A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism.

Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell KATP channels, results in dysregulated insulin secretion and persistent hypoglycemia. Children with KATP-HI are unresponsive to diazoxide, the only FDA-approved drug for HI, and utility of octreotide, the second-line therapy, is limited because of poor efficacy, desensitization, and somatostatin receptor type 2 (SST2)-mediated side effects. Selective targeting of SST5, an SST receptor associated with potent insulin secretion suppression, presents a new avenue for HI therapy. Here, we determined that CRN02481, a highly selective nonpeptide SST5 agonist, significantly decreased basal and amino acid-stimulated insulin secretion in both Sur1-/- (a model for KATP-HI) and wild-type mouse islets. Oral administration of CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle in Sur1-/- mice. During a glucose tolerance test, CRN02481 significantly increased glucose excursion in both WT and Sur1-/- mice compared to the control. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from healthy, control human islets similar to the effects observed with SS14 and peptide somatostatin analogs. Moreover, CRN02481 significantly decreased glucose- and amino acid-stimulated insulin secretion in islets from two infants with KATP-HI and one with Beckwith-Weideman Syndrome-HI. Taken together, these data demonstrate that a potent and selective SST5 agonist effectively prevents fasting hypoglycemia and suppresses insulin secretion not only in a KATP-HI mouse model but also in healthy human islets and islets from HI patients.

A targeting nanoplatform for chemo-photothermal synergistic therapy of small-cell lung cancer.

The precise delivery of drugs to tumor sites and the thermoresistance of tumors remain major challenges in photothermal therapy (PTT). Somatostatin receptor 2 (SSTR2) is proposed as an ideal target for the precise treatment of SCLC. We developed a targeting nano-drug delivery system comprising anti-SSTR2 monoclonal antibody (MAb) surface-modified nanoparticles co-encapsulating Cypate and gambogic acid (GA). The formed SGCPNs demonstrated excellent monodispersity, physiological stability, preferable biocompatibility, and resultant efficient photothermal conversion efficacy. SGCPNs were quickly internalized by SSTR2-overexpressing SCLC cells, triggering the release of GA under acidic and near-infrared (NIR) laser irradiation environments, leading to their escape from lysosomes to the cytosol and then diffusion into the nucleus. SGCPNs can not only decrease the cell survival rate but also inhibit the activity of heat shock protein 90 (HSP90). SGCPNs can be precisely delivered to xenograft tumors of SSTR2-positive SCLC in vivo. Upon NIR laser irradiation, therapy of SGCPNs showed significant tumor regression. In conclusion, SGCPNs provide a new chemo-photothermal synergistic treatment strategy for targeting SCLC.

Altered biodistribution of [68Ga]Ga-DOTA-TOC during somatostatin analogue treatment.

PURPOSE: The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. METHODS: Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. RESULTS: Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5 days, there was a significantly higher bloodpool activity than at longer intervals. CONCLUSION: Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5 days after the injection of lanreotide.

Gallium-68 labeled somatostatin receptor antagonist PET/CT in over 500 patients with neuroendocrine neoplasms: experience from a single center in China.

PURPOSE: Somatostatin receptor antagonists have shown promising performance for imaging neuroendocrine neoplasms. However, there is a lack of studies exploring the diagnostic performance of SSTR antagonists or comparing them with agonists in a large cohort of patients with NENs. This study aimed to retrospectively review all SSTR antagonist PET/CT scans conducted at Peking Union Medical College Hospital since November 2018 in patients with confirmed or suspected NENs. METHODS: Four types of SSTR antagonists were utilized, including [68Ga]Ga-NODAGA-LM3, [68Ga]Ga-DOTA-LM3, [68Ga]Ga-NODAGA-JR11, and [68Ga]Ga-DOTA-JR11. The reference standard was based on a combination of histopathology, clinical evaluation, imaging results, and follow-up. Patient-based sensitivity, specificity, and accuracy were evaluated. The SUVmax and tumor-to-liver ratio (TLR) of the hottest lesions was recorded and compared between antagonists and [68Ga]Ga-DOTATATE. RESULTS: A total of 622 antagonist scans from 549 patients were included in the analysis. The patient-level sensitivity, specificity, and accuracy of antagonist imaging (all tracers combined) were 91.0% (443/487), 91.9% (57/62), and 91.1% (500/549), respectively. In 181 patients with a comparative [68Ga]Ga-DOTATATE PET/CT scan, the patient-level sensitivity, specificity, and accuracy were 87.5% (147/168), 76.9% (10/13), and 86.7% (157/181), respectively. For the hottest lesions, SSTR antagonists all tracers combined demonstrated an overall comparable SUVmax to [68Ga]Ga-DOTATATE (40.1 ± 32.5 vs. 39.4 ± 23.8, p = 0.772). While [68Ga]Ga-NODAGA-LM3 showed significantly higher uptake than [68Ga]Ga-DOTATATE (57.4 ± 38.5 vs. 40.0 ± 22.8, p<0.001), [68Ga]Ga-NODAGA-JR11 (39.7 ± 26.5 vs. 34.3 ± 23.9, p = 0.108) and [68Ga]Ga-DOTA-LM3 (38.9 ± 32.1 vs. 37.2 ± 22.1, p = 0.858) showed comparable uptake to [68Ga]Ga-DOTATATE, and [68Ga]Ga-DOTA-JR11 showed lower uptake (28.9 ± 26.1 vs. 44.0 ± 25.7, p = 0.001). All antagonists exhibited significantly higher TLR than [68Ga]Ga-DOTATATE (12.1 ± 10.8 vs. 5.2 ± 4.5, p<0.001). CONCLUSION: Gallium-68 labeled SSTR antagonists could serve as alternatives to SSTR agonists for imaging of NENs. Among various antagonists, [68Ga]Ga-NODAGA-LM3 seems to have the best imaging profile.

Long-axial field-of-view PET/CT for the assessment of inflammation in calcified coronary artery plaques with [68 Ga]Ga-DOTA-TOC.

PURPOSE: Inflamed, prone-to-rupture coronary plaques are an important cause of myocardial infarction and their early identification is crucial. Atherosclerotic plaques are characterized by overexpression of the type-2 somatostatin receptor (SST2) in activated macrophages. SST2 ligand imaging (e.g. with [68 Ga]Ga-DOTA-TOC) has shown promise in detecting and quantifying the inflammatory activity within atherosclerotic plaques. However, the sensitivity of standard axial field of view (SAFOV) PET scanners may be suboptimal for imaging coronary arteries. Long-axial field of view (LAFOV) PET/CT scanners may help overcome this limitation. We aim to assess the ability of [68 Ga]Ga-DOTA-TOC LAFOV-PET/CT in detecting calcified, SST2 overexpressing coronary artery plaques. METHODS: In this retrospective study, 108 oncological patients underwent [68 Ga]Ga-DOTA-TOC PET/CT on a LAFOV system. [68 Ga]Ga-DOTA-TOC uptake and calcifications in the coronary arteries were evaluated visually and semi-quantitatively. Data on patients' cardiac risk factors and coronary artery calcium score were also collected. Patients were followed up for 21.5 ± 3.4 months. RESULTS: A total of 66 patients (61.1%) presented with calcified coronary artery plaques. Of these, 32 patients had increased [68 Ga]Ga-DOTA-TOC uptake in at least one coronary vessel (TBR: 1.65 ± 0.53). Patients with single-vessel calcifications showed statistically significantly lower uptake (SUVmax 1.10 ± 0.28) compared to patients with two- (SUVmax 1.31 ± 0.29, p < 0.01) or three-vessel calcifications (SUVmax 1.24 ± 0.33, p < 0.01). There was a correlation between coronary artery calcium score (CACS) and [68 Ga]Ga-DOTA-TOC uptake, especially in the LAD (p = 0.02). Stroke and all-cause death occurred more frequently in patients with increased [68 Ga]Ga-DOTA-TOC uptake (15.63% vs. 0%; p:0.001 and 21.88% vs. 6.58%; p: 0.04, respectively) during the follow-up period. CONCLUSION: [68 Ga]Ga-DOTA-TOC as a marker for the macrophage activity can reveal unknown cases of inflamed calcified coronary artery plaques using a LAFOV PET system. [68 Ga]Ga-DOTA-TOC uptake increased with the degree of calcification and correlated with higher risk of stroke and all-cause death. [68 Ga]Ga-DOTA-TOC LAFOV PET/CT may be useful to assess patients' cardiovascular risk.

Models using comprehensive, lesion-level, longitudinal [68Ga]Ga-DOTA-TATE PET-derived features lead to superior outcome prediction in neuroendocrine tumor patients treated with [177Lu]Lu-DOTA-TATE.

PURPOSE: Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy (PRRT). However, comprehensive (all metastatic lesions), longitudinal (temporal variation), and lesion-level measured features have never been explored. Such features allow for capturing the heterogeneity in disease response to treatment. Furthermore, models combining these features are lacking. In this work we evaluated the predictive power of comprehensive, longitudinal, lesion-level 68GA-SSTR-PET features combined with a multivariate linear regression (MLR) model. METHODS: This retrospective study enrolled NET patients treated with [177Lu]Lu-DOTA-TATE and imaged with [68Ga]Ga-DOTA-TATE at baseline and post-therapy. All lesions were segmented, anatomically labeled, and longitudinally matched. Lesion-level uptake and variation in uptake were measured. Patient-level features were engineered and selected for modeling of progression-free survival (PFS). The model was validated via concordance index, patient classification (ROC analysis), and survival analysis (Kaplan-Meier and Cox proportional hazards). The MLR was benchmarked against single feature predictions. RESULTS: Thirty-six NET patients were enrolled and stratified into poor and good responders (PFS ≥ 25 months). Four patient-level features were selected, the MLR concordance index was 0.826, and the AUC was 0.88 (0.85 specificity, 0.81 sensitivity). Survival analysis led to significant patient stratification (p<.001) and hazard ratio (3⨯10-5). Lastly, in a benchmark study, the MLR modeling approach outperformed all the single feature predictors. CONCLUSION: Comprehensive, lesion-level, longitudinal 68GA-SSTR-PET analysis, combined with MLR modeling, leads to excellent predictions of PRRT outcome in NET patients, outperforming non-comprehensive, patient-level, and single time-point feature predictions. MESSAGE: Neuroendocrine tumor, peptide receptor radionuclide therapy, Somatostatin Receptor Imaging, Outcome Prediction, Treatment Response Assessment.

Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma.

PURPOSE: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC. METHODS: We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC. RESULTS: LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC. CONCLUSION: [177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.

Joint EANM/EANO/RANO/SNMMI practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor ligands: version 1.0.

PURPOSE: To provide practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor (SSTR) ligands. METHODS: This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO). RESULTS: Positron emission tomography (PET) using somatostatin receptor (SSTR) ligands can detect meningioma tissue with high sensitivity and specificity and may provide clinically relevant information beyond that obtained from structural magnetic resonance imaging (MRI) or computed tomography (CT) imaging alone. SSTR-directed PET imaging can be particularly useful for differential diagnosis, delineation of meningioma extent, detection of osseous involvement, and the differentiation between posttherapeutic scar tissue and tumour recurrence. Moreover, SSTR-peptide receptor radionuclide therapy (PRRT) is an emerging investigational treatment approach for meningioma. CONCLUSION: These practice guidelines will define procedure standards for the application of PET imaging in patients with meningiomas and related SSTR-targeted PRRTs in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers, facilitate comparability of studies, and to collect larger databases. The current document provides additional information to the evidence-based recommendations from the PET/RANO Working Group regarding the utilization of PET imaging in meningiomas Galldiks (Neuro Oncol. 2017;19(12):1576-87). The information provided should be considered in the context of local conditions and regulations.

Evaluation of the safety, biodistribution, dosimetry of [18F]AlF-NOTA-LM3 and head-to-head comparison with [68Ga]Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors: an interim analysis of a prospective trial.

PURPOSE: 18F-labelled somatostatin receptor (SSTR) analogs offer several advantages over 68Ga in terms of yield, cost, spatial resolution and detection rate. This study presents an interim analysis of a prospective trial designed to assess the safety, biodistribution and dosimetry of [18F]AlF-NOTA-LM3, and compare its diagnostic efficacy and clinical management outcomes with [68Ga]Ga-DOTATATE or [68Ga]Ga-NODAGA-LM3 in patients with well-differentiated NETs. METHODS: Twenty-one patients with histologically confirmed well-differentiated neuroendocrine tumors (G1 and G2) were prospectively recruited. The first eight patients underwent serial PET scans at 5, 15, 30, 45, 60, and 120 min after [18F]AlF-NOTA-LM3 injection to assess biodistribution and dosimetry. The remaining patients underwent whole-body PET/CT scans. [18F]AlF-NOTA-LM3 and [68Ga]Ga-DOTATATE PET/CT were done within a week, with a minimum 24-hour interval between the two scans. Focal uptake above the surrounding background activity and could not be explained by physiologic uptake was considered lesions of NETs. Lesion number, tumor uptake, and tumor-to-background ratio (TBR) were compared. In patients with discrepant findings, the size of the smallest lesions (measured on coregistered CT) detected on [68Ga]Ga-DOTATATE and [18F]AlF-NOTA-LM3 was compared. RESULTS: [18F]AlF-NOTA-LM3 was safe and well-tolerated. Physiological uptake of [18F]AlF-NOTA-LM3 was significantly lower than that of [68Ga]Ga-DOTATATE in abdominal organs and bone marrow, but higher in blood pool and lung. The mean effective dose was 0.024 ± 0.014 mSv/MBq. [18F]AlF-NOTA-LM3 detected significantly more liver lesions (457 vs. 291, P = 0.006) and lymph node lesions (30 vs. 22, P = 0.011) compared to [68Ga]Ga-DOTATATE. The tumor uptake was comparable, but TBR was significantly higher with [18F]AlF-NOTA-LM3 for lesions from all sites except for the duodenum. The size of the minimum liver lesions (0.54 ± 0.15 vs. 1.01 ± 0.49, P<0.001) and lymph node lesions (0.50 ± 0.19 vs. 1.26 ± 0.86, P = 0.024) detected on [18F]ALF-NOTA-LM3 were significantly smaller than those detected on [68Ga]Ga-DOTATATE. CONCLUSION: [18F]AlF-NOTA-LM3 shows favorable biodistribution, higher spatial resolution and superior performance than [68Ga]Ga-DOTATATE in detecting liver and lymph node metastases, with higher TBR. Notably, it is the first SSTR analog to show superiority in detecting lymph node lesions when compared to [68Ga]Ga-DOTATATE. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06056362.

Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

Enhanced Detection of Early Pulmonary Fibrosis Disease Using 68Ga-FAPI-LM3 PET.

Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a 68Ga-radiolabeled heterobivalent molecular probe that targets fibroblast activating protein (FAP) and somatostatin receptor 2 (SSTR2), in the early detection of pulmonary fibrosis, leveraging its potential for early disease identification. A bleomycin-induced early pulmonary fibrosis model was established in C57BL/6 mice for 7 days. FAP and SSTR2 expression levels were quantitatively assessed in human idiopathic pulmonary fibrosis lung tissue samples and bleomycin-treated mouse lung tissues by using western blotting, real-time quantitative PCR (RT-qPCR), and immunofluorescence techniques. The diagnostic performance of FAPI-LM3 was investigated by synthesizing monomeric radiotracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3 alongside the heterobivalent probe 68Ga-FAPI-LM3. These imaging radiopharmaceuticals were used in small-animal PET to compare their uptake in fibrotic and normal lung tissues. Results indicated significant upregulation of FAP and SSTR2 at both RNA and protein levels in fibrotic lung tissues compared with that in normal controls. PET imaging demonstrated significantly enhanced uptake of the 68Ga-FAPI-LM3 probe in fibrotic lung tissues, with superior visual effects compared to monomeric tracers. At 60 min postinjection, early stage fibrotic tissues (day 7) demonstrated low-to-medium uptake of monomeric probes, including 68Ga-DOTA-LM3 (0.45 ± 0.04% ID/g) and 68Ga-FAPI-46 (0.78 ± 0.09% ID/g), whereas the uptake of the heterobivalent probe 68Ga-FAPI-LM3 (1.90 ± 0.10% ID/g) was significantly higher in fibrotic lesions than in normal lung tissue. Blockade experiments confirmed the specificity of 68Ga-FAPI-LM3 uptake, which was attributed to synergistic targeting of FAP and SSTR2. This study demonstrates the potential of 68Ga-FAPI-LM3 for early pulmonary fibrosis detection via molecular imaging, offering significant benefits over monomeric tracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3. This strategy offers new possibilities for noninvasive and precise early detection of pulmonary fibrosis.

The Application of 68Ga-Somatostatin Analog and 18F-FDG PET/CT for Bone Metastasis from Neuroendocrine Tumors.

INTRODUCTION: Aims of the study were to assess the differences in the diagnostic efficacy of 68Ga-somatostatin receptor analogs (68Ga-SSAs) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting bone metastases in neuroendocrine neoplasm (NEN) and to analyze the correlation between imaging features and clinical features of BMs. METHODS: We retrospectively analyzed the clinical and imaging data of 213 NEN patients who underwent 68Ga-SSA PET/CT and were finally diagnosed as BMs by pathology or follow-up. Of those, 103 patients underwent 18F-FDG PET/CT within 7 days after 68Ga-SSA PET/CT. RESULT: The BM detection rate of 68Ga-SSA PET/CT was higher than 18F-FDG PET/CT (86.4% vs. 66.0%, p = 0.02) in 103 patients with dual scanning. Meanwhile, the number of positive lesions in 68Ga-SSA PET/CT was significantly more than in 18F-FDG PET/CT (3.37 ± 1.95 vs. 2.23 ± 2.16, t = 4.137, p < 0.001). Most bone metastasis lesions presented as osteogenic change in CT (55.4%, 118/213). Concerning the primary tumor, the most frequent were of pancreatic origin (26.3%, 56/213), followed by rectal origin (22.5%, 48/213), thymic origin in 33 cases (15.5%), pulmonary origin in 29 cases (13.6%), paraganglioma in 20 cases (9.4%). The efficiency of 68Ga-SSA PET/CT to detect BMs was significantly correlated with the primary site (p = 0.02), with thymic carcinoid BMs being the most difficult to detect, and the positive rate was only 60.6% (20/33). However, 18F-FDG PET/CT positive rate was 76.92% (10/13) in thymic carcinoid BMs. In addition, the BMs of 7 patients in this study were detected by 68Ga-SSA PET earlier than CT for 4.57 months (range: 2-10 months). CONCLUSION: 68Ga-SSA PET/CT has higher sensitivity for detecting the BMs of NEN than 18F-FDG and detects the BM earlier than CT. Moreover, 18F-FDG PET/CT should be a complement for diagnosing the BMs of thymic carcinoids.

Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

PURPOSE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. CONCLUSION: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

Medical treatment of functional pituitary adenomas, trials and tribulations.

CONTEXT: Functioning pituitary adenomas (FPAs) include most frequently prolactinomas, somatotroph or corticotroph adenomas, while thyrotroph and gonadotroph adenomas are very rare. Despite their benign histological nature (aggressive tumors are rare and malignant ones exceptional), FPAs could cause significant morbidity and increased mortality due to complications associated with hormonal excess syndromes and/or mass effect leading to compression of adjacent structures. This mini review will focus on the increasing role of medical therapy in the multimodal treatment, which also includes transsphenoidal surgery (TSS) and radiotherapy. EVIDENCE SYNTHESIS: Most patients with prolactinomas are treated only with medications, but surgery could be considered for some patients in a specialized pituitary center, if higher chances of cure. Dopamine agonists, especially cabergoline, are efficient in reducing tumor size and normalizing prolactin. TSS is the first-line treatment for all other FPAs, but most patients require complex adjuvant treatment, including a combination of therapeutic approaches. Medical therapy is the cornerstone of treatment in all patients after unsuccessful surgery or when surgery cannot be offered and includes somatostatin receptor ligands and dopamine agonists (almost all FPAs), growth hormone receptor antagonists (acromegaly), adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers (Cushing's disease). Novel medical treatments, especially for acromegaly and Cushing's disease are under research. CONCLUSIONS: An enlarged panel of effective drugs available with increased knowledge of predictive factors for response and/or adverse effects will enhance the possibility to offer a more individualized treatment. This would not only improve disease control and prognosis, but also quality of life.

Structural insights into somatostatin receptor 5 bound with cyclic peptides.

Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 Å and 3.24 Å, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/DTrp of pasireotide and SSTR5. Moreover, we find that the Q2.63, N6.55, F7.35 and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.

Bone health and skeletal fragility in second- and third-line medical therapies for acromegaly: preliminary results from a pilot single center experience.

INTRODUCTION: Skeletal fragility is a clinically relevant and not-reversible complication of acromegaly, involving around 30-40% of patients since the disease diagnosis. Few studies have investigated the effects on skeletal health of medical therapies for acromegaly. In this retrospective longitudinal monocentre study, we investigated the outcome of skeletal fragility in patients treated with Pasireotide Lar in combination with Pegvisomant (Pasi-Lar + Peg-V), also comparing those observed in patients treated with conventional therapies. RESULTS: We included 6 patients treated with Pasi-Lar + Peg-V, 5 patients treated with Peg-V in monotherapy (m-Peg-V), 16 patients treated with Peg-V plus first-generation somatostatin receptor ligands (fg-SRLs + Peg-V), 9 patients treated with Pasi-Lar. None of the patients treated with Pasi-Lar + Peg-V experienced worsening of spine and femoral bone mineral density (BMD) and incident vertebral fractures (i-VFs). Eight patients experienced i-VFs. The frequency of i-VFs was significantly lower in patients treated with the Pasi-Lar + Peg-V (0/8; 0%), as compared to those observed in m-Peg-V treated patients (4/8; 50%, p = 0.02). The frequency of i-VFs was slightly but not significantly higher in Pasi-Lar treated patients (1/8; 12.5% p = 0.6) and in fg-SRLs + Peg-V treated patients (3/8; 37.5% p = 0.364), concerning those treated with Pasi-Lar + Peg-V (0/8; 0%). I-VFs occurred more frequently in patients with higher GH levels at acromegaly diagnosis (p < 0.001), and in patients who experienced a BMD worsening (p = 0.005). CONCLUSION: Our preliminary data suggested that in conventional and multi-drug resistant acromegaly, the combination therapy Pasi-Lar + Peg-V may prevent the worsening of BMD and the occurrence of i-VFs. Prospective and translational studies should further validate these results and ascertain underlying physiopathology mechanisms.

The Clinical Utility of Gallium-68-DOTATATE Positron Emission Tomography Scanning in Medullary Thyroid Cancer.

OBJECTIVE: Somatostatin receptor (SST) functional imaging with positron emission tomography (PET)/computed tomography (CT) has broadened the diagnostic and staging capabilities for medullary thyroid cancer (MTC). Gallium-68 (68Ga)-DOTA-conjugated peptide (Tyr3)-octreotate (DOTATATE) is a radiotracer with a high affinity for type 2 SSTs expressed in several, but not all, MTCs. The utility of 68Ga-DOTATATE PET/CT and 18fluorine-labeled fluoro-2-deoxy-D-glucose (18F-FDG)-PET/CT imaging in predicting MTC prognosis is also unknown. METHODS: In this single-center retrospective study, 103 of patients with MTC underwent assessment of SST2 and SST5 immunohistochemistry (IHC). A subgroup of 37 patients received 68Ga-DOTATATE PET/CT imaging, and 13 received contemporaneous 18F-FDG-PET/CT imaging. The maximum standardized uptake value (SUV), mean SUV, metabolic tumor volume, and total lesion activity (TLA) were assessed. RESULTS: Forty-two patients (41%) demonstrated positive expression of SST2, and 45 (44%) had a positive SST5 IHC result. Seventeen patients (17%) expressed both SST2 and SST5. No survival advantage was identified with SST2 or SST5 IHC positivity. No correlation was noted between the maximum SUV, mean SUV, metabolic tumor volume, or TLA and SST2 and/or SST5 expression by IHC. Shorter survival was associated with a TLA of >20 (P = .04). A RET-negative status also appeared to have shorter survival, although this may be because the small numbers did not reach statistical significance (P = .12). CONCLUSION: Assessment of TLA from 68Ga-DOTATATE PET/CT may predict survival. SST2 IHC was not correlated with 68Ga-DOTATATE avidity. Metastatic disease may be optimally assessed by concurrent 18F-FDG and 68Ga-DOTATATE imaging.

Loss of function in somatostatin receptor 5 has no impact on the growth of medaka fish due to compensation by the other paralogs.

Somatic growth in vertebrates is regulated endocrinologically by the somatotropic axis, headed by the growth hormone (GH) and the insulin growth factor-I (IGF-I). Somatostatin (Sst), a peptide hormone synthesized in the hypothalamus, modulates GH actions through its receptors (Sstr). Four Sstr subtypes (Sstr 1-3 and 5) have been identified in teleosts. However, little is known about whether they have a specific function or tissue expression. The aim of this study was to determine the role of sstr2 and sstr5 in the growth of the medaka (Oryzias latipes). The assessed expression pattern across diverse tissues highlighted greater prevalence of sstr1 and sstr3 in brain, intestine and muscle than in pituitary or liver. The expression of sstr2 was high in all the tissues tested, while sstr5 was predominantly expressed in the pituitary gland. A CRISPR/Cas9 sstr5 mutant with loss of function (sstr5-/-) was produced. Assessment of sstr5-/- indicated no significant difference with the wild type regarding growth parameters such as standard length, body depth, or peduncle depth. Furthermore, the functional loss of sstr5 had no impact on the response to a nutritional challenge. The fact that several sstr subtypes were upregulated in different tissues in sstr5-/- medaka suggests that in the mutant fish, there may be a compensatory effect on the different tissues, predominantly by sstr1 in the liver, brain and pituitary, with sstr2 being upregulated in pituitary and liver, and sstr3 only presenting differential expression in the brain. Analysis of the sstr subtype and the sstr5-/- fish showed that sstr5 was not the only somatostatin receptor responsible for Sst-mediated Gh regulation.

Insights from an Italian Delphi panel: exploring resistance to first-generation somatostatin receptor ligands and guiding second-line medical therapies in acromegaly management.

PURPOSE: First-line medical therapy for acromegaly management includes first-generation somatostatin receptor ligands (fgSRLs), but resistance limits their use. Despite international guidelines, the choice of second-line therapy is debated. METHODS: We aim to discuss resistance to fgSRLs, identify second-line therapy determinants and assess glycemia's impact to provide valuable insights for acromegaly management in clinical practice. A group of Italian endocrinologists expert in the pituitary field participated in a two-round Delphi panel between July and September 2023. The Delphi questionnaire encompassed a total of 75 statements categorized into three sections: resistance to fgSRLs therapy and predictors of response; determinants for the selection of second-line therapy; the role of glycemia in the therapeutic management. The statements were rated on a 6-point Likert scale. RESULTS: Fifty-nine (79%) statements reached a consensus. IGF-1 levels resulted central for evaluating resistance to fgSRLs, that should be defined considering also symptomatic clinical response, degree of tumor shrinkage and complications, using clinician- and patient-reported outcome tools available. Factors to be evaluated for the choice of second-line medical therapy are hyperglycemia-that should be managed as in non-acromegalic patients-tumor remnant, resistant headache and compliance. Costs do not represent a main determinant in the choice of second-line medical treatment. CONCLUSION: The experts agreed on a holistic management approach to acromegaly. It is therefore necessary to choose currently available highly effective second-line medical treatment (pegvisomant and pasireotide) based on the characteristics of the patients.

Pituitary apoplexy in endocrinologically silent adenoma during somatostatin analog administration for pancreatic neuroendocrine tumor: A case report.

A dopamine agonist administered for prolactinoma treatment and pituitary stimulation tests are reported as risk factors for pituitary apoplexy. We report a case of an 82-year-old patient who suffered from pituitary apoplexy in an endocrinologically silent adenoma during lanreotide administration. The patient was diagnosed with a pancreatic neuroendocrine tumor with lymph node metastasis and treated with lanreotide for two years. An endoscopic endonasal transsphenoidal approach was used for tumor and hematoma removal. The specimen showed growth hormone and prolactin positivity and was diagnosed as pit1-lineage plurihormonal adenoma. The tumor also showed positivity for somatostatin receptor 2. Thus, lanreotide treatment is a risk factor for pituitary apoplexy even in silent adenoma.