Dorte B. Bekker-Jensen
Apr 1, 2020; 19:716-729
Technological Innovation and Resources

Payman Samavarchi-Tehrani
May 1, 2020; 19:757-773
Review

By Lucy Martinez and Eduardo Torres Davila We attended the Joint Math Meetings (JMM) conference in Denver to present our research from our work at the Mathematical Sciences Research Institute Undergraduate Program. At JMM, there was a fair of graduate … Continue reading →

Invitation Only Research Event

8 April 2020

Background: ⁶⁸Ga PSMA PET CT (PSMA) is increasingly used in men with biochemical recurrence (BCR) post radical prostatectomy (RP), but its longer term prognostic / predictive potential in these men is unknown. The aim of this study was to evaluate the predictive value of PSMA PET for 3 year freedom from progression (FFP) in men with BCR post RP undergoing salvage radiotherapy (sRT). Methods: This prospective multi-center study enrolled 260 men between 2015 and 2017. Eligible patients were referred for PSMA with rising PSA following RP. Management following PSMA was recorded but not mandated. PSMA protocols were standardised across sites and reported prospectively. Clinical, pathological and surgical information, sRT, timing and duration of androgen deprivation (ADT), 3 year PSA results and clinical events were documented. FFP was defined as a PSA rise ≤ 0.2ng/mL above nadir post sRT, with no additional treatment. Results: The median PSA was 0.26ng/mL (IQR 0.15 - 0.59) and follow-up 38 months (IQR 31-43). PSMA was negative in 34.6% (90/260), confined to prostate fossa 21.5% (56/260), pelvic nodes 26.2% (68/260), and distant disease 17.7% (46/260). 71.5% (186/260) received sRT, 38.2% (71/186) to the fossa only, 49.4% (92/186) fossa + pelvic nodes and 12.4% (23/186) nodes alone/SBRT. PSMA was highly predictive of FFP at 3 years following sRT. Overall, FFP was achieved in 64.5% (120/186) of those who received sRT, 81% (81/100) with negative/fossa confined vs. 45% (39/86) for extra fossa disease (p<0.0001). On logistic regression PSMA was more independently predictive of FFP than established clinical predictors, including PSA, T-stage, surgical margin status or Gleason score (P < 0.002). 32% of men with a negative PSMA PET did not receive treatment. Of these, 66% (19/29) progressed, with a mean rise in PSA of 1.59ng/mL over the 3 years. Conclusion: PSMA PET result is highly predictive of FFP at 3 years in men undergoing sRT for BCR following RP. In particular, men with negative PSMA PET or disease identified as still confined to the prostate fossa demonstrate high FFP, despite receiving less extensive radiotherapy and lower rates of additional ADT than those with extra fossa disease.

Purpose: ⁶⁸Ga-DOTA-JR11 is an antagonist for somatostatin receptor used in neuroendocrine imaging. The purpose of this study is to compare ⁶⁸Ga-DOTA-JR11 and ⁶⁸Ga-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. Methods: Patients with histologically-proven, metastatic and/or unresectable, well-differentiated neuroendocrine tumors were prospectively recruited in this study. They received an intravenous injection of ⁶⁸Ga-DOTATATE (4.0 ± 1.3 mCi) on the first day and ⁶⁸Ga-DOTA-JR11 (4.0 ± 1.4 mCi) on the second day. Whole-body PET/CT scans were performed at 40 to 60 minutes after injection on the same scanner. Physiologic uptake of normal organs, lesion numbers, and lesion uptake were compared. Results: Twenty-nine patients were prospectively enrolled in the study. The SUV_max of the spleen, renal cortex, adrenal glands, pituitary glands, stomach wall, normal liver parenchyma, small intestine, pancreas, and bone marrow were significantly lower on ⁶⁸Ga-DOTA-JR11 than on ⁶⁸Ga-DOTATATE PET/CT (P<0.001). ⁶⁸Ga-DOTA-JR11 detected significantly more liver lesions (539 vs. 356, P = 0.002), but fewer bone lesions (156 vs. 374, P = 0.031, Figure 3) than ⁶⁸Ga-DOTATATE. The tumor-to-background ratio of liver lesions was significantly higher on ⁶⁸Ga-DOTA-JR11 (7.6 ± 5.1 vs. 3.4 ± 2.0, P<0.001). ⁶⁸Ga-DOTA-JR11 and ⁶⁸Ga-DOTATATE PET/CT showed comparable results for primary tumors and lymph node metastases based on either patient-based or lesion-based comparison. Conclusion: ⁶⁸Ga-DOTA-JR11 performs better in the detection ability and TBR of liver metastases. However, ⁶⁸Ga-DOTATATE outperforms ⁶⁸Ga-DOTA-JR11 in the detection of bone metastases. The differential affinity of different metastatic sites provides key information for patient selection in imaging and peptide receptor radionuclide therapy.

Rationale: Lymphatic tracers can help visualize the lymphatic drainage patterns and sentinel nodes of individual prostate cancer patients. To determine the role of nuclear medicine, in particular the positional guidance of a SPECT/CT-based 3D imaging roadmap, in this process we studied to which extend fluorescence-guidance underestimated the number of target lesions. Methods: SPECT/CT imaging was performed after intraprostatic tracer administration of either ICG-^99mTc-nanocolloid (hybrid tracer group) or ^99mTc-nanocolloid to create a roadmap that depicted all sentinel nodes (SNs). Patients who received ^99mTc-nanocolloid were injected with "free" ICG immediately prior to surgery ("free" ICG group). Before unblinding, fluorescence-guidance was used for intraoperative SN identification. This was followed by extended pelvic lymph node dissection (ePLND). Following unblinding of the SPECT/CT images, the number of missed SN’s were recorded and their resection was pursued when the anatomy allowed. Results: Preoperative SPECT/CT revealed no differences in the SN identification rate between ICG-^99mTc-nanocolloid and ^99mTc-nanocolloid. However, fluorescence-guidance only allowed intraoperative removal of all SNs in 40% of patients in the hybrid tracer group and in 20% of patients in the "free" ICG group. Overall, 75.9% of the intraoperatively resected SNs in the hybrid tracer group and 51.8% of the SNs in the "free" ICG group were removed solely under fluorescence-guidance. During ePLND 22 additional SNs were resected (7 in the hybrid tracer group and 15 in the "free" ICG group). After unblinding 18 remaining SNs were identified (6 in the hybrid group and 12 in the "free" ICG group). In the "free" ICG group, ex vivo evaluation of the excised specimens revealed that 14 SNs removed under ePLND or after unblinding contained radioactivity but no fluorescence. Conclusion: The preoperative imaging roadmap provided by SPECT/CT enhanced the detection of prostate SNs in more ectopic locations in 17 of the 25 patients and the hybrid tracer ICG-^99mTc-nanocolloid was shown to outperform "free" ICG. Overall, fluorescence-guided pelvic nodal surgery underestimated the number of SNs in 60-80% of patients.

Purpose: The aim of this retrospective multicentric study was to develop and evaluate a prognostic FDG PET/CT radiomics signature in early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic radiotherapy (SBRT). Material and Methods: Patients from 3 different centers (n = 27, 29 and 8) were pooled to constitute the training set, whereas the patients from a fourth center (n = 23) were used as the testing set. The primary endpoint was local control (LC). The primary tumour was semi-automatically delineated in the PET images using the Fuzzy locally adaptive Bayesian algorithm, and manually in the low-dose CT images. A total of 184 IBSI-compliant radiomic features were extracted. Seven clinical and treatment parameters were included. We used ComBat to harmonize radiomic features extracted from the four institutions relying on different PET/CT scanners. In the training set, variables found significant in the univariate analysis were fed into a multivariate regression model and models were built by combining independent prognostic factors. Results: Median follow-up was 21.1 (1.7 – 63.4) and 25.5 (7.7 – 57.8) months in training and testing sets respectively. In univariate analysis, none of the clinical variables, 2 PET and 2 CT features were significantly predictive of LC. The best predictive models in the training set were obtained by combining one feature from PET, namely information correlation 2 (IC2) and one from CT (Flatness), reaching a sensitivity of 100% and a specificity of 96%. Another model combining 2 PET features (IC2 and Strength), reached sensitivity of 100% and specificity of 88%, both with an undefined hazard ratio (HR) (p<0.001). The latter model obtained an accuracy of 0.91 (sensitivity 100%, specificity 81%), with a HR undefined (P = 0.023) in the testing set, however other models relying on CT radiomics features only or the combination of PET and CT features failed to validate in the testing set. Conclusion: We showed that two radiomic features derived from FDG PET were independently associated with LC in patients with NSCLC undergoing SBRT and could be combined in an accurate predictive model. This model could provide local relapse-related information and could be helpful in clinical decision-making.

Calculation of radiation dosimetry in targeted nuclear medicine therapies is traditionally resource-intensive requiring multiple post-therapy SPECT acquisitions. An alternative approach is to take advantage of existing pharmacokinetic data from these smaller cohorts to enable dose computation from a single post-treatment scan in a manner that may be applied to a much broader patient population. Methods: In this work, a technical description for simplified dose estimation is presented and applied to assessment of ¹⁷⁷Lu-PSMA-617 therapy (Prostate-Specific Membrane Antigen) for metastatic prostate cancer. By normalizing existing time-activity curves to a single measurement time, it is possible to calculate a mean and range of time-integrated activity values which relate to radiation absorbed dose. To assist with accurate pharmacokinetic modelling of the training cohort, a method for contour-guided image registration was developed. Results: Tissue-specific dose conversion factors for common post-treatment imaging times are reported along with a characterization of added uncertainty in comparison to a traditional serial imaging protocol. Single time point dose factors for tumor were determined to be 11.0, 12.1, 13.6, and 15.2 Gy per MBq/mL at image times of 24, 48, 72, and 96 hours, respectively. For normal tissues, parotid gland factors were 6.7, 9.4, 13.3, and 19.3 Gy per MBq/mL and kidneys were 7.1, 10.3, 15.0, and 22.0 Gy per MBq/mL at those times. Tumor dose estimates were most accurate using delayed scanning at times beyond 72 hours. Dose to healthy tissues is best characterized by scanning patients in the first two days of treatment owing to the larger degree of tracer clearance in this early phase. Conclusion: The work demonstrates a means for efficient dose estimation in ¹⁷⁷Lu-PSMA-617 therapy. By providing methods to simplify and potentially automate radiation dosimetry we hope to accelerate the understanding of radiobiology and development of dose-response models in this unique therapeutic context.

Background: Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy as they can constitute as much as 90% of tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP-inhibitor PET tracer, ⁶⁸Ga-FAPI-04, has been previously shown to yield high tumor-to-background ratios (TBR) in patients with various cancers. Recent developments towards an improved compound for therapeutic application have identified FAPI-46 as a promising agent due to a longer tumor retention time in comparison with FAPI-04. Here we present a PET biodistribution and radiation dosimetry study of ⁶⁸Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial ⁶⁸Ga-FAPI-46 PET/CT scans at three time points following radiotracer injection: 10 minutes, 1 hour, and 3 hours. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and body remainder. OLINDA/EXM v.1.1 software was used to fit and integrate the kinetic organ activity data to yield total body and organ time-integrated activity coefficients/residence times and finally organ absorbed doses. Standardized uptake values (SUV) and TBR were generated from the contoured tumor and source organ volumes. Spherical volumes in muscle and blood pool were also obtained for TBR (Tumor SUV_max / Organ SUVmean). Results: At all timepoints, the highest organ SUV_max was observed in the liver. Tumor and organ mean SUVs decreased whereas TBRs in all organs but the uterus increased with time. The highest TBRs at 3 hours were observed with the bone marrow (31.1), muscle (22.8), heart (19.1), and spleen (19.0). Organs with the highest effective doses were the bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04mSv/MBq). The average effective total body dose was 7.80E-03 mSv/MBq. Thus for administration of 200 MBq ⁶⁸Ga-FAPI-46 the effective total body dose is 1.56 mSv ± 0.26 mSv, in addition to approximately 3.7 mSv from one low-dose CT scan done for attenuation correction. Conclusion: ⁶⁸Ga-FAPI-46 PET/CT has a favorable dosimetry profile with an estimated whole body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of ⁶⁸Ga-FAPI-46 (1.56± 0.26 mSv from the PET tracer and 3.7 mSv from one low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

Due to improvements in quantitative SPECT/CT, voxel-based dosimetry for radionuclide therapies has aroused growing interest as it promises the visualization of absorbed doses at a voxel level. In this work, SPECT/CT-based voxel-based dosimetry of a 3D printed 2-compartment kidney phantom was performed, and the resulting absorbed dose distributions were examined. Additionally, the potential of the PETPVC partial-volume correction tool was investigated. Methods: Both kidney compartments (70% cortex, 30% medulla) were filled with different activity concentrations and SPECT/CT imaging was performed. The images were reconstructed using varying reconstruction settings (iterations, subsets, and post-filtering). Based on these activity concentration maps, absorbed dose distributions were calculated with pre-calculated ¹⁷⁷Lu voxel S values and an empirical kidney half-life. An additional set of absorbed doses was calculated after applying PETPVC for partial-volume correction of the SPECT reconstructions. Results: SPECT/CT imaging blurs the two discrete sub-organ absorbed dose values into a continuous distribution. While this effect is slightly improved by applying more iterations, it is enhanced by additional post-filtering. By applying PETPVC, the absorbed dose values are separated into 2 peaks. Although this leads to a better agreement between SPECT/CT-based and nominal values, considerable discrepancies remain. In contrast to the calculated nominal absorbed doses of 7.8/1.6 Gy (cortex/medulla), SPECT/CT-based voxel-level dosimetry resulted in mean absorbed doses ranging from 3.0-6.6 Gy (cortex) and 2.7-5.1 Gy (medulla). PETPVC led to improved ranges of 6.1-8.9 Gy (cortex) and 2.1-5.4 Gy (medulla). Conclusion: Our study shows that ¹⁷⁷Lu quantitative SPECT/CT imaging leads to voxel-based dose distributions largely differing from the real organ distribution. SPECT/CT imaging and reconstruction deficiencies might directly translate into unrealistic absorbed dose distributions, thus questioning the reliability of SPECT-based voxel-level dosimetry. Therefore, SPECT/CT reconstructions should be adapted to ensure an accurate quantification of the underlying activity and, therefore, absorbed dose in a volume-of-interest of the expected object size (e.g. organs, organ sub-structures, lesions or voxels). As an example, PETPVC largely improves the match between SPECT/CT-based and nominal dose distributions. In conclusion, the concept of voxel-based dosimetry should be treated with caution. Specifically, it should be kept in mind that the absorbed dose distribution is mainly a convolved version of the underlying SPECT reconstruction.

Prediction of post-operative pulmonary function in lung cancer patients before tumor resection is essential for patient selection for surgery and is conventionally done with a non-imaging segment counting method (SC) or a two-dimensional planar lung perfusion scintigraphy (PS). The purpose of this study was to compare quantitative analysis of PS to single photon emission computed tomography/computed tomography (SPECT/CT) and to estimate the accuracy of SC, PS and SPECT/CT in predicting post-operative pulmonary function in patients undergoing lobectomy. Methods: Seventy-five non-small cell lung cancer (NSCLC) patients planned for lobectomy were prospectively enrolled (68% males, average age 68.1±8 years ). All patients completed pre-operative forced expiratory volume capacity (FEV1), diffusing capacity of the lung for carbon monoxide (DLCO), Tc99m-MAA lung perfusion scintigraphy with PS and SPECT/CT quantification. A subgroup of 60 patients underwent video-assisted thoracoscopic (VATS) lobectomy and measurement of post-operative FEV1 and DLCO. Relative uptake of the lung lobes estimated by PS and SPECT/CT were compared. Predicted post-operative FEV1 and DLCO were derived from SC, PS and SPECT/CT. Prediction results were compared between the different methods and the true post-operative measurements in patients who underwent lobectomy. Results: Relative uptake measurements differed significantly between PS and SPECT/CT in right lung lobes, with a mean difference of -8.2±3.8, 18.0±5.0 and -11.5±6.1 for right upper, middle and lower lobes respectively (p<0.001). The differences between the methods in the left lung lobes were minor with a mean difference of -0.4±4.4 (p>0.05) and -2.0±4.0 (p<0.001) for left upper and lower lobes respectively. No significant difference and strong correlation (R=0.6-0.76, p<0.001) were found between predicted post-operative lung function values according to SC, PS, SPECT/CT and the actual post-operative FEV1 and DLCO. Conclusion: Although lobar quantification parameters differed significantly between PS and SPECT/CT, no significant differences were found between the predicted post-operative lung function results derived from these methods and the actual post-operative results. The additional time and effort of SPECT/CT quantification may not have an added value in patient selection for surgery. SPECT/CT may be advantageous in patients planned for right lobectomies but further research is warranted.

Triple negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer leading to the worst prognosis. Because current therapeutic approaches lack efficacy, there is a clinically unmet need for effective treatment alternatives. Herein, we demonstrate a promising strategy utilizing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with ¹⁷⁷Lu for targeted radionuclide therapy (TRT) of TNBC. In two murine syngeneic models of TNBC, we confirmed excellent tumor targeting and rapid normal tissue clearance of the PET imaging analog ⁸⁶Y-NM600. Based on longitudinal PET/CT data acquired with ⁸⁶Y-NM600, we estimated the dosimetry of therapeutic ¹⁷⁷Lu-NM600, which showed larger absorbed doses in the tumor compared to normal tissues. Administration of ¹⁷⁷Lu-NM600 resulted in significant tumor growth inhibition and prolonged overall survival in mice bearing syngeneic 4T07 and 4T1 tumors. Complete response was attained in 60% of 4T07 bearing mice, but animals carrying aggressive 4T1 tumor grafts succumbed to metastatic progression. The injected activities used for treatment (9.25 and 18.5 MBq) were well tolerated, and only mild transient cytopenia was noted. Overall, our results suggest that ¹⁷⁷Lu-NM600 TRT has potential for treatment of TNBC and merits further exploration in a clinical setting.

Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematological malignancy. Despite new treatments and protocols including high doses chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. Alpha-radioimmunotherapy (alpha-RIT) represents an attractive treatment strategy due to the high linear energy transfer and short path length of alpha-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of alpha-RIT with ²¹²Pb-Daratumumab (anti-CD38), in both in vitro and in vivo models, as well as an anti-mouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of RPMI8226 cell line with increasing activities (0.185-3.7 kBq/ml) of ²¹²Pb-isotypic control or ²¹²Pb-Daratumumab was evaluated. Biodistribution was performed in vivo by SPECT-CT imaging and post-mortem. Dose range finding (DRF) and acute toxicity studies were conducted. As Daratumumab does not bind the murine CD38, biodistribution and DRF were also determined using an anti-murine CD38 antibody. To evaluate in vivo efficacy of ²¹²Pb-Daratumumab, mice were engrafted subcutaneously with 5.106 RPMI8226 cells. Mice were treated 13 days post-engraftment with an intravenous injection of ²¹²Pb-Daratumumab or control solutions. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after three days of incubation with ²¹²Pb-Daratumumab compared to ²¹²Pb-Isotypic Control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of Daratumumab. No toxicity was observed with ²¹²Pb-Daratumumab up to 370 kBq due to the lack of cross-reactivity. Nevertheless, acute toxicity experiments with ²¹²Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of ²¹²Pb-Daratumumab. Marked tumor growth inhibition compared to controls was observed, with a median survival of 55 days for 277.5 kBq of ²¹²Pb-Daratumumab instead of 11 for PBS control groups. Conclusion: These results showed ²¹²Pb-Daratumumab efficacy on xenografted mice with significant tumor regression and increased survival. This study highlights alpha-RIT potency in MM treatment.

[S-Methyl-¹¹C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (¹¹C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within the N-methyl-D-aspartate receptor with positron emission tomography (PET). Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2B specific binding of radioligand in brain, various pre-blocking or displacing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline. ¹¹C-(S)-NR2B-SMe was studied extensively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. High-affinity NR2B ligands, Ro-25-6981, ifenprodil, and CO10124, showed increasing preblock of whole brain radioactivity retention with increasing dose (0.01 to 1.25 mg/kg, i.v.). Five 1 antagonists (FTC146, BD1407, F3, F4, and NE100) and four 1 agonists ((+)-pentazocine, (±)-PPCC, PRE-084, (+)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at high dose. Two potent 1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacological 1 receptor blockade with FTC146. Conclusion: ¹¹C-(S)-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have off-target binding to NR2B in vivo.

Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for positron emission tomography (PET) or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in a number of malignancies including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce ⁸⁹Zr-radiolabeled onartuzumab (a monovalent, anti-human c-MET antibody), starting directly from the fully formulated drug (MetMAb). Methods: Simultaneous ⁸⁹Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing ⁸⁹Zr-oxalate, the photoactive chelate DFO-aryl azide (DFO-ArN3) and MetMAb to give ⁸⁹ZrDFO-azepin-onartuzumab. As a control, ⁸⁹ZrDFO-Bn-NCS-onartuzumab was prepared via a conventional two-step process using pre-purified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0–72 h) was performed in female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image. Tumor specificity of ⁸⁹ZrDFO-azepin-onartuzumab was assessed by competitive inhibition (blocking) studies. Results: Initial photoradiosynthesis experiments produced ⁸⁹ZrDFO-azepin-onartuzumab in <15 min. with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity (RCP) ~90% and a molar activity (Am) of ~1.5 MBq nmol^-1. Reaction optimization improved the radiochemical conversion (RCC) of ⁸⁹ZrDFO-azepin-onartuzumab to 56.9±4.1% (n = 3), with isolated RCYs of 41.2±10.6% (n = 3), and RCPs >90%. Conventional methods produced ⁸⁹ZrDFO-Bn-NCS-onartuzumab with isolated RCY >97%, RCP >97% and Am ~14.0 MBq nmol^-1. Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake reached 15.37±5.21 %ID g^-1, 6.56±4.03 %ID g^-1, respectively for ⁸⁹ZrDFO-azepin-onartuzumab (n = 4), and 21.38±11.57 %ID g^-1 and 18.84±6.03 %ID g^-1 for ⁸⁹ZrDFO-Bn-NCS-onartuzumab (n = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34±0.47 %ID g^-1) of ⁸⁹ZrDFO-azepin-onartuzumab (n = 4). Conclusion: Experiments demonstrate that photoradiosynthesis is a viable alternative approach for producing ⁸⁹Zr-radiolabeled antibodies direct in protein formulation buffer which reduces protein aggregation and liver uptake.

Studies demonstrate that the investigational ⁶⁴Cu-DOTATATE radiopharmaceutical may provide diagnostic and logistical benefits over available imaging agents for patients with somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). Accordingly, we aimed to prospectively determine the lowest dose of ⁶⁴Cu-DOTATATE that facilitates diagnostic quality scans and evaluated the diagnostic performance and safety in a phase III study of patients with SSTR-expressing NETs. Methods: A dose-ranging study was conducted in 12 patients divided into 3 dose groups (111 MBq [3.0 mCi], 148 MBq [4.0 mCi], and 185 MBq [5.0 mCi] ± 10%) to determine the lowest dose of ⁶⁴Cu-DOTATATE that produced diagnostic quality PET/CT images. Using the ⁶⁴Cu-DOTATATE dose identified in the dose-ranging study, 3 independent nuclear medicine physicians who were blinded to all clinical information read PET/CT scans from 21 healthy volunteers and 42 NET-positive patients to determine those with "Disease" and "No Disease," as well as "Localized" versus "Metastatic" status. Blinded-reader evaluations were compared to a patient-specific standard of truth (SOT), which was established by an independent oncologist who used all previously available pathology, clinical, and conventional imaging data. Diagnostic performance calculated for ⁶⁴Cu-DOTATATE included sensitivity, specificity, negative predictive value, positive predictive value, and accuracy. Inter- and intra-reader reliability, as well as ability to differentiate between localized and metastatic disease, was also determined. Adverse events (AEs) were recorded from ⁶⁴Cu-DOTATATE injection through 48 hours post-injection. Results: The dose-ranging study identified 148 MBq (4.0 mCi) as the optimal dose to obtain diagnostic quality PET/CT images. Following database lock, diagnostic performance from an initial majority read of the 3 independent readers showed a significant 90.9% sensitivity (P = 0.0042) and 96.6% specificity (P < 0.0001) for detecting NETs, which translated to a 100.0% sensitivity and 96.8% specificity after correcting for an initial SOT misread. Excellent inter- and intra-reader reliability, as well as ability to distinguish between localized and metastatic disease, was also noted. No AEs were related to ⁶⁴Cu-DOTATATE, and no serious AEs were observed. Conclusion: ⁶⁴Cu-DOTATATE PET/CT is a safe imaging technique that provides high-quality and accurate images at a dose of 148 MBq (4.0 mCi) for the detection of somatostatin-expressing NETs.

Galectins are carbohydrate-binding proteins overexpressed in bladder cancer (BCa) cells. Dendritic galactose moieties have a high affinity for galectin-expressing tumor cells. We radiolabeled a dendritic galactose carbohydrate with fluorine-18 – ¹⁸F-labeled galactodendritic unit 4 – and examined its potential in imaging urothelial malignancies. Methods: The ¹⁸F-labeled 1st generation galactodendritic unit 4 was obtained from its tosylate precursor. We conducted in vivo studies in galectin-expressing UMUC3 orthotopic BCa model to determine the ability of ¹⁸F-labeled galactodendritic unit 4 to image BCa. Results: Intravesical administration of ¹⁸F-labeled galactodendritic unit 4 allowed specific accumulation of the carbohydrate radiotracer in galectin-1 overexpressing UMUC3 orthotopic tumors when imaged with PET. The ¹⁸F-labeled galactodendritic unit 4 was not found to accumulate in non-tumor murine bladders. Conclusion: The ¹⁸F-labeled galactodendritic unit 4 and similar analogs may be clinically relevant and exploitable for PET imaging of galectin-1 overexpressing bladder tumors.

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.

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.

Objective: To assess the feasibility and accuracy of Cerenkov Luminescence Imaging (CLI) for assessment of surgical margins intraoperatively during radical prostatectomy (RPE). Methods: A single centre feasibility study included 10 patients with high-risk primary prostate cancer (PC). ⁶⁸Ga-PSMA PET/CT scans were performed followed by RPE and intraoperative CLI of the excised prostate. In addition to imaging the intact prostate, in the first two patients the prostate gland was incised and imaged with CLI to visualise the primary tumour. We compared the tumour margin status on CLI to postoperative histopathology. Measured CLI intensities were determined as tumour to background ratio (TBR). Results: Tumour cells were successfully detected on the incised prostate CLI images as confirmed by histopathology. 3 of 10 men had histopathological positive surgical margins (PSMs), and 2 of 3 PSMs were accurately detected on CLI. Overall, 25 (72%) out of 35 regions of interest (ROIs) proved to visualize a tumour signal according to standard histopathology. The median tumour radiance in these areas was 11301 photons/s/cm²/sr (range 3328 - 25428 photons/s/cm²/sr) and median TBR was 4.2 (range 2.1 – 11.6). False positive signals were seen mainly at the prostate base with PC cells overlaid by benign tissue. PSMA-immunohistochemistry (PSMA-IHC) revealed strong PSMA staining of benign gland tissue, which impacts measured activities. Conclusion: This feasibility showed that ⁶⁸Ga-PSMA CLI is a new intraoperative imaging technique capable of imaging the entire specimen’s surface to detect PC tissue at the resection margin. Further optimisation of the CLI protocol, or the use of lower-energetic imaging tracers such as ¹⁸F-PSMA, are required to reduce false positives. A larger study will be performed to assess diagnostic performance.

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.

Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following ¹⁷⁷Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4–19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6–15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2–7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38–0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95–5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA.

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 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.

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.

Introduction: Neuroendocrine differentiation is associated with treatment failure and poor outcome in metastatic castration-resistant prostate cancer (mCRPC). We investigated the effect of circulating neuroendocrine biomarkers on the efficacy of PSMA-targeted radioligand therapy (RLT). Methods: Neuroendocrine biomarker profiles (progastrin-releasing peptide, neuron-specific enolase, and chromogranin-A) were analyzed in 50 patients commencing ¹⁷⁷Lu-PSMA-617 RLT. The primary endpoint was PSA response in relation to baseline neuroendocrine marker profiles. Additional endpoints included progression-free survival. Tumor uptake on post-therapeutic scans, a known predictive marker for response, was used as control-variable. Results: Neuroendocrine biomarker profiles were abnormal in the majority of patients. Neuroendocrine biomarker levels did not predict treatment failure or early progression (P ≥ 0.13). By contrast, intense PSMA-ligand uptake in metastases predicted both treatment response (P = 0.0030) and reduced risk of early progression (P = 0.0111). Conclusion: Neuroendocrine marker profiles do not predict adverse outcome of RLT. By contrast, high ligand uptake was confirmed to be crucial for achieving tumor-response.

para-Aminobenzoic acid (PABA) has been previously used as an exogenous marker to verify completion of 24-hour urine sampling. Therefore, we hypothesized that radiolabeled PABA with ¹¹C could allow high-quality dynamic PET of the kidneys while reducing the radiation exposure due to its short biological and physical half-lives. We evaluated if ¹¹C-PABA could visualize renal anatomy and quantify function in healthy rats, rabbits, and first-in-human studies in healthy volunteers. Methods: Healthy rats and rabbits were injected with ¹¹C-PABA intravenously. Subsequently, a dynamic PET was performed, followed by post-mortem tissue biodistribution studies. 11C-PABA PET was directly compared with the current standard, ^99mTc-MAG3 in rats. Three healthy human subjects also underwent dynamic PET after intravenous injection of ¹¹C-PABA. Results: In healthy rats and rabbits, dynamic PET demonstrated a rapid accumulation of ¹¹C-PABA in the renal cortex, followed by rapid excretion through the pelvicalyceal system. In humans, ¹¹C-PABA PET was safe and well tolerated. There were no adverse or clinically detectable pharmacologic effects in any subject. The cortex was delineated on PET, and the activity gradually transited to the medulla and then renal pelvis with high spatiotemporal resolution. Conclusion: ¹¹C-PABA demonstrated fast renal excretion with very low background signal in animals and humans. These results suggest that ¹¹C-PABA could be used as a novel radiotracer for functional renal imaging, providing high-quality spatiotemporal images with low radiation exposure.

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.

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.

Prostate specific membrane antigen (PSMA) targeting Positron Emission Tomography (PET) imaging is becoming the reference standard for prostate cancer (PC) staging, especially in advanced disease. Yet, the implications of PSMA-PET derived whole-body tumor volume for overall survival are poorly elucidated to date. This might be due to the fact that (semi-) automated quantification of whole-body tumor volume as PSMA-PET biomarker is an unmet clinical challenge. Therefore, a novel semi-automated software is proposed and evaluated by the present study, which enables the semi-automated quantification of PSMA-PET biomarkers such as whole-body tumor volume. Methods: The proposed quantification is implemented as a research prototype (MI Whole Body Analysis Suite, v1.0, Siemens Medical Solutions USA, Inc., Knoxville, TN). PSMA accumulating foci were automatically segmented by a percental threshold (50% of local SUV_max). Neural networks were trained to segment organs in PET-CT acquisitions (training CTs: 8,632, validation CTs: 53). Thereby, PSMA foci within organs of physiologic PSMA uptake were semi-automatically excluded from the analysis. Pretherapeutic PSMA-PET-CTs of 40 consecutive patients treated with ¹⁷⁷Lu-PSMA-617 therapy were evaluated in this analysis. The volumetric whole-body tumor volume (PSMATV50), SUV_max, SUVmean and other whole-body imaging biomarkers were calculated for each patient. Semi-automatically derived results were compared with manual readings in a sub-cohort (by one nuclear medicine physician using syngo.MM Oncology software, Siemens Healthineers, Knoxville, TN). Additionally, an inter-observer evaluation of the semi-automated approach was performed in a sub-cohort (by two nuclear medicine physicians). Results: Manually and semi automatically derived PSMA metrics were highly correlated (PSMATV50: R2=1.000; p<0.001; SUV_max: R2=0.988; p<0.001). The inter-observer agreement of the semi-automated workflow was also high (PSMATV50: R2=1.000; p<0.001; ICC=1.000; SUV_max: R2=0.988; p<0.001; ICC=0.997). PSMATV50 [ml] was a significant predictor of overall survival (HR: 1.004; 95%CI: 1.001-1.006, P = 0.002) and remained so in a multivariate regression including other biomarkers (HR: 1.004; 95%CI: 1.001-1.006 P = 0.004). Conclusion: PSMATV50 is a promising PSMA-PET biomarker that is reproducible and easily quantified by the proposed semi-automated software. Moreover, PSMATV50 is a significant predictor of overall survival in patients with advanced prostate cancer that receive ¹⁷⁷Lu-PSMA-617 therapy.

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.

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.

Purpose: This study is designed to assess the safety and therapeutic response to ¹⁷⁷Lu-EB-PSMA treatment with escalating doses in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: With institutional review board approval and informed consent, patients were randomly divided into three groups: Group A (n = 10) were treated with 1.18 ± 0.09 GBq/dose of ¹⁷⁷Lu-EB-PSMA. Group B (n = 10) were treated with 2.12 ± 0.19 GBq/dose of ¹⁷⁷Lu-EB-PSMA. Group C (n = 8) were treated with 3.52 ± 0.58 GBq/dose of ¹⁷⁷Lu-EB-PSMA. Eligible patients received up to three cycles of ¹⁷⁷Lu-EB-PSMA therapy, at eight-week intervals. Results: Due to disease progression or bone marrow suppression, 4 out of 10, 5 out of 10, and 5 out of 10 patients completed three cycles therapy as planned in Groups A, B, and C, respectively. The prostate-specific antigen (PSA) response was correlated with treatment dose, with PSA disease control rates in Group B (70%) and C (75%) being higher than that in Group A (10%) (P = 0.007), but no correlation between Group B and Group C was found. ⁶⁸Ga-PSMA PET/CT showed response in all the treatment groups, however, there was no significant difference between the three groups. Hematologic toxicity study found that platelets in Group B and Group C decreased more than those in Group A, and that Grade 4 thrombocytopenia occurred in 2 (25.0%) patients in Group C. No serious nephritic or hepatic side effects were observed. Conclusion: This study demonstrates that 2.12 GBq/dose of ¹⁷⁷Lu-EB-PSMA seems to be safe and adequate in tumor treatment. Further investigations with increased number of patients are warranted.

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.

Background: The management for totally thyroidectomized differentiated thyroid cancer (TT-DTC) patients with unexplained hyperthyroglobulinemia remains indeterminate due to evidence scarcity. This multicenter study aimed at prospectively evaluating the response to radioiodine (¹³¹I) adjuvant therapy (RAT) and its potential role in risk stratification and causal clarification. Methods: TT-DTC patients with stimulated serum thyroglobulin (Tgoff) levels > 10 ng/mL but no structurally evident disease were consecutively enrolled in five tertiary care institutions. After the administration of 5.55 GBq of ¹³¹I, the risk of presence of persistent/recurrent/metastatic DTC (prmDTC) was compared to that before RAT. The causes of hyperthyroglobulinemia were explored and the response to RAT was assessed 6-12 months post RAT. The change in suppressed thyroglobulin (Tgon) level was reported. Results: A cohort of 254 subjects with a median Tgoff of 27.1 ng/mL was enrolled for the analyses. Immediately after RAT, low-, intermediate-, and high-risk were identified in 5.9%, 88.6%, and 5.5% patients, respectively, with no significant difference in risk stratification compared with that before RAT (P = 0.952). During the follow-up (median, 10.6 months), hyperthyroglobulinemia was ultimately attributed to thyroid remnant, biochemical disease, and structural/functional disease in 17.3%, 54.3%, and 28.3% of subjects, respectively. In addition, excellent, indeterminate, biochemical incomplete, and structural/functional incomplete responses were achieved in 18.1%, 27.2%, 36.2%, and 18.5% of patients, respectively. Notably, distribution for either cause of hyperthyroglobulinemia or response to RAT was comparable among the three postoperative risk groups. Tgon levels in patients who merely received RAT declined significantly over time. Conclusion: Our study demonstrated that over 90% of TT-DTC patients with unexplained hyperthyroglobulinemia are stratified as intermediate-high risk, and RAT using 5.55 GBq of ¹³¹I reveals biochemical/functional/structural disease and yields non-structural/functional incomplete response in more than 80% patients, suggesting TT-DTC patients with unexplained hyperthyroglobulinemia as explicit candidates for RAT.

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

Abdirahman Abdishakur Warsame, Leader, Wadajir Party, Federal Republic of Somalia
Chair: Ahmed Soliman, Research Fellow, Africa Programme, Chatham House

10 December 2019