathways and specifically deliver anti-cancer agents to tumors. However, the development of CDCP1-targeting agents has been questioned by its frequent proteolytic processing which was thought to result in shedding of the CDCP1 extracellular domain limiting its targetability. In this study, we investigated the relevance of targeting CDCP1 in the context of pancreatic ductal adenocarcinoma (PDAC) and assess the impact of CDCP1 proteolysis on the effectiveness of CDCP1 targeting agents. Methods: The involvement of CDCP1 in PDAC progression was assessed by association analysis in several PDAC cohorts and the proteolytic processing of CDCP1 was evaluated in PDAC cell lines and patient-derived cells. The consequences of CDCP1 proteolysis on its targetability in PDAC cells was assessed using immunoprecipitation, immunostaining and biochemical assays. The involvement of CDCP1 in PDAC progression was examined by loss-of-function in vitro and in vivo experiments employing PDAC cells expressing intact or cleaved CDCP1. Finally, we generated antibody-based imaging and therapeutic agents targeting CDCP1 to demonstrate the feasibility of targeting this receptor for detection and treatment of PDAC tumors. Results: High CDCP1 expression in PDAC is significantly associated with poorer patient survival. In PDAC cells proteolysis of CDCP1 does not always result in the shedding of CDCP1-extracellular domain which can interact with membrane-bound CDCP1 allowing signal transduction between the different CDCP1-fragments. Targeting CDCP1 impairs PDAC cell functions and PDAC tumor growth independently of CDCP1 cleavage status. A CDCP1-targeting antibody is highly effective at delivering imaging radionuclides and cytotoxins to PDAC cells allowing specific detection of tumors by PET/CT imaging and superior anti-tumor effects compared to gemcitabine in in vivo models. Conclusion: Independent of its cleavage status, CDCP1 exerts oncogenic functions in PDAC and has significant potential to be targeted for improved radiological staging and treatment of this cancer. Its elevated expression by most PDAC tumors and lack of expression by normal pancreas and other major organs, suggest that targeting CDCP1 could benefit a significant proportion of PDAC patients. These data support the further development of CDCP1-targeting agents as personalizable tools for effective imaging and treatment of PDAC.

Would you bet on PET? Evaluation of the significance of positive PET scan results post-microwave ablation for non-small cell lung cancer.

Fluodeoxyglucose-positron emission tomography (FDG-PET) imaging is an acknowledged modality for the follow-up of solid tumours treated with thermal ablation, with persistent or new FDG uptake at the ablation site considered to be a reliable indicator of local recurrence. Several cases of proven false-positive FDG-PET scans are illustrated in this pictorial essay with uptake at the site of the ablated tumour, remote from the ablated lesion and in mediastinal and hilar lymph nodes. Positive FDG-PET scans post-thermal ablation of lung tumours therefore cannot always reliably predict local tumour recurrence or nodal spread. It is important to be familiar with FDG uptake patterns post-ablation and their significance. FDG-PET avid lesions post-ablation may require histological confirmation before further therapy is planned or management is changed.

Pharmacological approaches that slow lymphatic flow as a snakebite first aid.

BACKGROUND: This study examines the use of topical pharmacological agents as a snakebite first aid where slowing venom reaching the circulation prevents systemic toxicity. It is based on the fact that toxin molecules in most snake venoms are large molecules and generally first enter and traverse the lymphatic system before accessing the circulation. It follows on from a previous study where it was shown that topical application of a nitric oxide donor slowed lymph flow to a similar extent in humans and rats as well as increased the time to respiratory arrest for subcutaneous injection of an elapid venom (Pseudonaja textilis, Ptx; Eastern brown snake) into the hind feet of anaesthetized rats. METHODOLOGY/PRINCIPAL FINDINGS: The effects of topical application of the L-type Ca(2+) channel antagonist nifedipine and the local anesthetic lignocaine in inhibiting lymph flow and protecting against envenomation was examined in an anaesthetized rat model. The agents significantly increased dye-measured lymph transit times by 500% and 390% compared to controls and increased the time to respiratory arrest to foot injection of a lethal dose of Ptx venom by 60% and 40% respectively. The study also examined the effect of Ptx venom dose over the lethal range of 0.4 to 1.5 mg/kg finding a negative linear relationship between increase in venom dose and time to respiratory arrest. CONCLUSIONS/SIGNIFICANCE: The findings suggest that a range of agents that inhibit lymphatic flow could potentially be used as an adjunct treatment to pressure bandaging with immobilization (PBI) in snakebite first aid. This is important given that PBI (a snakebite first aid recommended by the Australian National Health and Medical research Council) is often incorrectly applied. The use of a local anesthetic would have the added advantage of reducing pain.

Economic analysis of FDG-PET-guided management of the neck after primary chemoradiotherapy for node-positive head and neck squamous cell carcinoma.

BACKGROUND: The aim of this economic analysis was to model different strategies using pre-treatment nodal stage or nodal response assessment with CT or positron emission tomography (PET)/CT to determine the need for neck dissection. METHODS: A cost-minimization analysis was developed on the basis of probability data from a prospective study of PET-guided management of the neck in patients achieving a complete response at the primary site. Costs were derived from our institution's activity-based clinical costing system. The effect of uncertainty was tested with sensitivity and scenario analyses including nationally representative cost data. RESULTS: Strategies incorporating PET had a 7% rate for neck dissection compared with 44% for CT-guided and 90% for planned neck dissection. The cost per patient was A$16,502 for planned neck dissection, A$8014 for CT-guided, and A$2573 for PET-guided. A policy with PET used only for incomplete response on CT was the least-cost strategy (A$2111). Policies incorporating PET remained the most efficient for all sensitivity/scenario analyses. CONCLUSION: The incorporation of PET/CT into nodal response assessment significantly reduced the number of unnecessary neck dissections and generated considerable cost savings in our cohort.

A novel microplate-based assay for screening radioprotectors and its validation based on DNA and membrane system.

Ionizing radiation leads to damage at various cellular and sub-cellular levels and can be prevented by radioprotectors. There are many in vitro and in vivo but rather expensive assays for screening of radioprotectors from natural and synthetic sources. We have developed a cell free radioprotector screening assay which involves bleaching of crocin pigment, isolated from saffron by radiolytic products of water. Any molecules/compounds which can inhibit the bleaching of the crocin will act as a radioprotector. The developed assay was further validated by the existing in vitro assays. Different radioprotectors have different level for inhibition of bleaching of crocin. The trends of radioprotection offered by crocin bleaching assay, plasmid relaxation and lipid peroxidation are TMG>FA>VA>Amifos>Trox, TMG>VA>FA>Amifos>Trox, and TMG>FA>Trox>VA>Amifos, respectively. We are getting different trends for different assays. This is because different drugs have different mechanisms of radioprotection in different assay systems. In conclusion, the crocin bleaching assay developed here is a simple, fast and economical screening assay and it will have great value in radioprotection programme for screening many potential compounds for radioprotection.

A pharmacological approach to first aid treatment for snakebite.

Snake venom toxins first transit the lymphatic system before entering the bloodstream. Ointment containing a nitric oxide donor, which impedes the intrinsic lymphatic pump, prolonged lymph transit time in rats and humans and also increased rat survival time after injection of venom. This pharmacological approach should give snakebite victims more time to obtain medical care and antivenom treatment.

Transition from planar to SPECT V/Q scintigraphy: rationale, practicalities, and challenges.

Compared with planar imaging, ventilation/perfusion scintigraphy performed with single-photon emission computed tomography (SPECT) has a greater sensitivity and specificity, greater accuracy, improved reproducibility, and a lower number of inconclusive reports in the detection of pulmonary embolism. Despite these improvements, there are several challenges that must be overcome for the transition from planar imaging to SPECT imaging to be successful, including a lack of familiarity with 3D imaging of the lungs by some reporting specialists, the selection of a ventilation agent appropriate for SPECT acquisitions, and a different approach in the image reporting. The transition to SPECT imaging can be facilitated by generating planar-like images from the SPECT data, with which many reporting specialists are more familiar. SPECT ventilation/perfusion acquisition times are generally equal to or shorter than conventional planar imaging, studies are easier for technologists to acquire, and modern computing provides several new approaches to image processing and display.

Indian herbs and herbal drugs used for the treatment of diabetes.

Traditional Medicines derived from medicinal plants are used by about 60% of the world's population. This review focuses on Indian Herbal drugs and plants used in the treatment of diabetes, especially in India. Diabetes is an important human ailment afflicting many from various walks of life in different countries. In India it is proving to be a major health problem, especially in the urban areas. Though there are various approaches to reduce the ill effects of diabetes and its secondary complications, herbal formulations are preferred due to lesser side effects and low cost. A list of medicinal plants with proven antidiabetic and related beneficial effects and of herbal drugs used in treatment of diabetes is compiled. These include, Allium sativum, Eugenia jambolana, Momordica charantia Ocimum sanctum, Phyllanthus amarus, Pterocarpus marsupium, Tinospora cordifolia, Trigonella foenum graecum and Withania somnifera. One of the etiologic factors implicated in the development of diabetes and its complications is the damage induced by free radicals and hence an antidiabetic compound with antioxidant properties would be more beneficial. Therefore information on antioxidant effects of these medicinal plants is also included.