Joint EANM/EANO/RANO/SNMMI practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor ligands: version 1.0.

PURPOSE: To provide practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor (SSTR) ligands. METHODS: This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO). RESULTS: Positron emission tomography (PET) using somatostatin receptor (SSTR) ligands can detect meningioma tissue with high sensitivity and specificity and may provide clinically relevant information beyond that obtained from structural magnetic resonance imaging (MRI) or computed tomography (CT) imaging alone. SSTR-directed PET imaging can be particularly useful for differential diagnosis, delineation of meningioma extent, detection of osseous involvement, and the differentiation between posttherapeutic scar tissue and tumour recurrence. Moreover, SSTR-peptide receptor radionuclide therapy (PRRT) is an emerging investigational treatment approach for meningioma. CONCLUSION: These practice guidelines will define procedure standards for the application of PET imaging in patients with meningiomas and related SSTR-targeted PRRTs in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers, facilitate comparability of studies, and to collect larger databases. The current document provides additional information to the evidence-based recommendations from the PET/RANO Working Group regarding the utilization of PET imaging in meningiomas Galldiks (Neuro Oncol. 2017;19(12):1576-87). The information provided should be considered in the context of local conditions and regulations.

An open-label, single-arm, prospective, multi-center, tandem two-stage designed phase II study to evaluate the efficacy of fulvestrant in women with recurrent/metastatic estrogen receptor-positive gynecological malignancies (FUCHSia study).

OBJECTIVE: This study aimed to evaluate fulvestrant efficacy in women with estrogen receptor-positive low-grade gynecological cancers. The primary objective was to determine the response rate. Secondary objectives were progression-free survival, clinical benefit, duration of response, safety, tolerability, and quality of life. METHODS: FUCHSia is an open-label, single-arm, prospective, multi-center phase II study. The study population included patients with recurrent/metastatic low-grade gynecological malignancies with estrogen receptor positivity who received a maximum of two lines of previous hormonal therapy. Patients received fulvestrant (FASLODEX, AstraZeneca) via two intramuscular injections (250 mg/5 mL each) in the gluteal muscle on day 1, day 15, day 29, and then every 28 days thereafter until disease progression, withdrawal from the trial due to any unacceptable adverse event, or withdrawal of patient consent. RESULTS: A total of 15 patients (uterine sarcoma n=4; sex cord-stromal ovarian tumors n=3; endometrial carcinoma n=4; serous ovarian cancer n=4) were enrolled. Median follow-up was 48 weeks (interquartile range (IQR) 26-122) in the uterine sarcoma cohort, 63 weeks (IQR 28-77) for sex cord-stromal tumors, 19 weeks (IQR 17-21) for endometrial carcinoma, and 60 weeks (IQR 40-119) for serous ovarian cancer. One partial response according to Response Evaluation Criteria in Solid Tumors v1.1 was observed in one uterine sarcoma patient. No responses were observed in the other cohorts. However, stable disease was observed in three uterine sarcomas (median duration 12 weeks), three sex cord-stromal tumors (median duration 32 weeks), and four low-grade serous ovarian cancer patients (median duration 20 weeks), leading to a disease control rate of 100% for these tumor types. All patients with endometrial carcinoma showed progressive disease. CONCLUSION: Fulvestrant may control tumor growth in recurrent/metastatic estrogen receptor-positive low-grade gynecological malignancies of specific histology. Further studies are needed to confirm these results.

Designing clinical trials based on modern imaging and metastasis-directed treatments in patients with oligometastatic breast cancer: a consensus recommendation from the EORTC Imaging and Breast Cancer Groups.

Breast cancer remains the most common cause of cancer death among women. Despite its considerable histological and molecular heterogeneity, those characteristics are not distinguished in most definitions of oligometastatic disease and clinical trials of oligometastatic breast cancer. After an exhaustive review of the literature covering all aspects of oligometastatic breast cancer, 35 experts from the European Organisation for Research and Treatment of Cancer Imaging and Breast Cancer Groups elaborated a Delphi questionnaire aimed at offering consensus recommendations, including oligometastatic breast cancer definition, optimal diagnostic pathways, and clinical trials required to evaluate the effect of diagnostic imaging strategies and metastasis-directed therapies. The main recommendations are the introduction of modern imaging methods in metastatic screening for an earlier diagnosis of oligometastatic breast cancer and the development of prospective trials also considering the histological and molecular complexity of breast cancer. Strategies for the randomisation of imaging methods and therapeutic approaches in different subsets of patients are also addressed.

[18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

PURPOSE: Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. METHODS: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. RESULTS: [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). CONCLUSION: [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. TRIAL REGISTRATION: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

Radioligand therapies in cancer: mapping the educational landscape in Europe.

AIM: We performed a systematic survey to assess the existing gaps in Europe in multidisciplinary education for integration of radioligand therapy (RLT) into cancer care and to obtain detailed information on the current limitations and key contents relevant. METHODS: A high-quality questionnaire, with emphasis on survey scales, formulation, and validity of the different items, was designed. An expert validation process was undertaken. The survey was circulated among medical specialties involved in cancer treatment, universities, and nursing organizations. Questionnaires (156) were distributed, and 95 responses received. RESULTS: Sevety-eight percent of medical societies indicated that training in RLT was very important and 12% important. Eighty-eight percent indicated that their specialty training program included RLT. Twenty-six percent were satisfied with the existing structure of training in RLTs. Ninety-four percent indicated that the existing training is based on theory and hands-on experience. Main identified limitations were lack of centers ready to train and of personnel available for teaching. Sixty-five percent indicated that national programs could be expanded. Fifty percent of consulted universities indicated partial or scarce presence of RLT contents in their teaching programs. In 26% of the cases, the students do not have the chance to visit a RLT facility. A large majority of the universities are interested in further expansion of RLT contents in their curriculums. Nursing organizations almost never (44.4%) or occasionally (33.3%) include RLT contents in the education of nurses and technologists. Hands-on experience is almost never (38%) and sometimes (38%) offered. However, 67% of centers indicated high interest in expanding RLT contents. CONCLUSION: Centers involved recognize the importance of the training and indicate a need for inclusion of additional clinical content, imaging analysis, and interpretation as well as extended hands-on training. A concerted effort to adapt current programs and a shift towards multidisciplinary training programs is necessary for proper education in RLT in Europe.

Role of immune checkpoint inhibitors in metastatic uveal melanoma: a single-center retrospective cohort study.

BACKGROUND: Uveal melanoma is an orphan malignancy with very limited data on treatment options in metastatic setting. METHODS: In this single-center retrospective study, we describe real-world epidemiological and survival data on 121 metastatic uveal melanoma (MUM) patients registered in our institution. As a large tertiary referral center, almost 30% of all diagnoses in the Flemish region of Belgium were covered. Primarily, we determined whether introduction of immune checkpoint inhibitors (ICI) led to improved overall survival (OS) in MUM patients. Secondarily, response rates to ICI were assessed and we evaluated whether first-line ICI could be a valid alternative to liver-directed therapy (LDT) in liver-only disease. RESULTS: The initially perceived 10.8 months survival benefit from treatment with ICI disappeared after correction for immortality bias. By analyzing treatment type as time-varying covariate on OS, no significant benefit of ICI over other systemic therapies (HR = 0.771) or best supportive care (BSC) (HR = 0.780) was found. Also comparison of the pre-ICI versus ICI era showed no OS improvement after introduction of ICI in our center (p = 0.7994). Only liver-directed and local oligometastatic approaches were associated with a lower chance of mortality when compared to ICI (p = 0.0025), other systemic therapies (p = 0.0001) and BSC (p = 0.0003), yet without correction for selection bias. We reported overall response rates on ICI ranging from 8-15% and we found some support for neoadjuvant strategies with ICI resulting in remission or downsizing, allowing oligometastatic approaches later on. In first-line liver-only disease, median real-world progression-free survival and OS did not significantly differ between patients treated with LDT or ICI upfront (p = 0.2930 and p = 0.5461 respectively). CONCLUSION: Although we documented responses to ICI, our analyses do not demonstrate an OS benefit of ICI over alternative treatment strategies for MUM. However, local treatment options, whether liver-directed or for oligometastatic disease, may be beneficial and should be considered.

Joint EANM/SNMMI/IHPBA procedure guideline for [99mTc]Tc-mebrofenin hepatobiliary scintigraphy SPECT/CT in the quantitative assessment of the future liver remnant function.

PURPOSE: The aim of this joint EANM/SNMMI/IHPBA procedure guideline is to provide general information and specific recommendations and considerations on the use of [99mTc]Tc-mebrofenin hepatobiliary scintigraphy (HBS) in the quantitative assessment and risk analysis before surgical intervention, selective internal radiation therapy (SIRT) or before and after liver regenerative procedures. Although the gold standard to estimate future liver remnant (FLR) function remains volumetry, the increasing interest in HBS and the continuous request for implementation in major liver centers worldwide, demands standardization. METHODS: This guideline concentrates on the endorsement of a standardized protocol for HBS elaborates on the clinical indications and implications, considerations, clinical appliance, cut-off values, interactions, acquisition, post-processing analysis and interpretation. Referral to the practical guidelines for additional post-processing manual instructions is provided. CONCLUSION: The increasing interest of major liver centers worldwide in HBS requires guidance for implementation. Standardization facilitates applicability of HBS and promotes global implementation. Inclusion of HBS in standard care is not meant as substitute for volumetry, but rather to complement risk evaluation by identifying suspected and unsuspected high-risk patients prone to develop post-hepatectomy liver failure (PHLF) and post-SIRT liver failure.

Characteristics and Outcome of Post-Transplant Lymphoproliferative Disorders After Solid Organ Transplantation: A Single Center Experience of 196 Patients Over 30 Years.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7 years (95% CI: 2.99-11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93-2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931-0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL.

International recommendations for personalised selective internal radiation therapy of primary and metastatic liver diseases with yttrium-90 resin microspheres.

PURPOSE: A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-resin microspheres. METHODS: A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%-79%, no agreement ≤ 49%). RESULTS: Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99mTc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100-120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement). CONCLUSION: Practitioners are encouraged to work towards adoption of these recommendations.

Incorporating radiomics into clinical trials: expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers.

Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. KEY POINTS: • Data-driven processes like radiomics risk false discoveries due to high-dimensionality of the dataset compared to sample size, making adequate diversity of the data, cross-validation and external validation essential to mitigate the risks of spurious associations and overfitting. • Use of radiomic signatures within clinical trials requires multistep standardisation of image acquisition, image analysis and data mining processes. • Biological correlation may be established after clinical validation but is not mandatory.

Whole liver segmentation based on deep learning and manual adjustment for clinical use in SIRT.

PURPOSE: In selective internal radiation therapy (SIRT), an accurate total liver segmentation is required for activity prescription and absorbed dose calculation. Our goal was to investigate the feasibility of using automatic liver segmentation based on a convolutional neural network (CNN) for CT imaging in SIRT, and the ability of CNN to reduce inter-observer variability of the segmentation. METHODS: A multi-scale CNN was modified for liver segmentation for SIRT patients. The CNN model was trained with 139 datasets from three liver segmentation challenges and 12 SIRT patient datasets from our hospital. Validation was performed on 13 SIRT datasets and 12 challenge datasets. The model was tested on 40 SIRT datasets. One expert manually delineated the livers and adjusted the liver segmentations from CNN for 40 test SIRT datasets. Another expert performed the same tasks for 20 datasets randomly selected from the 40 SIRT datasets. The CNN segmentations were compared with the manual and adjusted segmentations from the experts. The difference between the manual segmentations was compared with the difference between the adjusted segmentations to investigate the inter-observer variability. Segmentation difference was evaluated through dice similarity coefficient (DSC), volume ratio (RV), mean surface distance (MSD), and Hausdorff distance (HD). RESULTS: The CNN segmentation achieved a median DSC of 0.94 with the manual segmentation and of 0.98 with the manually corrected CNN segmentation, respectively. The DSC between the adjusted segmentations is 0.98, which is 0.04 higher than the DSC between the manual segmentations. CONCLUSION: The CNN model achieved good liver segmentations on CT images of good image quality, with relatively normal liver shapes and low tumor burden. 87.5% of the 40 CNN segmentations only needed slight adjustments for clinical use. However, the trained model failed on SIRT data with low dose or contrast, lesions with large density difference from their surroundings, and abnormal liver position and shape. The abovementioned scenarios were not adequately represented in the training data. Despite this limitation, the current CNN is already a useful clinical tool which improves inter-observer agreement and therefore contributes to the standardization of the dosimetry. A further improvement is expected when the CNN will be trained with more data from SIRT patients.

[18F]AlF-NOTA-octreotide PET imaging: biodistribution, dosimetry and first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour patients.

PURPOSE: The widespread use of gallium-68-labelled somatostatin analogue (SSA) PET, the current standard for somatostatin receptor (SSTR) imaging, is limited by practical and economic challenges that could be overcome by a fluorine-18-labelled alternative, such as the recently introduced [18F]AlF-NOTA-octreotide ([18F]AlF-OC). This prospective trial aimed to evaluate safety, dosimetry, biodistribution, pharmacokinetics and lesion targeting of [18F]AlF-OC and perform the first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour (NET) patients. METHODS: Six healthy volunteers and six NET patients with a previous clinical [68Ga]Ga-DOTATATE PET were injected with an IV bolus of 4 MBq/kg [18F]AlF-OC. Healthy volunteers underwent serial whole-body PET scans from time of tracer injection up to 90 min post-injection, with an additional PET/CT at 150 and 300 min post-injection. In patients, a 45-min dynamic PET was acquired and three whole-body PET scans at 60, 90 and 180 min post-injection. Absorbed organ doses and effective doses were calculated using OLINDA/EXM. Normal organ uptake (SUVmean) and tumour lesion uptake (SUVmax and tumour-to-background ratio (TBR)) were measured. A lesion-by-lesion analysis was performed and the detection ratio (DR), defined as the fraction of detected lesions was determined for each tracer. RESULTS: [18F]AlF-OC administration was safe and well tolerated. The highest dose was received by the spleen (0.159 ± 0.062 mGy/MBq), followed by the urinary bladder wall (0.135 ± 0.046 mGy/mBq) and the kidneys (0.070 ± 0.018 mGy/MBq), in accordance with the expected SSTR-specific uptake in the spleen and renal excretion of the tracer. The effective dose was 22.4 ± 4.4 µSv/MBq. The physiologic uptake pattern of [18F]AlF-OC was comparable to [68Ga]Ga-DOTATATE. Mean tumour SUVmax was lower for [18F]AlF-OC (12.3 ± 6.5 at 2 h post-injection vs. 18.3 ± 9.5; p = 0.03). However, no significant differences were found in TBR (9.8 ± 6.7 at 2 h post-injection vs. 13.6 ± 11.8; p = 0.35). DR was high and comparable for both tracers (86.0% for [68Ga]Ga-DOTATATE vs. 90.1% for [18F]AlF-OC at 2 h post-injection; p = 0.68). CONCLUSION: [18F]AlF-OC shows favourable kinetic and imaging characteristics in patients that warrant further head-to-head comparison to validate [18F]AlF-OC as a fluorine-18-labelled alternative for gallium-68-labelled SSA clinical PET. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03883776, EudraCT: 2018-002827-40.

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study.

PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. METHODS: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. RESULTS: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. CONCLUSIONS: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

Molecular imaging of norepinephrine transporter-expressing tumors: current status and future prospects.

The human norepinephrine transporter (hNET) is a transmembrane protein responsible for reuptake of norepinephrine in presynaptic sympathetic nerve terminals and adrenal chromaffin cells. Neural crest tumors, such as neuroblastoma, paraganglioma and pheochromocytoma often show high hNET expression. Molecular imaging of these tumors can be done using radiolabeled norepinephrine analogs that target hNET. Currently, the most commonly used radiopharmaceutical for hNET imaging is meta-[123I]iodobenzylguanidine ([123I]MIBG) and this has been the case since its development several decades ago. The γ-emitter, iodine-123 only allows for planar scintigraphy and single photon emission computed tomography imaging. These modalities typically have a poorer spatial resolution and lower sensitivity than positron emission tomography (PET). Additional practical disadvantages include the fact that a two-day imaging protocol is required and the need for thyroid blockade. Therefore, several PET alternatives for hNET imaging are actively being explored. This review gives an in-depth overview of the current status and recent developments in clinical trials leading to the next generation of clinical PET ligands for imaging of hNET-expressing tumors.

Peptide receptor radionuclide therapy controls inappropriate calcitriol secretion in a pancreatic neuro-endocrine tumor: a case report.

BACKGROUND: Hypercalcemia of malignancy is not uncommon in patients with advanced stage cancer. In rare cases the cause of the hypercalcemia is excessive production of calcitriol, the active form of vitamin D. Although inappropriate tumoral secretion of calcitriol is typically associated with lymphomas and some ovarian germ cell tumors, we present a case of calcitriol overproduction-induced hypercalcemia due to a pancreatic neuroendocrine tumor. The high expression of somatostatin receptors on this neuroendocrine neoplasm opened up the opportunity to treat the patient with radiolabelled somatostatin analogs, which successfully controlled the refractory hypercalcaemia and calcitriol levels. This case documents a rare finding of refractory hypercalcaemia of underlying malignancy due to a calcitriol-producing pancreatic neuroendocrine tumor, responding to peptide receptor radionuclide therapy (PRRT). CASE PRESENTATION: A 57 years-old patient presented with back pain, general discomfort, polydipsia, polyuria, fatigue and recent weight loss of 10 kg. Clinical examination was normal and there was no relevant medical history. Biochemical evaluation showed hypercalcemia with markedly increased calcitriol levels. CT-thorax-abdomen and ultrasound guided biopsy revealed a pancreatic neuroendocrine tumor with multifocal liver metastases, suggesting that excessive overproduction of calcitriol by this neuroendocrine tumor was the cause of the refractory hypercalcemia. The patient was eligible for PRRT. Four cycles of 177Lu-DOTATATE PRRT resulted in a morphological response and a normalization of serum calcium levels, confirming the hypothesis of a calcitriol producing pancreatic neuroendocrine tumor. Progression of liver metastases warranted further therapy and temozolomide-capecitabine was started with morphological and biochemical (serum calcium, calcitriol) stabilization. CONCLUSION: Although up to 30-40% of gastroenteropancreatic neuroendocrine tumors are known to be functional (i.e. producing symptoms associated with the predominant hormone/peptide secreted), calcitriol secreting pancreatic neuroendocrine tumors are very rare. However, treatment with PRRT resulted in normalization of calcium and calcitriol levels, strongly supporting the hypothesis of a calcitriol-producing pancreatic neuroendocrine tumor.

Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1-4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Personalised radioembolization improves outcomes in refractory intra-hepatic cholangiocarcinoma: a multicenter study.

PURPOSE: Reported outcomes of patients with intra-hepatic cholangiocarcinoma (IH-CCA) treated with radioembolization are highly variable, which indicates differences in included patients' characteristics and/or procedure-related variables. This study aimed to identify patient- and treatment-related variables predictive for radioembolization outcome. METHODS: This retrospective multicenter study enrolled 58 patients with unresectable and chemorefractory IH-CCA treated with resin 90Y-microspheres. Clinicopathologic data were collected from patient records. Metabolic parameters of liver tumor(s) and presence of lymph node metastasis were measured on baseline 18F-FDG-PET/CT. 99mTc-MAA tumor to liver uptake ratio (TLRMAA) was computed for each lesion on the SPECT-CT. Activity prescription using body-surface-area (BSA) or more personalized partition-model was recorded. The study endpoint was overall survival (OS) starting from date of radioembolization. Statistical analysis was performed by the log-rank test and multivariate Cox's proportional hazards model. RESULTS: Median OS (mOS) post-radioembolization of the entire cohort was 10.3 months. Variables associated with significant differences in terms of OS were serum albumin (hazard ratio (HR) = 2.78, 95%CI:1.29-5.98, p = 0.002), total bilirubin (HR = 2.17, 95%CI:1.14-4.12, p = 0.009), aspartate aminotransferase (HR = 2.96, 95%CI:1.50-5.84, p < 0.001), alanine aminotransferase (HR = 2.02, 95%CI:1.05-3.90, p = 0.01) and γ-GT (HR = 2.61, 95%CI:1.31-5.22, p < 0.001). The presence of lymph node metastasis as well as a TLRMAA < 1.9 were associated with shorter mOS: HR = 2.35, 95%CI:1.08-5.11, p = 0.008 and HR = 2.92, 95%CI:1.01-8.44, p = 0.009, respectively. Finally, mOS was significantly shorter in patients treated according to the BSA method compared to the partition-model: mOS of 5.5 vs 14.9 months (HR = 2.52, 95%CI:1.23-5.16, p < 0.001). Multivariate analysis indicated that the only variable that increased outcome prediction above the clinical variables was the activity prescription method with HR of 2.26 (95%CI:1.09-4.70, p = 0.03). The average mean radiation dose to tumors was significantly higher with the partition-model (86Gy) versus BSA (38Gy). CONCLUSION: Radioembolization efficacy in patients with unresectable recurrent and/or chemorefractory IH-CCA strongly depends on the tumor radiation dose. Personalized activity prescription should be performed.

Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC Imaging Group.

Oligometastatic disease represents a clinical and anatomical manifestation between localised and polymetastatic disease. In prostate cancer, as with other cancers, recognition of oligometastatic disease enables focal, metastasis-directed therapies. These therapies potentially shorten or postpone the use of systemic treatment and can delay further metastatic progression, thus increasing overall survival. Metastasis-directed therapies require imaging methods that definitively recognise oligometastatic disease to validate their efficacy and reliably monitor response, particularly so that morbidity associated with inappropriately treating disease subsequently recognised as polymetastatic can be avoided. In this Review, we assess imaging methods used to identify metastatic prostate cancer at first diagnosis, at biochemical recurrence, or at the castration-resistant stage. Standard imaging methods recommended by guidelines have insufficient diagnostic accuracy for reliably diagnosing oligometastatic disease. Modern imaging methods that use PET-CT with tumour-specific radiotracers (choline or prostate-specific membrane antigen ligand), and increasingly whole-body MRI with diffusion-weighted imaging, allow earlier and more precise identification of metastases. The European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group suggests clinical algorithms to integrate modern imaging methods into the care pathway at the various stages of prostate cancer to identify oligometastatic disease. The EORTC proposes clinical trials that use modern imaging methods to evaluate the benefits of metastasis-directed therapies.