Peptide receptor radiotherapy using ¹⁷⁷Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors (NET), with ¹⁷⁷Lu-DOTATATE having acquired marketing authorization in Europe and the USA. The investigation of the pharmacokinetics of those radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. It requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of in vivo stability of ¹⁷⁷Lu-DOTATATE in humans affected by NET. Unexpectedly, fast metabolism of the radiopharmaceutical was observed, with fraction of intact ¹⁷⁷Lu-DOTATATE in plasma decreasing rapidly to 23±5% (mean ± SD) at 24 h and 1.7±0.9% at 96 h after injection.

Objectives: Esthesioneuroblastoma (ENB) is rare with limited therapeutic options when unresectable or metastatic; however, expression of somatostatin receptors qualifies it for peptide receptor radionuclide therapy (PRRT). We report outcomes of PRRT in ENB from two referral centers. Methods: Using PRRT databases at two European Neuroendocrine Tumour Society Centers of Excellence, case finding was undertaken between 2004-2018 for patients who had PRRT with recurrent/metastatic ENB deemed unsuitable for further conventional therapies. Evaluations of response using a composite reference standard and for survival were performed. Results: Of seven patients, four had partial response, two had disease stabilization and one had early progression. Possible side effects include worsening CSF-leaks. Median progression-free survival was 17 months (range, 0-30), and median overall survival was 32 months (range, 4–53). Conclusion: PRRT shows promising efficacy and moderate survival duration in unresectable locally advanced or metastatic ENB warranting larger cohort studies incorporating measures of quality of life.

Purpose: PET using O-(2-[¹⁸F]Fluoroethyl)-L-tyrosine (¹⁸F-FET) is useful to detect residual tumor tissue after glioma resection. Recent animal experiments detected reactive changes of ¹⁸F-FET uptake at the rim of the resection cavity within the first two weeks after resection of gliomas. In the present study, we evaluated pre- and postoperative ¹⁸F-FET PET scans of glioma patients with particular emphasis on the identification of reactive changes after surgery. Methods: Forty-three patients with cerebral gliomas (9 low-grade, 34 high-grade; 9 primary tumors, 34 recurrent tumors) who had preoperative (time before surgery, median 23 d, range 6-44 d) and postoperative ¹⁸F-FET-PET (time after surgery, median 14, range 5–28 d) were included. PET scans (20-40 min p.i.) were evaluated visually for complete or incomplete resection (CR, IR) and compared with MRI. Changes of ¹⁸F-FET-uptake in residual tumor were evaluated by tumor-to-brain ratios (TBRmax) and in the vicinity of the resection cavity by maximum lesion-to-brain ratios (LBRmax). Results: Visual analysis of ¹⁸F-FET PET scans revealed CR in 16/43 patients and IR in the remaining patients. PET results were concordant with MRI in 69% of the patients. LBRmax of ¹⁸F-FET uptake in the vicinity of the resection cavity was significantly higher compared with preoperative values (1.59 ± 0.36 versus 1.14 ± 0.17; n = 43, p<0.001). In 11 patients (26%) a "flare phenomenon" was observed with a considerable increase of ¹⁸F-FET uptake compared with preoperative values in either the residual tumor (n = 5) or in areas remote from tumor in the preoperative PET scan (n = 6) (2.92 ± 1.24 versus 1.62 ± 0.75; p<0.001). Further follow-up in five patients showed decreasing ¹⁸F-FET uptake in the flare areas in four and progress in one case. Conclusion: Our study confirms that ¹⁸F-FET PET provides valuable information for assessing the success of glioma resection. Postoperative reactive changes at the rim of the resection cavity appear to be mild. However, in 23 % of the patients, a postoperative "flare phenomenon" was observed that warrants further investigation.

We aimed to evaluate the diagnostic performance of ¹⁸F-FDG PET/CT for the detection of post-transplantation lymphoproliferative disorder (PTLD) in a pediatric population and explore its feasibility during response assessment. Methods: This retrospective study included 28 pediatric transplant recipients who underwent a total of 32 ¹⁸F-FDG PET/CT scans due to clinical suspicion of PTLD within an 8-year period. Pathology reports and 2-year follow-up were used as reference standard. Twenty-one response assessment ¹⁸F-FDG PET/CT scans were re-evaluated according to the Lugano criteria. Results: The diagnosis of PTLD was established in 14 patients (49%). Sensitivity, specificity, positive predictive value, and negative predictive value of ¹⁸F-FDG PET/CT for the detection of PTLD in children with a clinical suspicion of this disease, was 50% (7/14), 100% (18/18), 100% (7/7), and 72% (18/25), respectively. False-negative results occurred in patients with PTLD in the Waldeyer’s ring, cervical lymph nodes or small bowel with either non-destructive or polymorphic PTLD. Two of 5 interim ¹⁸F-FDG PET/CT scans and 3 of 9 end-of-treatment ¹⁸F-FDG PET/CT scans were false-positive. Conclusion: ¹⁸F-FDG PET/CT had good specificity and positive predictive value but low to moderate sensitivity and negative predictive value for the detection of PTLD in a 28 pediatric patient cohort with a clinical suspicion of this disease. False-negative results were confirmed in the Waldeyer’s ring, cervical lymph nodes and small bowel with either non-destructive or polymorphic PTLD subtypes. ¹⁸F-FDG PET/CT appears to have a limited role in the response assessment setting of pediatric PTLD, given the observed high proportions of false-positives both at interim and end-of-treatment evaluations.

Introduction: To use positron emission tomography coupled with computed tomography (¹⁸FDG-PET/CT) to identify a high-risk subgroup requiring therapeutic intensification among patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) involvement. Methods: In this retrospective multicentric study, patients with LACC and PALN involvement concurrently treated with chemoradiotherapy and extended-field radiotherapy (EFR) between 2006 and 2016 were included. A senior nuclear medicine specialist in PET for gynaecologic oncology reviewed all ¹⁸FDG-PET/CT scans. Metabolic parameters including maximum standardised uptake value (SUV_max), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were determined for the primary tumour, pelvic lymph nodes and PALN. Associations between these parameters and overall survival (OS) were assessed with Cox's proportional hazards model. Results: Sixty-eight patients were enrolled in the study. Three-year OS was 55.5% (95% CI (40.8-68.0)). When adjusted for age, stage and histology, pelvic lymph node TLG, PALN TLG and PALN SUV_max were significantly associated with OS (p<0.005). Conclusion: FDG-PET/CT was able to identify predictors of survival in the homogeneous subgroup of patients with LACC and PALN involvement, thus allowing therapeutic intensification to be proposed.

Targeting tumor-expressed receptors using selective molecules for diagnostic, therapeutic or both diagnostic and therapeutic (theragnostic) purposes is a promising approach in oncological applications. Such approaches have increased significantly over the past decade. Peptides such as gastrin-releasing peptide receptors (GRPR) targeting radiopharmaceuticals are small molecules with fast blood clearance and urinary excretion. They demonstrate good tissue diffusion, low immunogenicity, and highly selective binding to their target cell-surface receptors. They are also easily produced. GRPR, part of the bombesin (BBN) family, are overexpressed in many tumors, including breast and prostate cancer, and therefore represent an attractive target for future development.

Respiratory gating is the standard to overcome respiration effects degrading image quality in positron emission tomography (PET). Data-driven gating (DDG) using signals derived from PET raw data are promising alternatives to gating approaches requiring additional hardware. However, continuous bed motion (CBM) scans require dedicated DDG approaches for axially-extended PET, compared to DDG for conventional step-and-shoot scans. In this study, a CBM-capable DDG algorithm was investigated in a clinical cohort, comparing it to hardware-based gating using gated and fully motion-corrected reconstructions. Methods: 56 patients with suspected malignancies in thorax or abdomen underwent whole-body ¹⁸F-FDG CBM-PET/CT imaging using DDG and hardware-based respiratory gating (pressure-sensitive belt gating, BG). Correlation analyses were performed on both gating signals. Besides static reconstructions, BG and DDG were used for optimally-gated PET (BG-OG, DDG-OG) and fully motion-corrected PET (elastic motion correction; BG-EMOCO, DDG-EMOCO). Metabolic volumes, SUV_max and SUVmean of lesions were compared amongst the reconstructions. Additionally, the quality of lesion delineation in different PET reconstructions was independently evaluated by three experts. Results: Global correlation coefficients between BG and DDG signals amounted to 0.48±0.11, peaking at 0.89±0.07 when scanning the kidney and liver region. In total, 196 lesions were analyzed. SUV measurements were significantly higher in BG-OG, DDG-OG, BG-EMOCO and DDG-EMOCO compared to static images (P<0.001; median SUV_max: static, 14.3±13.4; BG-EMOCO, 19.8±15.7; DDG-EMOCO, 20.5±15.6; BG-OG, 19.6±17.1; DDG-OG, 18.9±16.6). No significant differences between BG-OG and DDG-OG, and BG-EMOCO and DDG-EMOCO, respectively, were found. Visual lesion delineation was significantly better in BG-EMOCO and DDG-EMOCO than in static reconstructions (P<0.001); no significant difference was found comparing BG and DDG (EMOCO, OG, respectively). Conclusion: DDG-based motion-compensation of CBM-PET acquisitions outperforms static reconstructions, delivering qualities comparable to hardware-based approaches. The new algorithm may be a valuable alternative for CBM-PET systems.

For oncological management or radiotherapy planning, reliable staging tools are essential. Recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitors (FAPI)-positron-emission tomography (PET)/computed tomography (CT) for primary malignancies located within the lower gastrointestinal tract (LGT) as a very first clinical analysis. Methods: ⁶⁸Ga-FAPI-PET/CT was performed in a cohort of 22 patients with LGT including 15 patients with metastatic disease, 1 patient with suspected local relapse and 6 treatment-naïve patients. ⁶⁸Ga-FAPI-04 and ⁶⁸Ga-FAPI-46 uptake was quantified by standardized uptake values (SUV)max and (SUV)mean. After comparison with standard imaging, changes in tumor stage/ localization and (radio)oncological management were recorded. Results: The highest uptake of FAPI tracer was observed in liver metastases and anal cancer with a SUV_max of 9.1 and 13.9, respectively. Due to a low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50% while for patients with metastases new findings occurred in 47%. In total, FAPI-imaging caused a high, medium and low change of (radio)oncological management in 19%, 33% and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by ⁶⁸Ga-FAPI-PET/CT. Conclusion: The present study demonstrated that both primary and metastatic LGT were reliably detected by ⁶⁸Ga-FAPI-PET/CT leading to relevant changes in TNM status and (radio)oncological management. ⁶⁸Ga-FAPI-PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT, potentially opening new applications for tumor (re-)staging.

Purpose: The main objective of this prospective study was to determine the impact of multi-phasic acquisition of ⁶⁸Ga-PSMA PET/CT in the detection of recurrent prostate cancer (PCa) in the early stage of biochemical recurrence (BR) with prostate-serum-antigen (PSA) level <1ng/ml. Also, ⁶⁸Ga-PSMA PET/CT positivity was correlated with clinical parameters for the assessment of predictive markers. Methods: A prospective monocentric study was conducted on 135 PCa patients with BR and PSA<1ng/ml. All patients have undergone initial prostatectomy with additional radiation therapy in 19.3% and androgen-deprivation therapy (ADT) in 7.4% of patients. Dynamic acquisition [1–8min. post-injection (p.i.)] from the prostate bed, standard whole-body (60min. p.i.) and limited bed positions of delayed studies (120-150min. p.i.), were performed. Studies were reviewed by two board-certified nuclear medicine specialists, independently. A combination of visual and semi-quantitative analyses and correlation with morphological (e.g. MRI) and/or clinical follow-up findings was used for the final interpretation of abnormal lesions as benign or malignant. ⁶⁸Ga-PSMA PET/CT positivity was also correlated with primary clinical findings. Results: Incorporating the information of all phases, 116 lesions were detected in 49.6% of patients (22 local recurrences, 63 lymph nodes, and 31 distant metastases). The detection rates were 31.8%, 44.9%, and 71.4% for PSA<0.2ng/ml, 0.2≤PSA<0.5, and 0.5≤PSA<1, respectively. Additional dynamic and/or delayed phases resulted in better determination of equivocal lesions and a higher diagnostic performance in 25.9% of patients. Stand-alone dynamic and delayed images led to better interpretation of equivocal findings in the prostate bed (31.4%) and other (lymph node/bone) lesions (20%), respectively. Conclusion: ⁶⁸Ga-PSMA PET/CT revealed promising results for the early detection of recurrent disease in patients with PSA level of 0.5-1.0ng/ml. However, it showed limited value in cases with PSA<0.5ng/ml. Multi-phasic ⁶⁸Ga-PSMA PET/CT led to better determination of equivocal findings. Although, dynamic images may provide helpful information in assessment of the prostate bed; however, delayed acquisitions seem to have higher impact in clarifying of the equivocal findings.

Recently introduced PET systems using silicon photomultipliers with digital readout (dPET) have an improved timing and spatial resolution, aiming at a better image quality, over conventional PET (cPET) systems. We prospectively evaluated the performance of a dPET system in patients with cancer, as compared to high-resolution (HR) cPET imaging. Methods: After a single FDG-injection, 66 patients underwent dPET (Vereos, Philips Healthcare) and cPET (Ingenuity TF, Philips Healthcare) imaging in a randomized order. We used HR-reconstructions (2x2x2 mm³ voxels) for both scanners and determined SUV_max, SUVmean, lesion-to-background ratio (LBR), metabolic tumor volume (MTV) and lesion diameter in up to 5 FDG-positive lesions per patient. Furthermore, we counted the number of visible and measurable lesions on each PET scan. Two nuclear medicine specialists blindly determined the Tumor Node Metastasis (TNM) score from both image sets in 30 patients referred for initial staging. For all 66 patients, these specialists separately and blindly evaluated image quality (4-point scale) and determined the scan preference. Results: We included 238 lesions that were visible and measurable on both PET scans. We found 37 additional lesions on dPET in 27 patients (41%), which were unmeasurable (n = 14) or invisible (n = 23) on cPET. SUVmean, SUV_max, LBR and MTV on cPET were 5.2±3.9 (mean±SD), 6.9±5.6, 5.0±3.6 and 2991±13251 mm³, respectively. On dPET SUVmean, SUV_max and LBR increased 24%, 23% and 27%, respectively (p<0.001) while MTV decreased 13% (p<0.001) compared to cPET. Visual analysis showed TNM upstaging with dPET in 13% of the patients (4/30). dPET images also scored higher in image quality (P = 0.003) and were visually preferred in the majority of cases (65%). Conclusion: Digital PET improved the detection of small lesions, upstaged the disease and images were visually preferred as compared to high-resolution conventional PET. More studies are necessary to confirm the superior diagnostic performance of digital PET.

The aim of this work was to quantify the uptake of [¹⁸F]BMS-986192, a PD-L1 adnectin PET tracer, in patients with non-small-cell lung cancer (NSCLC). To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as standardized uptake value (SUV) was investigated. Methods: Data from a study with [¹⁸F]BMS-986192 in patients with advanced stage NSCLC eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of [¹⁸F]BMS-986192, a 60-minutes dynamic PET-CT scan was started, followed by a 30-min whole body PET-CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor to blood ratio as well as several SUV measures. Results: Twenty two tumors in nine patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 out of 18 tumor time activity curves. The distribution volume V_T ranged from 0.4 to 4.8 mL·cm-3. Similar values were obtained with an image derived input function. From the simplified measures, SUV normalized for body weight (SUV_BW) at 50 and 67 minutes post injection correlated best with V_T, with an R² > 0.9. Conclusion: A single tissue reversible model can be used for the quantification of tumor uptake of the PD-L1 PET tracer [¹⁸F]BMS-986192. SUV_BW at 60 minutes post injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. In order to assess its predictive value for response evaluation during PD-(L)1 immune checkpoint inhibition further validation of SUV against V_T based on an image derived input function is recommended.

The overexpression of integrin αvβ6 in pancreatic cancer makes it a promising target for noninvasive positron emission tomography (PET) imaging. However, currently, most integrin αvβ6-targeting radiotracers are based on linear peptides, which are quickly degraded in the serum by proteinases. Herein, we aimed to develop and assess a ⁶⁸Ga-labeled integrin αvβ6-targeting cyclic peptide (⁶⁸Ga-cycratide) for PET imaging of pancreatic cancer. Methods: ⁶⁸Ga-cycratide was prepared, and its PET imaging profile was compared with that of the linear peptide (⁶⁸Ga-linear-pep) in an integrin αvβ6-positive BxPC-3 human pancreatic cancer mouse model. Five healthy volunteers (two women and three men) underwent whole-body PET/CT imaging after injection of ⁶⁸Ga-cycratide, and biodistribution and dosimetry calculations were determined. PET/CT imaging of two patients was performed to investigate the potential role of ⁶⁸Ga-cycratide in pancreatic cancer diagnosis and treatment monitoring. Results: ⁶⁸Ga-cycratide exhibited significantly higher tumor uptake than did ⁶⁸Ga-linear-pep in BxPC-3 tumor-bearing mice, owing—at least in part—to markedly improved in vivo stability. ⁶⁸Ga-cycratide could sensitively detect the pancreatic cancer lesions in an orthotopic mouse model and was well tolerated in all healthy volunteers. Preliminary PET/CT imaging in patients with pancreatic cancer demonstrated that ⁶⁸Ga-cycratide was comparable to ¹⁸F-fludeoxyglucose for diagnostic imaging and post-surgery tumor relapse monitoring. Conclusion: ⁶⁸Ga-cycratide is an integrin αvβ6-specific PET radiotracer with favorable pharmacokinetics and dosimetry profile. ⁶⁸Ga-cycratide is expected to provide an effective noninvasive PET strategy for pancreatic cancer lesion detection and therapy response monitoring.

Recently, N-(4-¹⁸F-fluorobenzoyl)-interleukin-2 (¹⁸F-FB-IL2) was introduced as PET tracer for T-cell imaging. However, production is complex and time-consuming. Therefore, we developed two radiolabeled interleukin-2 (IL-2) variants, namely aluminum ¹⁸F-fluoride-(restrained complexing agent)-IL-2 (¹⁸F-AlF-RESCA-IL2) and ⁶⁸Ga-gallium-(1,4,7-triazacyclononane-4,7-diacetic acid-1-glutaric acid)-IL-2 (⁶⁸Ga-Ga-NODAGA-IL2) and compared their in-vitro and in-vivo characteristics with ¹⁸F-FB-IL2. Methods: Radiolabeling of ¹⁸F-AlF-RESCA-IL2 and ⁶⁸Ga-Ga-NODAGA-IL2 was optimized and stability was evaluated in human serum. Receptor binding was studied with activated human peripheral blood mononuclear cells (hPBMCs). Ex-vivo tracer biodistribution in immunocompetent BALB/cOlaHsd (BALB/c) mice was performed at 15, 60 and 90 min after tracer injection. In-vivo binding characteristics were studied in severe combined immune-deficient (SCID) mice inoculated with activated hPBMCs in Matrigel. Tracer was injected 15 min after hPBMCs inoculation and a 60-min dynamic PET scan was acquired, followed by ex-vivo biodistribution studies. Specific uptake was determined by co-injection of tracer with unlabeled IL2 and by evaluating uptake in a control group inoculated with Matrigel only. Results: ⁶⁸Ga-Ga-NODAGA-IL2 and ¹⁸F-AlF-RESCA-IL2 were produced with radiochemical purity >95% and radiochemical yield of 13.1±4.7% and 2.4±1.6% within 60 and 90 min, respectively. Both tracers were stable in serum, with >90% being intact tracer after 1h. In-vitro, both tracers displayed preferential binding to activated hPBMCs. Ex-vivo biodistribution studies in BALB/c mice showed higher uptake of ¹⁸F-AlF-RESCA-IL2 than ¹⁸F-FB-IL2 in liver, kidney, spleen, bone and bone marrow. ⁶⁸Ga-Ga-NODAGA-IL2 uptake in liver and kidney was higher than ¹⁸F-FB-IL2 uptake. In-vivo, all tracers revealed uptake in activated hPBMCs in SCID mice. Low uptake was seen after a blocking dose of IL2 or in the Matrigel control group. In addition, ¹⁸F-AlF-RESCA-IL2 yielded highest contrast PET images of target lymph nodes. Conclusion: Production of ¹⁸F-AlF-RESCA-IL2 and ⁶⁸Ga-Ga-NODAGA-IL2 is simpler and faster than ¹⁸F-FB-IL2. Both tracers showed good in-vitro and in-vivo characteristics with high uptake in lymphoid tissue and hPBMC xenografts.

The accuracy of lutetium-177 (¹⁷⁷Lu) radiotracer concentration measurements using quantitative clinical software was determined by comparing in vivo results for a digital solid-state cadmium-zinc-telluride SPECT/CT (single photon emission computed tomography / x-ray computed tomography) system to in vitro sampling. First, image acquisition parameters were assessed for an International Electrotechnical Commission (IEC) body phantom emulating clinical count rates loaded with a "lung" insert and 6 hot spheres with a 12:1 target-to-background ratio of ¹⁷⁷Lu solution. Then, the data of 28 whole-body SPECT/CT scans of 7 patients who underwent ¹⁷⁷Lu prostate membrane antigen (¹⁷⁷Lu-PSMA) radioligand therapy was retrospectively analyzed. Three users analyzed SPECT/CT images for in vivo urinary bladder radiotracer uptake using quantitative software (Q.Metrix, GE Healthcare). In vitro radiopharmaceutical concentrations were calculated using urine sampling obtained immediately after each scan, scaled to standardized uptake values (SUVs). Any in vivo/in vitro identity relations were determined by linear regression (ideally slope=1, intercept=0), within a 95 % confidence interval (CI). Phantom results demonstrated lower quantitative error for acquisitions using the 113 keV ¹⁷⁷Lu energy peak rather than including the 208 keV peak, given that only low-energy collimation was available in this camera configuration. In the clinical study, 24 in vivo/in vitro pairs were eligible for further analysis, having rejected 4 as outliers (via Cook’s distance calculations). All linear regressions (R2 ≥ 0.92, P<0.0001) provided identity in vivo/in vitro relations (95 % CI), with SUV averages from all users giving a slope of 1.03±0.09, an intercept of –0.25±0.64 g/mL, and an average residual difference of 20.4 %. Acquiring with the lower energy ¹⁷⁷Lu energy peak, solid-state SPECT/CT imaging provides an accuracy to within ~20 % for in vivo urinary bladder radiotracer concentrations. This non-invasive in vivo quantitation method can potentially improve diagnosis, improve patient management and treatment response assessment, and provide data essential to ¹⁷⁷Lu dosimetry.

Overexpression of somatostatin receptors in patients with neuroendocrine neoplasms (NEN) is utilized for both diagnosis and treatment. Receptor density may reflect tumor differentiation and thus be associated with prognosis. Non-invasive visualization and quantification of somatostatin receptor density is possible by somatostatin receptor imaging (SRI) using positron emission tomography (PET). Recently, we introduced ⁶⁴Cu-DOTATATE for SRI and we hypothesized that uptake of this tracer could be associated with overall (OS) and progression-free survival (PFS). Methods: We evaluated patients with NEN that had a ⁶⁴Cu-DOTATATE PET/CT SRI performed in two prospective studies. Tracer uptake was determined as the maximal standardized uptake value (SUV_max) for each patient. Kaplan-Meier analysis with log-rank was used to determine the predictive value of ⁶⁴Cu-DOTATATE SUV_max for OS and PFS. Specificity, sensitivity and accuracy was calculated for prediction of outcome at 24 months after ⁶⁴Cu-DOTATATE PET/CT. Results: A total of 128 patients with NEN were included and followed for a median of 73 (1-112) months. During follow-up, 112 experienced disease progression and 69 patients died. The optimal cutoff for ⁶⁴Cu-DOTATATE SUV_max was 43.3 for prediction of PFS with a hazard ratio of 0.56 (95% CI: 0.38-0.84) for patients with SUV_max > 43.3. However, no significant cutoff was found for prediction of OS. In multiple Cox regression adjusted for age, sex, primary tumor site and tumor grade, the SUV_max cutoff hazard ratio was 0.50 (0.32-0.77) for PFS. The accuracy was moderate for predicting PFS (57%) at 24 months after ⁶⁴Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of ⁶⁴Cu-DOTATATE PET/CT and outcome in patients with NEN, tumor somatostatin receptor density visualized with ⁶⁴Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 months after ⁶⁴Cu-DOTATATE PET/CT SRI was moderate limiting the value on an individual patient basis.

The kappa opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, ¹¹C-GR103545, for PET imaging of KOR in humans. Although ¹¹C-GR103545 showed high brain uptake, good binding specificity, and selectivity to KOR, it displayed slow kinetics and relatively large test-retest variability (TRV) of distribution volume (V_T) estimates (15%). Therefore we set out to develop two novel KOR agonist radiotracers, ¹¹C-EKAP and ¹¹C-FEKAP, and in nonhuman primates, both tracers exhibited faster kinetics and comparable binding parameters to ¹¹C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test-retest PET scans with both ¹¹C-EKAP and ¹¹C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were generated for 14 regions of interest. One- and two-tissue compartment models (1TC, 2TC) and the multilinear analysis-1 (MA1) method were applied to the regional TACs to calculate V_T. Time-stability of V_T values and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the non-displaceable binding potential (BP_ND) for the three tracers (¹¹C-EKAP, ¹¹C-FEKAP and ¹¹C-GR103545), were compared using a graphical method. Results: For both tracers, regional TACs were fitted well with the 2TC model and MA1 method (t*=20min), but not with the 1TC model. Given unreliably estimated parameters in several fits with the 2TC model and a good match between V_T values from MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 V_T values were highest for ¹¹C-GR103545, followed by ¹¹C-EKAP, then ¹¹C-FEKAP. Minimum scan time for stable V_T measurement was 90 and 110min for ¹¹C-EKAP and ¹¹C-FEKAP, respectively, compared with 140min for ¹¹C-GR103545. The mean absolute TRV in MA1 V_T estimates was 7% and 18% for ¹¹C-EKAP and ¹¹C-FEKAP, respectively. BP_ND levels were similar for ¹¹C-FEKAP and ¹¹C-GR103545, but ~25% lower for ¹¹C-EKAP. Conclusion: The two novel KOR agonist tracers showed faster tissue kinetics than ¹¹C-GR103545. Even with slightly lower BP_ND, ¹¹C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, based on the shorter minimum scan time and excellent test-retest.

We developed a first-of-kind dasatinib-derivative imaging agent, ¹⁸F-SKI-249380 (¹⁸F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assess the feasibility of using ¹⁸F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min post-injection of ¹⁸F-SKI (mean: 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately post-injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of three patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of ¹⁸F-SKI. A total of 27 tumor lesions were analyzed with median SUVpeak 1.4 (range, 0.7–2.3) and tumor-to-blood ratios of 1.6 (range, 0.8–2.5) at 90 min post-injection. Intratumoral drug concentrations calculated for four reference lesions ranged from 0.03–0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30–90 min post-injection. Blood radio-assay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time 1.31 ± 0.81 min, plasma 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time 285 ± 148.49 min, plasma 240 ± 84.85 min; n = 2) or a small rise to plateau (n = 2). Like dasatinib, ¹⁸F-SKI underwent extensive metabolism post-administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 (SD 0.0034) mSv/MBq. Conclusion: ¹⁸F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

We reviewed ¹¹¹In-DOTA-anti-CD45 antibody (BC8) imaging and bone marrow biopsy measurements to ascertain biodistribution and biokinetics of the radiolabeled antibody and to investigate differences based on type of hematologic malignancy. Methods: Serial whole-body scintigraphic images (4 time-points) were obtained after infusion of the ¹¹¹In-DOTA-BC8 (176-406 MBq) in 52 adult patients with hematologic malignancies (lymphoma, multiple myeloma, acute myeloid leukemia and myelodysplastic syndrome). Counts were obtained for the regions of interest for spleen, liver, kidneys, testicles (in males), and two marrow sites (acetabulum and sacrum) and correction for attenuation and background was made. Bone marrow biopsies were obtained 14-24 hours post-infusion and percent of administered activity was determined. Radiation absorbed doses were calculated. Results: Initial uptake in liver averaged 32% ± 8.4% (S.D.) of administered activity (52 patients), which cleared monoexponentially with biological half-time of 293 ± 157 hours (33 patients) or did not clear (19 patients). Initial uptake in spleen averaged 22% ± 12% and cleared with a biological half-time 271 ± 185 hours (36 patients) or longer (6 patients). Initial uptake in kidney averaged 2.4% ± 2.0% and cleared with a biological half-time of 243 ± 144 hours (27 patients) or longer (9 patients). Initial uptake in red marrow averaged 23% ± 11% and cleared with half-times of 215 ± 107 hours (43 patients) or longer (5 patients). Whole-body retention half-times averaged 198 ± 75 hours. Splenic uptake was higher in the AML/MDS group when compared to the lymphoma group (p ≤ 0.05) and to the multiple myeloma group (p ≤ 0.10). Liver represented the dose-limiting organ. For liver uptake, no significant differences were observed between the three malignancy groups. Average calculated radiation absorbed doses per unit administered activity for a therapy infusions of ⁹⁰Y-DOTA-BC8 were for red marrow: 470 ± 260 cGy/MBq, liver 1100 ± 330 cGy/MBq, spleen 4120 ± 1950 cGy/MBq, total body 7520 ± 20 cGy/MBq, osteogenic cells 290 ± 200 cGy/MBq, and kidneys 240 ± 200 cGy/MBqR. Conclusion: ¹¹¹In-DOTA-BC8 had long retention time in liver, spleen, kidneys, and red marrow, and the highest absorbed doses were calculated for spleen and liver. Few differences were observed by malignancy type. The exception was greater splenic uptake among leukemia/MDS group when compared to lymphoma and multiple myeloma groups.

Purpose: This prospective study evaluated the imaging performance of a novel immunological pretargeting positron-emission tomorgraphy (immuno-PET) method in patients with HER2-negative, carcinoembryonic antigen (CEA)-positive, metastatic breast cancer (BC), compared to computed tomography (CT), bone magnetic resonance imaging (MRI), and ¹⁸Fluorodeoxyglucose PET (FDG-PET). Patients and Methods: Twenty-three patients underwent whole-body immuno-PET after injection of 150 MBq ⁶⁸Ga-IMP288, a histamine-succinyl-glycine peptide given following initial targeting of a trivalent anti-CEA, bispecific, anti-peptide antibody. The gold standards were histology and imaging follow-up. Tumor standard uptake values (SUV_max and SUVmean) were measured, and tumor burden analyzed using Total Tumor Volume (TTV) and Total Lesion Activity (TLA). Results: Total lesion sensitivity of immuno-PET and FDG-PET was 94.7% (1116/1178) and 89.6% (1056/1178), respectively. Immuno-PET had a somewhat higher sensitivity than CT and FDG-PET in lymph nodes (92.4% vs 69.7% and 89.4%, respectively) and liver metastases (97.3% vs 92.1% and 94.8%, respectively), whereas sensitivity was lower for lung metastases (48.3% vs 100% and 75.9%, respectively). Immuno-PET showed higher sensitivity than MRI and FDG-PET for bone lesions (95.8% vs 90.7% and 89.3%, respectively). In contrast to FDG-PET, immuno-PET disclosed brain metastases. Despite equivalent tumor SUV_max, SUVmean, and TTV, TLA was significantly higher with immuno-PET compared to FDG PET (P = 0.009). Conclusion: Immuno-PET using anti-CEA/anti-IMP288 bispecific antibody, followed by ⁶⁸Ga-IMP288, is a potentially sensitive theranostic imaging method for HER2-negative, CEA-positive, metastatic BC patients, and warrants further research.

The majority of epithelial tumors recruits fibroblasts and other non-malignant cells and activates them into cancer-associated fibroblasts. This often leads to overexpression of the membrane serine protease fibroblast-activating protein (FAP). It has already been shown that DOTA-bearing FAP inhibitors (FAPIs) generate high contrast images with PET/CT scans. Since SPECT is a lower cost and more widely available alternative to PET, ^99mTc-labeled FAPIs represent attractive tracers for imaging applicable in a larger number of patients. Furthermore, the chemically homologous nuclide 188Re is available from generators, which allows FAP-targeted endoradiotherapy. Methods: For the preparation of ^99mTc tricarbonyl complexes, a chelator was selected whose carboxylic acids can easily be converted into various derivatives in the finished product. This enabled a platform strategy based on the original tracer. The obtained ^99mTc complexes were investigated in vitro by binding and competition experiments on FAP-transfected HT-1080 (HT-1080-FAP) and/or on mouse FAP expressing (HEK-muFAP) and CD26-expressing (HEKCD26) HEK cells and characterized by planar scintigraphy and organ distribution studies in tumor-bearing mice. Furthermore, a first-in-man application was done in two patients with ovarian and pancreatic cancer, respectively. Results: ^99mTc-FAPI-19 showed specific binding to recombinant FAP-expressing cells with high affinity. Unfortunately, liver accumulation, biliary excretion and no tumor uptake were observed in the planar scintigraphy of a HT-1080-FAP xenotranplanted mouse. To improve the pharmacokinetic properties hydrophilic amino acids were attached to the chelator moiety of the compound. The resulting ^99mTc-labeled FAPI tracers revealed excellent binding properties (up to 45 % binding; above 95 % internalization), high affinity (IC50 = 6.4 nM to 12.7 nM), and significant tumor uptake (up to 5.4 %ID/g) in biodistribution studies. The lead candidate ^99mTc-FAPI-34 was applied for diagnostic scintigraphy and SPECT of patients with metastasized ovarian and pancreatic cancer for follow-up to therapy with ⁹⁰Y-FAPI-46. ^99mTc-FAPI-34 accumulated in the tumor lesions also shown in PET/CT imaging using ⁶⁸Ga-FAPI-46. Conclusion: ^99mTc-FAPI-34 represents a powerful tracer for diagnostic scintigraphy, especially in cases where PET imaging is not available. Additionally, the chelator used in this compound allows labeling with the therapeutic nuclide 188Re which is planned for the near future.

The objective of this retrospective study was to determine the role of ¹⁸F-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with ¹⁷⁷Lu- and/or ⁹⁰Y- DOTATOC/DOTATATE PRRT between 2/2002 and 7/2018. All subjects received both ⁶⁸Ga-DOTATOC/TATE/NOC and ¹⁸F-FDG PET/CT prior to treatment and were followed 3-189 months. Kaplan-Meier analysis, log-rank test (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: 199 patients (40.2%) presented with pancreatic NEN, 49 with CUP (cancer of unknown primary), 139 with midgut NEN, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8 and other locations in 42 patients. FDG-PET/CT was positive in 382 (77.2%) patients and 113 (22.8%) were FDG-negative before PRRT, while 100% were ⁶⁸Ga-DOTATOC/TATE/NOC positive. For all patients, the median PFS and OS, defined from start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive FDG predicted shorter PFS (18.5 mo vs 24.1 mo; P = 0.0015) and OS (53.2 mo vs 83.1 mo; P < 0.001) than negative FDG. Amongst the pancreatic NEN, the median OS was 52.8 mo in FDG positive and 114.3 mo in FDG negative subjects (P = 0.0006). For all patients with positive ¹⁸F-FDG uptake, and a ratio of the highest SUV_max on ⁶⁸Ga-SSTR PET to the most ¹⁸F-FDG-avid tumor lesions >2, the median OS was 53.0 mo, compared to 43.4 mo in those patients with a ratio <2 (P = 0.030). For patients with no ¹⁸F-FDG uptake (complete "mismatch" imaging pattern), the median OS was 108.3 mo vs 76.9 mo for SUV_max >15.0 and ≤15.0 on ⁶⁸Ga-SSTR PET/CT, respectively. Conclusion: The presence of positive lesions on ¹⁸F-FDG PET is an independent prognostic factor in patients with NEN treated with PRRT. Metabolic imaging with ¹⁸F-FDG PET/CT compliments the molecular imaging aspect of ⁶⁸Ga-SSTR PET/CT for the prognosis of survival after PRRT. High SSTR expression combined with negative ¹⁸F-FDG PET/CT imaging is associated with the most favorable long-term prognosis.

Purpose: To determine the effect of smooth filter and partial volume correction (PVC) method on measured prostate-specific membrane antigen (PSMA) activity in small metastatic lesions and to determine the impact of these changes on the molecular imaging (mi) PSMA scoring. Materials & Methods: Men with biochemical recurrence of prostate cancer with negative CT and bone scintigraphy were referred for ¹⁸F-DCFPyL PET/CT. Examinations were performed on one of 2 PET/CT scanners (GE Discovery 610 or Siemens mCT40). All suspected tumor sites were manually contoured on co-registered CT and PET images, and each was assigned a miPSMA score as per the PROMISE criteria. The PVC factors were calculated for every lesion using the anatomical CT and then applied to the unsmoothed PET images. The miPSMA scores, with and without the corrections, were compared, and a simplified "rule of thumb" (RoT) correction factor (CF) was derived for lesions at various sizes (<4mm, 4-7mm, 7-9mm, 9-12mm). This was then applied to the original dataset and miPSMA scores obtained using the RoT CF were compared to those found using the actual corrections. Results: There were 75 men (median age, 69 years; median serum PSA of 3.69 ug/L) with 232 metastatic nodes < 12 mm in diameter (mean lesion volume of 313.5 ± 309.6 mm³). Mean SUV_max before and after correction was 11.0 ± 9.3 and 28.5 ± 22.8, respectively (p<0.00001). The mean CF for lesions <4mm (n = 22), 4-7mm (n = 140), 7-9mm (n = 50), 9-12 mm (n = 20) was 4 (range: 2.5-6.4), 2.8 (range: 1.6-4.9), 2.3 (range: 1.6-3.3) and 1.8 (range 1.4-2.4), respectively. Overall miPSMA scores were concordant between the corrected dataset and RoT in 205/232 lesions (88.4%). Conclusion: There is a significant effect of smooth filter and partial volume correction on measured PSMA activity in small nodal metastases, impacting the miPSMA score.

Latest digital whole-body PET scanners provide a combination of higher sensitivity and improved spatial and timing resolution. We performed a lesion detectability study on two generations of Siemens Biograph PET/CT scanners, the mCT and Vision, to study the impact of improved physical performance on clinical performance. Our hypothesis is that the improved performance of the Vision will result in improved lesion detectability, allowing shorter imaging times or equivalently, lower injected dose. Methods: Data were acquired with the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network torso phantom combined with a 20-cm diameter cylindrical phantom. Spherical lesions were emulated by acquiring spheres-in-air data, and combining it with the phantom data to generate combined datasets with embedded lesions of known contrast. Two sphere sizes and uptakes were used: 9.89 mm diameter spheres with 6:1 (lung) and 3:1 (cylinder) and 4.95 mm diameter spheres with 9.6:1 (lung) and 4.5:1 (cylinder) local activity concentration uptakes. Standard image reconstruction was performed: ordinary Poisson ordered subsets expectation maximization algorithm with point spread function and time-of-flight modeling and post-reconstruction smoothing with a 5 mm Gaussian filter. The Vision images were also generated without any post-reconstruction smoothing. Generalized scan statistics methodology was used to estimate the area under the localization receiver operating characteristic curve (ALROC). Results: Higher sensitivity and improved TOF performance of Vision leads to reduced contrast in the background noise nodule distribution. Measured lesion contrast is also higher on the Vision due to its improved spatial resolution. Hence, the ALROC values are noticeably higher for the Vision relative to the mCT. Conclusion: Improved overall performance of the Vision provides a factor of 4-6 reduction in imaging time (or injected dose) over the mCT when using the ALROC metric for lesions >9.89 mm in diameter. Smaller lesions are barely detected in the mCT, leading to even higher ALROC gains with the Vision. Improved spatial resolution of the Vision also leads to a higher measured contrast that is closer to the real uptake, implying improved quantification. Post-reconstruction smoothing, however, reduces this improvement in measured contrast, thereby reducing the ALROC values for small, high uptake lesions.

Objectives: The study compared the diagnostic performance of Planar Ventilation/perfusion (V/Q) and V/Q Single-photon computed tomography (SPECT), and determined whether combining perfusion scanning with low-dose computed tomography (Q-LDCT) may be equally effective in a prospective study of patients with chronic thromboembolic pulmonary hypertension (CTEPH) patients. Background: V/Q scanning is recommended for excluding CTEPH during the diagnosis of pulmonary hypertension (PH). However, Planar V/Q and V/Q SPECT techniques have yet to be compared in patients with CTEPH. Methods: Patients with suspected PH were eligible for the study. PH attributable to left heart disease or lung disease was excluded, and patients whose PH was confirmed by right heart catheterization and who completed Planar V/Q, V/Q-SPECT, Q-LDCT, and pulmonary angiography were included. V/Q images were interpreted and patients were diagnosed as instructed by the 2009 EANM guidelines, and pulmonary angiography analyses were used as a reference standard. Results: A total of 208 patients completed the study, including 69 with CTEPH confirmed by pulmonary angiography. Planar V/Q, V/Q-SPECT, and Q-LDCT were all highly effective for diagnosing CTEPH, with no significant differences in sensitivity or specificity observed among the three techniques (Planar V/Q [sensitivity/specificity]: 94.20%/92.81%; V/Q-SPECT: 97.10%/91.37%, Q-LCDT: 95.65%/90.65%). However, V/Q-SPECT was significantly more sensitive (V/Q-SPECT: 79.21%; Planar V/Q: 75.84%, P = 0.012; Q-LDCT: 74.91%, p<0.001), and Planar V/Q was significantly more specific (Planar V/Q: 54.14%; V/Q-SPECT 46.05%, p<0.001; Q-LDCT: 46.05%, P = 0.001) than the other two techniques for identifying perfusion defects in individual lung segments. Conclusion: Both Planar V/Q and V/Q-SPECT were highly effective for diagnosing CTEPH, and Q-LDCT may be a reliable alternative method for patients who are unsuitable for ventilation imaging.

Bone metastases are common, especially in more prevalent malignancies such as breast and prostate cancer. They cause significant morbidity and draw on healthcare resources. Molecular and hybrid imaging techniques, including single photon emission computed tomography with computed tomography (SPECT/CT), positron emission tomography / CT and whole-body MRI with diffusion-weighted imaging (WB-MRI), have improved diagnostic accuracy in staging the skeleton compared to previous standard imaging methods, allowing earlier tailored treatment. With the introduction of several effective treatment options, it is now even more important to detect and monitor response in bone metastases accurately. Conventional imaging, including radiographs, CT, MRI and bone scintigraphy, are recognized as being insensitive and non-specific for response monitoring in a clinically relevant time frame. Early reports of molecular and hybrid imaging techniques, as well as WB-MRI, promise earlier and more accurate prediction of response vs non-response but have yet to be adopted routinely in clinical practice. We summarize the role of new molecular and hybrid imaging methods including SPECT/CT, PET/CT and WB-MRI. These modalities are associated with improvements in diagnostic accuracy for staging and response assessment of skeletal metastases over standard imaging methods, being able to quantify biological processes related to the bone microenvironment as well as tumor cells. The described improvements in the imaging of bone metastases and their response to therapy have led to some being adopted into routine clinical practice in some centers and at the same time provide better methods to assess treatment response of bone metastases in clinical trials.

Rationale: Neuroinflammation has been implicated in Amyotrophic Lateral Sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, some challenges have to be overcome. We aimed to investigate whether multicenter data pooling of different TSPO tracers (¹¹C-PBR28 and ¹⁸F-DPA714) is feasible, after validation of an established ¹¹C-PBR28 PET pseudoreference analysis technique for ¹⁸F-DPA714. Methods: 7 ALS-Belgium (58.9±6.7 years,5M) and 8 HV-Belgium (52.1±15.2 years,3M); and 7 ALS-US (53.4±9.8 years,5M) and 7 HV-US (54.6±9.6 years,4M) from a previously published study (1) underwent dynamic ¹⁸F-DPA714 (Leuven, Belgium) or ¹¹C-PBR28 (Boston, US) PET-MR scans. For ¹⁸F-DPA714, volume of distribution (VT) maps were compared to standardized uptake value ratios (SUVR)40-60 calculated using the pseudoreference regions (1)cerebellum, (2)occipital cortex, and (3)whole brain without ventricles (WB-ventricles). Also for ¹¹C-PBR28, SUVR60-90 using WB-ventricles were calculated. Results: In line with previous studies, increased ¹⁸F-DPA714 uptake (17.0±5.6%) in primary motor cortices was observed in ALS, as measured by both VT and SUVR40-60 approaches. Highest sensitivity was found for SUVRWB-ventricles (average cluster 21.6±0.1%). ¹⁸F-DPA714 VT ratio and SUVR40-60 results were highly correlated (r>0.8, p<0.001). A similar pattern of increased uptake (average cluster 20.5±0.5%) in primary motor cortices was observed in ALS with ¹¹C-PBR28 using the SUVRWB-ventricles. Analysis of the ¹⁸F-DPA714 and ¹¹C-PBR28 data together, resulted in a more extensive pattern of significant increased glial activation in the bilateral primary motor cortices. Conclusion: The same pseudoreference region analysis technique for ¹¹C-PBR28 PET imaging can be extended towards ¹⁸F-DPA714 PET. Therefore, in ALS, standardized analysis across these two tracers enables pooling of TSPO PET data across multiple centers and increase power of TSPO as biomarker for future therapeutic trials.

Cancer Survival is related to tumor volume. FDG PET measurement of tumor volume holds promise but is not yet a clinical tool. Measurements come in two forms: the total lesion volume (TLV) based on the number of voxels in the tumor and secondly the total lesion glycolysis (TLG) which is the TLV multiplied by the average SUL per voxel of the tumor (SUL is the standardize uptake value normalized for lean mass). In this study we measured tumor volume in patients with malignant pleural mesothelioma (MPM). METHODS: A threshold-based program in IDL was developed to measure tumor volume in FDG PET images. 19 patients with malignant pleural mesothelioma (MPM) were studied before and after two cycles (6 weeks) of chemo-immunotherapy. Measurements included the total lesion volume (TLV), Total Lesion Glycolysis (TLG), the sum of the SULs in the tumor (SUL- total), a measure of total FDG uptake, and the average SUL per voxel. RESULTS: Baseline MPM volumes (TLV) ranged from 11 to 2610 cc. TLG values ranged from 32 to 8552 SUL-cc and were strongly correlated with TLV. While tumor volumes ranged over 3 orders of magnitude, the average SUL per voxel, SUL-average, stayed within a narrow range of 2.4 to 5.3 units. Thus, TLV was the major component of TLG while SUL-average was a minor component and was essentially constant. Further evaluation of SUL-average showed that in this cohort it’s two components SUL-total and tumor volume changed in parallel and were strongly correlated, r= 0.99, p<.01. Thus, whether the tumors were large or small, the FDG uptake as measured by SUL-total was proportional to the total tumor volume. Conclusion: TLG equals TLV multiplied by the average SUL per voxel, essentially TLV multiplied by a constant. Thus TLG, commonly considered a measure of "metabolic activity" in tumors, is also in this cohort a measure of tumor volume. The constancy of SUL per voxel is due to FDG uptake being proportional to tumor volume. Thus, in this study, the FDG uptake was also a measure of volume.

Rationale: Currently available imaging techniques have limited specificity for the detection of active myocardial inflammation. Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-N,N',N''-triacetic acid conjugated folate (¹⁸F-FOL) is a positron emission tomography (PET) tracer targeting folate receptor β (FR-β) that is expressed on activated macrophages at sites of inflammation. We evaluated ¹⁸F-FOL PET for the detection of myocardial inflammation in rats with autoimmune myocarditis and studied expression of FR-β in human cardiac sarcoidosis specimens. Methods: Myocarditis was induced by immunizing rats (n = 18) with porcine cardiac myosin in complete Freund’s adjuvant. Control rats (n = 6) were injected with Freund’s adjuvant alone. ¹⁸F-FOL was intravenously injected followed by imaging with a small animal PET/computed tomography (CT) scanner and autoradiography. Contrast-enhanced high-resolution CT or 2-deoxy-2-¹⁸F-fluoro-D-glucose (¹⁸F-FDG) PET images were used for co-registration. Rat tissue sections and myocardial autopsy samples of 6 patients with cardiac sarcoidosis were studied for macrophages and FR-β. Results: The myocardium of 10 out of 18 immunized rats showed focal macrophage-rich inflammatory lesions with FR-β expression occurring mainly in M1-polarized macrophages. PET images showed focal myocardial ¹⁸F-FOL uptake co-localizing with inflammatory lesions (SUVmean, 2.1 ± 1.1), whereas uptake in the remote myocardium of immunized rats and controls was low (SUVmean, 0.4 ± 0.2 and 0.4 ± 0.1, respectively; P < 0.01). Ex vivo autoradiography of tissue sections confirmed uptake of ¹⁸F-FOL in myocardial inflammatory lesions. Uptake of ¹⁸F-FOL to inflamed myocardium was efficiently blocked by a non-labeled FR-β ligand folate glucosamine in vivo. The myocardium of patients with cardiac sarcoidosis showed many FR-β-positive macrophages in inflammatory lesions. Conclusion: In a rat model of autoimmune myocarditis, ¹⁸F-FOL shows specific uptake in inflamed myocardium containing macrophages expressing FR-β, which were also present in human cardiac sarcoid lesions. Imaging of FR-β expression is a potential approach for the detection of active myocardial inflammation.

BiTE® (Bispecific T-cell engager) molecules are designed to engage and activate cytotoxic T-cells to kill tumor cells. Little is known about their biodistribution in immunocompetent settings. To explore their pharmacokinetics and the role of the immune cells, BiTE molecules were radiolabeled with positron emission tomography (PET) isotope zirconium-89 (89Zr) and studied in immunocompetent and immunodeficient mouse models. PET images and ex-vivo biodistribution in immunocompetent mice with 89Zr-muS110, targeting mouse CD3 (Kd = 2.9 nM) and mouse EpCAM (Kd = 21 nM), and 89Zr-hyS110, targeting only mouse CD3 (Kd = 2.9 nM), showed uptake in tumor, spleen and other lymphoid organs, while the human-specific control BiTE 89Zr-AMG 110 showed similar tumor uptake but lacked spleen uptake. 89Zr-muS110 spleen uptake was lower in immunodeficient than in immunocompetent mice. After repeated administration of non-radiolabeled muS110 to immunocompetent mice 89Zr-muS110 uptake in spleen, and other lymphoid tissues, decreased and was comparable to uptake in immunodeficient mice, indicating saturation of CD3 binding sites. Autoradiography and immunohistochemistry demonstrated colocalization of 89Zr-muS110 and 89Zr-hyS110 with CD3-positive T-cells in the tumor and spleen but not with EpCAM expression. Also, uptake in the duodenum correlated with a high incidence of T-cells. This study shows that in immunocompetent mice the BiTE 89Zr-muS110 distribution is predominantly based on its high affinity CD3 binding arm. Significance: 89Zr-muS110 biodistribution is mainly dependent on the T-cell targeting arm with limited contribution of its second arm, targeting EpCAM. These findings highlight the need for extensive biodistribution studies of novel bispecific constructs as results might have implications for their respective drug development and clinical translation.

McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3', 5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS, but not in humans with fibrous dysplasia. Positron emission tomography (PET) imaging of PDE4 with ¹¹C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods: ¹¹C-(R)-rolipram whole-body and brain PET scans were performed in six individuals with MAS (three for brain scans and six for whole-body scans) and nine healthy controls (seven for brain scans and six for whole-body scans). Results: ¹¹C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in ¹¹C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected, which could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with ¹¹C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.

Multidrug resistance-associated protein 1 (ABCC1) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. Aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-¹¹C-methylpurine (¹¹C-BMP), a prodrug radiotracer which is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-¹¹C-methylpurinyl))glutathione (¹¹C-MPG). Methods: Groups of Abcc1(-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571 and wild-type control rats underwent dynamic PET scans after administration of ¹¹C-BMP intravenously (i.v.) or by intratracheal aerosolization (i.t.). In vitro transport experiments were performed with unlabeled BMP in the human distal lung epithelial cell line NCI-H441. Results: Pulmonary kinetics of radioactivity were significantly different between wild-type and Abcc1(-/-) rats, but differences were more pronounced after i.t. than after i.v. administration. After i.v. administration lung exposure (AUClung) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower, whereas after i.t. administration AUClung was 352% higher and kE,lung was 86% lower in Abcc1(-/-) rats. Pretreatment with MK571 decreased kE,lung by 20% after i.t. radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in presence than in absence of MK571. Conclusion: PET with pulmonary administered ¹¹C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms or concomitant drug intake on pulmonary ABCC1 activity.

Radionuclide imaging of myocardial perfusion, function, and viability has been established for decades and remains a robust, evidence-based and broadly available means for clinical workup and therapeutic guidance in ischemic heart disease. Yet, powerful alternative modalities have emerged for this purpose, and their growth has resulted in increasing competition. But the potential of the tracer principle goes beyond the assessment of physiology and function, towards the interrogation of biology and molecular pathways. This is a unique selling point of radionuclide imaging, which has been under-recognized in cardiovascular medicine until recently. Now, molecular imaging methods for the detection of myocardial infiltration, device infection and cardiovascular inflammation are successfully gaining clinical acceptance. This is further strengthened by the symbiotic quest of cardiac imaging and therapy for an increasing implementation of molecular-targeted procedures, where specific therapeutic interventions require specific diagnostic guidance towards the most suitable candidates. This review will summarize the current advent of clinical cardiovascular molecular imaging and highlight its transformative contribution to the evolution of cardiovascular therapy beyond mechanical interventions and broad "blockbuster" medication, towards a future of novel, individualized molecular targeted and molecular imaging-guided therapies.

Introduction: Gastrin Releasing peptide receptors (GRPRs) are potential molecular imaging targets in a variety of tumors. Recently, a ⁶⁸Ga-labelled antagonist to GRPRs, NeoBOMB1, was developed for PET. We report on the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) within the EU-FP7 project Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with Metastatic Gastrointestinal Stromal Tumours (‘MITIGATE’) (grant agreement number 602306) in patients with oligometastatic gastrointestinal stromal tumors (GIST). Materials and Methods: The main objectives were evaluation of safety, biodistribution, dosimetry and preliminary tumor targeting of ⁶⁸Ga-NeoBOMB1 in patients with advanced TKI-treated GIST using PET/CT. Six patients with histologically confirmed GIST and unresectable primary or metastases undergoing an extended protocol for detailed pharmacokinetic analysis were included. ⁶⁸Ga-NeoBOMB1 was prepared using a kit procedure with a licensed ⁶⁸Ge/⁶⁸Ga generator. 3 MBq/kg body-weight were injected intravenously and safety parameters were assessed. PET/CT included dynamic imaging at 5 min, 11 min and 19 min as well as static imaging at 1, 2 and 3-4 h p.i. for dosimetry calculations. Venous blood samples and urine were collected for pharmacokinetics. Tumor targeting was assessed on a per-lesion and per-patient basis. Results: ⁶⁸Ga-NeoBOMB1 (50 µg) was prepared with high radiochemical purity (yield >97%). Patients received 174 ± 28 MBq of the radiotracer, which was well tolerated in all patients over a follow-up period of 4 weeks. Dosimetry calculations revealed a mean adsorbed effective dose of 0.029 ± 0.06 mSv/MBq with highest organ dose to the pancreas (0.274 ± 0.099 mSv/MBq). Mean plasma half-life was 27.3 min with primarily renal clearance (mean 25.7 ± 5.4% of injected dose 4h p.i.). Plasma metabolite analyses revealed high stability, metabolites were only detected in the urine. In three patients a significant uptake with increasing maximum standard uptake values (SUV_max at 2h p.i.: 4.3 to 25.9) over time was found in tumor lesions. Conclusion: This Phase I/IIa study provides safety data for ⁶⁸Ga-NeoBOMB1, a promising radiopharmaceutical for targeting GRPR-expressing tumors. Safety profiles and pharmacokinetics are suitable for PET imaging and absorbed dose estimates are comparable to other ⁶⁸Ga-labelled radiopharmaceuticals used in clinical routine.

C-X-C chemokine receptor 4 is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. Magnetic resonance imaging (MRI) is the standard imaging technology for central nervous system involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. Methods: In this proof-of-concept study, 11 patients with lymphoma of the CNS (CNSL, n = 8 primary and n = 3 secondary involvement) were imaged with the CXCR4-directed positron emission tomography (PET) tracer ⁶⁸Ga-Pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by ⁶⁸Ga-Pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. Results: ⁶⁸Ga-Pentixafor-PET showed excellent contrast characteristics to the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. Conclusion: ⁶⁸Ga-Pentixafor-PET represents a novel diagnostic tool for central nervous system lymphoma with potential implications for theranostic approaches as well as response and risk assessment.

Fibroblast activation protein (FAP) has emerged as an interesting molecular target used in the imaging and therapy of various types of cancers. Gallium-68–labeled chelator-linked FAP inhibitors (FAPIs) have been successfully applied to positron emission tomography (PET) imaging of various tumor types. To broaden the spectrum of applicable PET tracers for extended imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of an ¹⁸F–labeled glycosylated FAP inhibitor ([¹⁸F]FGlc-FAPI). Methods: An alkyne-bearing precursor was synthesized and subjected to click chemistry–based radiosynthesis of [¹⁸F]FGlc-FAPI by two-step ¹⁸F-fluoroglycosylation. FAP-expressing HT1080hFAP cells were used to study competitive binding to FAP, cellular uptake, internalization, and efflux of [¹⁸F]FGlc-FAPI in vitro. Biodistribution studies and in vivo small animal PET studies of [¹⁸F]FGlc-FAPI compared to [⁶⁸Ga]Ga-FAPI-04 were conducted in nude mice bearing HT1080hFAP tumors or U87MG xenografts. Results: [¹⁸F]FGlc-FAPI was synthesized with a 15% radioactivity yield and a high radiochemical purity of >99%. In HT1080hFAP cells, [¹⁸F]FGlc-FAPI showed specific uptake, a high internalized fraction, and low cellular efflux. Compared to FAPI-04 (IC50 = 32 nM), the glycoconjugate, FGlc-FAPI (IC50 = 167 nM), showed slightly lower affinity for FAP in vitro, while plasma protein binding was higher for [¹⁸F]FGlc-FAPI. Biodistribution studies revealed significant hepatobiliary excretion of [¹⁸F]FGlc-FAPI; however, small animal PET studies in HT1080hFAP xenografts showed higher specific tumor uptake of [¹⁸F]FGlc-FAPI (4.5 % injected dose per gram of tissue [ID/g]) compared to [⁶⁸Ga]Ga-FAPI-04 (2 %ID/g). In U87MG tumor–bearing mice, both tracers showed similar tumor uptake, but [¹⁸F]FGlc-FAPI showed a higher tumor retention. Interestingly, [¹⁸F]FGlc-FAPI demonstrated high specific uptake in bone structures and joints. Conclusion: [¹⁸F]FGlc-FAPI is an interesting candidate for translation to the clinic, taking advantage of the longer half-life and physical imaging properties of F-18. The availability of [¹⁸F]FGlc-FAPI may allow extended PET studies of FAP-related diseases, such as cancer, but also arthritis, heart diseases, or pulmonary fibrosis.

Purpose: We aimed to conduct a systematic review and meta-analysis of studies reporting the performance of radioactive iodine therapy (131-I therapy) in differentiating thyroid cancer (DTC) patients requiring a completion treatment following lobectomy. We also evaluated the response to 131-I therapy according to 2015ATA guidelines and the adverse events. Methods: A specific search strategy was designed to find articles evaluating the use of I-131 in patients with evidence of DTC after lobectomy. PubMed, CENTRAL, Scopus and Web of Science were searched. The search was updated until January 2020, without language restriction. Data were cross-checked and any discrepancy discussed. A proportion meta-analysis (with 95%CI) was performed using the random-effects model. Meta-regressions on I-131 success were attempted. Results: The pooled success ablation rate was 69% with better results in patients receiving a single administration of about 3.7 GBq; high heterogeneity was found (I2 85%), and publication bias was absent (Egger test: P = 0.57). Incomplete structural responses were recorded in only 14 of 695 (2%) patients enrolled in our analysis. Incomplete biochemical responses were observed in 8 to 24% of patients, with higher rates (24%) in patients receiving low radioiodine activities (~1.1 GBq) and lower rates (from 8 to 18%) in patients receiving higher activities of radioiodine (~3.7 Gbq). Neck pain due to thyroiditis was reported in up to 18% of patients but, in most cases, symptoms resolved after oral paracetamol or a short course of prednisone. Conclusion: Lobar ablation with 131-I is effective especially when high ¹³¹I activities are used. However, the rate of incomplete biochemical response to initial treatment appears to be slightly higher than the classical scheme of initial treatment of DTC. "Radioisotopic lobectomy" should be considered for patients with low-to-intermediate risk DTC requiring completion treatment after lobectomy due to specific individual risk factors and/or patient’s preferences.

The purpose of this study was to establish the dose-response relationship of selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer (mCRC), when informed by radiobiological sensitivity parameters derived from mCRC cell lines exposed to yttrium-90 (⁹⁰Y). Methods: 23 mCRC patients with liver metastases refractory to chemotherapy were included. ⁹⁰Y bremsstrahlung SPECT images were transformed into dose maps assuming the local dose deposition method. Baseline and follow-up CT scans were segmented to derive liver and tumor volumes. Mean, median, and D₇₀ (minimum dose to 70% of tumor volume) values determined from dose maps were correlated with change in tumor volume and vRECIST response using linear and logistic regression, respectively. Radiosensitivity parameters determined by clonogenic assays of mCRC cell lines HT-29 and DLD-1 after exposure to ⁹⁰Y or external beam radiotherapy (EBRT; 6MV photons) were used in biological effective dose (BED) calculations. Results: Mean administered radioactivity was 1469±428 MBq (847-2185 MBq), achieving a mean radiation absorbed tumor dose of 35.5±9.4 Gy and mean normal liver dose of 26.4±6.8 Gy. A 1.0 Gy increase in mean, median, and D₇₀ absorbed dose was associated with reduction in tumor volume of 1.8%, 1.8%, and 1.5%, respectively, and increased probability of vRECIST response (odds ratio: 1.09, 1.09, and 1.10 respectively). Threshold mean, median and D₇₀ doses for response were 48.3, 48.8, and 41.8 Gy respectively. EBRT-equivalent BEDs for ⁹⁰Y are up to 50% smaller than those calculated by applying protraction-corrected radiobiological parameters derived from EBRT alone. Conclusion: Dosimetric studies have assumed equivalence between ⁹⁰Y SIRT and EBRT, leading to inflation of BED for SIRT and possible under-treatment. Radiobiological parameters for ⁹⁰Y were applied to a BED model, providing a calculation method that has the potential to improve assessment of tumor control.

Background: Functional magnetic resonance imaging (fMRI) studies have reported altered integrity of large-scale neurocognitive networks (NCNs) in dementing disorders. However, findings on specificity of these alterations in patients with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are still very limited. Recently, NCNs have been successfully captured using positron emission tomography (PET) with F18-fluordesoxyglucose (FDG). Methods: Network integrity was measured in 72 individuals (38 male) with mild AD, bvFTD, and healthy controls using a simultaneous resting state fMRI and FDG-PET. Indices of network integrity were calculated for each subject, network, and imaging modality. Results: In either modality, independent component analysis revealed four major NCNs: anterior default mode network (DMN), posterior DMN, salience network, and right central executive network (CEN). In fMRI data, integrity of posterior DMN was found to be significantly reduced in both patient groups relative to controls. In the AD group anterior DMN and CEN appeared to be additionally affected. In PET data, only integrity of posterior DMN in patients with AD was reduced, while three remaining networks appeared to be affected only in patients with bvFTD. In a logistic regression analysis, integrity of anterior DMN as measured with PET alone accurately differentiated between the patient groups. A correlation between indices of two imaging modalities was overall low. Conclusion: FMRI and FDG-PET capture partly different aspects of network integrity. A higher disease specificity of NCNs as derived from PET data supports metabolic connectivity imaging as a promising diagnostic tool.

It was hypothesized that the brain β-amyloid buildup curve plateaus at an early symptomatic Alzheimer's disease (AD) stage. Atrophy-related partial volume effects (PVEs) degrade signal in hot-spot imaging techniques, such as amyloid positron emission tomography (PET). This longitudinal analysis of amyloid-sensitive PET data investigated the shape of the β-amyloid curve in AD applying PVE correction (PVEC). We analyzed baseline and 2-year follow-up data of 216 symptomatic individuals on the AD continuum (positive amyloid status) enrolled in Alzheimer's Disease Neuroimaging Initiative (17 AD dementia, 199 mild cognitive impairment), including 18F-florbetapir PET, magnetic resonance imaging and mini mental state examination (MMSE) scores. For PVEC, the modified Müller-Gärtner method was performed. Compared to non-PVE-corrected data, PVE-corrected data yielded significantly higher regional and composite standardized uptake value ratio (SUVR) changes over time (P=0.0002 for composite SUVRs). Longitudinal SUVR changes in relation to MMSE decreases showed a significantly higher slope of the regression line in the PVE-corrected as compared to the non-PVE-corrected PET data (F=7.1, P=0.008). These PVEC results indicate that the β-amyloid buildup curve does not plateau at an early symptomatic disease stage. A further evaluation of the impact of PVEC on the in-vivo characterization of time-dependent AD pathology, including the reliable assessment and comparison of other amyloid tracers, is warranted.

¹⁸F-BMS-986192, an adnectin-based human programmed cell death ligand 1 (PD-L1) tracer, was developed to non-invasively determine whole-body PD-L1 expression by positron emission tomography (PET). We evaluated usability of ¹⁸F-BMS-986192 PET to detect different PD-L1 expression levels and therapy-induced changes of PD-L1 expression in tumors. Methods: In vitro binding assays with ¹⁸F-BMS-986192 were performed in human tumor cell lines with different total cellular and membrane PD-L1 protein expression levels. Subsequently, PET imaging was executed in immunodeficient mice xenografted with these cell lines. Mice were treated with interferon gamma (IFN) intraperitoneally for 3 days or with the mitogen-activated protein kinase kinase (MEK1/2) inhibitor selumetinib by oral gavage for 24 hours. Thereafter ¹⁸F-BMS-986192 was administered intravenously, followed by a 60-minute dynamic PET scan. Tracer uptake was expressed as percentage injected dose per gram tissue (%ID/g). Tissues were collected to evaluate ex vivo tracer biodistribution and to perform flow cytometric, Western blot, and immunohistochemical tumor analyses. Results: ¹⁸F-BMS-986192 uptake reflected PD-L1 membrane levels in tumor cell lines, and tumor tracer uptake in mice was associated with PD-L1 expression measured immunohistochemically. In vitro IFN treatment increased PD-L1 expression in the tumor cell lines and caused up to 12-fold increase in tracer binding. In vivo, IFN did neither affect PD-L1 tumor expression measured immunohistochemically nor ¹⁸F-BMS-986192 tumor uptake. In vitro, selumetinib downregulated cellular and membrane levels of PD-L1 of tumor cells by 50% as measured by Western blotting and flow cytometry. In mice, selumetinib lowered cellular, but not membrane PD-L1 levels of tumors and consequently no treatment-induced change in ¹⁸F-BMS-986192 tumor uptake was observed. Conclusion: ¹⁸F-BMS-986192 PET imaging allows detection of membrane-expressed PD-L1, as soon as 60 minutes after tracer injection. The tracer can discriminate a range of tumor cell PD-L1 membrane expression levels.

In randomized clinical trials (RCTs), no survival benefit has been observed for selective internal radiotherapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to assess by means of a meta-analysis whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is non-inferior to sorafenib, and compare safety profiles for patients with aHCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify RCTs comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with aHCC. The main outcomes were OS and frequency of treatment-related severe adverse events (AEs grade ≥3). The per-protocol population was the primary analysis population. A non-inferiority margin of 1.08 in terms of hazard ratio (HR) was pre-specified for the upper boundary of 95% confidence interval (CI) for OS. Pre-specified subgroup analyses were performed. Results: Three RCTs, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411/635 (64.7%) patients allocated to SIRT and 522/608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was non-inferior to sorafenib (10.2 and 9.2 months, [HR 0.91, 95% CI 0.78–1.05]). Treatment-related severe adverse events were reported in 149/515 patients (28.9%) who received SIRT and 249/575 (43.3%) who received sorafenib only (p<0.01). Conclusion: SIRT as initial therapy for aHCC is non-inferior to sorafenib in terms of OS, and offers a better safety profile.

Introduction: Prostate-specific membrane antigen ligand positron emission tomography (PSMA PET) induces management changes in patients with prostate cancer. We aim to better characterize the impact of PSMA PET on management of recurrent prostate cancer in a large prospective cohort. Methods: We report management changes following PSMA PET, a secondary endpoint of a prospective multicenter trial in men with prostate cancer biochemical recurrence. Pre-PET (Q1), Post-PET (Q2) and Post-Treatment (Q3) questionnaires were sent to referring physicians recording site of recurrence, intended (Q1 to Q2 change) and implemented (Q3) therapeutic and diagnostic management. Results: Q1/Q2 response was collected for 382/635 (60%, intended cohort), Q1/Q2/Q3 for 206 patients (32%, implemented cohort). Intended management change (Q1/2) occurred in 260/382 (68%) patients. Intended change (Q1/2) was considered major in 176/382 (46%) patients. Major changes occurred most often for patients with PSA of 0.5 to <2.0 ng/mL (81/147, 55%). By analysis of stage-groups, management change was consistent with PET disease location, i.e. majority of major changes towards active surveillance (47%) for unknown disease site (103/382, 27%), towards local/focal therapy (56%) for locoregional disease (126/382, 33%), and towards systemic therapy (69% M1a; 43% M1b/c) for metastatic disease (153/382, 40%). According to Q3 responses, intended management was implemented in 160/206 (78%) patients. A total of 150 intended diagnostic tests, mostly CT (n = 43, 29%) and bone Scans/NaF-PET (n = 52, 35%), were prevented by PSMA PET; 73 tests, mostly biopsies (n = 44, 60%) as requested by the study protocol, were triggered (Q1/2). Conclusion: According to referring physicians, sites of recurrence were clarified by PSMA PET and disease localization translated into management changes in more than half of patients with biochemical recurrence of prostate cancer.

Treatment of hyperinsulinemic hypoglycemia is challenging. Surgical treatment of insulinomas and focal lesions in congenital hyperinsulinism (CHI) is invasive and carries major risks of morbidity. Medication to treat nesidioblastosis and diffuse CHI has varying efficacy and causes significant side effects. Here, we describe a novel method for therapy of hyperinsulinemic hyperglycemia, highly selectively killing beta cells by targeted photodynamic therapy (tPDT) with exendin-4-IRDye700DX, targeting the glucagon-like peptide 1 receptor (GLP-1R). A competitive binding assay was performed using Chinese hamster lung (CHL) cells transfected with the GLP-1R. The efficacy and specificity of tPDT with exendin-4-IRDye700DX was examined in vitro in cells with different levels of GLP-1R expression. Tracer biodistribution was determined in BALB/c nude mice bearing subcutaneous CHL-GLP-1R xenografts. Induction of cellular damage and the effect on tumor growth were analyzed to determine treatment efficacy. Exendin-4-IRDye700DX has a high affinity for the GLP-1R with an IC50 value of 6.3 nM. TPDT caused significant specific phototoxicity in GLP-1R positive cells (2.3 ± 0.8 % and 2.7 ± 0.3 % remaining cell viability in CHL-GLP-1R and INS-1 cells resp.). The tracer accumulates dose-dependently in GLP-1R positive tumors. In vivo tPDT induces cellular damage in tumors, shown by strong expression of cleaved-caspase-3 and leads to a prolonged median survival of the mice (36.5 vs. 22.5 days resp. p<0.05). These data show in vitro as well as in vivo evidence for the potency of tPDT using exendin-4-IRDye700DX. This could in the future provide a new, minimally invasive and highly specific treatment method for hyperinsulinemic hypoglycemia.

Rationale: To conduct a retrospective study comparing three ¹²³I-FP-CIT-SPECT quantitative methods in patients with neurodegenerative syndromes as referenced to neuropathological findings. Methods: ¹²³I-FP-CIT-SPECT and neuropathological findings among patients with neurodegenerative syndromes from the Mayo Alzheimer's Disease Research Center and Mayo Clinic Study of Aging were examined. Three ¹²³I-FP-CIT-SPECT quantitative assessment Methods: MIMneuro (MIM Software Inc.), DaTQUANT (GE Healthcare), and manual region of interest (ROI) creation on an Advantage Workstation (GE Healthcare) were compared to neuropathological findings describing the presence or absence of Lewy body disease (LBD). Striatum to background ratios (SBRs) generated by DaTQUANT were compared to the calculated SBRs of the manual method and MIMneuro. The left and right SBRs for caudate, putamen and striatum were evaluated with the manual method. For DaTQUANT and MIMneuro the left, right, total and average SBRs and z-scores for whole striatum, caudate, putamen, anterior putamen, and posterior putamen were calculated. Results: The cohort included 24 patients [20 (83%) male, aged 75.4 +/- 10.0 at death]. The antemortem clinical diagnoses were Alzheimer’s disease dementia (ADem, N = 6), probable dementia with Lewy bodies (pDLB, N = 12), mixed ADem/pDLB (N = 1), Parkinson’s disease with mild cognitive impairment (N = 2), corticobasal syndrome (N = 1), idiopathic rapid eye movement sleep behavior disorder (iRBD) (N = 1) and behavioral variant frontotemporal dementia (N = 1). Seventeen (71%) had LBD pathology. All three ¹²³I-FP-CIT-SPECT quantitative methods had area under the receiver operating characteristics (AUROC) values above 0.93 and up to 1.000 (p<0.001) and showed excellent discrimination between LBD and non-LBD patients in each region assessed, p<.001. There was no significant difference between the accuracy of the regions in discriminating the two groups, with good discrimination for both caudate and putamen. Conclusion: All three ¹²³I-FP-CIT-SPECT quantitative methods showed excellent discrimination between LBD and non-LBD patients in each region assessed, using both SBRs and z-scores.

The value of interim ¹⁸F-fluorodeoxyglucose positron emission tomography (iPET) guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the deltaSUV_max (SUV_max) approach – two methods to assess early metabolic response to standard chemotherapy in DLBCL. Methods: Of 609 DLBCL patients participating in the Positron Emission Tomography-guided Therapy of Aggressive non-Hodgkin Lymphomas (PETAL) trial, iPET scans of 596 patients originally evaluated using the SUV_max method were available for post-hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the SUV_max approach is characterized as a relative reduction of the maximum standardized uptake value between baseline and iPET staging of less than or equal to 66%. We investigated the two methods’ correlation and concordance by Spearman’s rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the pre-specified cut-offs. Time-dependent receiver operating curve analysis provided information on the methods’ respective discrimination performance. Results: Deauville score and SUV_max approach differed in their iPET-based prognosis. The SUV_max approach outperformed the Deauville score in terms of discrimination performance – most likely due to a high number of false-positive decisions by the Deauville score. Cut-off-independent discrimination performance remained low for both methods, but cut-off-related analyses showed promising results. Both favored the SUV_max approach, e.g. for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval (CI): 2.22 – 4.46) for SUV_max and 1.70 (95% CI: 1.29 – 2.24) for the Deauville score. Conclusion: When considering treatment intensification, the currently used Deauville score cut-off of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The SUV_max criterion of a relative reduction of the maximum standardized uptake value of less than or equal to 66% should be considered as an alternative.

The prostate-specific membrane antigen (PSMA) is an excellent target for theranostic applications in prostate cancer (PCa). However, PSMA-targeted radioligand therapy can cause undesirable effects due to high accumulation of PSMA radiotracers in salivary glands and kidneys. This study assessed orally administered monosodium glutamate (MSG) as a potential means of reducing kidney and salivary gland radiation exposure using a PSMA targeting radiotracer. Methods: This prospective, double-blind, placebo-controlled study enrolled 10 biochemically recurrent PCa patients. Each subject served as his own control. [¹⁸F]DCFPyl PET/CT imaging sessions were performed 3 – 7 days apart, following oral administration of either 12.7 g of MSG or placebo. Data from the two sets of images were analyzed by placing regions of interest on lacrimal, parotid and submandibular glands, left ventricle, liver, spleen, kidneys, bowel, urinary bladder, gluteus muscle and malignant lesions. The results from MSG and placebo scans were compared by paired analysis of the ROI data. Results: A total of 142 pathological lesions along with normal tissues were analyzed. As hypothesized a priori, there was a significant decrease in maximal standardized uptake values corrected for lean body mass (SULmax) on images obtained following MSG administration in the parotids (24 ± 14%, P = 0.001), submandibular glands (35 ± 11%, P<0.001) and kidneys (23 ± 26%, P = 0.014). Significant decreases were also observed in lacrimal glands (49 ± 13%, P<0.001), liver (15 ± 6%, P<0.001), spleen (28 ± 13%, P = 0.001) and bowel (44 ± 13%, P<0.001). Mildly lower blood pool SULmean was observed after MSG administration (decrease of 11 ± 13%, P = 0.021). However, significantly lower radiotracer uptake in terms of SULmean, SULpeak, and SULmax was observed in malignant lesions on scans performed after MSG administration compared to the placebo studies (SULmax median decrease 33%, range -1 to 75%, P<0.001). No significant adverse events occurred and vital signs were stable following placebo or MSG administration. Conclusion: Orally administered MSG significantly decreased salivary gland, kidney and other normal organ PSMA radiotracer uptake in human subjects, using [¹⁸F]DCFPyL as an exemplar. However, MSG caused a corresponding reduction in tumor uptake, which may limit the benefits of this approach for diagnostic and therapeutic applications.

Research Event

Event participants

Louise Mushikiwabo, Secretary General, Organisation Internationale de la Francophonie (OIF)
Chair: Bob Dewar CMG, Associate Fellow, Africa Programme, Chatham House