Evaluating the Utility of 18F-FDG PET/CT in Cancer of Unknown Primary.

Cancer of unknown primary (CUP) represents a heterogeneous group of metastatic tumors for which standardized diagnostic work-up fails to identify the primary site. We aimed to describe the Peter MacCallum Cancer Centre experience with 18F-FDG PET/CT in extracervical CUP with respect to detection of a primary site and its impact on management. A secondary aim was to compare overall survival (OS) in patients with and without a detected primary site. Methods: CUP patients treated between 2014 and 2020 were identified from medical oncology clinics and 18F-FDG PET/CT records. Information collated from electronic medical records included the suspected primary site and treatment details before and after 18F-FDG PET/CT. Clinicopathologic details and genomic analysis were used to determine the clinically suspected primary site and compared against 2 independent masked reads of 18F-FDG PET/CT images by nuclear medicine specialists to determine sensitivity, specificity, accuracy, and the rate of detection of the primary site. Results: We identified 147 patients, 65% of whom had undergone molecular profiling. The median age at diagnosis was 61 y (range, 20-84 y), and the median follow-up time was 74 mo (range, 26-83 mo). Eighty-two percent were classified as having an unfavorable CUP subtype as per international guidelines.18F-FDG PET/CT demonstrated a primary site detection rate of 41%, resulted in a change in management in 22%, and identified previously occult disease sites in 37%. Median OS was 16.8 mo for all patients and 104.7 and 12.1 mo for favorable and unfavorable CUP subtypes, respectively (P < 0.0001). Median OS in CUP patients when using 18F-FDG PET/CT, clinicopathologic, and genomic information was 19.8 and 8.5 mo when a primary site was detected and not detected, respectively (P = 0.016). Multivariable analysis of survival adjusted for age and sex remained significant for identification of a potential primary site (P < 0.001), a favorable CUP (P < 0.001), and an Eastern Cooperative Oncology Group status of 1 or less (P < 0.001). Conclusion: 18F-FDG PET/CT plays a complementary role in CUP diagnostic work-up and was able to determine the likely primary site in 41% of cases. OS is improved with primary site identification, demonstrating the value of access to diagnostic 18F-FDG PET/CT for CUP patients.

Total-Body PET/CT: Pros and Cons.

PET/CT devices with an axial field-of-view (FOV) of 1 m allow simultaneous imaging from the head to the upper thighs, the typical axial extent of many "whole-body" oncological studies acquired by moving a patient sequentially through a conventional FOV device, or rapid total-body imaging using the same approach. Increasing the FOV to around 2 m provides true simultaneous total-body imaging. Either approach dramatically increases the sensitivity for detection of annihilation events arising within the body. For the purposes of this review, both configurations are considered to represent "total-body" PET/CT devices because they share both advantages and disadvantages. These pros and cons are discussed in the context of both clinical and research applications from a patient and institutional perspective.

Dose-Response Relationships Between Radiation Exposure, Bone Marrow Function as Measured by 18F-Fluorothymidine Positron Emission Tomography, and Lymphocyte Counts During Chemoradiation for Non-Small Cell Lung Cancer.

PURPOSE: 18F-fluorothymidine (FLT) positron emission tomography (PET) enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/computed tomography scans before and during chemoradiation therapy (CRT) for non-small cell lung cancer were repurposed to investigate the dose-response effects of radiation on BM proliferation. METHODS AND MATERIALS: Twenty-six non-small cell lung cancer patients underwent platinum-based CRT to 60 Gy in 30 fractions with FLT-PET/computed tomography scans at baseline, week 2 (20 Gy), and week 4 (40 Gy). FLT uptake in BM was isolated using Medical Image Merge software. Weeks 2 and 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (highest standardized uptake values within the volume and visual parameters) were analyzed using generalized linear and restricted cubic spline models. Percentage volumes of total BM without appreciable FLT uptake ("ablated") on weeks 2 and 4 FLT-PET scans were calculated by comparisons with baseline scans. RESULTS: Thoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3 Gy by week 2. In all cases, BM FLT's highest standardized uptake values within the volume declined rapidly as the radiation dose increased. BM proliferation significantly decreased by >95% after ≥3 to 4 Gy at 2 weeks and ≥4 to 5 Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. The median percentage of total BM ablated was 13.1% (range, 5.6%-20.3%) at 2 weeks and 15.7% (range, 9.2%-24.1%) at 4 weeks. Mean lymphocyte counts fell from a baseline of 2.01 × 109/L to 0.77 at week 2 and 0.60 at week 4. Lymphocyte decline strongly correlated with the percentage of total BM ablated by week 4 (y = -46 to 1.64x; R2adj = 0.34; P = .001). CONCLUSIONS: BM ablation associated with low-dose radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ at risk, and reducing the BM volume exposed to ≥3 Gy may help preserve lymphocytes, which is essential for effective adjuvant immunotherapy.

International Benchmark for Total Metabolic Tumor Volume Measurement in Baseline 18F-FDG PET/CT of Lymphoma Patients: A Milestone Toward Clinical Implementation.

Total metabolic tumor volume (TMTV) is prognostic in lymphoma. However, cutoff values for risk stratification vary markedly, according to the tumor delineation method used. We aimed to create a standardized TMTV benchmark dataset allowing TMTV to be tested and applied as a reproducible biomarker. Methods: Sixty baseline 18F-FDG PET/CT scans were identified with a range of disease distributions (20 follicular, 20 Hodgkin, and 20 diffuse large B-cell lymphoma). TMTV was measured by 12 nuclear medicine experts, each analyzing 20 cases split across subtypes, with each case processed by 3-4 readers. LIFEx or ACCURATE software was chosen according to reader preference. Analysis was performed stepwise: TMTV1 with automated preselection of lesions using an SUV of at least 4 and a volume of at least 3 cm3 with single-click removal of physiologic uptake; TMTV2 with additional removal of reactive bone marrow and spleen with single clicks; TMTV3 with manual editing to remove other physiologic uptake, if required; and TMTV4 with optional addition of lesions using mouse clicks with an SUV of at least 4 (no volume threshold). Results: The final TMTV (TMTV4) ranged from 8 to 2,288 cm3, showing excellent agreement among all readers in 87% of cases (52/60) with a difference of less than 10% or less than 10 cm3 In 70% of the cases, TMTV4 equaled TMTV1, requiring no additional reader interaction. Differences in the TMTV4 were exclusively related to reader interpretation of lesion inclusion or physiologic high-uptake region removal, not to the choice of software. For 5 cases, large TMTV differences (>25%) were due to disagreement about inclusion of diffuse splenic uptake. Conclusion: The proposed segmentation method enabled highly reproducible TMTV measurements, with minimal reader interaction in 70% of the patients. The inclusion or exclusion of diffuse splenic uptake requires definition of specific criteria according to lymphoma subtype. The publicly available proposed benchmark allows comparison of study results and could serve as a reference to test improvements using other segmentation approaches.

18F-DCFPyL PSMA PET/CT Tracheobronchial Uptake in Patients with Prostate Cancer: Incidence and Etiology.

We evaluated the incidence and potential etiology of tracheobronchial uptake in patients being evaluated by 18F-DCFPyL PET/CT for prostate cancer (PCa). Methods: The study included a consecutive 100 PCa patients referred for 18F-DCFPyL PET/CT. The PET/CT scans were retrospectively reviewed. The presence or absence of physiologic tracheobronchial uptake on PET/CT was recorded. To further evaluate tracheal prostate-specific membrane antigen (PSMA) expression, immunohistochemistry was performed on tracheal samples taken from 2 men who had surgical resection of lung cancer. Results: Tracheal uptake was present in 31 of 100 patients (31%). When tracheal uptake was present, the SUVmax was significantly higher in the left main bronchus (mean, 2.7) than in the right (mean, 2.3) (P < 0.001). Histopathologic testing of tracheobronchial samples showed PSMA expression in bronchial submucosal glands. Conclusion: In PCa patients undergoing 18F-DCFPyL PET/CT, tracheobronchial uptake occurred in 31% of patients. This is attributed to normal physiologic PSMA expression in bronchial submucosal glands.

Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles.

Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we performed multi-omic analysis on 94 tumours from 79 patients using seven molecular methods. Sympathetic (chromaffin cell) and parasympathetic (non-chromaffin cell) PCPG had distinct molecular profiles reflecting their cell-of-origin and biochemical profile. TERT and ATRX-alterations were associated with metastatic PCPG and these tumours had an increased mutation load, and distinct transcriptional and telomeric features. Most PCPG had quiet genomes with some rare co-operative driver events observed, including EPAS1/HIF-2α mutations. Two mechanisms of acquired resistance to DNA alkylating chemotherapies were also detected - MGMT overexpression and mismatch repair-deficiency causing hypermutation. Our comprehensive multi-omic analysis of SDHB-mutant PCPG therefore identified features of metastatic disease and treatment response, expanding our understanding of these rare neuroendocrine tumours.

Positron emission tomography in the evaluation of endometriosis: A systematic review.

Despite the profound impact of endometriosis worldwide, delays in diagnosis and suboptimal surveillance techniques are well-recognised issues. Case studies have reported incidental uptake of 18F-FDG PET tracer in endometriotic lesions. However, the utility of PET imaging as a non-invasive diagnostic tool for endometriosis is currently unclear. The purpose of this systematic review was to summarise the existing evidence and determine the value of available PET scanning techniques in the detection and monitoring of endometriosis. MEDLINE, EMBASE, CENTRAL, SCOPUS and Web of Science were searched from conception to 05/03/23. Eligible studies included participants with a history of known or suspected endometriosis who underwent a PET scan for any indication. All PET tracers and protocols were eligible. Outcomes included correlation of PET tracer uptake with the presence of endometriosis seen at laparoscopy or confirmed on histology, sensitivity of tracer uptake, specificity of tracer uptake, site of lesions with tracer uptake, stage of lesions with tracer uptake, SUVmax of endometriosis lesions and adverse reactions to PET imaging. The protocol for this review was registered with PROSPERO (ID: CRD42023405260). Eight studies describing 110 participants were eligible for inclusion. Six studies assessed 18F-FDG with combined PET-CT, one study assessed 18F-FDG PET alone, and the remaining study assessed PET-CT with an alternative tracer, 68Ga-DOTATATE. For 18F-FDG imaging, the correlation of PET avidity with lesions or sites of endometriosis ranged from 0-55 %. Pre-operative 68Ga-DOTATATE PET-CT detected endometriosis in 33 % of cases. All included studies were cohort studies, six were assessed to have low risk of bias, one with moderate risk and one with high risk of bias. Overall, 18F-FDG PET scanning does not appear to consistently identify endometriotic lesions, and therefore its reliability and usefulness in endometriosis diagnosis is limited. The utility of 68Ga-DOTATATE PET-CT remains uncertain. Findings are constrained by limited available evidence reporting outcomes of PET imaging for endometriosis. Other existing PET tracers with biological plausibility in the detection or monitoring of endometriosis warrant further investigation.

Clinical management of typical and atypical carcinoids/neuroendocrine tumors in ENETS centres of excellence (CoE): Survey from the ENETS lung NET task force.

Lung carcinoid tumours are neuroendocrine neoplasms originating from the bronchopulmonary tract's neuroendocrine cells, accounting for only 1%-3% of all lung cancers but 30% of all neuroendocrine tumours. The incidence of lung carcinoids, both typical and atypical, has been increasing over the years due to improved diagnostic methods and increased awareness among clinicians and pathologists. The most recent WHO classification includes a subgroup of lung carcinoids with atypical morphology and higher mitotic count and/or Ki67 labelling index. Despite appropriate surgery, the 5-year survival rate for atypical carcinoids barely exceeds 50%-70%. The role of adjuvant therapy in lung carcinoids is not well-defined, and clinical decisions are generally based on the presence of high-risk features. Long-term follow-up is essential to monitor for recurrence, although the optimal follow-up protocol remains unclear. To address the lack of consensus in clinical management decisions, the European Neuroendocrine Tumor Society (ENETS) initiated a survey among 20 expert centres. The survey identified varied opinions on approaches to imaging, surgery, use of adjuvant therapy, and follow-up protocols. Notably, the absence of dedicated multidisciplinary lung neuroendocrine tumour boards in some centres was evident. Experts agreed on the need for a prospective adjuvant trial in high-risk patients, emphasizing the feasibility of such a study. In conclusion, the study highlights the need for a more uniform adoption of existing guidelines in the management of lung carcinoid tumours and emphasizes the importance of international collaboration to advance research and patient care. Close collaboration between healthcare providers and patients is vital for effective long-term surveillance and management of these rare tumours.

Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions.

ABSTRACT: In the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on retreatment. Time-to-treatment failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

PET/Computed Tomography Transformation of Oncology: Immunotherapy Assessment.

Immunotherapy approaches have changed the treatment landscape in a variety of malignancies with a high anti-tumor response. Immunotherapy may be associated with novel response and progression patterns that pose a substantial challenge to the conventional criteria for assessing treatment response, including response evaluation criteria in solid tumors (RECIST) 1.1. In addition to the morphologic details provided by computed tomography (CT) and MRI, hybrid molecular imaging emerges as a comprehensive imaging modality with the capacity to interrogate pathophysiological mechanisms like glucose metabolism. This review highlights the current status of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in prognostication, response monitoring, and identifying immune-related adverse events. Furthermore, it investigates the potential role of novel immuno-PET tracers that could complement the utilization of 18F-FDG PET/CT by imaging the specific pathways involved in immunotherapeutic strategies.

Use and perceived utility of [18 F]FDG PET/CT in neuroendocrine neoplasms: A consensus report from the European Neuroendocrine Tumor Society (ENETS) Advisory Board Meeting 2022.

Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research.

Evaluation of manual and automated approaches for segmentation and extraction of quantitative indices from [18F]FDG PET-CT images.

Utilisation of whole organ volumes to extract anatomical and functional information from computed tomography (CT) and positron emission tomography (PET) images may provide key information for the treatment and follow-up of cancer patients. However, manual organ segmentation, is laborious and time-consuming. In this study, a CT-based deep learning method and a multi-atlas method were evaluated for segmenting the liver and spleen on CT images to extract quantitative tracer information from Fluorine-18 fluorodeoxyglucose ([18F]FDG) PET images of 50 patients with advanced Hodgkin lymphoma (HL). Manual segmentation was used as the reference method. The two automatic methods were also compared with a manually defined volume of interest (VOI) within the organ, a technique commonly performed in clinical settings. Both automatic methods provided accurate CT segmentations, with the deep learning method outperforming the multi-atlas with a DICE coefficient of 0.93 ± 0.03 (mean ± standard deviation) in liver and 0.87 ± 0.17 in spleen compared to 0.87 ± 0.05 (liver) and 0.78 ± 0.11 (spleen) for the multi-atlas. Similarly, a mean relative error of -3.2% for the liver and -3.4% for the spleen across patients was found for the mean standardized uptake value (SUVmean) using the deep learning regions while the corresponding errors for the multi-atlas method were -4.7% and -9.2%, respectively. For the maximum SUV (SUVmax), both methods resulted in higher than 20% overestimation due to the extension of organ boundaries to include neighbouring, high-uptake regions. The conservative VOI method which did not extend into neighbouring tissues, provided a more accurate SUVmaxestimate. In conclusion, the automatic, and particularly the deep learning method could be used to rapidly extract information of the SUVmeanwithin the liver and spleen. However, activity from neighbouring organs and lesions can lead to high biases in SUVmaxand current practices of manually defining a volume of interest in the organ should be considered instead.

Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.

Introduction: Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. Methods: This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. Results: There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Conclusion: Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.

Evaluating the cost-effectiveness of [18F]FDG-PET/CT for investigation of persistent or recurrent neutropenic fever in high-risk haematology patients.

BACKGROUND: A recent randomised trial demonstrated [18F]fluorodeoxyglucose positron-emission tomography in combination with low-dose CT (FDG-PET/CT), compared to standard of care computed tomography (CT) imaging, positively impacted antimicrobial management and outcomes of acute leukaemia and haematopoietic stem cell transplant recipients with persistent and recurrent neutropenic fever. We conducted an economic evaluation from a healthcare perspective alongside the clinical trial. METHODS: Unit costs in Australian dollars were applied to all resources used (antimicrobials, diagnostic tests, ICU and hospital bed days). Effectiveness was measured as number of patients with antimicrobial rationalisation, 6-month mortality and quality-adjusted life years (QALYs) derived from patient-reported trial-based health-related quality-of-life. Generalised linear models were used to analyse costs and outcomes. Incremental cost-effectiveness ratios (ICERs) for all outcomes and net monetary benefit (NMB) for QALYs were calculated. We performed bootstrapping with 1000 replications using the recycled predictions method. RESULTS: The adjusted healthcare costs were lower for FDG-PET/CT (mean $49,563; 95%CI 36,867, 65,133) compared to CT (mean $57,574; 95% CI 44,837, 73,347). The difference in QALYs between the two groups was small (0.001; 95% CI -0.001, 0.004). When simulated 1000 times, FDG-PET/CT was the dominant strategy as it was cheaper with better outcomes than the standard CT group in 74% of simulations. The estimated NMBs at willingness-to-pay thresholds of $50,000 and $100,000 per QALY were positive, thus FDG-PET/CT remained cost-effective at these thresholds. CONCLUSIONS: FDG-PET/CT is cost effective when compared to CT for investigation of persistent/recurrent neutropenic fever in high-risk patients, providing further support for incorporation of FDG-PET/CT into clinical guidelines and funding. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT03429387.

Increased Thyroidal Activity on Routine FDG-PET/CT after Combination Immune Checkpoint Inhibition: Temporal Associations with Clinical and Biochemical Thyroiditis.

BACKGROUND: FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction. METHODS: A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded. RESULTS: At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3-32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4-98.0), kappa 0.83. CONCLUSION: Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammatory response beyond the initial thyrotoxic phase may be indicative of thyroid destruction.

A genome-wide CRISPR/Cas9 screen identifies DNA-PK as a sensitiser to 177Lutetium-DOTA-octreotate radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) using 177Lutetium-DOTA-octreotate (LuTate) for neuroendocrine tumours (NET) is now an approved treatment available in many countries, though primary or secondary resistance continue to limit its effectiveness or durability. We hypothesised that a genome-wide CRISPR/Cas9 screen would identify key mediators of response to LuTate and gene targets that might offer opportunities for novel combination therapies for NET patients. Methods: We utilised a genome-wide CRISPR-Cas9 screen in LuTate-treated cells to identify genes that impact on the sensitivity or resistance of cells to LuTate. Hits were validated through single-gene knockout. LuTate-resistant cells were assessed to confirm LuTate uptake and retention, and persistence of somatostatin receptor 2 (SSTR2) expression. Gene knockouts conferring LuTate sensitivity were further characterised by pharmacological sensitisation using specific inhibitors and in vivo analysis of the efficacy of these inhibitors in combination with LuTate. Results: The CRISPR-Cas9 screen identified several potential targets for both resistance and sensitivity to PRRT. Two gene knockouts which conferred LuTate resistance in vitro, ARRB2 and MVP, have potential mechanisms related to LuTate binding and retention, and modulation of DNA-damage repair (DDR) pathways, respectively. The screen showed that sensitivity to LuTate treatment in vitro can be conferred by the loss of a variety of genes involved in DDR pathways, with loss of genes involved in Non-Homologous End-Joining (NHEJ) being the most lethal. Loss of the key NHEJ gene, PRKDC (DNA-PK), either by gene loss or inhibition by two different inhibitors, resulted in significantly reduced cell survival upon exposure of cells to LuTate. In SSTR2-positive xenograft-bearing mice, the combination of nedisertib (a DNA-PK specific inhibitor) and LuTate produced a more robust control of tumour growth and increased survival compared to LuTate alone. Conclusions: DDR pathways are critical for sensing and repairing radiation-induced DNA damage, and our study shows that regulation of DDR pathways may be involved in both resistance and sensitivity to PRRT. Additionally, the use of a DNA-PK inhibitor in combination with LuTate PRRT significantly improves the efficacy of the treatment in pre-clinical models, providing further evidence for the clinical efficacy of this combination.

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours.

PURPOSE: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 µg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment­related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.