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Abstract: We report on a 70-year-old man affected with prostate carcinoma (PC) scheduled for prostate-specific membrane antigen (PSMA) PET/CT using 18 F-PSMA1007. Because of uptake in the liver and corresponding findings on magnetic resonance, diagnosis of hepatocellular carcinoma (HCC, G1) was established. The patient was then scheduled for antihormonal treatment for PC and locoregional therapy due to HCC. On follow-up PSMA-targeted PET/CT, we observed durable response to PC-associated therapy, whereas hepatic lesions showed progressive disease. As such, we herein report on a dual-cancer targeting molecular imaging strategy to determine disease extent in a patient affected with both PC and HCC, along with potential of monitoring both systemic and locoregional treatment., Competing Interests: Disclosure: R.A.W. has received speaker honoraria from Novartis and reports advisory board work for Novartis and Bayer. All other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: We report on an adrenocortical carcinoma (ACC) patient, which has exhausted previous treatment options and was scheduled for prostate-specific membrane antigen (PSMA)- and C-X-C motif chemokine receptor 4 (CXCR4)-targeted PET/CT. We identified PSMA-avid pulmonary metastases exhibiting modest radiotracer accumulation, while chemokine receptor PET/CT provided intense uptake. This dual-tracer molecular imaging approach revealed that chemokine receptor PET appears to be more suitable in patients with advanced ACC, indicating that CXCR4-directed radioligand therapy may be considered in such patients suffering from end-stage disease. Given its dismal prognosis, chemokine receptor-directed theranostics may therefore extend the therapeutic armamentarium as last-line option in advanced ACC., Competing Interests: Conflicts of interest and sources of funding: This study was partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science (T.H.), and the German Research Foundation (453989101, R.A.W., T.H.; 507803309, R.A.W.). This work was supported by the Deutsche Forschungsgemeinschaft (DFG AL 203/1-1 and CRC/Transregio 205 “The Adrenal: Central Relay in Health and Disease”). R.A.W. and A.K.B. have received speaker honoraria from Novartis/AAA and PentixaPharm. R.A.W. reports advisory board work for Novartis/AAA and Bayer. A.K.B. is a member of the advisory board of PentixaPharm. All other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: After C-X-C motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT), lymphoma patients are scheduled for conditioning therapy (CON) followed by hematopoietic stem cell transplantation (HSCT). We aimed to determine whether CXCR4-RLT can achieve bone marrow ablation and direct antilymphoma activity independent from CON/HSCT and also evaluated the safety profile of this theranostic approach in an acute setting., Patients and Methods: After CXCR4-directed 68 Ga-pentixafor PET/CT, 21 heavily pretreated patients with hematological malignancies underwent CXCR4-directed RLT using 90 Y-pentixather. The extent of myeloablative efficacy was determined by investigating hematologic laboratory parameters before RLT (day -1), at the day of RLT (day 0), 2 days after RLT (day 2), and before CON (median day 10). Serving as surrogate marker of antilymphoma activity, lactate dehydrogenase (LDH) levels were also assessed until CON. We also screened for laboratory-defined tumor lysis syndrome after the Cairo-Bishop definition and recorded acute laboratory adverse events using the Common Terminology Criteria for Adverse Events version 5.0., Results: After RLT, we observed a significant decline of leukocyte levels by 79.4% ± 18.7% till CON (granulocytes, drop by 70.3% ± 21%; platelets, reduction by 43.1% ± 36%; P ≤ 0.0005 vs day 0, respectively). After RLT, LDH levels already reached a peak at day 2, which was followed by a rapid decline thereafter (peak vs day of CON, P = 0.0006), indicating that 90 Y-pentixather exhibits direct antilymphoma activity. At day of CON, LDH levels were also significantly lower when compared with day -1 ( P = 0.04), suggestive for durable response mediated by RLT. No patient fulfilled the criteria of tumor lysis syndrome, whereas 25 laboratory adverse events attributable to CXCR4-directed treatment were identified (≥grade 3 in 2/25 [8%]). During further treatment course, all patients (100%) received HSCT., Conclusions: CXCR4-directed RLT causes effective myeloablation, which allows for HSCT. In addition, it also exerts direct antilymphoma activity independent of subsequent therapeutic steps, whereas safety profile was acceptable., Competing Interests: Conflicts of interest and sources of funding: This project is partially supported by the German Research Foundation (453989101, R.A.W. and T.H.; 507803309, R.A.W.). This work was sponsored in part by Okayama University “RECTOR” Program, KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science (T.H.). R.A.W. has received speaker honoraria from Novartis/AAA and PentixaPharm, reports advisory board work for Novartis/AAA and Bayer, and is involved in 68 Ga-pentixafor PET imaging in marginal zone lymphoma (LYMFOR). A.K.B. has received speaker’s honoraria from PentixaPharm and is a member of the advisory board of PentixaPharm. All authors declare that there is no conflict of interest as well as consent for scientific analysis and publication., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Given their neuroendocrine origin, head and neck paragangliomas (HNPGLs) can be imaged with somatostatin receptor (SSTR)-directed PET/CT. We aimed to determine whether the in vivo PET signal can differentiate between varying HNPGL subtypes., Patients and Methods: Fourteen patients with HNPGL received pretherapeutic SSTR-PET/CTs using 68 Ga-DOTATOC. Six (42.9%) patients had a jugular paraganglioma (PGL-J), 5 (35.7%) were diagnosed with carotid paraganglioma (PGL-Cs), and the remaining 3 patients (21.4%) had PGL-C with pathogenic SDHx germline variants (PGL-C-SDH). A visual and quantitative assessment of the primary tumor on SSTR-PET was performed, including SUV max and target-to-background ratio (TBR). Quantitative values were then compared between subgroups of patients affected with different HNPGL entities., Results: On visual assessment, all primary HNPGLs could be identified on SSTR-PET/CT. Quantification of HNPGL revealed substantially elevated SUV max in PGL-J (101.7 ± 58.5) when compared with PGL-C-SDH (13.4 ± 5.6, P < 0.05), but not when compared with PGL-C (66.7 ± 27.3, P = 0.4; PGL-C vs PGL-C-SDH, P = 0.2). TBR of PGL-J (202.9 ± 82.2), however, further differentiated between PGL-C (95.7 ± 45.4, P < 0.05) and PGL-C-SDH (20.4 ± 12.2, P < 0.01; PGL-C vs PGL-C-SDH, P = 0.3). Moreover, whole-body readout revealed metastases in 2/3 (66.7%) of PGL-C-SDH patients, with a single SSTR-expressing skeletal lesion in one subject and bipulmonary lesions in the other patient., Conclusions: In patients with HNPGL, SSTR-PET/CT identified the primary and metastatic disease and provides substantially elevated TBR, indicating excellent image contrast. PET-based quantification can also differentiate between varying HNPGL subtypes., Competing Interests: Conflicts of interest and sources of funding: speaker honoraria from Novartis/AAA (R.A.W.), advisory board work for Novartis/AAA (R.A.W.). No conflict of interest was reported by any of the other authors. This study was partially funded by the German Research Foundation (453989101, T.H., R.A.W.; 507803309, R.A.W.)., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To elucidate the influence of CXC motif chemokine receptor 4 (CXCR4)-directed imaging on staging and proposed oncologic management in patients with digestive system tumors compared with guideline-appropriate imaging (GAI)., Methods: From our PET/CT database, we retrospectively identified 37 patients with advanced digestive system tumors, which had been scheduled for CXCR4-targeted [ 68 Ga]Ga-pentixafor PET/CT for potential theranostic considerations. In all subjects, concurrent GAI was also available. Patients were afflicted with gastroenteropancreatic neuroendocrine neoplasms (21/37 [56.8%]), pancreatic duct adenocarcinoma (6/37 [16.2%]), cholangiocarcinoma (5/37 [13.5%]), hepatocellular carcinoma (4/37 [10.8%]), and colorectal carcinoma (1/37 [2.7%]). Staging results and impact on proposed oncologic management by a board-certified gastroenterologist were compared between GAI and [ 68 Ga]Ga-pentixafor PET/CT., Results: Relative to GAI, CXCR4-directed PET/CT resulted in staging changes in 14 of 37 patients (37.8%). Upstaging was seen in 1 of 14 patients (7.1%), whereas downstaging was recorded in the remaining 13 of 14 patients (92.9%). Among those, staging changes would not have triggered any changes in oncological management in 4 of 14 (28.6%). For the remaining 10 of 14 patients (71.4%), however, findings on [ 68 Ga]Ga-pentixafor PET/CT would have impacted subsequent clinical algorithm, including the necessity for further diagnostic steps or failure to initiate antitumor therapy., Conclusion: [ 68 Ga]Ga-pentixafor PET/CT missed tumor lesions in 13 patients with digestive system tumors, which would have led to inappropriate downstaging and clinical treatment of 10 patients. As such, our results do not support a more widespread use of [ 68 Ga]Ga-pentixafor PET/CT for clinical staging in those tumor entities., Competing Interests: Conflicts of interest and sources of funding: This project was partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (21K19450) from the Japan Society for the Promotion of Science (to T.H.) and the German Research Foundation (507803309, to R.A.W.; 453989101, to R.A.W., T.H.). R.A.W. and A.K.B. have received speaker's honoraria from PentixaPharm. A.K.B. is a member of the advisory board of PentixaPharm. All other authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: We report on a patient diagnosed with an aggressive pancreatic neuroendocrine tumor (NET G3; Ki67 = 60%), who underwent pancreatic resection with partial removal of liver lesions. The patient refused chemotherapy. Dual-tracer imaging with 18 F-FDG and somatostatin receptor (SSTR)-targeted PET/CT was conducted. Radiotracer accumulation on both imaging modalities in bilobar hepatic lesions was observed. "Cold" somatostatin analogues with four cycles of peptide receptor radionuclide therapy (PRRT) were initiated, leading to partial response. Even in highly proliferative but differentiated G3 NET (Ki67>55%), SSTR expression in sites of disease should be evaluated, which may then allow PRRT, even as first-line systemic treatment., Competing Interests: Conflicts of interest and sources of funding: This project is partially supported by the Okayama University “RECTOR” Program (T.H.) and the German Research Foundation (507803309, R.A.W.; 453989101, R.A.W., T.H.). T.H. received a KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science. R.A.W. has received speaker’s honoraria from Novartis and Triple A. The other authors have no conflicts to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We aimed to evaluate the interobserver agreement rates in patients scanned with C-X-C motif chemokine receptor 4 (CXCR4)-directed PET/CT, including the rate of patients eligible for CXCR4-targeted radioligand therapy (RLT) based on scan results., Methods: Four independent observers reviewed 50 CXCR4-targeted [ 68 Ga]pentixafor PET/CT of patients with various solid cancers. On a visual level, the following items were assessed by each reader: overall scan impression, number of organ and lymph node (LN) metastases and number of affected organs and LN regions. For a quantitative investigation, readers had to choose a maximum of 3 target lesions, defined as largest in size and/or most intense uptake per organ compartment. Reference tissues were also quantified, including unaffected hepatic parenchyma and blood pool. Last, all observers had to decide whether patients were eligible for CXCR4-targeted RLT. Concordance rates were tested using intraclass correlation coefficients (ICCs). For interpretation, we applied the definition of Cicchetti (with 0.4-0.59 indicating fair; 0.6-0.74, good; 0.75-1, excellent agreement)., Results: On a visual level, fair agreement was achieved for an overall scan impression (ICC, 0.58; 95% confidence interval, 0.45-0.71). Organ and LN involvement (ICC, ≥0.4) demonstrated fair, whereas CXCR4 density and number of LN and organ metastases showed good agreement rates (ICC, ≥0.65). Number of affected organs and affected LN areas, however, showed excellent concordance (ICC, ≥0.76). Quantification in LN and organ lesions also provided excellent agreement rates (ICC, ≥0.92), whereas quantified uptake in reference organs provided fair concordance (ICC, ≥0.54). Again, excellent agreement rates were observed when deciding on patients eligible for CXCR4-RLT (ICC, 0.91; 95% confidence interval, 0.85-0.95)., Conclusions: In patients scanned with CXCR4-targeted PET/CT, we observed fair to excellent agreement rates for both molecular imaging and therapy parameters, thereby favoring a more widespread adoption of [ 68 Ga]pentixafor in the clinic., Competing Interests: Conflicts of interest and sources of funding: This project was partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (21K19450) from the Japan Society for the Promotion of Science (T.H.) and the German Research Foundation (507803309, R.A.W.; 453989101, R.A.W., T.H.). R.A.W. and A.K.B. have received speaker's honoraria from PentixaPharm. A.K.B. is a member of the advisory board of PentixaPharm. R.A.B. is consultant to and has received speaker's honoraria from Bayer Healthcare (Leverkusen, Germany) and Eisai GmbH (Frankfurt, Germany). The other authors have no conflicts to report., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Somatostatin receptor (SSTR)-targeted PET/CT is used for patients affected with small cell lung cancer (SCLC), but the clinical impact has not been elucidated yet. We aimed to determine whether SSTR PET/CT can trigger relevant therapeutic management changes in patients with SCLC and whether those modifications achieve disease control and are associated with prolonged survival., Methods: One hundred patients with SCLC received SSTR PET/CT. In a retrospective setting, we evaluated the diagnostic performance of PET versus CT and compared therapies before and after PET/CT to determine the impact of molecular imaging on treatment decision. We also determined the rate of disease control after therapeutic modifications and assessed survival in patients with and without changes in the therapeutic regimen., Results: Relative to CT, SSTR PET alone was superior for assessing bone lesions in 19 of 39 instances (49%). Treatment was modified in 59 of 100 (59%) after SSTR PET/CT. Forty of 59 (74.6%) received systemic treatment after hybrid imaging, with the remaining 15 of 59 (25.4%) scheduled for nonsystemic therapy. In the latter group, 13 of 15 (86.7%) received local radiation therapy or active surveillance (2/15 [13.3%]). Individuals scheduled for systemic treatment after imaging received peptide receptor radionuclide therapy (PRRT) in 28 of 44 (63.6%), followed by chemotherapy in 10 of 44 (22.7%), change in chemotherapy regimen in 3 of 44 (6.8%), and initiation of tyrosine kinase inhibitor in the remaining 3 of 44 (6.8%). Among patients with modified treatment, follow-up was available in 53 subjects, and disease control was achieved in 14 of 53 (26.4%). However, neither change to systemic treatment (155 days; hazard ratio, 0.94; 95% confidence interval, 0.53-1.67) nor change to nonsystemic treatment (210 days; hazard ratio, 0.67; 95% confidence interval, 0.34-1.34) led to a prolonged survival when compared with subjects with no change (171 days, P ≥ 0.22, respectively)., Conclusions: In patients with SCLC, SSTR-targeted hybrid imaging provides complementary information on the disease status. PET/CT led to management changes in 59% (mainly PRRT), achieving disease control in >26%. The high fraction of patients scheduled for PRRT may lay the foundation for combination strategies to achieve synergistic antitumor effects, for example, by combining PRRT plus recently introduced RNA polymerase II inhibitors., Competing Interests: Conflicts of interest and sources of funding: This study was partially funded by the German Research Foundation (453989101, T.H., R.A.W.; 507803309, R.A.W.); Okayama University (RECTOR Program, T.H.); and Japan Society for the Promotion of Science (22H03027, T.H.). R.A.W. has received speaker's honoraria from Triple A/Novartis. The other authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: We report the case of a 52-year-old man affected with a metastasized neuroendocrine tumor (G2) of the pancreas. After surgical removal, follow-up imaging 36 months later revealed somatostatin receptor-positive liver lesions. Because of disease progression under cold somatostatin analogs 6 months later, peptide receptor radionuclide therapy was performed, that induced complete remission (CR), supporting the notion that "hot" somatostatin analogs can achieve CR even in patients affected with pancreatic G2 neuroendocrine tumor. Of note, such cases exhibiting CR upon peptide receptor radionuclide therapy are extremely rare and further investigations may pool those exceptional treatment responders., Competing Interests: Conflicts of interest and sources of funding: R.A.W. has received speaker's honoraria from Advanced Accelerator Applications. This project was partially supported by the Okayama University “RECTOR” Program (T.H.) and the German Research Foundation (507803309, R.A.W.; 453989101, R.A.W., T.H.). T.H. received a KAKENHI grant (21K19450) from the Japan Society for the Promotion of Science. The other authors have none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: We aimed to determine the impact of fibroblast activation protein inhibitor (FAPI)-directed molecular imaging on staging and therapeutic management in patients affected with digestive system tumors when compared with guideline-compatible imaging (GCI)., Patients and Methods: Thirty-two patients with tumors of the digestive system were included: colon adenocarcinoma, 2/32 (6.3%); hepatocellular carcinoma (HCC), 6/32 (18.8%); pancreatic duct adenocarcinoma (PDAC), 6/32 (18.8%), and gastroenteropancreatic neuroendocrine neoplasms, 18/32 (56.3%). All patients underwent GCI and 68 Ga-FAPI-04 PET/CT within median 4 days. Staging outcomes and subsequent treatment decisions were compared between GCI and 68 Ga-FAPI-04 PET/CT., Results: Compared with GCI, 68 Ga-FAPI-04 PET/CT led to staging changes in 15/32 patients (46.9%). Among those, downstaging was recorded in 3/15 cases (20.0%) and upstaging in the remaining 12/15 patients (HCC, 4/12 [33.3%]; PDAC, 4/12 [33.3%]; neuroendocrine neoplasms, 3/12 [25%]; colon adenocarcinoma, 1/12 [8.3%]). Therapeutic management was impacted in 8/32 patients (25.0%), including 4 instances of major and 4 instances of minor therapeutic changes. The highest proportion of treatment modifications was observed in patients diagnosed with PDAC and HCC in 6/8 (75%)., Conclusions: In patients affected with digestive system tumors, 68 Ga-FAPI-04 PET/CT resulted in staging changes in more than 46% and therapeutic modifications in 25% of the cases, in particular in patients with HCC and PDAC. In clinical routine, such findings may favor a more widespread adoption of FAP-directed imaging in those tumor types., Competing Interests: Conflicts of interest and sources of funding: This project is partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (21K19450) from the Japan Society for the Promotion of Science (T.H.) and the German Research Foundation (507803309, R.A.W.; 453989101, R.A.W., T.H.). T.L. is a co-inventor of a patent application for quinolone-based FAP-targeting agents for imaging and therapy in nuclear medicine. T.L. also has shares of a consultancy group for iTheranostics. All other authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Here, we report a case of a 52-year-old woman with a well-differentiated, metastasized neuroendocrine tumor (NET G1) of the duodenum. Initial imaging with 68 Ga-DOTATOC revealed multiple sites of disease with intense uptake. Peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATOC induced partial remission. Treatment was then switched to cold somatostatin analog as a maintenance therapy. After 2 years of follow-up, progressive disease with multiple lesions in the skeleton was noted. Given the initial response to PRRT, a rechallenge with another 2 cycles of PRRT were given, and the patient had an excellent response to treatment, in particular in the skeleton., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Fibroblast activation protein (FAP) has emerged as a novel target for FAP inhibitor (FAPI)-directed molecular imaging and endoradiotherapy (ERT). We aimed to assess the interobserver agreement rates for interpretation of 68Ga-FAPI-4 PET/CT and decision for ERT., Patients and Methods: A random order of 68Ga-FAPI-4 PET/CTs from 49 oncology patients were independently interpreted by 4 blinded readers. Per scan, visual assessment was performed, including overall scan impression, number of organ/lymph node (LN) metastases, and number of affected organs/LN regions. Moreover, a maximum of 3 target lesions, defined as largest in size and/or most intense, per organ compartment were identified, which allowed for an additional quantitative interobserver assessment of LN and organ lesions. To investigate potential reference tissues, quantification also included unaffected liver parenchyma and blood pool. Readers also had to indicate whether FAPI-directed ERT should be considered (based on intensity of uptake and widespread disease). Interobserver agreement rates were evaluated using intraclass correlation coefficients (ICCs) and interpreted according to Cicchetti (with 0.4-0.59 indicating fair, and 0.6-0.74 good, agreement)., Results: On a visual basis, the agreement rate for an overall scan impression was fair (ICC, 0.42; 95% confidence interval [CI], 0.27-0.57). The concordance rate for number of affected LN areas was also fair (ICC, 0.59; 95% CI, 0.45-0.72), whereas the number of LN metastases, number of affected organs, and number of organ metastases achieved good agreement rates (ICC, ≥0.63). In a quantitative analysis, concordance rates for LN were good (ICC, 0.70; 0.48-0.88), but only fair for organ lesions (ICC, 0.43; 0.26-0.60). In regards to background tissues, ICCs were good for unaffected liver parenchyma (0.68; 0.54-0.79) and fair for blood pool (0.43; 0.29-0.58). When readers should decide on ERT, concordance rates were also fair (ICC, 0.59; 95% CI, 0.46-0.73)., Conclusions: For FAPI-directed molecular imaging and therapy, a fair to good interobserver agreement rate was achieved, supporting the adoption of this radiotracer for clinical routine and multicenter trials., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)