Purpose
Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the ...disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.
Methods
Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals.
Conclusion
Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (
68
Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (
123
I)/iodine-131 (
131
I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.
Background Previous studies have identified clinical or inflammatory phenotypes of asthma on the basis of clinical and demographic parameters or sputum cell counts; however, few studies have defined ...transcriptional phenotypes of asthma. Objective To investigate asthma phenotypes at a transcriptional level by using gene expression profiling of induced sputum. Methods Induced sputum samples were collected from 59 people with asthma with a mean age of 58 years and an FEV1 % predicted of 76%, and 69% were taking inhaled corticosteroids. Thirteen healthy controls without asthma were also assessed. Inflammatory cell counts were performed, and RNA was extracted from selected sputum. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by using GeneSpring GX11. Results Unsupervised hierarchical clustering of gene expression profiles in asthma revealed 3 distinct groups. The first transcriptional phenotype (n = 21) had lower FEV1 % predicted and higher asthma control questionnaire scores, exhaled nitric oxide, and sputum eosinophils. The second transcriptional phenotype (n = 14) had lower FEV1 % predicted and forced vital capacity % predicted and higher sputum neutrophils compared with a third transcriptional phenotype (n = 24) that had higher sputum macrophages and resembled healthy controls. Differentially expressed genes between transcriptional asthma phenotypes were related to inflammatory and immune responses. Genes in the IL-1 and TNF-α/nuclear factor-κB pathways were overexpressed and correlated with clinical parameters and neutrophilic airway inflammation. Conclusion Gene expression profiling provides a novel means to investigate the molecular mechanisms and classifications of asthma phenotypes. There are 3 distinct transcriptional phenotypes of asthma that relate to both clinical and inflammatory parameters.
Background Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective This study aimed to identify and validate a sputum gene expression ...signature that discriminates asthma inflammatory phenotypes. Methods An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. Results From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC) ; carboxypeptidase A3 (CPA3) ; deoxyribonuclease I-like 3 (DNASE1L3) ; IL-1β (IL1B) ; alkaline phosphatase, tissue-nonspecific isozyme (ALPL) ; and chemokine (C-X-C motif) receptor 2 (CXCR2) , was reproducible and could significantly ( P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1 ; AUC, 91.5%). ICS treatment reduced the expression of CLC , CPA3 , and DNASE1L3 in patients with eosinophilic asthma. Conclusions A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.
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 ...177Lu-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 177Lu-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 PSMA-expression. Eligible patients had progressive disease defined by imaging (according to Response Evaluation Criteria In Solid Tumours RECIST or bone scan) or new pain in an area of radiographically evident disease, and were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower. Eligible patients received up to four cycles of intravenous 177Lu-PSMA-617, at six weekly intervals. The primary endpoint was PSA response according to Prostate Cancer Clinical Trial Working Group criteria defined as a greater than 50% PSA decline from baseline and toxicity according to CTCAE. Additional primary endpoints were imaging responses (as measured by bone scan, CT, PSMA, and FDG PET/CT) and quality of life (assessed with the EORTC-Q30 and Brief Pain Inventory-Short Form questionnaires), all measured up to 3 months post completion of treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12615000912583.
Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both. The mean administered radioactivity was 7·5 GBq per cycle. 17 (57%) of 30 patients (95% CI 37–75) achieved a PSA decline of 50% or more. There were no treatment-related deaths. The most common toxic effects related to 177Lu-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and G1–2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to 177Lu-PSMA-617 occurred in four (13%) patients. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all timepoints. 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment.
Our findings show that radionuclide treatment with 177Lu-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care.
None.
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.
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.
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.
PSMA PET-CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning.
Movember and Prostate Cancer Foundation of Australia.
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Background
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.
Objectives and Methods
The proPSMA trial is a prospective, multicentre study in which patients with untreated high‐risk PCa will be randomized to gallium‐68‐PSMA‐11 PET/CT or conventional imaging, consisting of CT of the abdomen/pelvis and bone scintigraphy with single‐photon emission CT/CT. Patients eligible for inclusion are those with newly diagnosed PCa with select high‐risk features, defined as International Society of Urological Pathology grade group ≥3 (primary Gleason grade 4, or any Gleason grade 5), prostate‐specific antigen level ≥20 ng/mL or clinical stage ≥T3. Patients with negative, equivocal or oligometastatic disease on first line‐imaging will cross over to receive the other imaging arm. The primary objective is to compare the accuracy of PSMA‐PET/CT with that of conventional imaging for detecting nodal or distant metastatic disease. Histopathological, imaging and clinical follow‐up at 6 months will define the primary endpoint according to a predefined scoring system. Secondary objectives include comparing management impact, the number of equivocal studies, the incremental value of second‐line imaging in patients who cross over, the cost of each imaging strategy, radiation exposure, inter‐observer agreement and safety of PSMA‐PET/CT. Longer‐term follow‐up will also assess the prognostic value of a negative PSMA‐PET/CT.
Outcome and Significance
This trial will provide data to establish whether PSMA‐PET/CT should replace conventional imaging in the primary staging of select high‐risk localized PCa, or whether it should be used to provide incremental diagnostic information in selected cases.
•Group model building is a participatory approach to system dynamics.•This paper reviews 45 published studies of group model building effectiveness.•Different research designs report a wide range of ...beneficial outcomes.•More emphasis is needed on comparative rather than exploratory research.•Settings should shift from controlled experiments to applied problems.
Group model building (GMB) is a participatory approach to using system dynamics in group decision-making and problem structuring. This paper considers the published quantitative evidence base for GMB since the earlier literature review by Rouwette et al. (2002), to consider the level of understanding on three basic questions: what does it achieve, when should it be applied, and how should it be applied or improved? There have now been at least 45 such studies since 1987, utilising controlled experiments, field experiments, pretest/posttest, and observational research designs. There is evidence of GMB achieving a range of outcomes, particularly with regard to the behaviour of participants and their learning through the process. There is some evidence that GMB is more effective at supporting communication and consensus than traditional facilitation, however GMB has not been compared to other problem structuring methods. GMB has been successfully applied in a range of contexts, but there is little evidence on which to select between different GMB tools, or to understand when certain tools may be more appropriate. There is improving evidence on how GMB works, but this has not yet been translated into changing practice. Overall the evidence base for GMB has continued to improve, supporting its use for improving communication and agreement between participants in group decision processes. This paper argues that future research in group model building would benefit from three main shifts: from single cases to multiple cases; from controlled settings to applied settings; and by augmenting survey results with more objective measures.
Epigenetic reprogramming in cancer genomes creates a distinct methylation landscape encompassing clustered methylation at regulatory regions separated by large intergenic tracks of hypomethylated ...regions. This methylation landscape that we referred to as Methylscape is displayed by most cancer types, thus may serve as a universal cancer biomarker. To-date most research has focused on the biological consequences of DNA Methylscape changes whereas its impact on DNA physicochemical properties remains unexplored. Herein, we examine the effect of levels and genomic distribution of methylcytosines on the physicochemical properties of DNA to detect the Methylscape biomarker. We find that DNA polymeric behaviour is strongly affected by differential patterning of methylcytosine, leading to fundamental differences in DNA solvation and DNA-gold affinity between cancerous and normal genomes. We exploit these Methylscape differences to develop simple, highly sensitive and selective electrochemical or colorimetric one-step assays for the detection of cancer. These assays are quick, i.e., analysis time ≤10 minutes, and require minimal sample preparation and small DNA input.
Lynch Syndrome (LS) is a highly variable entity with some patients presenting at very young ages with malignancy whereas others may never develop a malignancy yet carry an unequivocal genetic ...predisposition to disease. The most frequent LS malignancy remains colorectal cancer, a disease that is thought to involve genetic as well as environmental factors in its aetiology. Environmental insults are undeniably associated with cancer risk, especially those imparted by such activities as smoking and excessive alcohol consumption. Notwithstanding, in an inherited predisposition the expected exposures to an environmental insult are considered to be complex and require knowledge about the respective exposure and how it might interact with a genetic predisposition. Typically, smoking is one of the major confounders when considering environmental factors that can influence disease expression on a background of significant genetic risk. In addition to environmental triggers, the risk of developing a malignancy for people carrying an inherited predisposition to disease can be influenced by additional genetic factors that do not necessarily segregate with a disease predisposition allele. The purpose of this review is to examine the current state of modifier gene detection in people with a genetic predisposition to develop LS and present some data that supports the notion that modifier genes are gene specific thus explaining why some modifier gene studies have failed to identify associations when this is not taken into account.
Objective Video-assisted thoracoscopic lobectomy remains controversial. We compared outcomes from participants in a randomized study comparing lymph node sampling versus dissection for early-stage ...lung cancer who underwent either video-assisted thoracoscopic or open lobectomy. Methods Data from 964 participants in the American College of Surgeons Oncology Group Z0030 trial were used to construct propensity scores for video-assisted thoracoscopic versus open lobectomy (based on age, gender, histology, performance status, tumor location, and T1 vs T2). Propensity scores were used to estimate the adjusted risks of short-term outcomes of surgery. Patients were classified into 5 equal-sized groups and compared using conditional logistic regression or repeated measures analysis of variance. Results A total of 752 patients (66 video-assisted and 686 open procedures) were analyzed on the basis of propensity score stratification. Median operative time was shorter for video-assisted thoracoscopic lobectomy (video-assisted thoracoscopy 117.5 minutes vs open 171.5 minutes; P < .001). Median total number of lymph nodes retrieved (dissection group only) was similar (video-assisted thoracoscopy 15 nodes vs open 19 nodes; P = .147), as were instances of R1/R2 resection (video-assisted thoracoscopy 0% vs open 2.3%; P = .368). Patients undergoing video-assisted thoracoscopic lobectomy had less atelectasis requiring bronchoscopy (0% vs 6.3%, P = .035), fewer chest tubes draining greater than 7 days (1.5% vs 10.8%; P = .029), and shorter median length of stay (5 days vs 7 days; P < .001). Operative mortality was similar (video-assisted thoracoscopy 0% vs open 1.6%, P = 1.0). Conclusion Patients undergoing video-assisted lobectomy had fewer respiratory complications and shorter length of stay. These data suggest video-assisted thoracoscopic lobectomy is safe in patients with resectable lung cancer. Longer follow-up is needed to determine the oncologic equivalency of video-assisted versus open lobectomy.
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