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01 juli 2023, Contains fulltext : 294539.pdf (Publisher’s version ) (Open Access), Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [(177)Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that (177)Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [(177)Lu]Lu-PSMA-617 and [(177)Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from (177)Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [(177)Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naive primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.Copyright © 2021, The Author(s).

Contains fulltext : 238612.pdf (Publisher’s version ) (Closed access), 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 (68)gallium-labelled somatostatin analogue ([(68)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 (18)fluorine

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. Method(s): 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. Finding(s): 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 conv

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Contains fulltext : 200014.pdf (publisher's version ) (Closed access), Rapid developments in imaging and treatment with radiopharmaceuticals targeting prostate cancer pose issues for the development of guidelines for their appropriate use. To tackle this problem, international experts representing medical oncologists, urologists, radiation oncologists, radiologists, and nuclear medicine specialists convened at the European Association of Nuclear Medicine Focus 1 meeting to deliver a balanced perspective on available data and clinical experience of imaging in prostate cancer, which had been supported by a systematic review of the literature and a modified Delphi process. Relevant conclusions included the following: diphosphonate bone scanning and contrast-enhanced CT are mentioned but rarely recommended for most patients in clinical guidelines; MRI (whole-body or multiparametric) and prostate cancer-targeted PET are frequently suggested, but the specific contexts in which these methods affect practice are not established; sodium fluoride-18 for PET-CT bone scanning is not widely advocated, whereas gallium-68 or fluorine-18 prostate-specific membrane antigen gain acceptance; and, palliative treatment with bone targeting radiopharmaceuticals (rhenium-186, samarium-153, or strontium-89) have largely been replaced by radium-223 on the basis of the survival benefit that was reported in prospective trials, and by other systemic therapies with proven survival benefits. Although the advances in MRI and PET-CT have improved the accuracy of imaging, the effects of these new methods on clinical outcomes remains to be established. Improved communication between imagers and clinicians and more multidisciplinary input in clinical trial design are essential to encourage imaging insights into clinical decision making.

Contains fulltext : 172154.pdf (publisher's version ) (Open Access), This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tubingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.

Neuroblastoma is the most common extra-cranial malignancy in childhood and accounts for 15% of childhood cancer deaths. Amplification of MYCN in neuroblastoma is associated with aggressive disease and predicts for poor prognosis. Novel therapeutic approaches are therefore essential to improving patient outcomes in this setting. The histone deacetylases are known to interact with N-Myc and regulate numerous cellular processes via epigenetic modulation, including differentiation. In this study, we used the TH-MYCN mouse model of neuroblastoma to investigate the antitumor activity of the pan-HDAC inhibitor, panobinostat. In particular we sought to explore the impact of long term, continuous panobinostat exposure on the epigenetically driven differentiation process. Continuous treatment of tumor bearing TH-MYCN transgenic mice with panobinostat for nine weeks led to a significant improvement in survival as compared with mice treated with panobinostat for a three-week period. Panobinostat induced rapid tumor regression with no regrowth observed following a nine-week treatment period. Initial tumor response was associated with apoptosis mediated via upregulation of BMF and BIM. The process of terminal differentiation of neuroblastoma into benign ganglioneuroma, with a characteristic increase in S100 expression and reduction of N-Myc expression, occurred following prolonged exposure to the drug. RNA-sequencing analysis of tumors from treated animals confirmed significant upregulation of gene pathways associated with apoptosis and differentiation. Together our data demonstrate the potential of panobinostat as a novel therapeutic strategy for high-risk neuroblastoma patients.Copyright © 2016 UICC.

Background iNafa-paclitaxel (nafa-PC) and gemcitabine (GEM) are effective for metastatic PDAC. Efficacy of nafa-PC and GEM as perioperative chemotherapy (CX) for resectable PDAC is unknown. The GAP trial assessed feasibility and outcomes of preoperative CX in operable PDAC patients (pts). Methods : A multi-centre single arm, phase 2 trial. ECOG 0/1 pts with operable PDAC received 2 cycles of preoperative nafa-PC 125 mg/m2 and GEM 1000mg/m2on D1, D8, D15 (28 day cycle) and 4 cycles postoperatively if PDAC resected. Response to CX was measured via CT (baseline (BL) and prior surgery) and FDG-PET scans (BL and D15 of cycle 1). Progression-free survival (PFS) defined as period from registration to progression and recurrence-free survival (RFS) is from surgery to relapse. Median follow up for PFS was 27.5 months (mths). Results : 42 pts were enrolled with 39 analysed for response (3 pts excluded-1 had no PDAC and 2 unresectable at BL), 41 analysed for safety (1 unresectable at BL with no treatment given). The median tumour size was 26mm (IQR 25-35). 93% of pts received nafa-PC and GEM preoperatively but only 60% postoperatively. 78% of those pts tolerated adjuvant CX. 5/41 pts did not have surgery (2 progressed, 2 refused, 1 had sepsis). 36 had surgery, of which 6 were unresectable, 1 had no PDAC, 15 had R0 ( > 1mm) resection and 14 had R1 ( < 1mm). PFS (n = 39) was 12.3mths and RFS (n = 28) was 11.7mths (R0 pts 17.7 mths vs R1 pts 10 mths), with 7 pts progression free. 10/39 (26%) pts had a partial response (PR) to neoadjuvant CX while 26 (66%) had stable disease (SD). 15 (48%) had partial metabolic response on PET. Pts with PR on CT were 2.45 times (p = 0.01) more likely to have R0 resection but no correlation was seen with D15 PET response. As per NCCN guidelines at central review 29/39 pts were resectable (7 borderline and 3 unresectable). Median PFS for these pts classed as resectable was 12.3 mths, 21/29 were resected with median RFS 17.2 mths. Conclusions : GAP pt

Rationale: Pediatric patients with refractory neuroblastoma have limited therapeutic options. Neuroblastoma may express somatostatin receptors (SSTRs) allowing imaging with 68Ga-DOTA-Octreotate (GaTATE) positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT). We reviewed our experience with this theranostic combination. Material(s) and Method(s): GaTATE studies (8 patients; 2 to 9 years old) were reviewed and compared with 123I-MIBG or posttreatment 131I-MIBG studies. Immunohistochemistry (IHC) for SSTR subtype 2 was performed in 5 patients. Four patients received PRRT. Result(s): GaTATE PET showed additional disease in 38% (3/8 patients), and upstaged 1 patient by detecting marrow involvement. IHC detected SSTR 2 in all patients assessed. Six patients were deemed suitable for PRRT on imaging. Four patients received 17 cycles of palliative PRRT (10 111In-DOTATATE; 5 177Lu-DOTATATE; 1 combined 111In and 177Lu-DOTATATE; 1 combined 177Lu and 90Y-DOTATATE) with no significant toxicity attributed to PRRT. All had objective responses. Two survivors are now 40 and 56 months from PRRT commencement. Conclusion(s): GaTATE PET was positive in a high proportion of patients with refractory neuroblastoma, correlating with SSTR 2 on IHC, with additional disease identified compared with MIBG imaging. PRRT seems safe, feasible, with responses observed in patients with progression despite multimodality treatment. These data support ongoing clinical trials in such patients.Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

1 september 2012, Item does not contain fulltext, Over the last decade, small-animal PET imaging has become a vital platform technology in cancer research. With the development of molecularly targeted therapies and drug combinations requiring evaluation of different schedules, the number of animals to be imaged within a PET experiment has increased. This paper describes experimental design requirements to reach statistical significance, based on the expected change in tracer uptake in treated animals as compared to the control group, the number of groups that will be imaged, and the expected intra-animal variability for a given tracer. We also review how high-throughput studies can be performed in dedicated small-animal PET, high-resolution clinical PET systems and planar positron imaging systems by imaging more than one animal simultaneously. Customized beds designed to image more than one animal in large-bore small-animal PET scanners are described. Physics issues related to the presence of several rodents within the field of view (i.e. deterioration of spatial resolution and sensitivity as the radial and the axial offsets increase, respectively, as well as a larger effect of attenuation and the number of scatter events), which can be assessed by using the NEMA NU 4 image quality phantom, are detailed.

Objective: To assess the impact of FDG PET-CT on the management of patients with suspected recurrent ovarian cancer and to determine the incremental information provided by PET-CT. Method(s): This was a prospective, multi-centre, cohort study. Ninety women (mean age 59.9 years; age range 35-85 years) with a previous history of treated epithelial ovarian carcinoma and suspected recurrence based on elevated CA-125, anatomical imaging or clinical symptoms were studied with FDG PET-CT across two States. Referring doctors were asked to specify a management plan pre-PET, if management was altered after PET-CT and, the impact (rated - none, low, medium, high) of PET-CT on patient management. The pre-PET management plan could include radiotherapy, chemotherapy, surgery, and 'other' including observation. Patients were followed at 6 and 12 months and clinical status, evidence of recurrence and progression were recorded. Result(s): Patients were referred by 34 individual specialists. At least 168 additional sites of disease in 61 patients (68%), not identified by conventional imaging were identified by PET-CT. In 77% the additional lesions were located below the diaphragm and most were nodal or peritoneal. PET-CT affected management in 60% (49% high, 11% medium impact). Patients where more disease was detected with PET-CT were more likely to progress in the following 12 months. Conclusion(s): For women with previously treated ovarian carcinoma with recurrent disease, PET-CT can: a) alter management in close to 60% of patients, b) detect more sites of disease than abdominal and pelvic CT, c) is superior in the detection of nodal, peritoneal and subcapsular liver disease and d) offers the opportunity for technology replacement in this setting. © 2008 Elsevier Inc. All rights reserved.

Background/Aims: Optimal delivery of intraperitoneal (IP) chemotherapy is dependent on adequate drug distribution. An accurate understanding of the limitations of IP distribution is critical if we are to improve cytotoxic delivery through this route. Method(s): Using repeated scintigraphic peritoneography we investigated peritoneal fluid distribution in patients receiving IP therapy. Both early (1-6h) and late (24-48h) images were performed. The peritoneal cavity was divided into six regions; pouch of Douglas, left and right paracolic gutters, left and right subphrenic spaces and the right subhepatic space. The distribution in each region was classified as absent (0), faint (1) or intense (2). A total distribution score was calculated from the summation of distribution values for each of the six regions. Distribution was then graded according to the total distribution score as follows: Grade 0 = 0-3; Grade 1 = 4-6; Grade 2 = 7-9; and Grade 3 = 10-12. Result(s): Twenty-six participants were included in the study: all 26 patients had early imaging performed and 21 of these also had late imaging. Thirteen (50%) and 15 (71%) patients had grade 1 or 2 IP distribution on early and late imaging respectively. The most common abdominal regions to show maldistribution were the subphrenic spaces. Conclusion(s): This study highlights the deficiencies of distribution following IP drug delivery, with the majority of patients demonstrating multiple regions of faint or absent uptake on scintigraphic peritoneography imaging. Future large clinical studies investigating IP chemotherapy should include analyses of IP distribution to improve our understanding of optimal drug delivery through this route. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.