Head-to-Head Comparison of SSTR Antagonist [68Ga]Ga-DATA5m-LM4 with SSTR Agonist [68Ga]Ga-DOTANOC PET/CT in Patients with Well Differentiated Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Imaging Study.

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 [68Ga]Ga-DOTANOC and [68Ga]Ga-DATA5m-LM4 in the detection of primary and metastatic lesions in patients with well differentiated gastroenteropancreatic (GEP) NETs. Histologically proven GEP-NET patients underwent [68Ga]Ga-DOTANOC & [68Ga]Ga-DATA5m-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 [68Ga]Ga-DATA5m-LM4 PET/CT was 94.28% (462/490) and 83.46% (409/490) for [68Ga]Ga-DOTANOC PET/CT (p < 0.0001). [68Ga]Ga-DATA5m-LM4 had statistical significance over [68Ga]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. [68Ga]Ga-DATA5m-LM4 showed better sensitivity and a higher target-to-background ratio than [68Ga]Ga-DOTANOC PET/CT. [68Ga]Ga-DATA5m-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.

[177Lu]Lu-PSMA-617 as first-line systemic therapy in patients with metastatic castration-resistant prostate cancer: a real-world study.

PURPOSE: The use of [177Lu]Lu-PSMA-617 radioligand therapy has become increasingly recognized as a viable therapeutic approach for patients in the advanced stages of metastatic castration-resistant prostate cancer (mCRPC). However, there is limited data regarding its effectiveness and safety in earlier lines. This study aims to present our institution's experience with [177Lu]Lu-PSMA-617 as a first-line systemic therapy for mCRPC. METHODS: We collected and analyzed data from consecutive mCRPC patients who underwent first-line treatment with [177Lu]Lu-PSMA-617 at our center from 2015 to 2023. The various outcome measures included best prostate-specific antigen-response rate (PSA-RR) (proportion of patients achieving a ≥ 50% decline in PSA); objective radiographic response rate (ORR) (proportion of patients achieving complete or partial radiographic responses); radiographic progression-free survival (rPFS) (measured from treatment initiation until radiographic progression or death from any cause); overall survival (OS) (measured from treatment initiation until death from any cause); and adverse events. RESULTS: Forty treatment-naïve mCRPC patients with PSMA-positive disease on [68Ga]Ga-PSMA-11 PET/CT were included (median age: 68.5 years, range: 45-78; median PSA: 41 ng/mL, range: 1-3028). These patients received a median cumulative activity of 22.2 GBq (range: 5.55-44.4) [177Lu]Lu-PSMA-617 over 1-6 cycles at 8-12 week intervals. A ≥ 50% decline in PSA was observed in 25/40 (62.5%) patients (best PSA-RR). Radiographic responses were evaluated for thirty-eight patients, with thirteen showing partial responses (ORR 34.2%). Over a median follow-up of 36 months, the median rPFS was 12 months (95% confidence interval, CI: 9-15), and the median OS was 17 months (95% CI: 12-22). Treatment-emergent grade ≥ 3 anemia, leucopenia, and thrombocytopenia were noted in 4/40 (10%), 1/40 (2.5%), and 3/40 (7.5%) patients, respectively. CONCLUSION: The findings suggest that [177Lu]Lu-PSMA-617 is a safe and effective option as a first-line treatment in mCRPC. Further trials are needed to definitively establish its role as an upfront treatment modality in this setting.

Optimal Cumulative I-131 Activity in Metastatic Differentiated Thyroid Cancer: Balancing Efficacy and Adverse Events.

BACKGROUND: The optimal cumulative activity (CA) of I-131 therapy for patients with metastatic differentiated thyroid cancer (mDTC) remains contentious. This study aimed to determine the maximum CA of I-131 that could be administered without a significant increase in adverse events (AEs) by analyzing a long-term cohort of patients. METHODS: Data from mDTC patients treated with I-131 therapy and followed for at least two years from 1967 to 2019 were reviewed. Patients were categorized into three groups based on the received CA: Group-A (≤600mCi), Group-B (>600-1000mCi), and Group-C (>1000mCi). The study assessed long-term AEs and survival outcomes. RESULTS: The study included 671 adult mDTC patients (mean age 48 years, range: 19-81) with a median follow-up of 122 months (IQR: 82-180). Group A, Group B, and Group C comprised 269 (40.0%), 212 (31.6%), and 190 (28.4%) patients, respectively. Ten-year survival rates were 72%, 42.7%, and 29% in Groups A, B, and C, respectively. A total of 40/671 (6%) AEs were observed in 38 patients: 3 (1.1%), 12 (5.7%), and 25 (13.2%) in Groups A, B, and C, respectively. Five patients developed second primary malignancy (SPM): 3 in Group A and one each in Group B and C. However, CA >1000mCi of I-131 was associated with significant increase in bone marrow suppression, decreased pulmonary function, and xerostomia (p < 0.001). CONCLUSIONS: The study suggests that a maximum CA of up to 1000mCi strikes a favorable balance between keeping AEs low and benefiting a subset of patients with extensive metastases showing intense I-131 concentration.

[177Lu]Lu-DOTAGA.Glu.(FAPi)2 Radionuclide Therapy: a New Treatment Option for Patients with Glioblastoma Multiforme.

In this case report, we present the clinical management of a 52-year-old female patient with a recurrent right temporo-parietal glioblastoma multiforme (GBM). The patient presented with symptoms of headache and loss of balance and recurrence on magnetic resonance imaging (MRI). To evaluate the fibroblast activation protein inhibitor (FAPi) expression in the recurrent lesion, an exploratory [68 Ga]Ga-DOTA.SA.FAPi PET/CT scan was performed. The imaging results revealed FAPi expression in the lesion located in the right temporo-parietal region. Based on the findings of FAPi expression, the patient underwent [177Lu]Lu-DOTAGA.Glu.(FAPi)2 treatment. After completing two cycles of [177Lu]Lu-DOTAGA.Glu.(FAPi)2 therapy, a follow-up [68 Ga]Ga-DOTA.SA.FAPi PET/CT scan was conducted. The post-treatment imaging showed a significant reduction in FAPi uptake and regression in the size of the lesion, as well as a decrease in perilesional edema, as observed on the MRI. Furthermore, the patient experienced an improvement in symptoms and performance status. These results suggest that [68 Ga]Ga-DOTA.SA.FAPi monomer imaging and [177Lu]Lu-DOTAGA.Glu.(FAPi)2 dimer therapeutics hold promise for patients with recurrent GBM when other standard-line therapeutic options have been exhausted. This case highlights the potential of using FAPi-based theranostics in the management of recurrent GBM, providing a potential avenue for personalized treatment in patients who have limited treatment options available.

Promising Therapeutic Activity of 177 Lu-PSMA-617 in Synchronous High-Volume Metastatic Hormone-Sensitive Prostate Cancer : A Pilot Experience.

PURPOSE: 177 Lu-PSMA-617 has been shown to improve survival outcomes in patients with end-stage metastatic castration-resistant prostate cancer. However, data in earlier lines remain limited. In this study, we intended to evaluate the efficacy and safety of 177 Lu-PSMA-617 in patients with synchronous high-volume metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS: Hormone-sensitive prostate cancer patients with synchronous high-volume metastases (defined as ≥4 skeletal metastases with ≥1 extra-axial site or any visceral metastasis) showing high PSMA expression on 68 Ga-PSMA-11 PET/CT and ineligible/unwilling for conventional chemohormonal treatment options were selected. Approximately, ~5.55-7.4 GBq of 177 Lu-PSMA-617 was administered intravenously at 8-12 weeks intervals, up to 6 cycles. All patients underwent concomitant androgen deprivation therapy/orchiectomy. The outcome measures included the proportion of patients achieving an undetectable serum prostate-specific antigen (PSA) (ie, ≤0.2 ng/mL) at any time point after therapy, best PSA response rate, objective radiographic response rate, radiographic progression-free survival, overall survival, and adverse events. RESULTS: Ten patients with high-volume mHSPC received a median cumulative activity of 32.4 GBq (range, 7.4-44.4) of 177 Lu-PSMA-617 over 1-6 cycles. Five patients (50%) achieved an undetectable PSA with 9 patients (90%) showing a ≥50% decline in PSA from baseline. Nine patients underwent radiological follow-up, of which 7 (77.8%) had an objective response. The median radiographic progression-free survival was 24 months (95% confidence interval, 18-30), whereas the median overall survival was not reached. None of the patients had any grade 3/4 adverse event. CONCLUSIONS: 177 Lu-PSMA-617 seems to be a promising efficacious and safe treatment option for patients with synchronous high-volume mHSPC.

Therapeutic potential of [177Lu]Lu-DOTAGA-FAPi dimers in metastatic breast cancer patients with limited treatment options: efficacy and safety assessment.

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 18F-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 [177Lu]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 [177Lu]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 [177Lu]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 [177Lu]Lu-DOTAGA.FAPi dimer therapy is well-tolerated, safe, and effective for treating end-stage metastatic breast cancer patients. [177Lu]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.

Complete Response to 177 Lu-DOTATATE PRRT in a 9-Year-Old Child With Metastatic Carotid Body Paraganglioma.

ABSTRACT: We present a case involving a 9-year-old boy diagnosed with metastatic carotid body paraganglioma. The metastases were detected in cervical lymph nodes and lungs using 68 Ga-DOTANOC PET/CT imaging. The patient received peptide receptor radionuclide therapy with 177 Lu-DOTATATE. Following 3 treatment cycles, a significant improvement was observed in the metastatic lesions. After 4 cycles, the patient achieved a complete response, with a cumulative administered activity of 16.65 GBq during the therapy. This case underscores the effectiveness of using 177 Lu-DOTATATE in managing metastatic carotid body paraganglioma, offering promising results in terms of tumor regression and overall therapeutic response.

A long-term retrospective cohort-based risk-benefit analysis of augmenting total cumulative I-131 activity to 37GBq in differentiated thyroid cancer patients with skeletal metastases.

OBJECTIVE: Skeletal metastases in differentiated thyroid cancer (DTC) patients are associated with poor prognosis. The objective was to determine the maximum I-131 cumulative activity that could be safely administered without compromising efficacy. The secondary objective was to identify other prognostic factors affecting survival outcomes. MATERIALS AND METHODS: This was a retrospective cohort study done at a tertiary-care institution comprising of data from January 1990-June 2020. 489 DTC patients having skeletal metastases with ≥12 months follow-up were included. Ninety-six percent of patients had thyroidectomy followed by radioiodine therapy for skeletal metastases. All patients were on oral suppressive levothyroxine tablets. External beam radiotherapy (EBRT) and oral tyrosine kinase inhibitors were used whenever indicated. The main outcome measures were overall survival (OS), progression-free survival (PFS), and adverse-events. RESULTS: There were 347 (71%) females and 324 (66%) had follicular carcinoma thyroid. Median follow-up was 78 (interquartile range, IQR: 37-153) months. 333 patients (68%) received ≤37GBq I-131 cumulative activity (group 1) and 156 patients (32%) received >37GBq cumulative RAI activity (group 2). Overall median OS and PFS were 74 (95% confidence interval (CI): 62.2-85.8) and 48 (95%CI: 40.5-55.4) months, respectively. The 5-, 10-, 15- and 20-year estimated overall survival probabilities were 55.7%, 28.4%, 14% and 8.3%, respectively. On multivariate analysis, age(<55years) (p<0.001), female gender(p = 0.01), cumulative I-131 activity >37GBq (p<0.001) and EBRT(p = 0.001) were favourably associated with OS; no factors were significantly associated with PFS. The median OS for groups 1 & 2 were 51 versus 90 months (p<0.001) & median PFS for groups 1 & 2 were 45 versus 53 months respectively (p = 0.9). However, cumulative activity >37GBq resulted in more adverse events (2.4%), particularly bone marrow suppression (3.5%). CONCLUSION: For better survival outcomes, cumulative I-131 activity upto 37GBq could be administered with acceptable toxicity to DTC patients with skeletal metastases.

Head-to-head comparison of [68Ga]Ga-DOTA.SA.FAPi with [18F]F-FDG PET/CT in radioiodine-resistant follicular-cell derived thyroid cancers.

PURPOSE: In the context of radioiodine-resistant follicular-cell derived thyroid cancers (RAI-R-FCTC), [18F]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 [68Ga]Ga-DOTA.SA.FAPi and [18F]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 [68Ga]Ga-DOTA.SA.FAPi and [18F]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. [68Ga]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 [18F]F-FDG. The detection rates for pleural and bone metastases were similar between the two radiotracers. For lung metastases, [68Ga]Ga-DOTA.SA.FAPi showed a detection rate of 81.7%, whereas [18F]F-FDG had a detection rate of 64.6%. Remarkably, [68Ga]Ga-DOTA.SA.FAPi was able to detect a bowel metastasis that was missed on [18F]F-FDG scan. The median standardized uptake values (SUL) were generally comparable between the two radiotracers, except for brain metastases (SULpeak [68Ga]Ga-DOTA.SA.FAPi vs. [18F]F-FDG: 13.9 vs. 6.7, p-0.0001) and muscle metastases (SULpeak [68Ga]Ga-DOTA.SA.FAPi vs. [18F]F-FDG: 9.56 vs. 5.62, p-0.0085), where [68Ga]Ga-DOTA.SA.FAPi exhibited higher uptake. CONCLUSION: The study results demonstrate the superior performance of [68Ga]Ga-DOTA.SA.FAPi compared to [18F]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 [68Ga]Ga-DOTA.SA.FAPi as a theranostic tool that can complement the benefits of [18F]F-FDG PET/CT in the imaging of RAI-R-FCTC.

Radioiodine versus no radioiodine outcomes in low-risk differentiated thyroid cancers: A propensity-score matched analysis.

OBJECTIVE: The 2015 American Thyroid Association guidelines recommend against radioiodine (RAI) ablation for patients with low-risk papillary microcarcinoma. However, its role in other low-risk differentiated thyroid cancer (DTC) patients remains controversial. Here, we compare long-term outcomes with RAI versus no-RAI in a large cohort comprising all low-risk DTCs. METHODS: Patients with low-risk, histologically-proven DTC post-thyroidectomy, treated with RAI or kept on follow-up without RAI, between 1990 and 2019 were included. The main outcomes included recurrence rate and recurrence-free survival (RFS), and were validated by propensity-score matching analysis. RESULTS: Of the 2074 low-risk DTC patients (median age: 35 years), 1686 patients underwent RAI-ablation (RAI group), while 388 patients underwent no-RAI follow-up (NOI group). Over a median follow-up of 8 years (range: 3-29), the recurrence rates were similar between the RAI and NOI groups (2.0% vs. 3.3%, p = .161). The 5- and 10-year RFS probabilities were 99.2% and 97.4%, respectively in RAI group versus 98.4% and 96.2%, respectively, in NOI group (p = .055). Subgroup regression analyses showed that patients with age <55 years (p = .044), male sex (p = .015), papillary histology (p = .043), pT3a tumours (p = .049) and postoperative thyroglobulin ≥5 ng/mL (p = .002) had significantly better RFS with RAI compared to NOI follow-up. Propensity-score matching generated 776 matched pairs with no significantly different outcomes between the two groups. CONCLUSIONS: In low-risk DTC patients post-thyroidectomy, RAI ablation does not confer significant survival advantage over no-RAI follow-up. Further studies are required to demonstrate any long-term benefit with RAI, specifically in patients with tumour size >4 cm and elevated postoperative thyroglobulin.

Appropriateness of 14-year cutoff in pediatric differentiated thyroid cancer: Comparison of clinical characteristics and long-term outcomes in 14 years and younger and 15-18 years age groups.

BACKGROUND: Pediatric differentiated thyroid cancers (DTCs) differ in pathophysiology, presentation, and clinical outcomes from adult DTCs. However, the cutoff age for defining pediatric DTCs remains debatable, with the American Thyroid Association (ATA) and International Incidence of Childhood Cancer (IICC) report recommending different cutoffs of 18 and 14 years, respectively. In this study, we investigated the appropriateness of 14-year cutoff by comparing the clinical characteristics and long-term outcomes in the 14 years and younger and 15-18 years age groups. METHODS: Data of DTC patients, aged 18 years and older, from 1981 to 2016, were sequentially extracted and compared between two age groups: ≤14 and 15-18 years. RESULTS: Total of 176 pediatric DTC patients were included (age group ≤14 years: n = 75; age group 15-18 years: n = 101). None of the baseline clinical characteristics were significantly different between the two age groups. At 2-year follow-up, patients in the age group ≤14 years had significantly higher incomplete response rate compared to those in the age group 15-18 years (69% vs. 42%, respectively, p < .001). However, over a median follow-up of 10.6 years (interquartile range: 7.7-15.5), the 5- and 10-year Disease-free survival (DFS) probabilities were not significantly different (p = .406). On multivariate analysis, incomplete response at 2-year follow-up was the sole independent predictor of poor DFS (hazard ratio: 5.85, 95% confidence interval: 1.69-20.23). CONCLUSIONS: Subdivision of pediatric DTCs into less than or equal to 14 years and 15-18 years age groups did not have any long-term predictive value. The cutoff of 18 years as recommended by ATA is reasonable and should be uniformly followed to avoid inconsistencies and confusion.

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study.

PURPOSE: Despite the existence of various treatment options, the prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unfavorable. One potential therapeutic approach is the use of [225Ac]Ac-PSMA-617, a targeted alpha therapy (TAT) that administers alpha-particle radiation specifically to prostate cancer cells expressing PSMA. In this study, we report the long-term survival outcomes of this novel therapy in a series of patients with mCRPC who have exhausted all standard treatment options. METHODS: The study enrolled patients with mCRPC who had shown resistance to standard lines of therapies, including next-generation anti-androgen therapies and taxane-based chemotherapies. These eligible patients received treatment with [225Ac]Ac-PSMA-617 at 100-150 kBq/kg doses administered every 8 weeks. The primary objective of the study was to assess overall survival (OS), while secondary objectives included evaluating radiological progression-free survival (rPFS), monitoring serum prostate-specific antigen (PSA) levels as a measure of biochemical response, and assessing adverse events using the CTCAE v5.0 grading system. RESULTS: Among the 63 initially enrolled patients, a total of 56 patients who had completed at least two cycles of [225Ac]Ac-PSMA-617 were included in this study. The mean age was 67 years (range, 39-87) and patients received a total of 204 cycles of [225Ac]Ac-PSMA-617 TAT. 91% of patients exhibited any PSA decline, with 67.8% experiencing a decline of 50% or more. The median follow-up was of 22 months (range: 6-59 months). Imaging-based disease progression was observed in 68% of patients, and 66% of patients succumbed to the disease. The median OS was 15 months (95% CI: 10-19). In univariate analysis, factors such as lack of >50% PSA decline (P=0.031), Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher (P=0.048), and radiological progression (rPD) (P<0.001) were found to be predictors of poor OS. However, in multivariate analysis, only rPD emerged as an independent prognostic factor with a hazard ratio (HR) of 8.264 (95% CI: 1.429-16.497, P=0.004). The estimated median rPFS was 9 months (95% CI: 7-15). Moreover, patients who demonstrated any PSA decline had a median rPFS of 10 months compared to only 3 months in patients without any PSA decline (multivariate HR: 6.749; 95% CI: 1.949-23.370; P=0.002). Fatigue was one of the most common treatment-emergent adverse events, with grades 1/2 occurring in 70% of patients and grades 3 or higher in 3.5% of patients. This fatigue was transient and resolved before the next treatment cycle. Additionally, approximately one-third of patients experienced xerostomia (grades 1/2: 32.1%). CONCLUSION: [225Ac]Ac-PSMA-617 targeted alpha therapy, was found to be well-tolerated with acceptable adverse events and effective in the treatment of patients with end-stage mCRPC.

Differentiated Thyroid Cancers in Young Adults Versus Children: Clinical Characteristics and 10-year Follow-up Outcomes.

BACKGROUND: Differentiated thyroid cancer (DTC) in young adults has been steadily rising in incidence over the decades. However, data on long-term outcomes in this specific cohort remain limited. In this study, we intended to evaluate young adults with DTC with regard to their clinical characteristics and treatment outcomes and compare the same vis-à-vis pediatric patients with DTC. METHODS: Data of pediatric (≤18 years) and young adult (19-39 years) patients with DTC, from 1971 to 2016, were sequentially extracted and analyzed for clinical characteristics, treatment responses, rates of recurrent/persistent disease, and disease-free survival (DFS). RESULTS: A total of 1803 patients with DTC were included (pediatric cohort: n = 176; young adult cohort: n = 1627). Pediatric patients with DTC had more frequent adverse baseline features including extrathyroidal extension (P = .040), nodal and distant metastases, and American Thyroid Association high-risk disease (P < .001 each). At 2 years posttreatment, young adult patients with DTC had significantly lower incomplete responses compared with pediatric patients with DTC (223/1627; 13.7% vs 94/176, 53.4%, respectively; P < .001). Over a median follow-up of 10.7 years, 120/1627 (7.4%) young adult patients with DTC had recurrent/persistent disease vs 23/176 (13.1%) pediatric patients with DTC (P = .012). The 10-year DFS probability was 93.6% for the young adult patients with DTC vs 88.7% for the pediatric patients with DTC (P = .007). American Thyroid Association high-risk disease and incomplete response at 2 years were independent predictors of significantly worse DFS in the young adult cohort (P < .001 each). CONCLUSIONS: Young adult DTCs behave less aggressively compared with their pediatric counterparts with excellent long-term outcomes. Appropriate initial and dynamic risk stratification can help optimize treatment decisions and follow-up strategies.

Head-to-Head Comparison of [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTANOC Positron Emission Tomography/Computed Tomography Imaging for the Follow-Up Surveillance of Patients with Medullary Thyroid Cancer.

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. [68Ga]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 [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTANOC positron emission tomography (PET) radiotracers. Materials and Methods: In this retrospective study, [68Ga]Ga-DOTANOC and [68Ga]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. [68Ga]Ga-DOTA.SA.FAPi had similar sensitivities as that of [68Ga]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%). [68Ga]Ga-DOTA.SA.FAPi demonstrated significantly higher sensitivities than [68Ga]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 [68Ga]Ga-DOTA.SA.FAPi compared with that of [68Ga]Ga-DOTANOC. Conclusion: [68Ga]Ga-DOTA.SA.FAPi outperformed [68Ga]Ga-DOTANOC PET/CT in the detection of distant metastases with both patient-based and lesion-based analysis in MTCs.

Head-to-Head Comparison between [68Ga]Ga-DOTA.SA.FAPi and [18F]F-FDG PET/CT Imaging in Patients with Breast Cancer.

This study aimed to compare the diagnostic performance of [68Ga]Ga-DOTA.SA.FAPi with that of [18F]F-FDG PET/CT in detecting primary and metastatic lesions of breast cancer. [18F]F-FDG and [68Ga]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 [68Ga]Ga-DOTA.SA.FAPi than with [18F]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 [18F]F-FDG. In patient-based analysis the sensitivity of [68Ga]Ga-DOTA.SA.FAPi PET/CT was higher, but not significant than that of [18F]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. [68Ga]Ga-DOTA.SA.FAPi scan identified more abnormal lesions than [18F]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]. [68Ga]Ga-DOTA.SA.FAPi PET/CT was superior to [18F]F-FDG PET/CT in the imaging of breast cancers.

[111In]In/[177Lu]Lu-AAZTA5-LM4 SST2R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results.

Aiming to expand the application of the SST2R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2) beyond [68Ga]Ga-DATA5m-LM4 PET/CT (DATA5m, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA5-LM4 (AAZTA5, 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 [111In]In-AAZTA5-LM4 and [177Lu]Lu-AAZTA5-LM4 were compared in HEK293-SST2R cells and double HEK293-SST2R/wtHEK293 tumor-bearing mice using [111In]In-DOTA-LM3 and [177Lu]Lu-DOTA-LM3 as references. The biodistribution of [177Lu]Lu-AAZTA5-LM4 was additionally studied for the first time in a NET patient. Both [111In]In-AAZTA5-LM4 and [177Lu]Lu-AAZTA5-LM4 displayed high and selective targeting of the HEK293-SST2R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [177Lu]Lu-AAZTA5-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 [177Lu]Lu-AAZTA5-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST2R-expressing human NETs, based on previous [68Ga]Ga-DATA5m-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [111In]In-AAZTA5-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available.

Novel Generation of FAP Inhibitor-Based Homodimers for Improved Application in Radiotheranostics.

Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC-1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides 177Lu and 225Ac. This was improved with the dimer DOTAGA.(SA.FAPi)2, but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi)2 and DOTAGA.Glu.(FAPi)2. were synthesized and quantitatively radiolabeled with 68Ga, 90Y, 177Lu and 225Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [225Ac]Ac-DOTAGA.Glu.(FAPi)2 in PBS. In vitro affinity studies resulted in subnanomolar IC50 values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [natLu]Lu-DOTAGA.Glu.(FAPi)2. In a first proof-of-principle patient study (medullary thyroid cancer), [177Lu]Lu-DOTAGA.Glu.(FAPi)2 was compared to [177Lu]Lu-DOTAGA.(SA.FAPi)2. High uptake and long tumor retention was observed in both cases, but [177Lu]Lu-DOTAGA.Glu.(FAPi)2 significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi)2 showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTAGA.Glu.(FAPi)2 and [225Ac]Ac-DOTAGA.Glu.(FAPi)2 appear promising for translational application in patients.

Dynamic Risk Stratification for Predicting Long-term Outcomes in Pediatric Differentiated Thyroid Cancers.

CONTEXT: The American Thyroid Association (ATA) guidelines recommend Dynamic Risk Stratification (DRS) for predicting long-term outcomes and personalizing management in adult differentiated thyroid cancers (DTCs). However, its applicability in pediatric DTCs needs to be validated. OBJECTIVE: We have attempted a validation study concerning the use of DRS in pediatric DTCs. METHODS: Data of children (age ≤18 years) with DTCs and follow-up of ≥5 years were extracted. All patients were classified according to DRS (excellent biochemical or structural incomplete responses). Univariate and multivariate analyses were done to identify factor(s) affecting disease-free survival (DFS). RESULTS: We included 176 pediatric patients with DTC (median age at diagnosis 15 years). All patients underwent thyroidectomy and received radioiodine as part of initial management. On the basis of clinical, biochemical, and imaging findings acquired during the first 2 years of follow-up, the DRS system divided patients into 3 response categories: excellent response in 82/176 (46.6%), biochemical incomplete response in 56/176 (31.8%), and structural incomplete response in 38/176 (21.6%) patients. The median follow-up was 10.6 years (interquartile range 7.7-15.5). Ten-year overall survival and DFS rates were 100% and 88.7%, respectively. In univariate analysis, DFS was significantly affected by extrathyroidal extension (P = .002), lymph node metastasis (P = .018), ATA initial risk stratification (P = .033), and DRS (P = .004). However, in multivariate analysis, DRS alone showed a significant association with DFS (P = .016). CONCLUSION: Like adults, DRS correctly predicts long-term outcomes in pediatric DTC. In addition to ATA initial risk stratification, DRS could further refine risk in pediatric DTCs and help in planning more personalized treatment and follow-up strategies.

Propensity Score Matched Outcome Analysis of Lobar Ablation Versus Completion Thyroidectomy in Low-Risk Differentiated Thyroid Cancer Patients: Median Follow-Up of 11 Years.

Background: Radioactive iodine lobar ablation (RAILA) of the contralateral thyroid lobe has been suggested as an alternative to completion thyroidectomy in patients of differentiated thyroid cancer (DTC) who underwent initial hemithyroidectomy. However, data on long-term outcomes are scarce. In this study, we intended to describe the long-term outcomes of RAILA versus completion thyroidectomy in a cohort of low-risk DTC patients. Methods: Data of patients with low-risk DTC who underwent initial hemithyroidectomy, and were subsequently treated with either completion thyroidectomy or RAILA between 1996 and 2015, were collected and analyzed. The treatment outcomes included ablation rate, recurrence rate, recurrence-free survival (RFS), and adverse events, and were validated by propensity score matching analysis. Results: Of the 1243 patients (median age: 34 years, range: 5-78) with low-risk DTC, 514 patients underwent upfront RAILA while 729 patients underwent completion thyroidectomy followed by remnant ablation. The ablation rate following the first radioactive iodine (131I) cycle was 75.3% [95% confidence interval (CI) 71.3-78.9] in the RAILA group versus 84.1% [CI 81.2-86.6] in the completion thyroidectomy group (p < 0.001). Over median follow-up of 11.4 years (interquartile range: 8.3-15.8), the recurrence rates between the two groups were not significantly different (1.6% [CI 0.7-3.2] vs. 1.0% [CI 0.4-2.1], respectively, p = 0.343). The product limit estimate of RFS at 10 years was 98.6% [CI 97.6-99.6%] in the RAILA group versus 99.1% [CI 98.3-99.9%] in the completion thyroidectomy group (p = 0.391). The outcomes in 497 matched pairs generated through propensity score analysis were similar. None of the patients in the RAILA group experienced permanent hypocalcemia or recurrent laryngeal nerve palsy, while the corresponding rates in the completion thyroidectomy group were 10/729 (1.4%) (p = 0.006) and 5/729 (0.7%) (p = 0.080), respectively. Radiation thyroiditis was seen in 25/514 (4.9%) patients in the RAILA group versus 3/729 (0.4%) in the completion thyroidectomy group (p < 0.001). Conclusions: Upfront RAILA is seen to be a noninvasive, safe, and effective alternative to surgical completion thyroidectomy in low-risk DTC patients in the absence of macroscopic malignancy in the remaining thyroid lobe.

Survival Outcomes in Metastatic Gastroenteropancreatic Neuroendocrine Tumor Patients receiving Concomitant 225Ac-DOTATATE Targeted Alpha Therapy and Capecitabine: A Real-world Scenario Management Based Long-term Outcome Study.

Rationale: Although the short-term results of targeted alpha therapy (TAT) with 225Ac-DOTATATE in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have proven effective, none have assessed the long-term outcome results. In this study, we aimed to evaluate the long-term outcome of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with somatostatin receptor (SSTR)-expressing advanced-stage metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Patients with 68Ga-DOTANOC PET/CT scans showing moderate-to-high SSTR expression were recruited. Systemic TAT was performed in 91 adults with GEP-NET [54 males, and 37 females] mean age 54 years (y) (range: 25-75y)] using 225Ac-DOTATATE (100-120 kBq/kg body weight). All patients were given capecitabine therapy as a radiosensitizer (dose 2 g/day) from day 0 to 14 of every 225Ac-DOTATATE treatment cycle. Patients were categorized into three groups based on the status of prior 177Lu-PRRT: prior 177Lu-PRRT-refractory-group; prior 177Lu-PRRT-disease-control group; and 177Lu-PRRT naïve group. Primary endpoints were overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective tumour response, clinical response, and the assessment of treatment-related toxicities. Results: Among the 91 patients, 57 underwent prior 177Lu-DOTATATE therapy [24 disease controlled (PR/SD), 33 progressive diseases (PD)]. A total of 453 225Ac-DOTATATE TAT cycles were administered [median four cycles per patient; range 1-10] in a median follow-up duration of 24 months (range 5-41mo). Median OS was not attained with a 24-month overall survival probability of 70.8%. In multivariate analysis, prognostic factors associated with a poor OS included, the presence bone metastases [HR: 2.501; 95% CI: 1.826 - 5.791; P<0.032], and 225Ac-DOTATATE therapy refractory disease [HR: 8.781; 95% CI: 3.843 - 20.062; P<0.0001]. Median PFS was also not reached with a 24-month progression-free survival probability of 67.5%. The multivariate analysis revealed only 177Lu-PRRT refractory disease significantly associated with a reduced PFS. [HR: 14.338; 95% CI: 1.853 - 97.698; P = 0.011]. Two of 79 patients (2.5%) with assessable disease experienced complete response; 38 (48%) had a partial response, 23 (29%) had SD, and 16 (20.2%) had PD. PD was observed in more patients from the prior 177Lu-PRRT-refractory group (11/33; 34%) as compared to 177Lu-PRRT-naïve patients (4/24; 11%), P-0.056. Patients from the prior 177Lu-PRRT-refractory group had the highest risk of poor PFS [HR:13.91; 95% CI: 4.45 - 42.271; P = 0.0009]. A significant clinical benefit was achieved post 225Ac-DOTATATE therapy with minimal treatment-related toxicities. Conclusion: The long-term results reveal 225Ac-DOTATATE TAT has shown promising results and improves overall survival, even in patients refractory to prior 177Lu-DOTATATE treatment, with transient and acceptable adverse effects.