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Study Design: retrospective comparative study (Level III). Objective: to compare the operative results of posterior fusion and a 2-stage anterior L5-S1 fusion followed by posterior fusion in neuromuscular scoliosis patients with significant pelvic obliquity (PO). Summary Of Background Data: PO in neuromuscular scoliosis is common and a challenging problem that affects proper sitting balance, necessarily addressing the deformity and proper maintenance of the correction. Methods: a total of 54 patients with neuromuscular scoliosis and significant PO (>10°) were divided into 2 groups. Group 1 (n = 24) was operated on for posterior fusion and pelvic fixation. Group 2 (n = 30) included patients who were subjected to a first-stage procedure consisting of a lumbosacral junction release and fusion through a midline retroperitoneal approach and then a second-stage procedure of posterior fusion and pelvic fixation. Parameters measured included length of the follow-up, number of fusion levels, age at operation, forced vital capacity, operative time, estimated blood loss, and postoperative complications. Radiologic parameters measured before surgery, after surgery at the time of discharge, and at a final follow-up included Cobb angle, T1 translation, sitting pelvic obliquity (PO) in the frontal plane, C7 plumb line, thoracic kyphosis, lumbar lordosis, and sacral inclination angle in the sagittal plane. Results: the correction of scoliosis was similar in both groups. The preoperative PO averaged 19.5° in Group I and 22.9° in Group II (P = 0.22), which corrected after surgery to 9.7° versus 7.4° (P = 0.23), respectively. Group II correction progressively improved significantly compared to Group I (7.0° vs. 11.6° at P = 0.046) at the latest follow-up. A 40.6% correction (mean correction = 7.9) in sitting PO in Group I compared to 70.7% correction (mean correction = 5.9°) in Group II was observed (P = 0.004). The average loss of correction of PO at the final follow-up was lesser in group II, but not statistically significant (P = 0.07). Conclusion: anterior fusion of the lumbosacral junction followed by posterior fusion provides superior correction and maintenance of PO in patients with neuromuscular scoliosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Osteochondral grafting for the treatment of osteochondral lesions of the talus (OLT) usually requires a medial malleolar osteotomy (MMO) to achieve adequate intraarticular exposure. This study describes the technique used and the results obtained using a modified step-cut MMO for osteochondral grafting of talar dome lesions. MATERIALS AND METHOD: Eleven feet in ten patients underwent modified step-cut MMO prior to osteochondral grafting for OLT. The patients included three women and seven men with a mean age of 40 (range, 20 to 51) years. Modified step-cut MMO consisted of an oblique osteotomy, which was made at approximately 45 degrees to the transverse plane of the proposed traditional step-cut osteotomy, and a vertical osteotomy to the axilla on the medial tibial plafond. RESULTS: In all patients, modified step-cut MMO provided better perpendicular access to lesions than traditional step-cut osteotomy. In all cases, the osteochondral graft plug was accurately set perpendicular to the defect area, and all ten patients experienced uncomplicated osteotomy healing at a mean 8 weeks postoperatively without loss of reduction or malreduction. CONCLUSION: Modified step-cut MMO is an excellent, reproducible method for perpendicular access to a talar dome lesion. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective study.Objective: To evaluate the prognostic value of preoperative pulmonary function test (PFT) for postoperative pulmonary complications and to identify the operability associated with severely decreased forced vital capacity (FVC) (<30%) status in flaccid neuromuscular scoliosis.Summary Of Background Data: The preoperative PFT, especially more than 30% FVC, is known as a critical factor for the operability of flaccid neuromuscular scoliosis. But only one study reported that patients with pre-existing respiratory failure on nocturnal noninvasive ventilation can undergo an operation for deformity correction without mortality and severe complications.Methods: A total of 74 patients (45 male and 29 female) presented with flaccid neuromuscular scoliosis. For all patients, preoperative PFTs were evaluated and subdivided into three groups (<30% FVC, 30%-50% FVC, and >50% FVC). Then postoperative pulmonary complications, pneumothorax, pneumonia, atelectasis, prolonged ventilator care in the intensive care unit (more than 72 hours), and postoperative tracheostomy were evaluated.Results: Among these patients, 59 had muscular dystrophy; 5, spinal muscular atrophy; 2, cerebral palsy; and 8, others. The mean age at surgery was 16.8 years (range, 5-32 years). The mean preoperative Cobb angle was 54.6° (16°-135°). The overall postoperative pulmonary complication rate was 31% (23 complications in 74 patients). The less than 30% FVC group had 6 complications among 18 patients; the 30% to 50% FVC group had 7 complications among 18 patients; and the more than 50% FVC group had 10 complications among 38 patients. There were no deaths during the perioperative period. There is no statistical difference between the three groups (P = 0.6195).Conclusion: Patients with flaccid neuromuscular scoliosis can undergo an operation for deformity correction regardless of the severely decreased pulmonary function. [ABSTRACT FROM AUTHOR]

Abstract: Metastatic or recurrent adrenocortical carcinoma is a potentially lethal malignancy, presenting significant challenges in disease management owing to absence of effective systemic treatments. Significantly diminished survival rates necessitate rapid identification of specific molecules for the development of targeted therapeutics. Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts have been a major breakthrough causing a paradigm shift in targeted theranostics focusing on the tumor microenvironment. The effectiveness of various FAP inhibitors (FAPis) and FAP targeting peptide has been extensively documented in diverse clinical investigations. We have evaluated 3 molecules, that is, DOTA.SA.FAPi (SA.FAPi), FAPi46, and FAP2286, as potential theranostic probes for adrenocortical carcinoma., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: We report a case of a 48-year-old man with recurrent hepatocellular carcinoma, who underwent FDG PET for restaging and demonstrated mildly tracer-avid arterial enhancing lesion in segment III (SUV max , 5.7). Owing to low FDG uptake, patient was planned for 68 Ga-SA.FAPi PET, which demonstrated higher tracer avidity in the lesion (SUV max , 24.4). Subsequently, patient underwent 177 Lu-microsphere SIRT (2.2 GBq) in segment III. The 3- and 6-month posttherapy SA.FAPi PET demonstrated an interval decrease in tracer uptake and size of treated lesion. This case highlighted the promising role of SA.FAPi PET in patient selection for 177 Lu-SIRT and subsequent response assessment., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 , a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC)., Methods: Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18 F-FDG, [ 18 F]AlF-NOTA-FAPI-04, and [ 68 Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen., Results: CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18 F-FDG and [ 18 F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12., Conclusion: The combination of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs., (© 2024. The Author(s).)

Background: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi) 2 , labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs., Methods: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [ 68 Ga]Ga-DOTA.SA.FAPi and [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 . [ 177 Lu]Lu-DOTA.SA.FAPi and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 , were evaluated in PC3 xenografts. Biodistribution studies of [ 68 Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice., Results: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 was retained longer in CAFs. [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 displayed elevated lipophilicity and affinity for human serum proteins compared to [ 68 Ga]Ga-DOTA.SA.FAPi and [ 177 Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 within 3 h compared to [ 68 Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 versus [ 68 Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 maintained a significant tumor uptake even after 96 h p.i. compared to [ 177 Lu]Lu-DOTA.SA.FAPi., Conclusions: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.

Rationale and Objectives: Fibroblast Activation Protein (FAP) expressing cancer-associated fibroblasts has been a major breakthrough causing a paradigm shift in targeted theranostics focusing on the tumor microenvironment. In this study, a squaric acid derivative DOTA.SA.FAPi (SA.FAPi) has been evaluated as a potential diagnostic probe in diverse epithelial cancers and compared to the standard-of-care 18 F-FDG., Methods: 25 patients enrolled in this prospective study underwent 18 F-FDG and 68 Ga-SA.FAPi PET scans on two different days. For biodistribution, standardized uptake values (SUV) were computed by delineating region-of-interest on various body organs. For comparative analysis in disease identification, lesion tracer uptake was quantified using SUVs corrected for lean body mass (SUL), SUV max , tumor-to-background ratio (TBR) with liver and blood pool as the reference, total lesion glycolysis (TLG for 18 F-FDG) and total lesion FAP expression (TLF for 68 Ga-SA.FAPi)., Results: 25 patients (mean age: 58 ± 8 years) with four types of cancers including hepatocellular carcinoma (HCC, 56% of cohort), gall bladder carcinoma (GB Ca, 12%), adrenocortical carcinoma (ACC, 16%), and breast carcinoma (breast Ca, 16%) were prospectively evaluated. Physiological tracer uptake of 68 Ga-SA.FAPi was noted in the salivary glands, thyroid, liver, pancreas, muscles and kidneys with variable uptake in the lacrimal glands, extra-ocular muscles, oral mucosa and uterus. Lesion-based comparative analysis between both the radiotracers demonstrated complete concordant findings in detection of all primary lesions and distant metastases in liver, bones, adrenals and peritoneum whereas discordant findings were noted in lung nodules (20%) and lymph nodes (13%). In overall analysis, 68 Ga-SA.FAPi exhibited significantly higher SUV max (10.3 vs 8.8, p-0.019), SUL peak (6.8 vs 4.9, p-0.000) and SUL avg (5.4 vs 4.1, p-0.019) in comparison to 18 F-FDG whereas TBR was comparable for both the tracers [TBR Liver : median 1.9 (IQR: 2.6-1.4) vs 1.8 (2.6-1.1), p-0.275; TBR Bloodpool : 2.1 (3.7-1.4) vs 2.0 (2.7-1.4), p-0.207]. In subcategorical analysis, 68 Ga-SA.FAPi demonstrated higher SUV max , SUL peak and SUL avg values for primary disease (SUV max : 14.8 (18.7-9.7) vs (12.9-6.6), p-0.087; SUL peak : 8.2 (11.2-6.8) vs 6.3 (8.5-4.4), p-0.037; SUL avg : 6.9 ± 2.5 vs 5.1 ± 2.2, p-0.023] and distant metastases (8.8 vs 7.2, p-0.038); 6.3 (8.8-4.4) vs 3.6 (4.4-2.0), p-0.000; 5.4 vs 3.5, p-0.000] whereas comparable values were noted for both the tracers in nodal metastases [9 (13.5-4.1) vs 8 (12.7-4.7), p-0.726; 4.5 (6.2-1.8) vs 4.3 (5.7-2.2), p-0.727; 4.1 ± 2.3 vs 3.7 ± 1.8, p-0.129]. In primary disease, highest 68 Ga-SA.FAPi avidity was noted in ACC followed by GB Ca and HCC. In distant metastases, gall bladder, lung and skeletal lesions demonstrated higher 68 Ga-SA.FAPi avidity. Moreover, 68 Ga-SA.FAPi identified five additional lung lesions which were missed by 18 F-FDG in one case of ACC., Conclusion: 68 Ga-SA.FAPi emerged as an effective, versatile diagnostic probe for imaging various epithelial malignancies similar to 18 F-FDG., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Jaya Shukla reports financial support was provided by Post Graduate Institute of Medical Education and Research., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Fibroblast activation protein (FAP) is a very reliable biomarker for tissue remodeling. FAP has so far mainly been studied in oncology, but there is growing interest in the enzyme in other diseases like fibrosis. Recently, FAP-targeting diagnostics and therapeutics have emerged, of which the so-called FAPIs are among the most promising representatives. FAPIs typically have a relatively high molecular weight and contain very polar, multicharged chelator moieties. While this is not limiting the application of FAPIs in oncology, more druglike FAPIs could be required to optimally study diseases characterized by denser, less permeable tissue. In response, we designed the first druglike 18 F-labeled FAPIs. We report target potencies, biodistribution, and pharmacokinetics and demonstrate FAP-dependent uptake in murine tumor xenografts. Finally, this paper puts forward compound 10 as a highly promising, druglike FAPI for 18 F-PET imaging. This molecule is fit for additional studies in fibrosis and its preclinical profile warrants clinical investigation.

Neuroendocrine tumors (NETs) are slow-growing tumors that express high levels of somatostatin receptors (SSTRs). Recent studies have shown the superiority of radiolabeled SSTR antagonists in theranostics compared to agonists. In this prospective study, we compared the diagnostic efficacy between [ 68 Ga]Ga-DOTANOC and [ 68 Ga]Ga-DATA 5m -LM4 in the detection of primary and metastatic lesions in patients with well differentiated gastroenteropancreatic (GEP) NETs. Histologically proven GEP-NET patients underwent [ 68 Ga]Ga-DOTANOC & [ 68 Ga]Ga-DATA 5m -LM4 PET/CT scans, which were analyzed. The qualitative analysis involved the visual judgment of radiotracer uptake validated by the morphological findings using CT, which was considered as the reference standard. Quantitative comparisons were presented as the standardized uptake value (SUV) corrected for lean body mass: SULpeak, SULavg, and tumor-to-background ratios (TBR). In total, 490 lesions were confirmed via diagnostic CT. The lesion-based sensitivity of [ 68 Ga]Ga-DATA 5m -LM4 PET/CT was 94.28% (462/490) and 83.46% (409/490) for [ 68 Ga]Ga-DOTANOC PET/CT ( p < 0.0001). [ 68 Ga]Ga-DATA 5m -LM4 had statistical significance over [ 68 Ga]Ga-DOTANOC in liver metastases [100% vs. 89.4%; p < 0.0001 (292 vs. 253 {283 lesions on CT})] and bone metastases [100% vs. 82.9%; p = 0.005 (45 vs. 34 {41 lesions on CT})]. Statistical significance was also noted for the TBR SULpeak of the primary and liver lesions. [ 68 Ga]Ga-DATA 5m -LM4 showed better sensitivity and a higher target-to-background ratio than [ 68 Ga]Ga-DOTANOC PET/CT. [ 68 Ga]Ga-DATA 5m -LM4 PET/CT can be used to quantify the extent of skeletal and liver metastases for better planning of SSTR agonist- or antagonist-based therapy.

Purpose: The upregulation of fibroblast activation protein (FAP) expression has been observed in various cancers, including metastatic breast carcinoma, prompting research into small molecule inhibitors for both diagnostic and therapeutic purposes. While the diagnostic value of PET/CT imaging using 68  Ga- or 18 F-labelled FAPi-monomers in breast cancer diagnosis is well-established, there is a significant need for therapeutic analogs. This retrospective study aimed to assess the safety and effectiveness of [ 177 Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy in patients with advanced-stage breast cancer who had previously undergone [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans to confirm the expression of FAP., Materials and Methods: Between November 2020 and March 2023, a compassionate treatment approach was utilized to administer [ 177 Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy to heavily pretreated patients with advanced breast cancer. Nineteen patients (18 females, 1 male) with metastatic breast cancer participated in the study, with an average age of 44.6 ± 10.7 years. The therapy was administered at intervals of 8 to 12 weeks, and the median follow-up duration was 14 months. The primary objective of the study was to assess molecular response using [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans, with response evaluation based on the PERCIST criteria. Secondary endpoints included overall survival (OS), progression-free survival (PFS), clinical response assessment, and safety evaluation using CTCAE v5.0 guidelines., Results: A total of 65 cycles were administered, with a mean cumulative activity of 19 ± 5.7 GBq (510 ± 154 mCi) ranging from 11 to 33.3 GBq (300 to 900 mCi) of [ 177 Lu]Lu-DOTAGA.FAPi dimer. The number of cycles ranged from 2 to 6, with a median of 3 cycles. The treatment protocol consisted of different numbers of cycles administered to the patients: specifically, two cycles were given to five patients, three cycles to nine patients, four cycles to one patient, and six cycles to four patients. Most patients had invasive/infiltrative ductal carcinoma (94.7%), while a small percentage had invasive lobular carcinoma (5.3%). All patients had bone metastases, and five of them also had liver involvement, while seven had brain metastases. Response assessment using [ 68  Ga]Ga-DOTA.SA.FAPi PET/CT scans showed that 25% of the 16 patients evaluated had partial remission, while 37.5% exhibited disease progression. According to the VAS response criteria, 26.3% achieved complete response, 15.7% had partial response, 42% showed minimal response, 11% had stable disease, and 5% had no response. The clinical disease control rate was promising, with 95% of patients achieving disease control. The clinical objective response rate was 84%. The median follow-up period was 14 months. At the time of analysis, the median overall survival was 12 months, and the median progression-free survival was 8.5 months. Notably, no severe hematological, renal, or hepatic toxicities, electrolyte imbalances, or adverse events of grade 3 or 4 were observed during the study., Conclusion: The findings suggest that [ 177 Lu]Lu-DOTAGA.FAPi dimer therapy is well-tolerated, safe, and effective for treating end-stage metastatic breast cancer patients. [ 177 Lu]Lu-DOTAGA.FAPi dimer treatment demonstrated promising efficacy in patients with advanced breast cancer, as indicated by high disease control rates, favorable response outcomes, and acceptable safety profile. Further research and longer follow-up are warranted to assess long-term outcomes and validate these findings., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Small-molecular fibroblast activation protein inhibitor (FAPI)-based tracer have been shown to be promising Positron Emission Tomography (PET) 68 Ga-labeled radiopharmaceuticals to image a variety of tumors including pancreatic, breast, and colorectal cancers, among others. In this study, we developed a novel 18 F-labeled FAPI derivative. [ 18 F]6 was labeled using a synthon approach based on the tetrazine ligation. It showed subnanomolar affinity for the FAP protein and a good selectivity profile against known off-target proteases. Small animal PET studies revealed high tumor uptake and good target-to-background ratios. [ 18 F]6 was excreted via the liver. Overall, [ 18 F]6 showed promising characteristics to be used as a PET tracer and could serve as a lead for further development of halogen-based theranostic FAPI radiopharmaceuticals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Matthias M. herth reports a relationship with Tetrakit Technologies that includes: board membership, consulting or advisory, and equity or stocks. Christian B. M. Poulie reports a relationship with Tetrakit Technologies that includes: board membership, employment, and equity or stocks. Vladimir Shalgunov reports a relationship with Tetrakit Technologies that includes: board membership, employment, and equity or stocks. Umberto Maria Battisti reports a relationship with Tetrakit technologies that includes: board membership, employment, and equity or stocks., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: In the context of radioiodine-resistant follicular-cell derived thyroid cancers (RAI-R-FCTC), [ 18 F]F-FDG PET/CT serves as a widely used and valuable diagnostic imaging method. However, there is growing interest in utilizing molecular imaging probes that target cancer-associated fibroblasts (CAFs) as an alternative approach. This study sought to compare the diagnostic capabilities of [ 68 Ga]Ga-DOTA.SA.FAPi and [ 18 F]F-FDG PET/CT in patients with RAI-R-FCTC., Methods: In this retrospective study, a total of 117 patients with RAI-R-FCTC were included. The study population consisted of 68 females and 49 males, with a mean age of 53.2 ± 11.7 years. The aim of the study was to perform a comprehensive qualitative and quantitative assessment of [ 68 Ga]Ga-DOTA.SA.FAPi and [ 18 F]F-FDG PET/CT scans in RAI-R-FCTC patients. The qualitative assessment involved comparing patient-based and lesion-based visual interpretations of both scans, while the quantitative assessment included analyzing standardized uptake values corrected for lean body mass (SULpeak and SULavg). The findings obtained from the scans were validated by correlating them with morphological findings from diagnostic computed tomography and/or histopathological examination., Results: Among the 117 RAI-R-FCTC patients, 60 had unilateral local disease, and 9 had bilateral lesions with complete concordance in the detection rate on both PET scans. [ 68 Ga]Ga-DOTA.SA.FAPi had a higher detection rate for lymph nodes (95.4% vs 86.6%, p<0.0001), liver metastases (100% vs. 81.3%, p<0.0001), and brain metastases (100% vs. 39%, p<0.0001) compared to [ 18 F]F-FDG. The detection rates for pleural and bone metastases were similar between the two radiotracers. For lung metastases, [ 68 Ga]Ga-DOTA.SA.FAPi showed a detection rate of 81.7%, whereas [ 18 F]F-FDG had a detection rate of 64.6%. Remarkably, [ 68 Ga]Ga-DOTA.SA.FAPi was able to detect a bowel metastasis that was missed on [ 18 F]F-FDG scan. The median standardized uptake values (SUL) were generally comparable between the two radiotracers, except for brain metastases (SULpeak [ 68 Ga]Ga-DOTA.SA.FAPi vs. [ 18 F]F-FDG: 13.9 vs. 6.7, p-0.0001) and muscle metastases (SULpeak [ 68 Ga]Ga-DOTA.SA.FAPi vs. [ 18 F]F-FDG: 9.56 vs. 5.62, p-0.0085), where [ 68 Ga]Ga-DOTA.SA.FAPi exhibited higher uptake., Conclusion: The study results demonstrate the superior performance of [ 68 Ga]Ga-DOTA.SA.FAPi compared to [ 18 F]F-FDG PET/CT in detecting lymph nodal, liver, bowel, and brain metastases in patients with RAI-R-FCTC. These findings highlight the potential of [ 68 Ga]Ga-DOTA.SA.FAPi as a theranostic tool that can complement the benefits of [ 18 F]F-FDG PET/CT in the imaging of RAI-R-FCTC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The present study aims at evaluating the preclinical and the clinical performance of [ 68 Ga]Ga-DATA 5m. SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature., Methods: [ 68 Ga]Ga-DATA 5m .SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [ 68 Ga]Ga-DATA 5m .SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake., Results: [ 68 Ga]Ga-DATA 5m .SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [ 68 Ga]Ga-DATA 5m .SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high., Conclusion: The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [ 68 Ga]Ga-DATA 5m .SA.FAPi as a diagnostic tool for FAP imaging., (© 2023. The Author(s).)

Background: A theranostic probe for accurate staging and treatment is crucial for the management of medullary thyroid cancers (MTCs). The abundance of stroma in most of thyroid cancers, including MTC, opens new avenues for selecting cancer-associated fibroblasts (CAFs) as new molecular imaging and therapeutic targets. [ 68 Ga]Ga-labeled fibroblast activation protein inhibitor (FAPi) molecules have gained importance as alternative molecular imaging agents in the imaging of thyroid cancers. The purpose of this study was to compare the detection efficiency of primary and metastatic lesions of MTCs between [ 68 Ga]Ga-DOTA.SA.FAPi and [ 68 Ga]Ga-DOTANOC positron emission tomography (PET) radiotracers. Materials and Methods: In this retrospective study, [ 68 Ga]Ga-DOTANOC and [ 68 Ga]Ga-DOTA.SA.FAPi PET/CT (computed tomography) images were compared using patient-based and lesion-based analysis in patients with MTC for follow-up assessment. The quantitative assessment included comparing standardized uptake values corrected for lean body mass (SULpeak) and tumor-to-background ratios (TBR). The findings on both scans were validated with the morphological findings of the diagnostic CT. Results: Twenty-seven patients (21 males and 6 females) with a mean age of 42.4 ± 13.2 years (range 14-66 years) were included in the study. [ 68 Ga]Ga-DOTA.SA.FAPi had similar sensitivities as that of [ 68 Ga]Ga-DOTANOC PET/CT for detecting primary tumors (100% [18 of 18] vs. 94.4% [17 of 18], p  = 0.979) involved lymph nodes (98.3% [118 of 120] vs. 95% [114 of 120], p  = 0.288), and brain metastases (100%). [ 68 Ga]Ga-DOTA.SA.FAPi demonstrated significantly higher sensitivities than [ 68 Ga]Ga-DOTANOC PET/CT for detecting lung nodules (93.5% [87 of 93] vs. 68.9% [64 of 93], p  < 0.0001), liver (100% [105 of 105] vs. 46.4% [49 of 105], p  < 0.0001), bone (92.4% [110 of 119] vs. 76.5% [91 of 119], p  = 0.001), and pleural metastases 98.2% versus 0%. Higher uptake values and TBR values were reported with [ 68 Ga]Ga-DOTA.SA.FAPi compared with that of [ 68 Ga]Ga-DOTANOC. Conclusion: [ 68 Ga]Ga-DOTA.SA.FAPi outperformed [ 68 Ga]Ga-DOTANOC PET/CT in the detection of distant metastases with both patient-based and lesion-based analysis in MTCs.

Fibroblast activation protein (FAP) is highly expressed in many tumor types and constitutes a promising target for tumor-specific delivery of therapeutic radionuclides. [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 is a novel radiopharmaceutical based on a novel bidentate inhibitor of FAP that is excreted more slowly than its monomeric counterparts. Still, the efficacy of radiotherapy is mitigated by cascades of DNA damage repair signaling in tumor cells including those via Poly(ADP-ribose) polymerase (PARP). We hereby aimed to evaluate the efficacy of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 in combination with a PARP inhibitor, Olaparib, in the 4T1 murine triple negative breast cancer (TNBC) model. The therapeutic efficacy was visualized using 18 F-FDG and [ 68 Ga]Ga-FAPI-04 positron emission imaging/computer tomography (PET/CT). Our results demonstrated that Olaparib suppressed BALB/3T3 fibroblasts in vitro and sensitized the efficacy of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 in mice bearing 4T1 tumors via enhancement of DNA damage. Treatment-associated toxicity was tolerable with only mild leukopenia. Therefore, the combination of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 and Olaparib is a feasible treatment against TNBC.

Abstract: Metastatic or recurrent adrenocortical carcinoma (ACC) is a potentially fatal malignancy, which poses major challenges in disease management owing to lack of effective systemic therapies. The drastically reduced survival rates require prompt identification of selective molecules for development of targeted therapeutics. We evaluated the squaric acid containing FAPI derivative, DOTA.SA.FAPI (FAPI), as a potential diagnostic probe in 2 cases of histopathologically proven metastatic and recurrent ACC. Both patients underwent 18 F-FDG and 68 Ga-FAPI PET/CT scans for comparative analysis. 68 Ga-DOTA.SA.FAPI emerged as an excellent diagnostic agent for ACC and performed similar to 18 F-FDG., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to compare the diagnostic performance of [ 68 Ga]Ga-DOTA.SA.FAPi with that of [ 18 F]F-FDG PET/CT in detecting primary and metastatic lesions of breast cancer. [ 18 F]F-FDG and [ 68 Ga]Ga-DOTA.SA.FAPi PET/CT scans of histologically proven breast cancer patients were compared according to patient-based and lesion-based analysis. Forty-seven patients with a mean age of 44.8 ± 9.9 years (range: 31-66 years) were evaluated. A total of 85% of patients had invasive ductal carcinoma, and 15% had invasive lobular carcinoma. The tracer uptake [SULpeak, SULavg, and the median tumor-to-background ratio (TBR)] was significantly higher in [ 68 Ga]Ga-DOTA.SA.FAPi than with [ 18 F]F-FDG PET/CT for lymph nodes, pleural metastases, and liver lesions ( p < 0.05). However, for brain metastasis, only the median TBR was significantly higher ( p < 0.05) compared to [ 18 F]F-FDG. In patient-based analysis the sensitivity of [ 68 Ga]Ga-DOTA.SA.FAPi PET/CT was higher, but not significant than that of [ 18 F]F-FDG PET/CT in the detection of both primary tumors and metastatic lesions. According to lesion-based analysis, on diagnostic CT, 47 patients had 44 primary tumors, 248 lymph nodes, 15 pleural, 88 liver, and 42 brain metastases. [ 68 Ga]Ga-DOTA.SA.FAPi scan identified more abnormal lesions than [ 18 F]F-FDG in all the primary and metastatic sites with a maximum marked difference in the primary site [88.6% vs. 81.8%; p -0.001], lymph nodes [89.1% vs. 83.8%; p -0.0001], pleural metastases [93.3% vs. 73%; p -0.096] and brain metastasis [100% vs. 59.5%; p -0.0001]. [ 68 Ga]Ga-DOTA.SA.FAPi PET/CT was superior to [ 18 F]F-FDG PET/CT in the imaging of breast cancers.

Aiming to expand the application of the SST 2 R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH 2 ) beyond [ 68 Ga]Ga-DATA 5m -LM4 PET/CT (DATA 5m , (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA 5 -LM4 (AAZTA 5 , 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [ 111 In]In-AAZTA 5 -LM4 and [ 177 Lu]Lu-AAZTA 5 -LM4 were compared in HEK293-SST 2 R cells and double HEK293-SST 2 R/wtHEK293 tumor-bearing mice using [ 111 In]In-DOTA-LM3 and [ 177 Lu]Lu-DOTA-LM3 as references. The biodistribution of [ 177 Lu]Lu-AAZTA 5 -LM4 was additionally studied for the first time in a NET patient. Both [ 111 In]In-AAZTA 5 -LM4 and [ 177 Lu]Lu-AAZTA 5 -LM4 displayed high and selective targeting of the HEK293-SST 2 R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [ 177 Lu]Lu-AAZTA 5 -LM4 in the patient according to SPECT/CT results in a monitoring time span of 4-72 h pi. In view of the above, we may conclude that [ 177 Lu]Lu-AAZTA 5 -LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST 2 R-expressing human NETs, based on previous [ 68 Ga]Ga-DATA 5m -LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [ 111 In]In-AAZTA 5 -LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available.

Radiolabeled FAPI (fibroblast activation protein inhibitors) recently gained attention as widely applicable imaging and potential therapeutic compounds targeting CAF (cancer-associated fibroblasts) or DAF (disease-associated fibroblasts in benign disorders). Moreover, the use of FAPI has distinct advantages compared to FDG (e.g., increased sensitivity in regions with high glucose metabolism, no need for fasting, and rapid imaging). In this study, we wanted to evaluate the radiochemical synthesis and the clinical properties of the new CAF-targeting tracer [ 68 Ga]Ga-DATA 5m .SA.FAPi. The compound consists of a (radio)chemically easy to use hybrid chelate DATA.SA, which can be labeled at low temperatures, making it an interesting molecule for 'instant kit-type' labeling, and a squaric acid moiety that provides distinct advantages for synthesis and radiolabeling. Our work demonstrates that automatic synthesis of the FAP inhibitor [ 68 Ga]Ga-DATA 5m .SA.FAPi is feasible and reproducible, providing convenient access to this new hybrid chelator-based tracer. Our studies demonstrated the diagnostic usability of [ 68 Ga]Ga-DATA 5m .SA.FAPi for the unambiguous detection of cancer-associated fibroblasts of various carcinomas and their metastases (NSCLC, liposarcoma, parotid tumors, prostate cancer, and pancreas adenocarcinoma), while physiological uptake in brain, liver, intestine, bone, and lungs was very low.

Background and Aims: Initial reports on US COVID-19 showed different outcomes in different races. In this study we use a diverse large cohort of hospitalized COVID-19 patients to determine predictors of mortality., Methods: We analyzed data from hospitalized COVID-19 patients (n = 5852) between March 2020- August 2020 from 8 hospitals across the US. Demographics, comorbidities, symptoms and laboratory data were collected., Results: The cohort contained 3,662 (61.7%) African Americans (AA), 286 (5%) American Latinx (LAT), 1,407 (23.9%), European Americans (EA), and 93 (1.5%) American Asians (AS). Survivors and non-survivors mean ages in years were 58 and 68 for AA, 58 and 77 for EA, 44 and 61 for LAT, and 51 and 63 for AS. Mortality rates for AA, LAT, EA and AS were 14.8, 7.3, 16.3 and 2.2%. Mortality increased among patients with the following characteristics: age, male gender, New York region, cardiac disease, COPD, diabetes mellitus, hypertension, history of cancer, immunosuppression, elevated lymphocytes, CRP, ferritin, D-Dimer, creatinine, troponin, and procalcitonin. Use of mechanical ventilation (p = 0.001), shortness of breath (SOB) (p < 0.01), fatigue (p = 0.04), diarrhea (p = 0.02), and increased AST (p < 0.01), significantly correlated with death in multivariate analysis. Male sex and EA and AA race/ethnicity had higher frequency of death. Diarrhea was among the most common GI symptom amongst AAs (6.8%). When adjusting for comorbidities, significant variables among the demographics of study population were age (over 45 years old), male sex, EA, and patients hospitalized in New York. When adjusting for disease severity, significant variables were age over 65 years old, male sex, EA as well as having SOB, elevated CRP and D-dimer. Glucocorticoid usage was associated with an increased risk of COVID-19 death in our cohort., Conclusion: Among this large cohort of hospitalized COVID-19 patients enriched for African Americans, our study findings may reflect the extent of systemic organ involvement by SARS-CoV-2 and subsequent progression to multi-system organ failure. High mortality in AA in comparison with LAT is likely related to high frequency of comorbidities and older age among AA. Glucocorticoids should be used carefully considering the poor outcomes associated with it. Special focus in treating patients with elevated liver enzymes and other inflammatory biomarkers such as CRP, troponin, ferritin, procalcitonin, and D-dimer are required to prevent poor outcomes., (© 2022. The Author(s).)

Purpose: Masticatory loading triggers active bone remodeling, altering alveolar bone mineral density (BMD). While dental implants are placed to bear masticatory loading, their influence on changing bone properties has not been fully investigated. Objective of this pilot study was to examine whether the dental implantation has an effect on BMD distribution of bone by comparing dentate, edentulous, and edentulous patients with implants., Materials and Methods: Cone beam computed tomography (CBCT) images of 19 partially edentulous patients (Dent), 19 edentulous patients (Edent), and 16 edentulous patients who received implants in the mandible (Edent+Im), were obtained. CBCT images were also obtained from 5 patients within Edent+Im group, before implant placement and after implant loading. Basal cortical bone region of the mandible was digitally isolated. A histogram of gray levels proportional to BMD was obtained to assess mean, histogram standard deviation (HSD), fifth percentile of low and high values (Low 5 and High 5 ) of the BMD distribution. Multivariate analysis of variance and paired t-test were used to compare the BMD parameters among the 3 dental status groups and between pre- and post-implantation, respectively., Results: Edentulous patients with implants had significantly greater HSD and High 5 values compared to edentulous patients ( P < .013). All other comparisons were not significant ( P > .097). Mean, HSD, and High 5 values significantly increased after receiving implants ( P < .022)., Conclusion: The current findings suggested that receiving dental implants promoted oral bone mineralization for edentulous patients. The longitudinal investigation could provide valuable information on understanding the effects of implantation on the behavior of oral bone quality., (© 2022 The Korean Academy of Prosthodontics.)

Abstract: A 56-year-old man was diagnosed with calcitonin negative, plasma chromogranin A-positive, immunohistochemistry-negative, high-grade MTC (medullary thyroid cancer) behaving clinically like anaplastic thyroid cancer and presented with progressive disease after conventional therapies. A theranostic approach of 68Ga-DOTA.SA.FAPi-guided 177Lu-DOTAGA.(SA.FAPi)2 radionuclide therapy was administered on compassionate grounds as per the Declaration of Helsinki because known standard lines of treatment were ineffective. Treatment with a single cycle of 1.65 GBq 177Lu-DOTAGA.(SA.FAPi)2 demonstrated a sustainable reduction in the neck mass with significant improvement in the quality of life of the patient. 177Lu-DOTAGA.(SA.FAPi)2 is a potential theranostic option for high-grade MTC refractory to standard therapeutic options., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Listeria monocytogenes ( Lm ) bacterial ghosts (LMGs) were produced by the minimum inhibitory concentration (MIC) of HCl, H 2 SO 4 , and NaOH. Acid and alkali effects on the LMGs were compared by in vitro and in vivo analyses. Scanning electron microscope showed that all chemicals form lysis pores on the Lm cell envelopes. Real-time qPCR revealed a complete absence of genomic DNA in HCl- and H 2 SO 4 -induced LMGs but not in NaOH-induced LMGs. HCl-, H 2 SO 4 - and NaOH-induced LMGs showed weaker or missing protein bands on SDS-PAGE gel when compared to wild-type Lm . Murine macrophages exposed to the HCl-induced LMGs showed higher cell viability than those exposed to NaOH-induced LMGs or wild-type Lm . The maximum level of cytokine expression (TNF-α, iNOS, IFN-γ, and IL-10 mRNA) was observed in the macrophages exposed to NaOH-induced LMGs, while that of IL-1β mRNA was observed in the macrophages exposed to HCl-induced LMGs. To investigate LMGs as a vaccine candidate, mice were divided into PBS buffer-injected, HCl- and NaOH-induced LMGs immunized groups. Mice vaccinated with HCl- and NOH-induced LMGs, respectively, significantly increased in specific IgG antibodies, bactericidal activities of serum, and CD4 + and CD8 + T-cell population. Antigenic Lm proteins reacted with antisera against HCl- and NOH-induced LMGs, respectively. Bacterial loads in HCl- and NaOH-induced LMGs immunized mice were significantly lower than PBS-injected mice after virulent Lm challenges. It suggested that vaccination with LMGs induces both humoral and cell-mediated immune responses and protects against virulent challenges.

Background: This exploratory study was meant to assess clinical and safety data with a novel fibroblast activation protein inhibitor-based targeted theranostics as a salvage treatment option in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients who had progressed on tyrosine kinase inhibitors. Methods: Patients with metastatic RR-DTC who progressed on sorafenib/lenvatinib were prospectively recruited. If [ 68 Ga]Ga-DOTA.SA.FAPi positron emission tomography/computed tomography scan demonstrated moderate-to-excellent uptake in metastases, and patients had given informed consent, they received intravenous [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 as therapy at eight-weekly intervals. The primary endpoints were thyroglobulin (Tg) response and functional imaging response. The secondary endpoints were visual analog score (VAS) and Eastern Cooperative Oncology Group (ECOG) performance status. The grading of toxicities was performed by using Common Terminology Criteria for Adverse Events (CTCAEV5.0). The sequential images were acquired by a dual-headed gamma camera, and dosimetric calculations were performed by using OLINDA/EXM V2.1. Results: Fifteen patients were recruited [age: 55 ± 9 years (range: 39-67)]. [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 had median whole-body Teff of 88.06 hours (interquartile range [IQR]: 86.6-99). The colon was identified as a critical organ. The whole-body effective dose was 1.62E-01 ± 1.53E-02 mSv/MBq. A total of 45 cycles were administered, and the median cumulative administered activity was 8.2 ± 2.7 GBq (range 5.5-14 GBq). The median absorbed doses to the tumor lesions were 1.08E+01 (IQR: 4.16E+00 to 8.97E+01) mSv/MBq per cycle. The Serum Tg level significantly decreased after treatment [(median Tg: baseline-10,549 ng/mL (IQR: 3066.5-39,450) versus at the time of assessment: 5649 ng/mL (IQR: 939.5-17,099), p  = 0.0005)]. Molecular response assessment revealed no complete response; however, partial response was documented in four, and stable disease in three patients. The VASmax scores [pre-therapy: 9 (IQR: 8-10) versus follow-up: 6 (3-6) ( p -0.0001)], and ECOG [3, (IQR: 2-3 vs. 2, (IQR: 2-3) ( p -0.0078)] performance scores significantly improved after treatment. None of the patients experienced grade III/IV hematological, renal, or hepatotoxicity. Conclusion: These preliminary data suggest that the novel molecule [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 is safe, seems effective, and, most importantly, opens up a new avenue for the treatment of aggressive RR-DTC patients who have exhausted all standard line of treatments.

Several radiopharmaceuticals targeting fibroblast activation protein (FAP) based on the highly potent FAP inhibitor UAMC1110 are currently under investigation. Pre-clinical as well as clinical research exhibited the potential of these imaging agents. However, the monomeric small molecules seemed to have a short retention time in the tumor in combination with fast renal clearance. Therefore, our strategy was to develop homodimeric systems having two FAP inhibitors to improve residence time and tumor accumulation. The homodimers with two squaramide coupled FAP inhibitor conjugates DOTA.(SA.FAPi) 2 and DOTAGA.(SA.FAPi) 2 were synthesized and radiochemically evaluated with gallium-68. [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 was tested for its in vitro stability, lipophilicity and affinity properties. In addition, human PET/CT scans were performed for [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 with a head-to-head comparison with [ 68 Ga]Ga-DOTA.SA.FAPi and [ 18 F]FDG. Labeling with gallium-68 demonstrated high radiochemical yields. Inhibition measurements revealed excellent affinity and selectivity with low nanomolar IC 50 values for FAP. In PET/CT human studies, significantly higher tumor uptake as well as longer tumor retention could be observed for [ 68 Ga]Ga-DOTAGA.(SA.FAPi) 2 compared to [ 68 Ga]Ga-DOTA.SA.FAPi. Therefore, the introduction of the dimer led to an advance in human PET imaging indicated by increased tumor accumulation and prolonged retention times in vivo and thus, the use of dimeric structures could be the next step towards prolonged uptake of FAP inhibitors resulting in radiotherapeutic analogs of FAP inhibitors., Competing Interests: None., (AJNMMI Copyright © 2021.)

A Korean isolate of the sacbrood virus infecting Apis cerana (AcSBV-Kor) is the most destructive honeybee virus, causing serious economic damage losses in Korean apiculture. To address this, here, we attempted to develop an assay for the rapid detection of AcSBV-Kor based on immunochromatographic detection of constituent viral proteins. Genes encoding VP1 and VP2 proteins of AcSBV-Kor were cloned into an expression vector (pET-28a) and expressed in Escherichia coli BL21(DE3). During purification, recombinant VP1 (rVP1) and VP2 (rVP2) proteins were found in the insoluble fraction, with a molecular size of 26.7 and 24.9 kDa, respectively. BALB/c mice immunized with the purified rVP1 and rVP2 produced polyclonal antibodies (pAbs) such as pAb-rVP1 and pAb-rVP2. Western blot analysis showed that pAb-rVP1 strongly reacted with the homologous rVP1 but weakly reacted with heterologous rVP2. However, pAb-rVP2 strongly reacted not only with the homologous rVP2 but also with the heterologous rVP1. Spleen cells of the immunized mice fused with SP2/0-Ag14 myeloma cells produced monoclonal antibodies (mAbs) such as mAb-rVP1-1 and mAb-rVP2-13. Western blot analysis indicated that pAb-rVP1, pAb-rVP2, mAb-rVP1-1, and mAb-rVP2-13 reacted with AcSBV-infected honeybees and larvae as well as the corresponding recombinant proteins. These antibodies were then used in the development of a rapid immunochromatography (IC) strip assay kit with colloidal gold coupled to pAb-rVP1 and pAb-rVP2 at the conjugate pad and mAb-rVP1-1 and mAb-rVP2-13 at the test line. One antibody pair, pAb-rVP1/mAb-VP1-1, showed positive reactivity as low as 1.38 × 10 3 copies, while the other pair, pAb-rVP2/mAb-VP2-13, showed positive reactivity as low as 1.38 × 10 4 copies. Therefore, the antibody pair pAb-rVP1/mAb-VP1-1 was selected as a final candidate for validation. To validate the detection of AcSBV, the IC strip tests were conducted with 50 positive and 50 negative samples and compared with real-time PCR tests. The results confirm that the developed IC assay is a sufficiently sensitive and specific detection method for user-friendly and rapid detection of AcSBV.

Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [ 68 Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [ 177 Lu]Lu-DOTA.SA.FAPi, and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 in patients with various cancers. The FAPi agents, [ 177 Lu]Lu-DOTA.SA.FAPi and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 , were administered in two different groups of patients. Three patients (mean age-50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2-3 GBq) [ 177 Lu]Lu-DOTA.SA.FAPi and seven (mean age-51 years) were treated with 1.48 GBq (IQR: 0.6-1.5) of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 . Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [ 177 Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [ 177 Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [ 177 Lu]Lu-DOTA.SA.FAPi ( p < 0.011). [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 had significantly longer median whole-body Te compared to that of [ 177 Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5-70.1) vs. 23.1 h (IQR: 17.8-31.5); p -0.0167]. The Te of tumor lesions was significantly higher for [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 compared to [ 177 Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3-94.6) vs. 14 h (IQR: 12.8-15.5); p -0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230-1.810) Gy/GBq and 6.70 (IQR: 3.40-49) Gy/GBq dose per cycle in the [ 177 Lu]Lu-DOTA.SA.FAPi, and [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 compared to [ 177 Lu]Lu-DOTA.SA.FAPi. [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.

Background: The coronavirus disease 2019 (COVID-19) disproportionately affected African Americans (AA) and Hispanics (HSP)., Aim: To analyze the significant effectors of outcome in African American patient population and make special emphasis on gastrointestinal (GI) symptoms, laboratory values and comorbidities., Methods: We retrospectively evaluated the medical records of 386 COVID-19 positive patients admitted at Howard University Hospital between March and May 2020. We assessed the symptoms, including the GI manifestations, comorbidities, and mortality, using logistic regression analysis., Results: Of these 386 COVID-19 positive patients, 257 (63.7%) were AAs, 102 (25.3%) HSP, and 26 (6.45%) Whites. There were 257 (63.7%) AA, 102 (25.3%) HSP, 26 (6.45%) Whites. The mean age was 55.6 years (SD = 18.5). However, the mean age of HSP was the lowest (43.7 years vs 61.2 for Whites vs 60 for AAs). The mortality rate was highest among the AAs (20.6%) and lowest among HSP (6.9%). Patients with shortness of breath (SOB) (OR2 = 3.64, CI = 1.73-7.65) and elevated AST (OR2 = 8.01, CI = 3.79-16.9) elevated Procalcitonin (OR2 = 8.27, CI = 3.95-17.3), AST (OR2 = 8.01, CI = 3.79-16.9), ferritin (OR2 = 2.69, CI = 1.24-5.82), and Lymphopenia (OR2 = 2.77, CI = 1.41-5.45) had a high mortality rate. Cough and fever were common but unrelated to the outcome. Hypertension and diabetes mellitus were the most common comorbidities. Glucocorticoid treatment was associated with higher mortality (OR2 = 5.40, CI = 2.72-10.7). Diarrhea was prevalent (18.8%), and GI symptoms did not affect the outcome., Conclusion: African Americans in our study had the highest mortality as they consisted of an older population and comorbidities. Age is the most important factor along with SOB in determining the mortality rate. Overall, elevated liver enzymes, ferritin, procalcitonin and C-reactive protein were associated with poor prognosis. GI symptoms did not affect the outcome. Glucocorticoids should be used judiciously, considering the poor outcomes associated with it. Attention should also be paid to monitor liver function during COVID-19, especially in AA and HSP patients with higher disease severity., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this paper., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Over the past decade, the tumor microenvironment (TME) has become a new paradigm of cancer diagnosis and therapy due to its unique biological features, mainly the interconnection between cancer and stromal cells. Within the TME, cancer-associated fibroblasts (CAFs) demonstrate as one of the most critical stromal cells that regulate tumor cell growth, progression, immunosuppression, and metastasis. CAFs are identified by various biomarkers that are expressed on their surfaces, such as fibroblast activation protein (FAP), which could be utilized as a useful target for diagnostic imaging and treatment. One of the advantages of targeting FAP-expressing CAFs is the absence of FAP expression in quiescent fibroblasts, leading to a controlled targetability of diagnostic and therapeutic compounds to the malignant tumor stromal area using radiolabeled FAP-based ligands. FAP-based radiopharmaceuticals have been investigated strenuously for the visualization of malignancies and delivery of theranostic radiopharmaceuticals to the TME. This review provides an overview of the state of the art in TME compositions, particularly CAFs and FAP, and their roles in cancer biology. Moreover, relevant reports on radiolabeled FAP inhibitors until the year 2021 are highlighted-as well as the current limitations, challenges, and requirements for those radiolabeled FAP inhibitors in clinical translation.

Aim: Gallium-68-labelled inhibitors of the fibroblast activation protein (FAPi) enable positron emission tomography/computed tomography (PET/CT) imaging of fibroblast activation. We evaluated if [ 68 Ga]Ga-DATA5m.SA.FAPi PET/CT is related to Ki-67 as a marker of tumour aggressiveness in patients with liver metastases of NET., Methods: Thirteen patients with liver metastases of a histologically confirmed NET who underwent PET/CT with [ 68 Ga]Ga-DATA5m.SA.FAPi, [18F]FDG and [ 68 Ga]Ga-DOTA-TOC were retrospectively analyzed. PET-positive liver tumour volumes were segmented for calculation of volume, SUVmax and PET-positive tumour fraction (TF). PET parameters were correlated with Ki-67., Results: FDG SUVmax correlated positively (rho = 0.543, p < 0.05) and DOTATOC SUVmax correlated negatively (rho = -0.618, p < 0.05) with Ki-67, the correlation coefficients were in the moderate range. There was no significant correlation between FAPi SUVmax and Ki-67 (rho = 0.382, p > 0.05). FAPi TF correlated positively (rho = 0.770, p < 0.01) and DOTATOC TF correlated negatively (rho = -0.828, p < 0.01) with Ki-67, both significantly with high correlation coefficients. FDG TF also correlated significantly with Ki-67, with a moderate correlation coefficient (rho = 0.524, p < 0.05). The ratio FAPi VOL :DOTATOC VOL showed a significant and strong correlation with Ki-67 (rho = 0.808, p < 0.01)., Conclusion: The ratio FAPi VOL :DOTATOC VOL might serve as a clinical parameter for the assessment of dedifferentiation and aggressiveness of liver metastases in patients with NET. [ 68 Ga]Ga-DATA5m.SA.FAPi might hold potential for identification of high-risk patients. Further studies are warranted to evaluate its prognostic significance in comparison to [ 18 F]FDG in patients with NET., Competing Interests: Financial interests: RAB is a consultant for Bayer Healthcare (Leverkusen, Germany) and Eisai GmbH (Frankfurt, Germany). RAB has received speaker honorarium from Mediso Medical Imaging Systems Ltd., (Budapest, Hungary). ME is a consultant to Bayer, Novartis, Eisai and Ipsen. Non-financial interests: RAB has a non-commercial research agreement with Mediso Medical Imaging Systems Ltd., (Budapest, Hungary). Funding: The authors did not receive support from any organization for the submitted work., (Thieme. All rights reserved.)

Targeting vectors bound to a chelator represent a significant fraction of radiopharmaceuticals used nowadays for diagnostic and therapeutic purposes in nuclear medicine. The use of squaramides as coupling units for chelator and targeting vector helps to circumvent the disadvantages of several common coupling methods. This review gives an overview of the use of squaric acid diesters (SADE) as linking agents. It focuses on the conjugation of cyclic chelators, e.g., DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), as well as hybrid chelators like AAZTA 5 (6-pentanoic acid-6-amino-1,4-diazepine tetracetic acid) or DATA 5m (6-pentanoic acid-6-amino-1,4-diazapine-triacetate) to different targeting vectors, e.g., prostate-specific membrane antigen inhibitors (KuE; PSMAi), fibroblast activation protein inhibitors (FAPi), and monoclonal antibodies (mAbs). An overview of the synthesis, radiolabeling, and in vitro and in vivo behavior of the described structures is given. The unique properties of SADE enable a fast and simple conjugation of chelators to biomolecules, peptides, and small molecules under mild conditions. Furthermore, SA-containing conjugates could not only display similar in vitro characteristics in terms of binding affinity when compared to reference compounds, but may even induce beneficial effects on the pharmacokinetic properties of these radiopharmaceuticals.

Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA 5m .SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [ 68 Ga]Ga-DOTA.SA.FAPi, the first patient studies were realized for both compounds. Here, we present a new squaramide-containing compound targeting FAP, based on the AAZTA 5 chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA 5 .SA.FAPi), complexation with radionuclides such as gallium-68, scandium-44, and lutetium-177 was investigated, and the in vitro properties of the complexes were characterized and compared with those of DOTA.SA.FAPi. AAZTA 5 .SA.FAPi and its derivatives labelled with non-radioactive isotopes demonstrated similar excellent inhibitory potencies compared to the previously published SA.FAPi ligands, i.e., sub-nanomolar IC 50 values for FAP and high selectivity indices over the serine proteases PREP and DPPs. Labeling with all three radiometals was easier and faster with AAZTA 5 .SA.FAPi compared to the corresponding DOTA analogue at ambient temperature. Especially, scandium-44 labeling with the AAZTA derivative resulted in higher specific activities. Both DOTA.SA.FAPi and AAZTA 5 .SA.FAPi showed sufficiently high stability in different media. Therefore, these FAP inhibitor agents could be promising for theranostic approaches targeting FAP.

Purpose: [ 68 Ga]Ga-labeled fibroblast activation protein inhibitors ([ 68 Ga]Ga-FAPi) have shown promising preclinical and clinical results in PET imaging. The present study aimed to evaluate the biodistribution, pharmacokinetics, and dosimetry of [ 68 Ga]Ga-DOTA.SA.FAPi, another modified FAPi tracer, and performed a head-to-head comparison with [ 18 F]F-FDG PET/CT scans in patients with various cancers., Methods: In this prospective study, patients underwent both [ 18 F]F-FDG and [ 68 Ga]Ga-DOTA.SA.FAPi PET/CT scans 60 min post-injection (p.i.). Dosimetry studies were conducted in three patients using [ 68 Ga]Ga-DOTA.SA.FAPi serial time-point imaging. The absorbed dose was calculated using OLINDA/EXM 2.2 software. Quantification of the uptake of the tracers was assessed using standardized uptake values corrected for lean body mass (SUL)., Results: Fifty-four patients (mean age; 48.4 years) with 14 types of cancers involving 37% breast, 24% lung, 7.4% head and neck (H&N), and remaining 31.6% patients with other histologies were evaluated prospectively. Physiological uptake of [ 68 Ga]Ga-DOTA.SA.FAPi was observed in the liver, kidneys, pancreas, heart contents, and to a lesser extent in the lacrimals, oral mucosa, salivary glands, and thyroid glands. Uptake in the target lesions on [ 68 Ga]Ga-DOTA.SA.FAPi scan was initiated at 10 min, and no additional lesions were detected in the delayed acquisition time points. The pancreas was the organ with the highest absorbed dose (5.46E-02 mSv/MBq). While the patient-based comparison between the radiotracers revealed complete concordance in the detection of primary, pleural thickening, bone and liver metastases, and second primary malignancy, discordant findings were observed in the detection of lymph node (7.5%), lung nodules (5.6%), and brain metastases (2%). According to the site of primary disease, patients with H&N cancers demonstrated the highest SULpeak and average (avg) values on [ 68 Ga]Ga-DOTA.SA-FAPi which was similar to the values of [ 18 F]F-FDG [(SULpeak: 15.4 vs. 14.2; P-0.680) (SULavg: 8.3 vs. 7.9; P-0.783)]. The lowest uptake was observed in lung cancers with both the radiotracers [(SULpeak: 5.8 vs. 7.4; P-0.238) (SULavg: 4.9 vs. 5.3; P-0.313)]. A significantly higher SULpeak and SULavg for brain metastases to normal brain parenchyma ratios were observed on [ 68 Ga]Ga-DOTA.SA.FAPi in contrast to the [ 18 F]F-FDG values {SULpeak: median: 59.3 (IQR: 33.5-130.8) versus 1.5 (1-2.3); P-0.028}. Except for brain metastases, comparable SULpeak and average values were noted between the radiotracers in all other regions of metastases with no significant difference., Conclusion: [ 68 Ga]Ga-DOTA.SA.FAPi is a promising alternative among the FAPI class of molecules and performed well as compared to standard-of-care radiotracer [ 18 F]F-FDG in the diagnosis of various cancers.

Background: Combining the advantages of both cyclic and acyclic chelator systems, AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) is well suited for complexation of various diagnostic and therapeutic radiometals such as gallium-68, scandium-44 and lutetium-177 under mild conditions. Due to its specificity for primary amines and pH dependent binding properties, squaric acid (SA) represents an excellent tool for selective coupling of the appropriate chelator to different target vectors. Therefore, the aim of this study was to evaluate radiolabeling properties of the novel bifunctional AAZTA 5 -SA being coupled to a model antibody (bevacizumab) in comparison to DOTA-SA, DTPA-p-Bn-SA and CHX-A″-DTPA-p-Bn-SA using the therapeutic nuclide lutetium-177., Methods and Results: As proof-of-concept, bevacizumab was first functionalized with AAZTA 5 -SA, DOTA-SA, DTPA-p-Bn-SA or CHX-A″-DTPA-p-Bn-SA. After purification via fractionated size exclusion chromatography (SEC), the corresponding immunoconjugates were subsequently radiolabeled with lutetium-177 at pH 7 and room temperature (RT) as well as 37 °C. After 90 min, labeling of AAZTA 5 -SA-mAb resulted in almost quantitative radiochemical yields (RCY) of >98% and >99%, respectively. Formation of [ 177 Lu]Lu-DTPA-p-Bn-SA-mAb indicated rapid labeling kinetics reaching similar yields at RT already after 30 min. Fast but incomplete radiolabeling of the CHX-A″-analogue could be observed with a yield of 74% after 10 min and no further significant increase. In contrast, 177 Lu-labeling of DOTA-SA-mAb showed negligible radiochemical yields of <2% both at room temperature and 37 °C. In vitro complex stability measurements of [ 177 Lu]Lu-AAZTA 5 -SA-mAb at 37 °C indicated >94% protein bound activity in human serum and >92% in phosphate buffered saline (PBS), respectively within 15 days. [ 177 Lu]Lu-DTPA-p-Bn-SA-mAb and [ 177 Lu]Lu-CHX-A″-DTPA-p-Bn-SA-mAb revealed similar to even slightly higher in vitro stability in both media., Conclusion: Coupling of AAZTA 5 -SA to the monoclonal antibody bevacizumab allowed for 177 Lu-labeling with almost quantitative radiochemical yields both at room temperature and 37 °C. Within 15 days, the resulting radioconjugate indicated very high in vitro complex stability both in human serum and PBS. Therefore, AAZTA 5 -SA is a promising tool for 177 Lu-labeling of sensitive biomolecules such as antibodies for theranostic applications., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

44 Sc is an increasingly investigated positron emitter for use in positron emission tomography (PET) imaging. However, 44 Sc is a non-pure positron emitter, since prompt photons are co-emitted during the decay process. This study investigates coincidence energy spectra of 44 Sc and its impact on PET quantification on a preclinical and clinical PET system in comparison with 18 F. The raw data of the coincidence events revealed characteristic differences comparing the photon energy distribution of 44 Sc and 18 F. Due to prompt gamma emission of 44 Sc, activity recovery is underestimated on PET systems. However, clinical PET imaging of 44 Sc with acceptable quantitative accuracy appears feasible by using a single, constant correction factor., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Gastrin Releasing Peptide receptor (GRPr)-based radioligands have shown great promise for diagnostic imaging of GRPr-positive cancers, such as prostate and breast. The present study aims at developing and evaluating a versatile GRPr-based probe for both PET/SPECT imaging as well as intraoperative and therapeutic applications. The influence of the versatile chelator AAZTA 5 on the radiometal labelling properties and the in vitro performance of the generated radiotracers were thoroughly investigated. The GRPr-based antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 was functionalized with the chelator 6-[Bis (carboxymethyl)amino]-1,4-bis (carboyxmethyl)-6-methyl-1,4-diazepane (AAZTA 5 ) through the spacer 4-amino-1-carboxymethyl-piperidine (Pip) to obtain AAZTA 5 -Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 (LF1). LF1 was radiolabelled with gallium-68 (PET), indium-111 (SPECT, intraoperative applications) and lutetium-177 (therapy, SPECT). In vitro evaluation included stability studies, determination of lipophilicity, protein-binding studies, determination of K d and B max as well as internalization studies using the epithelial human prostate cancer cell line PC3. In vitro monotherapy as well as combination therapy studies were further performed to assess its applicability as a theranostic compound., Results: LF1 was labelled with gallium-68, indium-111 and lutetium-177 within 5 min at room temperature (RT). The apparent molar activities (A m ) were ranging between 50 and 60 GBq/μmol for the 68 Ga-labelled LF1, 10-20 GBq/μmol for the 111 In- and 177 Lu-labelled LF1. The radiotracers were stable for a period of 4 h post labeling exhibiting a hydrophilic profile with an average of a LogD octanol/PBS of - 3, while the bound activity to the human serum protein was approximately 10%. 68/nat Ga-LF1, 177/nat Lu-LF1 and 111/nat In-LF1 exhibited high affinity for the PC3 cells, with K d values of 16.3 ± 2.4 nM, 10.3 ± 2.73 nM and 5.2 ± 1.9 nM, respectively, and the required concentration of the radiotracers to saturate the receptors (B max ) was between 0.5 and 0.8 nM which corresponds to approximately 4 × 10 5 receptors per cell. Low specific internalization rate was found in cell culture, while the total specific cell surface bound uptake always exceeded the internalized activity. In vitro therapy studies showed that inhibition of PC3 cells growth is somewhat more efficient when combination of 177 Lu-labelled LF1 with rapamycin is applied compared to 177 Lu-laballed LF1 alone., Conclusion: Encouraged by these promising in vitro data, preclinical evaluation of the LF1 precursor are planned in tumour models in vivo.