The inferior performance of [68Ga]Ga-FAPI-04 PET/CT as a diagnostic and theranostic biomarker in [177Lu]Lu-DOTATATE refractory well-differentiated neuroendocrine tumors.

PURPOSE: We aimed to investigate the potential of [68Ga]Ga-FAPI-04 PET/CT as an alternative diagnostic and theranostic tool in well-differentiated NETs refractory to [177Lu]Lu-DOTATATE therapy. METHODS: Patients who received at least two cycles of [177Lu]Lu-DOTATATE therapy for metastatic NETs and progressed under treatment were included. All patients had performed [68Ga]Ga-DOTATATE and [68Ga]Ga-FAPI-04 PET/CT within 3 weeks. The number of PET-positive lesions related to NETs and tumor sites was documented. Mann-Whitney U and chi-square tests were used to compare SUVmax levels of tracers and the number of detected metastases. RESULTS: Twelve patients (7 male, 5 female) who met the eligibility criteria were included in the study. Ten patients had grade 1-2 NET of various origins, and two had paraganglioma and pheochromocytoma. One hundred ninety-eight of 230 lesions (86%) were SSTR positive with a median SUVmax of 16.6 (2.2-76.5), and 88 of 230 lesions (38.2%) were [68Ga]Ga-FAPI-04 positive with a median SUVmax of 5.1 (2.3-21). Median SUVmax level and detected number of tumors were significantly higher in [68Ga]Ga-DOTATATE PET/CT (p=<0.001). [68Ga]Ga-FAPI-04 PET/CT was completely (n:2) or almost completely (n:3) negative in 5 (42%) patients. Two (17%) patients had flip-flop SSTR/FAPI uptake in tumors. In four patients (33%), tumor uptake or the number of PET-positive lesions was inferior in [68Ga]Ga-FAPI-04 PET/CT. In only one patient (8%), tumor uptakes were higher in [68Ga]Ga-FAPI-04 PET/CT. Low-dose [177Lu]Lu-FAPI-46 dosimetry was performed on the FAPI-dominant patient; absorbed radiation doses per GBq were 1.26 Gy, 0.36 Gy, 0.32 Gy, and 0.2 Gy for kidneys, liver, spleen, and total body, respectively. The mean absorbed dose per GBq was 0.33 Gy for liver mass and 0.41 Gy for metastatic lymph nodes. CONCLUSION: Our preliminary results demonstrated that [68Ga]Ga-FAPI-04 PET/CT mainly failed in well-differentiated NETs refractory to [177Lu]Lu-DOTATATE therapy and had a limited role as an alternative diagnostic or theranostic agent. Further investigations with a larger patient population are required to determine the impact of [68Ga]Ga-FAPI-04 PET/CT on NETs.

Utility of 68 Ga-FAPI-04 PET/CT in Adenoid Cystic Carcinoma Compared With 18 F-FDG PET/CT : Two Case Reports.

ABSTRACT: 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/CT is an emerging imaging modality with high sensitivity and high tumor-to-background ratio in various cancers including in the head and neck regions. The authors present 2 cases of adenoid cystic carcinoma who underwent 68 Ga-FAPI-04 and 18 F-FDG PET/CT. Locoregional recurrence has been detected more precisely in the first case with 68 Ga-FAPI-04. In the second case, 68 Ga-FAPI-04 outperformed 18 F-FDG in the number of lesions and demonstrated intense FAP uptake on widespread metastases, which could provide a treatment option as a theranostic concept. These cases highlight that 68 Ga-FAPI-04 PET/CT may be useful for detecting local recurrence and metastases and help select patients for radionuclide treatments targeting cancer-associated fibroblasts.

68 Ga-FAPI04 Versus 68 Ga-DOTATATE PET/CT in a Patient With Multiple Meningioma.

ABSTRACT: We present the 68 Ga-DOTATATE and 68 Ga-FAPI (fibroblast activation protein inhibitor) PET/CT findings of a 61-year-old man diagnosed with atypical World Health Organization grade II multiple meningiomas. The patient has been stable for 2 years following multiple surgeries and external radiotherapy because of recurring disease until he recently described frequent headaches, and a follow-up examination confirmed new meningioma lesions on MRI. However, the patient was inoperable and was referred for 68 Ga-DOTATATE PET/CT to determine eligibility for salvage peptide receptor radionuclide therapy. He also underwent fibroblast activation protein-targeted imaging using 68 Ga-FAPI04 PET/CT, which revealed heterogeneous, low to mild fibroblast activation protein expression across multiple meningioma lesions.

An Analysis for Therapeutic Doses of Patients with Neuroendocrine Tumor Treated with Lutetium 177 (177Lu)-DOTATATE.

Background: The aim of this study is to clarify the critical organs that limit treatment scheme and also evaluate the validity of currently used critical organ threshold values in neuroendocrine tumor (NET) patients, receiving peptide receptor radionuclide therapy (PRRT) with Lutetium 177 (177Lu)-DOTATATE. Materials and Methods: Thirty-six NET patients (ages 16-73 years) who received 177Lu-DOTATATE treatment were evaluated retrospectively in this study. Dosimetric calculations were made using medical internal radionuclide dose method. For calculation of organ doses, Internal Dose Assessment at Organ Level/Exponential Modelling 1.1 software program was used. Follow-up data were used to determine the organ failure. Results: A total of 141 cycles and mean of 3.91 (±1.33) cycles were applied to the patients. A mean of 691 mCi (±257 mCi) 177Lu-DOTATATE infusion in total and a dose between 70 and 200 mCi per treatment was applied to patients. Seven of 36 patients reached 23 Gy renal dose limit. In these patients, although kidney doses were between 23 and 29 Gy, there was no diminution in renal functions during follow-up. Two of 36 patients reached total bone marrow dose of 2 Gy limit. Bone marrow suppression did not develop in these patients. Conclusion: The critical organs that seem to affect the treatment scheme in PRRT with 177Lu-DOTATATE are kidney and bone marrow. Although there are established threshold levels, derived from radiotherapy experience, more studies are needed to clarify these dose limits in systemic radionuclide therapies such as PRRT.

225Ac-Prostate-Specific Membrane Antigen Therapy for Castration-Resistant Prostate Cancer: A Single-Center Experience.

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeted therapies are among the current promising treatments. We present our preliminary results on the use of 225Ac-PSMA therapy in patients with metastatic castration-resistant prostate cancer as a single center. METHODS: Twelve advanced stage metastatic castration-resistant prostate cancer patients who received 225Ac-PSMA therapy were recruited in this retrospective study. Patients were treated with 225Ac-PSMA therapy every 8 weeks, and prostate-specific antigen (PSA) response was analyzed. Meanwhile, overall survival (OS) and progression-free survival (PFS) were estimated. Hematological and nonhematological adverse effects were recorded before and at 8 weeks after the last treatment cycle. RESULTS: In total, 25 cycles of 225Ac-PSMA were administered to 12 patients. The pretreatment median PSA level was 129 ng/mL. After the first cycle of therapy, any PSA response was observed in 9 of 12 patients, whereas 6 of them had biochemical response of >50%. Four of 12 patients reached the best PSA response after the first treatment cycle, whereas 3 patients after the second and 2 patients after the third cycle. The median PFS and OS were 4 and 10 months, respectively. For patients with any PSA response after the first cycle, OS was found to be higher despite without any statistical significance (10 vs 4 months; P = 0.301) when compared with the nonresponsive group. No significant difference was encountered in terms of adverse effect in the pretreatment and posttreatment era. CONCLUSIONS: Our preliminary results are encouraging, especially patients who had PSA response after the first cycle of 225Ac-PSMA therapy.

Prognostic significance of 68Ga-Pentixafor PET/CT in multiple myeloma recurrence: a comparison to 18F-FDG PET/CT and laboratory results.

PURPOSE: This study investigates the prognostic value of 68Ga-Pentixafor PET/CT using PET-derived quantitative in multiple myeloma (MM) patients with suspected recurrence in comparison to 18F-FDG PET/CT and clinical data. METHODS: Twenty-four MM patients with suspicion for relapse who underwent 68Ga-Pentixafor and 18F-FDG PET/CT were retrospectively evaluated. Total bone marrow glycolysis for 18F-FDG (TBMFDG) and total bone marrow uptake for 68Ga-Pentixafor PET/CT (TBMCXCR4) were calculated using whole-body metabolic tumor burden obtained by dedicated software (MIM 7.0.6). The patients were followed for 19-24 months, and the association of PET-derived quantitative data with overall survival (OS) was analyzed. RESULTS: 68Ga-Pentixafor PET/CT was positive in 17 patients, of which 13 were also positive on 18F-FDG PET/CT, whereas 7 patients were negative on both scans. The positive rate of 68Ga-Pentixafor and 18F-FDG PET/CT on a patient-based approach was 70.8% and 54.1%, respectively. 68Ga-Pentixafor positivity was significantly associated with OS (p = 0.009), and 18F-FDG positivity was at the margin of statistical significance (p = 0.056). TBMCXCR4 and TBMFDG were negatively correlated with OS (r = -0.457, p = 0.025 and r = -0.617, p = 0.001, respectively). The OS was negatively correlated with beta-2-microglobulin levels (r = -0.511, p = 0.01) and CRAB score (r = -0.592, p = 0.002) as an indicator of the end-organ disease, which confirmed these results. Serum beta-2-microglobulin levels and CRAB score were also correlated with TBMCXCR4 (r = 0.442, p = 0.039 and r = 0.573, p = 0.003, respectively) and TBMFDG (r = 0.543, p = 0.009 and r = -0.424, p = 0.003, respectively). CONCLUSION: 68Ga-Pentixafor PET/CT positivity is a negative prognostic factor in the survival outcome of MM patients. Complementary 68Ga-Pentixafor PET/CT has the potential to overcome 18F-FDG PET/CT limitations and helps a more precise risk stratification.

Safety of Fibroblast Activation Protein-Targeted Radionuclide Therapy by a Low-Dose Dosimetric Approach Using 177Lu-FAPI04.

OBJECTIVES: This study is set out to estimate the radiation-absorbed doses to normal organs and tumor tissue using low-dose 177Lu-FAPI04 dosimetry to determine the safety and theranostic potential of fibroblast activation protein-targeted radionuclide therapy. PATIENTS AND METHODS: Four patients with metastatic advanced-stage cancer were administered low-dose 177Lu-FAPI04 for dosimetry measurements. Data acquisition for dosimetry of normal organs and tumors was performed by whole-body and 3D SPECT/CT imaging at 4, 24, 48, and 96 hours after administering 177Lu-FAPI04. Blood samples were drawn at 5, 15, 30, 60, 60, 120, and 180 minutes, and at 24, 48, and 96 hours for bone marrow dosimetry calculations. RESULTS: Mean absorbed doses per megabecquerel were 0.25 ± 0.16 mGy (range, 0.11-0.47 mGy), 0.11 ± 0.08 mGy (range, 0.06-0.22 mGy), and 0.04 ± 0.002 mGy (range, 0.04-0.046 mGy) for kidneys, liver, and bone marrow, respectively. The respective maximum estimated amount of radioactivity to reach radiation-absorbed dose limits were 120.9 ± 68.6 GBq, 47.5 ± 2.8 GBq, 397.8 ± 217.1 GBq, and 52.4 ± 15.3 GBq for kidneys, bone marrow, liver, and total body. The mean absorbed dose per megabecquerel was 0.62 ± 0.55 mGy for bone metastases, 0.38 ± 0.22 mGy for metastatic lymph nodes, 0.33 ± 0.21 mGy for liver metastases, and 0.37 ± 0.29 for metastatic soft tissue. The maximum absorbed dose in a tumor lesion was 1.67 mGy/MBq for bone, 0.6 mGy/MBq for lymph node, 0.62 mGy/MBq for liver, and 1 mGy/MBq for soft tissue. CONCLUSIONS: The mean absorbed dose to organs at risk with 177Lu-FAPI04 is reasonably low, allowing for low tumor-absorbed dose rates by administering a higher dose. Further research on optimizing therapeutic efficacy and using alternative radioisotopes is necessary, along with an individualized dosimetric approach.

Y90 selective internal radiation therapy and peptide receptor radionuclide therapy for the treatment of metastatic neuroendocrine tumors: combination or not?

BACKGROUND: Peptide receptor radionuclide therapy and selective internal radiation therapy are effective radionuclide therapy modalities for unresectable metastatic neuroendocrine tumor patients that cannot be controlled with somatostatin analogs. The present study is intended to evaluate the therapeutic efficacy and toxicity of the combined therapy of selective internal radiation therapy and peptide receptor radionuclide therapy and stand-alone selective internal radiation therapy in patients with neuroendocrine tumor, a liver-dominant disease. METHODS: This cohort consists of 27 patients with metastatic neuroendocrine tumor and liver-dominant disease. They were grouped as the patients who were treated with selective internal radiation therapy for unresectable liver metastasis (n = 15) and the patients who received a combination of selective internal radiation therapy and peptide receptor radionuclide therapy (n = 12) for hepatic and extrahepatic metastasis. Treatment efficacy and treatment-associated toxicity were retrospectively assessed in both groups. RESULTS: The objective treatment response and stable disease were found in 13 patients (86.6%) in the selective internal radiation therapy group and eight patients (66.6%) in the selective internal radiation therapy + peptide receptor radionuclide therapy group. The median overall survival rate was found to be 34.9 months, in the selective internal radiation therapy group and 67.5 months in the selective internal radiation therapy + peptide receptor radionuclide therapy group (P = 0.217). The median progression-free survival data was not reached, and the mean values of progression-free survival were 53.1 ± 9.9 months in the selective internal radiation therapy group, and 27.2 ± 5.9 months in the selective internal radiation therapy + peptide receptor radionuclide therapy group (P = 0.561). Temporary lymphopenia was the most common side effect. Grade 1-2 hepatotoxicity was observed to be 6.6% in the selective internal radiation therapy group, while it was not observed in selective internal radiation therapy + peptide receptor radionuclide therapy group. CONCLUSIONS: In the neuroendocrine tumors with liver-dominant metastatic disease, personalized selective internal radiation therapy and peptide receptor radionuclide therapy and their combinations result in increased survival rates. Selective internal radiation therapy alone could be an effective treatment in patients with liver-limited and -dominant disease.

Evidence of Prostate-Specific Membrane Antigen Expression in Hepatocellular Carcinoma Using 68Ga-PSMA PET/CT.

Prostate specific membrane antigen (PSMA) expression has been demonstrated in tumor neovasculature of many solid tumors, including hepatocellular carcinoma (HCC). The purpose of this study is to evaluate PSMA expression in patients with HCC. MATERIALS AND METHODS: Nineteen HCC patients who underwent F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) as part of restaging procedure also underwent Ga-PSMA PET. F-FDG PET and Ga-PSMA findings were compared visually as well as quantitatively using maximized standardized uptake values (SUVmax). RESULTS: FDG was positive in 15 patients while 16 patients demonstrated PSMA expression. The only extrahepatic finding was one metastatic lymph node detected by both tracers. Mean SUVmax of liver lesions on FDG PET/CT was 8.3 ± 2.3 and mean tumor to background ratio was 2.3 ± 1.5. Respective values for Ga-PSMA PET/CT were 17.4 ± 9 and 3.3 ± 2.2. On visual and quantitative evaluation uptake was higher with PSMA in nine patients and higher with FDG in four patients. PSMA and FDG activity were similar in three patients. One of the FDG positive patients was PSMA negative whereas two patients were PSMA positive but FDG negative. Heterogeneous uptake pattern was observed in three patients. Comparison of mean SUVmax and T/B values between PET studies revealed no statistically significant difference (P > 0.1). The mean survival was 25 months (range: 18-32 months) and SUVmax of PSMA (P = 0.05) and FDG (P = 0.012) showed medium strength of correlation with overall survival. CONCLUSION: PSMA expression in advanced HCC can be demonstrated by Ga-PSMA PET but is not superior to FDG PET however it could be useful for identifying patients with limited therapeutic options.

Clinical Impact of Lower-Limb Imaging in 68Ga-PSMA PET/CT for Patients with Prostate Cancer.

Our purpose was to determine whether there is a clinical benefit to add lower-limb imaging in 68Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT scans for patients with prostate cancer. Methods: In total, 701 patients with prostate cancer who underwent 68Ga-PSMA PET/CT were evaluated retrospectively. All patients underwent additional lower-limb imaging. Images were reanalyzed by experienced nuclear medicine physicians, and metastatic sites were documented. The prostate-specific antigen (PSA) level and Gleason score were also compared with 68Ga-PSMA PET/CT findings. Results: In 601 patients (85.7%), at least 1 tumoral lesion was observed on 68Ga-PSMA PET/CT. The number of patients with bone metastasis in 2 forms was 278 patients (39.6%); 108 (15.4%) were oligometastatic (<4 metastases) and 170 (24.2%) were multimetastatic (≥4 metastases). In lower-limb imaging, bone metastasis was detected in 61 patients (8.7%), the specific locations of which were as follows: middle-distal femur (n = 54), tibia (n = 19), fibula (n = 24), and calcaneus (n = 1). Lower-limb metastasis was detected mostly in symptom-positive patients (70.1%) but in only 4% of the symptom-negative group. All patients with lower-extremity metastasis also had multiple bone metastases shown on limited whole-body 68Ga-PSMA PET/CT. The median PSA level was significantly higher in multimetastatic patients with lower-limb metastasis than in those without lower-limb metastasis (P < 0.001, Mann-Whitney U test), but no statistical differences was found in terms of Gleason score (χ2 = 0.042, P = 0.837). According to receiver-operating-characteristic analysis, PSA has a good predictive value for detecting lower-limb metastasis, with 76.6% sensitivity and 72% specificity (using a reference cutoff PSA level of 24 ng/mL [area under the curve, 0.81; 95% confidence interval, 0.74-0.87]). Conclusion: Lower-limb imaging did not change the metastatic status of disease or significantly affect the therapeutic approach. However, if multimetastatic patients present relevant symptoms for lower-limb metastasis, it could be beneficial to consider including lower-limb imaging for possible palliative therapies.

Imaging of Chemokine Receptor CXCR4 in Mycosis Fungoides Using 68Ga-Pentixafor PET/CT.

A 52-year-old woman diagnosed with mycosis fungoides was referred for F-FDG PET/CT before treatment for the evaluation of disease severity. The patient also underwent Ga-pentixafor PET/CT for further evaluation. FDG uptake was observed in cervical, axillary, and pelvic lymph nodes and multiple widespread skin lesions throughout the body, suggestive of extensive involvement of mycosis fungoides. All lesions were visually identifiable with high target-to-background ratio on Ga-pentixafor PET/CT which demonstrated marked CXCR4 expression in all lesions that were detected using F-FDG PET/CT.

Relationships between serum PSA levels, Gleason scores and results of 68Ga-PSMAPET/CT in patients with recurrent prostate cancer.

AIM: To investigate the relationship between serum PSA level, Gleason score of PCa and the outcomes of Ga68-PSMA PET/CT in patients with recurrent PCa. METHODS: A total of 109 consecutive patients (median age 71 years; range 48-89 years) who had PSA recurrence after RP and/or hormonotherapy and/or radiotherapy were included in this study. Local recurrences, lymph node metastasis (pelvic, abdominal and/or supradiaphragmatic), bone metastases (oligometastatic/multimetastatic) and other metastatic sites (lung, liver, brain, etc) were documented. RESULTS: In 91(83.4%) patients at least one lesion characteristic for PCa was detected by68Ga-PSMA PET/CT. The median serum total PSA (tPSA) was 6.5 (0.2-640) ng/ml.There was a significant difference between 68Ga-PSMA PET/CT positive and negative patients in terms of serum total PSA value. No statistical significance was found between positive and negative 68Ga-PSMA PET/CT findings in terms of Gleason score. Local recurrence was detected in 56 patients. whereas lymph node metastases were demonstrated in 46 patients. Pelvic nodal disease was the most frequent presentation followed by abdominal and supradiaphragmaticnodal involvement. Bone metastases [oligometastasis, (n = 20); multimetastasis, (n = 35)⦌ were also detected in 55 patients. In the ROC analysis for the study cohort, the optimal cut-off value of total serum PSA was determined as 0.67 ng/ml for distinguishing between positive and negative 68Ga-PSMA PET/CT images, with an area under curve of 0.952 (95% CI 0.911-0.993). CONCLUSIONS: 68Ga-PSMA PET/CT was found to be an effective tool for the detection of recurrent PCa. Even though no relationship was detected between the GS and 68Ga-PSMA PET/CT findings, serum total PSA values may be used for estimating the likelihood of positive 68Ga-PSMA PET/CT results.

PET/CT and Bremsstrahlung Imaging After 90Y DOTANOC Therapy for Rectal Net With Liver Metastases.

Peptide receptor radionuclide therapy with Lu or Y is promising with successful results in somatostatin receptor-positive tumors. In all radiation therapies, knowledge of the radiation dose received by the target, and other organs in the body is essential to evaluate the risks and benefits of any procedure. We report a case of liver metastases from a rectal neuroendocrine tumor, which was treated with Y DOTANOC. Posttreatment whole-body planar images were acquired through Bremsstrahlung radiations of Y on a γ-camera, and thoracolumbar PET/CT images were acquired on PET.