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Background: Distribution of mAbs into tumour tissue may occur via different processes contributing differently to the 89Zr-mAb uptake on PET. Target-specific binding in tumours is of main interest; however, non-specific irreversible uptake may also be present, which influences quantification. The aim was to investigate the presence of non-specific irreversible uptake in tumour tissue using Patlak linearization on 89Zr-immuno-PET data of biopsy-proven target-negative tumours. Data of two studies, including target status obtained from biopsies, were retrospectively analysed, and Patlak linearization provided the net rate of irreversible uptake (Ki). Results: Two tumours were classified as CD20-negative and two as CD20-positive. Four tumours were classified as CEA-negative and nine as CEA-positive. Ki values of CD20-negative (0.43 µL/g/h and 0.92 µL/g/h) and CEA-negative tumours (mdn = 1.97 µL/g/h, interquartile range (IQR) = 1.50–2.39) were higher than zero. Median Ki values of target-negative tumours were lower than CD20-positive (1.87 µL/g/h and 1.90 µL/g/h) and CEA-positive tumours (mdn = 2.77 µL/g/h, IQR = 2.11–3.65). Conclusion: Biopsy-proven target-negative tumours showed irreversible uptake of 89Zr-mAbs measured in vivo using 89Zr-immuno-PET data, which suggests the presence of non-specific irreversible uptake in tumours. Consequently, for 89Zr-immuno-PET, even if the target is absent, a tumour-to-plasma ratio always increases over time. [ABSTRACT FROM AUTHOR]

Background: PET scans using zirconium-89 labelled monoclonal antibodies (89Zr-mAbs), known as 89Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89Zr-immuno-PET scans. Methods: PET imaging and blood sampling of two 89Zr-mAbs were included, 89Zr-cetuximab and 89Zr-durvalumab. For seven patients receiving 89Zr-cetuximab, PET scans on 1–2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland–Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC. Results: Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89Zr-cetuximab and 89Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was − 10.9% and − 11.4% for 89Zr-cetuximab and 89Zr-durvalumab, respectively. Conclusions: Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations. [ABSTRACT FROM AUTHOR]

Simple Summary: The uptake on a 89Zr-immuno-PET scan is not just the result of the binding of a radiolabeled antibody with its target (i.e., target engagement) but also includes background factors such as non-specific binding (for example, catabolism of antibodies inside endothelial cells). In this study, we wanted to isolate target engagement. We used data from five previously performed 89Zr-immuno-PET studies with immune-targeting 89Zr-radiolabeled antibodies. First, via Patlak analysis, we separated reversible from irreversible uptake, and by using a baseline of target-negative organs, we further defined target-specific irreversible uptake. Second, we compared different mass doses (ratios of labeled and unlabeled antibody) and looked for saturation effects. Evidence for target engagement was based on the following two things: (1) when the target-specific irreversible uptake exceeded the baseline, and (2) when the signal showed saturation. We found target engagement for the different antibodies in several lymphoid organs, for example, in the spleen, while the brain had close to zero target engagement. We propose a new baseline for bone marrow and brain. In conclusion, we promote the use of Patlak analysis for 89Zr-immuno-PET studies, or similar simplified outcomes such as a tissue-to-blood ratio. Introduction: 89Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([89Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [89Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses. Method: 89Zr-immuno-PET data from five [89Zr]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2–3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (Ki). To identify target engagement, Ki values were compared to ns-baseline Ki values previously reported, and the effect of increasing mass doses on Ki was investigated. Results: All mAbs, except ipilimumab, showed Ki values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing Ki values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed Ki values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. Ki values were near zero in brain tissue for all mass doses of all mAbs. Conclusion: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the Ki values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior. [ABSTRACT FROM AUTHOR]

Purpose: Although lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [89Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration. Methods: Patients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3). After baseline tumor biopsy and [18F]FDG-PET, patients were given 240 mg of BI 754091, followed 8 days later by administration of [89Zr]Zr-BI 754111 (37 MBq, 4 mg). PET scans were performed 2 h, 96 h, and 144 h post-injection. To investigate target specificity, a second tracer administration was given two weeks later, this time with pre-administration of 40 (N = 3) or 600 mg (N = 3) unlabeled BI 754111, followed by PET scans at 96 h and 144 h post-injection. Tumor immune cell infiltration was assessed by immunohistochemistry and RNA sequencing. Results: Tracer uptake in tumors was clearly visible at the 4-mg mass dose (tumor-to-plasma ratio 1.63 [IQR 0.37-2.89]) and could be saturated by increasing mass doses (44 mg: 0.67 [IQR 0.50–0.85]; 604 mg: 0.56 [IQR 0.42–0.75]), demonstrating target specificity. Tumor uptake correlated to immune cell-derived RNA signatures. Conclusions: [89Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies. Trial registration: ClinicalTrials.gov, NCT03780725. Registered 19 December 2018 [ABSTRACT FROM AUTHOR]

Purpose: Positron emission tomography imaging of zirconium-89-labelled monoclonal antibodies (89Zr-Immuno-PET) allows for visualisation and quantification of antibody uptake in tumours in vivo. Patlak linearization provides distribution volume (VT) and nett influx rate (Ki) values, representing reversible and irreversible uptake, respectively. Standardised uptake value (SUV) and tumour-to-plasma/tumour-to-blood ratio (TPR/TBR) are often used, but their validity depends on the comparability of plasma kinetics and clearances. This study assesses the validity of SUV, TPR and TBR against Patlak Ki for quantifying irreversible 89Zr-Immuno-PET uptake in tumours. Methods: Ten patients received 37 MBq 10 mg 89Zr-anti-EGFR with 500 mg/m2 unlabelled mAbs. Five patients received two doses of 37 MBq 89Zr-anti-HER3: 8–24 mg for the first administration and 24 mg–30 mg/kg for the second. Seven tumours from four patients showed 89Zr-anti-EGFR uptake, and 18 tumours from five patients showed 89Zr-anti-HER3 uptake. SUVpeak, TPRpeak and TBRpeak values were obtained from one to six days p.i. Patlak linearization was applied to tumour time activity curves and plasma samples to obtain Ki. Results: For 89Zr-anti-EGFR, there was a small variability along the linear regression line between SUV (− 0.51–0.57), TPR (− 0.06‒0.11) and TBR (− 0.13‒0.16) on day 6 versus Ki. Similar doses of 89Zr-anti-HER3 showed similar variability for SUV (− 1.3‒1.0), TPR (− 1.1‒0.53) and TBR (− 1.5‒0.72) on day 5 versus Ki. However, for the second administration of 89Zr-anti-HER3 with a large variability in administered mass doses, SUV showed a larger variability (− 1.4‒2.3) along the regression line with Ki, which improved when using TPR (− 0.38–0.32) or TBR (− 0.56‒0.46). Conclusion: SUV, TPR and TBR at late time points were valid for quantifying irreversible lesional 89Zr-Immuno-PET uptake when constant mass doses were administered. However, for variable mass doses, only TPR and TBR provided reliable values for irreversible uptake, but not SUV, because SUV does not take patient and mass dose-specific plasma clearance into account. [ABSTRACT FROM AUTHOR]

Purpose: Zirconium-89-immuno-positron emission tomography (89Zr-immuno-PET) has enabled visualization of zirconium-89 labelled monoclonal antibody (89Zr-mAb) uptake in organs and tumors in vivo. Patlak linearization of 89Zr-immuno-PET quantification data allows for separation of reversible and irreversible uptake, by combining multiple blood samples and PET images at different days. As one can obtain only a limited number of blood samples and scans per patient, choosing the optimal time points is important. Tissue activity concentration curves were simulated to evaluate the effect of imaging time points on Patlak results, considering different time points, input functions, noise levels and levels of reversible and irreversible uptake. Methods: Based on 89Zr-mAb input functions and reference values for reversible (VT) and irreversible (Ki) uptake from literature, multiple tissue activity curves were simulated. Three different 89Zr-mAb input functions, five time points between 24 and 192 h p.i., noise levels of 5, 10 and 15%, and three reference Ki and VT values were considered. Simulated Ki and VT were calculated (Patlak linearization) for a thousand repetitions. Accuracy and precision of Patlak linearization were evaluated by comparing simulated Ki and VT with reference values. Results: Simulations showed that Ki is always underestimated. Inclusion of time point 24 h p.i. reduced bias and variability in VT, and slightly reduced bias and variability in Ki, as compared to combinations of three later time points. After inclusion of 24 h p.i., minimal differences were found in bias and variability between different combinations of later imaging time points, despite different input functions, noise levels and reference values. Conclusion: Inclusion of a blood sample and PET scan at 24 h p.i. improves accuracy and precision of Patlak results for 89Zr-immuno-PET; the exact timing of the two later time points is not critical. [ABSTRACT FROM AUTHOR]

Background: 89Zirconium-immuno-positron emission tomography (89Zr-immuno-PET) is used for assessment of target status to guide antibody-based therapy. We aim to determine the relation between antibody tumor uptake and target concentration to improve future study design and interpretation. Methods: The relation between tumor uptake and target concentration was predicted by mathematical modeling of 89Zr-labeled antibody disposition in the tumor. Literature values for trastuzumab kinetics were used to provide an example. Results: 89Zr-trastuzumab uptake initially increases with increasing target concentration, until it levels off to a constant value. This is determined by the total administered mass dose of trastuzumab. For a commonly used imaging dose of 50 mg 89Zr-trastuzumab, uptake can discriminate between immunohistochemistry score (IHC) 0 versus 1–2–3. Conclusion: The example for 89Zr-trastuzumab illustrates the potential to assess target expression. The pitfall of false-positive findings depends on the cut-off to define clinical target positivity (i.e., IHC 3) and the administered mass dose. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic pancreatic ductal adenocarcinoma has a dismal prognosis, and to date no curative treatment options exist. The image guided tumor ablation technique irreversible electroporation (IRE) employs high-voltage electrical pulses through the application of several needle electrodes in and around the tumor in order to induce cell death. IRE ablation of the primary tumor has the ability to reduce pancreatic tumor induced immune suppression while allowing the expansion of tumor specific effector T cells, hereby possibly shifting the pancreatic tumor microenvironment into a more immune permissive state. The addition of immune enhancing therapies to IRE might work synergistically and could potentially induce a clinically significant treatment effect. This study protocol describes the rationale and design of the PANFIRE-III trial that aims to assess the safety of the combination of IRE with IMO-2125 (toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma. Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor's immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC's dismal prognosis. [ABSTRACT FROM AUTHOR]

Background: Addition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome., Methods: In this study, 16 evaluable patients with stage III/IV oral cancer were treated with one dose of 480 mg nivolumab 3 weeks prior to surgery. Primary objectives were safety, feasibility, and suitability of programmed death receptor ligand-1 positron emission tomography (PD-L1 PET) as a biomarker for response. Imaging included 18 F-BMS-986192 (PD-L1) PET and 18 F-fluorodeoxyglucose (FDG) PET before and after nivolumab treatment. Secondary objectives included clinical and pathological response, and immune profiling of peripheral blood mononuclear cells (PBMCs) for response prediction. Baseline tumor biopsies and postnivolumab resection specimens were evaluated by histopathology., Results: Grade III or higher adverse events were not observed and treatment was not delayed in relation to nivolumab administration and other study procedures. Six patients (38%) had a pathological response, of whom three (19%) had a major (≥90%) pathological response (MPR). Tumor PD-L1 PET uptake (quantified using standard uptake value) was not statistically different in patients with or without MPR (median 5.3 vs 3.4). All major responders showed a significantly postnivolumab decreased signal on FDG PET. PBMC immune phenotyping showed higher levels of CD8 + T cell activation in MPR patients, evidenced by higher baseline expression levels of PD-1, TIGIT, IFNγ and lower levels of PD-L1., Conclusion: Together these data support that neoadjuvant treatment of advanced-stage oral cancers with nivolumab was safe and induced an MPR in a promising 19% of patients. Response was associated with decreased FDG PET uptake as well as activation status of peripheral T cell populations., Competing Interests: Competing interests: RvdV has received research funding from Genmab BV. TDdG is scientific advisor to Immunicum, GE Health, and Lava Therapeutics, holds stock from LAVA Therapeutics and received research funding from Idera Pharmaceuticals (now Aceragen). RHB received research grants from KWF Kankerbestrijding/Dutch Cancer Society, Cancer Center Amsterdam Foundation, ZonMW and NWO, Genmab BV and the Hanarth Foundation and is on the advisory board of Nanobiotix. He has a scientific collaboration with Orfenix BV and Qialix DoT. CRL received research grants from KWF Kankerbestrijding/Dutch Cancer Society, Cancer Center Amsterdam Foudation, Genmab BV, BMS and the Hanarth Foundation and is on the advisory board of Merck & Co. CWM-vdHvO received research grants from BMS, Boeringher Ingelheim, GSK, Pfizer and AstraZeneca and consulted for GE Health Care, Novartis and EliLilly. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using 18 F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events., Methods: Four 18 F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV) mean , lymph node SUV max ) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted., Results: Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUV mean 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUV max 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUV max 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity., Conclusion: PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer., Competing Interests: Competing interests: RvdV: Research funding for Institute: Genmab B.V. TDdG: Research funding for Institute: Idera Pharmaceuticals (now Aceragen); Consultancy: GE Health, LAVA Therapeutics, Mendus (all to Institute); holds stocks from LAVA Therapeutics. GAPH: Research funding for Institute: Bristol-Myers Squibb, Seerave. Consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, Pierre Fabre. AJdL: Research funding for Institute: Bristol-Myers Squibb, MSD, Boehringer Ingelheim, AstraZeneca. Non-financial support from Merck Serono, non-financial support from Roche. CWM-vdHvO: Research funding for Institute: Bristol-Myers Squibb, Boehringer Ingelheim, GSK, Pfizer; AstraZeneca. Consultancy: GE Health Care, Novartis, Eli Lilly. IHCM, JEEP, AK, GJCZ, MCH, FEFT: No competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Distribution of mAbs into tumour tissue may occur via different processes contributing differently to the 89 Zr-mAb uptake on PET. Target-specific binding in tumours is of main interest; however, non-specific irreversible uptake may also be present, which influences quantification. The aim was to investigate the presence of non-specific irreversible uptake in tumour tissue using Patlak linearization on 89 Zr-immuno-PET data of biopsy-proven target-negative tumours. Data of two studies, including target status obtained from biopsies, were retrospectively analysed, and Patlak linearization provided the net rate of irreversible uptake (K i )., Results: Two tumours were classified as CD20-negative and two as CD20-positive. Four tumours were classified as CEA-negative and nine as CEA-positive. K i values of CD20-negative (0.43 µL/g/h and 0.92 µL/g/h) and CEA-negative tumours (mdn = 1.97 µL/g/h, interquartile range (IQR) = 1.50-2.39) were higher than zero. Median K i values of target-negative tumours were lower than CD20-positive (1.87 µL/g/h and 1.90 µL/g/h) and CEA-positive tumours (mdn = 2.77 µL/g/h, IQR = 2.11-3.65)., Conclusion: Biopsy-proven target-negative tumours showed irreversible uptake of 89 Zr-mAbs measured in vivo using 89 Zr-immuno-PET data, which suggests the presence of non-specific irreversible uptake in tumours. Consequently, for 89 Zr-immuno-PET, even if the target is absent, a tumour-to-plasma ratio always increases over time., (© 2024. The Author(s).)

Background: PET scans using zirconium-89 labelled monoclonal antibodies ( 89 Zr-mAbs), known as 89 Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89 Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89 Zr-immuno-PET scans., Methods: PET imaging and blood sampling of two 89 Zr-mAbs were included, 89 Zr-cetuximab and 89 Zr-durvalumab. For seven patients receiving 89 Zr-cetuximab, PET scans on 1-2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89 Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland-Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC., Results: Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89 Zr-cetuximab and 89 Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was - 10.9% and - 11.4% for 89 Zr-cetuximab and 89 Zr-durvalumab, respectively., Conclusions: Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89 Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations., (© 2024. The Author(s).)

Purpose: Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC., Experimental Design: Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients., Results: The median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53)., Conclusions: In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the "W&W criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this., (©2022 The Authors; Published by the American Association for Cancer Research.)

Introduction: Anaplastic thyroid cancer (ATC) is one of the most lethal diseases known to humans with a median survival of 5 months. The American Thyroid Association (ATA) recently published guidelines for the treatment of this dreadful thyroid malignancy., Areas Covered: This review presents the current therapeutic landscape of this challenging disease. We also present the results from trials published over the last five years and summarize currently active clinical trials., Expert Opinion: Recent attempts to improve the prognosis of these tumors are moving toward personalized medicine, basing the treatment decision on the specific genetic profile of the individual tumor. The positive results of dabrafenib and trametinib for ATC harboring the BRAF V600E mutation have provided a useful treatment option. For the other genetic profiles, different drugs are available and can be used to individualize the treatment, likely using drug combinations. Combinations of drugs act on different molecular pathways and achieve inhibition at separate areas. With new targeted therapies, average survival has improved considerably and death from local disease progression or airway compromise is less likely with improvement in quality of life. Unfortunately, the results remain poor in terms of survival.