Somatostatin Receptor Research Articles

8773 CD44 Variant Isoforms Expressed Within PAX7/SOX2-Positive Pituitary Neuroendocrine Tumors Attribute To Therapy Resistance And Recurrence Of Cushing’s Disease

Abstract Disclosure: J. Chakrabarti: None. J. Eschbacher: None. S. Mallick: None. E. Ferris: None. B. Hermes: None. A. Little: None. Y. Zavros: None. Background: Cushing’s disease (CD) is a serious rare endocrine disease caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that subsequently stimulates the adrenal glands to overproduce cortisol. Approximately 56% of patients will experience disease recurrence during the 2 to 10-year follow-up period. Surgical failures and late recurrences of CD are common, and despite multiple treatments, biochemical control is achieved in only 50% of patients. Therefore, there is a need to advance targeted therapies that prevent recurrence and therapy resistance. The Cluster of Differentiation (CD) 44 transmembrane glycoprotein (CD44) is a prominent WNT signaling target, and deregulation of the Wnt pathway is associated with constitutively active βcatenin in SOX2-positive cells. Although a similar mechanism has been proposed in PitNETs, it has not been fully tested. The alternative mRNA splice variant, CD44v9 is expressed on cancer stem cells promotes resistance to ROS through the stabilization of the SLC7A11 (xCT) cystine glutamate transporter. Proteolytic cleavage of CD44 releases the CD44 intracellular domain which translocates to the nucleus activating cell stemness genes including SOX2. Although CD44 is a known cancer stem cell marker that plays multiple key roles including drug resistance and tumor cell invasiveness, the mechanisms underlying human PitNET tumorigenesis are unclear. Hypothesis: CD44 expressed on PAX7/SOX2-positive corticotroph PitNET cells define a cell population that attributes to therapy resistance and disease recurrence. Methods: CD patient PitNET tissues and matched PitNET-generated organoids (PitNETOs) were used for CosMx™ Spatial Molecular Imaging (SMI) and scRNAseq analyses respectively. Resistance to drug- and radiation-induced apoptosis was analyzed using PitNETOs generated. Results: SMI and scRNAseq data revealed a cell population co-expressing PAX7 and SOX2, CD44 and EpCAM that was abundant in invasive and silent corticotroph PitNET subtypes with Knosp grades 3-4. Invasive and silent corticotroph PitNETs also expressed an increased cell population of CD163+ macrophages, myofibroblast cancer associated fibroblasts (myCAFs), inflammatory CAFs. While cells isolated from the dura revealed growth of PitNETOs, adherent cells expressed increased proliferation (Ki67), and expression of somatostatin receptor subtype 2, cancer stem markers (CD44, SOX2, NESTIN, FUT4, PROM1), PAX7 progenitor cell population expressing stem cell markers NESTIN, SOX2, CD44 and EpCAM. Increased CD44/SLCA7A11 expression in CD44/PAX7/SOX2-positive PitNETOs rendered tumor cells resistant to radiation-induced apoptosis. Conclusions: Drugs targeting the CD44 variant isoforms may increase the efficacy of medical therapies and stereotactic radiosurgery to prevent residual and recurrent PitNETs in CD patients. Presentation: 6/3/2024

7242 Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) In A Patient With Recurrent Carcinoid

Abstract Disclosure: F. Woron: None. T.L. Anderson: None. P. Madhavan: None. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare generalized proliferation of pulmonary neuroendocrine cells. It is considered to be a pre-invasive lesion for pulmonary carcinoid, a rare neuroendocrine tumor (NET). DIPNECH is thought to be underdiagnosed, as patients can be asymptomatic or present with nonspecific cough and dyspnea, though it is also associated with fibrotic lung changes. Long-term annual surveillance imaging is recommended for due to the potential for development and metastasis of carcinoid tumors. We present a patient with recurrent pulmonary carcinoid later diagnosed with probable DIPNECH based on CT findings. The patient is a 72-year-old female with a prior 15 pack-year smoking history, who initially had a left lower lobe typical carcinoid tumor diagnosed and resected in 2018, with no evidence of lymph node metastasis. The patient’s medical history also includes pulmonary sarcoidosis, adrenal adenoma, thyroid nodule, hiatal hernia, and prediabetes. She has no family history of neuroendocrine tumors. Physical exam showed stable vitals with blood pressure of 112/70 mmHg in the right upper arm, heart rate of 84 bpm, and a body mass index of 39. Physical exam was unremarkable except for thyroid nodularity and obesity. Extensive biochemical evaluation for markers including chromogranin A and 24-hour urine 5-HIAA levels were within normal limits. In 2022, surveillance CT imaging showed a new 9 mm nodule in the right lobe within the bronchus, which was shown to be carcinoid on FNA. She complained of dyspnea and wheezing at this time, which has been managed with an albuterol inhaler. In 2023, PET/CT copper 64 dotatate scan showed a focal area of activity related to the nodule in the superior segment, also identified on recent CT scan, with the nodule measuring approximately 2.05 cm x 1.8 cm with a maximal SUV of 4.2. Interestingly, somatostatin receptor scintigraphy did not show any pick-up in the lung in 2018 or 2022. In 2023, the patient underwent right lower lobe superior segmentectomy after the nodule was found to have increased in size. Pathology showed G1, well-differentiated 1.1 cm typical carcinoid tumor with margins negative for invasive carcinoma. All 18 regional lymph nodes were negative for tumor. Immunohistochemical tests show that the tumor cells were positive for INSM1 and chromogranin with a low Ki-67 proliferation index (<2%), supporting the diagnosis. The patient is currently being monitored by yearly CT imaging and followed by both endocrinology and pulmonology. Given this case, we propose that DIPNECH should be considered as a differential in cases of pulmonary carcinoid, especially recurrent ones. Given that DIPNECH is thought to be underdiagnosed and a precursor for carcinoid associated with fibrotic lung changes, it is essential for this disease to be identified in order for patients to receive appropriate long-term monitoring. Presentation: 6/1/2024

Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3

Somatostatin receptors (SSTRs) exert critical biological functions such as negatively regulating hormone release and cell proliferation, making them popular targets for developing therapeutics to treat endocrine disorders, especially neuroendocrine tumors. Although several panagonists mimicking the endogenous ligand somatostatin are available, the development of more effective and safer somatostatinergic therapies is limited due to a lack of molecular understanding of the ligand recognition and regulation of divergent SSTR subtypes. Here, we report four cryoelectron microscopy structures of Gi-coupled SSTR1 and SSTR3 activated by distinct agonists, including the FDA-approved panagonist pasireotide as well as their selective small molecule agonists L-797591 and L-796778. Our structures reveal a conserved recognition pattern of pasireotide in SSTRs attributed to the binding with a conserved extended binding pocket, distinct from SST14, octreotide, and lanreotide. Together with mutagenesis analyses, our structures further reveal the dynamic feature of ligand binding pockets in SSTR1 and SSTR3 to accommodate divergent agonists, the key determinants of ligand selectivity lying across the orthosteric pocket of different SSTR subtypes, as well as the molecular mechanism underlying diversity and conservation of receptor activation. Our work provides a framework for rational design of subtype-selective SSTR ligands and may facilitate drug development efforts targeting SSTRs with improved therapeutic efficacy and reduced side effects.

Routine Use of [64Cu]Cu-DOTATATE PET/CT in a Neuroendocrine Tumor Center: Referral Patterns and Image Results of 2,249 Consecutive Scans.

The role of somatostatin receptor (SSTR) PET/CT, using 68Ga-based tracers or [64Cu]Cu-DOTATATE (64Cu-DOTATATE), in the management of patients with neuroendocrine neoplasm (NEN) is guided by appropriate use criteria (AUC). In this study, we performed systematic analyses of referral patterns and image findings of routine 64Cu-DOTATATE PET/CT scans to support AUC development. Methods: We included all clinical routine 64Cu-DOTATATE PET/CT scans performed between April 10, 2018 (start of clinical use), and May 2, 2022, at Copenhagen University Hospital-Rigshospitalet. We reviewed the referral text and image report of each scan and classified the indication according to clinical scenarios as listed in the AUC. Results: In total, 1,290 patients underwent 2,249 64Cu-DOTATATE PET/CT scans. Monitoring of patients with NEN seen both on conventional imaging and on SSTR PET without clinical evidence of progression was the most common indication (defined as "may be appropriate" in the AUC) and accounted for 703 (31.3%) scans. Initial staging after NEN diagnosis ("appropriate" in the AUC) and restaging after curative-intent surgery ("may be appropriate" in the AUC) accounted for 221 (9.8%) and 241 (10.7%) scans, respectively. Selection of patients eligible for peptide receptor radionuclide therapy ("appropriate" in the AUC) and restaging after peptide receptor radionuclide therapy completion ("appropriate" in the AUC) accounted for 95 (4.2%) and 115 (5.1%) scans, respectively. The number of scans performed for indications not defined in the AUC was 371 (16.5%). Image result analysis revealed no disease in 669 scans (29.7%), stable disease in 582 (25.9%), and progression in 461 (20.5%). In 99 of the 461 (21.5%) scans, progression was detected on PET but not on CT. Conclusion: Our study provided real-life data that may contribute to support development of 64Cu-DOTATATE/SSTR PET/CT guidelines including AUC. Some scenarios listed as "may be appropriate" in the current AUC were frequent in our data. Monitoring of patients with NEN without clinical evidence of progression was the most frequent indication for 64Cu-DOTATATE PET/CT, in which disease progression was detected in more than one third, and a large proportion was visible by PET only. We therefore conclude that this scenario could potentially be classified as appropriate.

Value of 68 Ga-DOTATATE PET/CT in Follow-up of Renal Cell Carcinoma With Multiple Atypical Metastatic Sites.

The development of late metastatic recurrence after nephrectomy is a well-known characteristic of renal cell carcinoma (RCC). Correct diagnosis is often challenging due to the long time between primary tumor excision and the development of metastases. 68 Ga-DOTATATE PET/CT has the potential to be employed in the follow-up of RCC, because RCC expresses somatostatin receptors. However, limited cases have been reported demonstrating 68 Ga-DOTATATE uptake in the metastases of RCC. Herein, we describe a unique case of RCC with multiple atypical metastatic sites, emphasizing the usefulness of 68 Ga-DOTATATE PET/CT in the evaluation and follow-up of patients with RCC.

Hybrid Somatostatin Receptor PET/MRI of the Head and Neck.

Hybrid PET/MRI has the potential to transform neuro-oncologic imaging, particularly in diagnosis and treatment planning of somatostatin receptor-expressing tumors of the head and neck. Hybrid PET/MRI combines high-resolution MRI with functional information from PET, providing precise anatomic information and overcoming difficulties in localization inherent to PET alone. There is a range of tumors in the head and neck that overexpress somatostatin receptors and are therefore amenable to evaluation with somatostatin receptor PET/MRI. These include meningiomas, paragangliomas, olfactory neuroblastomas, pituitary neuroendocrine tumors, middle ear neuroendocrine tumors, and medullary thyroid carcinomas. The combination of PET and MRI is superior to either modality alone and can address several unique diagnostic challenges associated with these lesions. The authors discuss the superior capabilities of somatostatin receptor PET/MRI, including improved lesion localization, more sensitive demonstration of disease extent, enhanced surveillance, optimized radiation therapy planning, and accurate prediction of response to somatostatin analog therapy. Although there are only a few dedicated PET/MRI units available in clinical practice, commercial software is now available that can automatically fuse PET/CT data with recently acquired MRI data, increasing the availability of this approach. Radiologists should be aware of the advantages of somatostatin receptor PET/MRI in evaluation of head and neck tumors as well as the potential pitfalls of this approach so that they can accurately advise clinicians and better interpret these studies. ©RSNA, 2024 See the invited commentary by Shatzkes and Strauss in this issue.

Peptide receptor radionuclide therapy for ectopic Cushing’s syndrome caused by metastatic neuroendocrine neoplasia

Background: Metastatic gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) can cause ectopic Cushing’s syndrome (ECS). ECS is highly morbid and medical therapy is complex and can be ineffective. Patients unsuitable for bilateral adrenalectomy (BA) have dismal outcomes. Peptide receptor radionuclide therapy (PRRT) is a rational option for hormone and disease control in ECS caused by NEN with high somatostatin receptor (SSTR) expression. Aim: To describe characteristics and outcomes of patients with ECS treated with PRRT. Methods: Single-centre, retrospective analysis of imaging, biochemistry and outcomes of seven consecutive patients with ECS caused by metastatic GEPNEN treated with PRRT from 2006-2023. Results: Patients were aged 17–75 (female n=6). The primary site was pancreas (5/7) and rectum (2/7). Six patients were on medical therapy for ECS at baseline (one previous BA). A median of 34.4GBq of [177Lu]Lu-DOTA-octreotate was given. [90Y]Y-DOTA-octreotate (one patient) and [111In]In-octreotide (one patient) was also used. Five patients had radiosensitising chemotherapy. Five patients had a flare of ECS within one week of PRRT cycle 1 (PRRT-C1). Following PRRT-C1, 5/7 patients had complete biochemical resolution of ECS at 1.5–6 months (four ongoing; one recurred after 12 months and had elective BA at 18 months). Best metabolic response on [18F]F-FDG PET/CT: Four patients had a complete metabolic response (CMR), one had a partial metabolic response. PFS was 3–208 months. Two patients progressed at first follow-up. The longest ECS remission and CMR continues at >17 years. Conclusion: PRRT can be effective for ECS caused by metastatic SSTR-positive GEPNEN and should be considered in its treatment algorithm.

Neuropeptide therapeutics to repress lateral septum neurons that disable sociability in an autism mouse model.

Confronting oxytocin and vasopressin deficits in autism spectrum disorders and rare syndromes brought promises and disappointments for the treatment of social disabilities. We searched downstream of oxytocin and vasopressin for targets alleviating social deficits in a mouse model of Prader-Willi syndrome and Schaaf-Yang syndrome, both associated with high prevalence of autism. We found a population of neurons in the lateral septum-activated on termination of social contacts-which oxytocin and vasopressin inhibit as per degree of peer affiliation. These are somatostatin neurons expressing oxytocin receptors coupled to GABA-B signaling, which are inhibited via GABA-A channels by vasopressin-excited GABA neurons. Loss of oxytocin or vasopressin signaling recapitulated the disease phenotype. By contrast, deactivation of somatostatin neurons or receptor signaling alleviated social deficits of disease models by increasing the duration of contacts with mates and strangers. These findings provide new insights into the treatment framework of social disabilities in neuropsychiatric disorders.

Metachronous Second Primary in the Form of Nasopharyngeal Carcinoma Following Treatment of Small Cell Neuroendocrine Carcinoma of the Head and Neck: Dual Tracer PET/CT Findings Highlighting SSTR2 Expression and Its Theranostic Implications

AbstractPatients of head and neck squamous cell carcinoma (HNSCC) experience increased risk of developing second primary cancer (SPC) necessitating active surveillance during their disease course. SPCs are associated with poor prognosis and are the leading cause of long-term morbidity and mortality impacting survival of patients with HNSCC. Small cell neuroendocrine carcinoma (SmNEC) is a rare but aggressive neoplasm with poor prognosis and high risk of local recurrence and distant metastasis. We report an exceedingly rare case of nasopharyngeal carcinoma (NPC) presenting as a recurrence in the form of metachronous second primary to primary SmNEC 9 years after chemotherapy. The dual tracer positron emission tomography and computed tomography (PET/CT) imaging approach ([68Ga]Ga-DOTATATE-PET/CT with 18F-FDG-PET/CT) was explored in such metachronous NPCs, and the findings are illustrated with its potential for theranostic applications. NPC is a rare malignancy with significant geographical variations in incidence rates. Somatostatin receptor 2 (SSTR2) expression in NPC is well documented and can serve as a potential theragnostic marker in advanced NPC where the successful outcome is minimal with currently available treatment modalities.

Somatostatin Receptor Type 2 as a Potential Marker of Local Myocardial Inflammation in Myocardial Infarction: Morphologic Data on Distribution in Infarcted and Normal Human Myocardium.

Nuclear imaging modalities can detect somatostatin receptor type 2 (SSTR2) in vivo as a potential marker of local post-MI inflammation. SSTR2+ macrophages are thought to be the main substrate for SSTR-targeted radioimaging. However, the distribution of SSTR2+ cells in the MI patients' myocardium is unknown. Using immunohistochemistry, we investigated the distribution of SSTR2+ cells in the myocardium of patients who died during the MI inflammatory phase (n = 7) compared to the control group of individuals with fatal trauma (n = 3). Inflammatory cellular landscapes evolve in a wave front-like pattern, so we divided the myocardium into histological zones: the infarct core (IC), the border zone (BZ), the remote zone (RZ), and the peri-scar zone (PSZ). The number of SSTR2+ neutrophils (NPs), SSTR2+ monocytes/macrophages (Mos/MPs), and SSTR2+ vessels were counted. In the myocardium of the control group, SSTR2+ NPs and SSTR2+ Mos/MPs were occasional, SSTR2+ vessels were absent. In the RZ, the picture was similar to the control group, but there was a lower number of SSTR2+ Mos/MPs in the RZ. In the PSZ, SSTR2+ vessel numbers were highest in the myocardium. In the IC, the median number of SSTR2+ NPs was 200 times higher compared to the RZ or control group myocardium, which may explain the selective uptake of SSTR-targeted radiotracers in the MI area during the inflammatory phase of MI.

Phosphaturic mesenchymal tumor demonstrated by 68Ga-DOTATATE PET/CT in a patient: a case report

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome caused by abnormally high levels of fibroblast growth factor 23 (FGF-23), most commonly produced and secreted by small phosphaturic mesenchymal tumors (PMT). These tumors can show various anatomic locations throughout soft tissue and bone. The presence of the tumor itself rarely causes symptoms. Nonspecific symptoms such as muscle weakness and musculoskeletal pain are related to the developing hypophosphatemia and osteomalacia as a secondary effect of the increased circulating levels of FGF-23. Therefore, as the initial presentation can mimic a wide range of metabolic or inflammatory diseases, proper diagnosis is often delayed. Localization of the tumor is crucial, as its complete surgical resection is the only curative treatment. Whole-body functional imaging targeting the overexpression of somatostatin receptors (SSTR) on the surface of the PMT cells, is a highly specific and sensitive imaging method to detect the primary tumor site. Here, we discuss a case of TIO in a patient initially presenting with symptoms of inflammatory spondyloarthritis. SSTR positron emission imaging using 68Ga-DOTATATE was central in diagnosing and localizing the primary tumor.

Laparoscopic Central Pancreatectomy with Modified Blumgart Pancreatojejunostomy for Pancreatic Neuroendocrine Tumor.

This report with a video describes a laparoscopic central pancreatectomy with modified Blumgart pancreatojejunostomy for pancreatic neuroendocrine tumor. A 71-year-old woman presented with a single 17 mm lesion in the pancreatic neck, responsible for dilatation of the main pancreatic duct. Cancer staging showed no additional location. Somatostatin receptor imaging was positive. After a multidisciplinary discussion in the French national reference network for the management of neuroendocrine tumor (RENATEN) surgery with central pancreatectomy was decided. The operation time was 320 min and the estimated blood loss was less than 100 ml. Final pathology confirmed a pancreatic NET of 13 mm staged as T1 N0 M0 R0 G1 with a Ki-67 of 2%. After lymph node dissection, five nodes were analyzed and were found to be noninvaded. The postoperative course was uneventful. Laparoscopic central pancreatectomy is an excellent alternative for sparing pancreatic parenchyma.

68 Ga-DOTATATE PET/CT Versus 18 F-FDG PET/CT in TENIS Syndrome: A Head-to-Head Comparison With Elevated and Suppressed TSH Levels in Papillary Thyroid Carcinoma-A Pilot Study.

TENIS syndrome is characterized by reduced expression of sodium-iodine symporter, rising serum thyroglobulin (Tg) levels, and negative whole-body 131 I scans. In such patients, somatostatin receptor imaging with 68 Ga-DOTATATE PET/CT (somatostatin receptor [SSR] PET/CT) and 18 F-FDG PET/CT (FDG PET/CT) can identify metastases and were compared under 2 conditions: elevated (eTSH) and suppressed (sTSH) TSH serum levels. Potential candidates for peptide receptor radionuclide therapy (PRRNT) were identified in 15 patients prospectively enrolled. All patients underwent 4 examinations. Images were blindly evaluated for differences in SUV max values and lesion detectability. Reference standard consisted of neck ultrasound, CT, MRI, PET/CT, biopsy, and follow-up. Three patients were received PRRNT. sTSH SSR PET/CT detected a greater number of cervical ( P = 0.0253 and P = 0.0176) and distant LNs ( P = 0.0253 and P = 0.0391) when compared with sTSH FDG PET/CT, respectively, in a per-patient and on a per-lesion based analysis. Likewise, eTSH SSR PET/CT detected a greater number of patients with local recurrences ( P = 0.0455) and distant LN metastases ( P = 0.0143). Per-lesion analysis revealed greater number of cervical and distant LNs ( P = 0.0337 and P = 0.0039, respectively) when compared with eTSH FDG PET/CT. There was no difference in detection of distant metastases by both tracers for lung and bone metastases (κ = 1). Both skeletal and pulmonary lesions were also detected by conventional CT part of FDG or DOTATATE PET/CT scans. TSH stimulation had no additional value in a per-patient analysis for both FDG and DOTATATE PET scans (κ varying from 0.6087 to 1). However, TSH stimulation led to more lesion identifications in DOTATATE PET/CT; most of those metastases were not confirmed by the reference standard leading to a decrease in specificity (84% vs 74%). One of 3 patients submitted to 3 cycles of PRRNT presented with a visual partial response, a 20% reduction in quantitative analyses, and stable disease regarding Tg and TgAb levels. Patients with TENIS syndrome can be imaged with SSR PET/CT as well as FDG PET/CT with high overall accuracy regardless of TSH levels (86% to 92% and 92% to 85%, respectively, with eTSH and sTSH). SSR PET/CT detected a greater number of locoregional and distant LN metastases than FDG PET/CT with both sTSH and eTSH. One of 3 patients submitted to PRRNT presented a partial response to treatment. Our findings may impact in patient restaging, management, and theranostics strategies with radiolabeled somatostatin analogs.

Combination of the amide-to-triazole substitution strategy with alternative structural modifications for the metabolic stabilization of tumor-targeting, radiolabeled peptides.

Radiolabeled peptides play a key role in nuclear medicine to selectively deliver radionuclides to malignancies for diagnosis (imaging) and therapy. Yet, their efficiency is often compromised by low metabolic stability. The use of 1,4-disubstituted 1,2,3-triazoles (1,4-Tzs) as stable amide bond bioisosteres can increase the half-life of peptides in vivo while maintaining their biological properties. Previously, the amide-to-triazole substitution strategy was used for the stabilization of the pansomatostatin radioligand [111In]In-AT2S, resulting in the mono-triazolo-peptidomimetic [111In]In-XG1, a radiotracer with moderately enhanced stability in vivo and retained ability to bind multiple somatostatin receptor (SSTR) subtypes. However, inclusion of additional 1,4-Tz led to a loss of affinity towards SST2R, the receptor overexpressed by most SSTR-positive cancers. To enhance further the stability of [111In]In-XG1, alternative modifications at the enzymatically labile position Thr10-Phe11 were employed. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide conjugates were synthesized with a 1,4-Tz (Asn5-Ψ[Tz]-Phe6) and either a β-amino acid (β-Phe11), reduced amide bond (Thr10-Ψ[NH]-Phe11), or N-methylated amino acid (N-Me-Phe11). Two of the new peptidomimetics were more stable in blood plasma in vitro than [111In]In-XG1. Yet none of them retained high affinity towards SST2R. We demonstrate for the first time the combination of the amide-to-triazole substitution strategy with alternative stabilization methods to improve the metabolic stability of tumor-targeting peptides.

Immune Cell Molecular Pharmacodynamics of Lanreotide in Relation to Treatment Response in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

The CLARINET trial led to the approval of lanreotide for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs). It is hypothesized that lanreotide regulates proliferation, hormone synthesis, and other cellular functions via binding to somatostatin receptors (SSTR1-5) present in NETs. However, our knowledge of how lanreotide affects the immune system is limited. In vitro studies have investigated functional immune response parameters with lanreotide treatment in healthy donor T cell subsets, encompassing the breadth of SSTR expression, apoptosis induction, cytokine production, and activity of transcription factor signaling pathways. In our study, we characterized in vitro immune mechanisms in healthy donor T cells in response to lanreotide. We also studied the in vivo effects by looking at differential gene expression pre- and post-lanreotide therapy in patients with NET. Immune-focused gene and protein expression profiling was performed on peripheral blood samples from 17 NET patients and correlated with clinical response. In vivo, lanreotide therapy showed reduced effects on wnt, T cell receptor (TCR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling in CD8+ T cells in responders compared to non-responders. Compared to non-responders, responders showed reduced effects on cytokine and chemokine signaling but greater effects on ubiquitination and proteasome degradation genes. Our results suggest significant lanreotide pharmacodynamic effects on immune function in vivo, which correlate with responses in NET patients. This is not evident from experimental in vitro settings.

Regional distribution of mechanical strain and macrophage-associated lung inflammation after ventilator-induced lung injury: an experimental study

BackgroundAlveolar macrophages activation to the pro-inflammatory phenotype M1 is pivotal in the pathophysiology of Ventilator-Induced Lung Injury (VILI). Increased lung strain is a known determinant of VILI, but a direct correspondence between regional lung strain and macrophagic activation remains unestablished. [68Ga]Ga-DOTA-TATE is a Positron Emission Tomography (PET) radiopharmaceutical with a high affinity for somatostatin receptor subtype 2 (SSTR2), which is overexpressed by pro-inflammatory-activated macrophages. Aim of the study was to determine, in a porcine model of VILI, whether mechanical strain correlates topographically with distribution of activated macrophages detected by [68Ga]Ga-DOTA-TATE uptake.MethodsSeven anesthetized pigs underwent VILI, while three served as control. Lung CT scans were acquired at incremental tidal volumes, simultaneously recording lung mechanics. [68Ga]Ga-DOTA-TATE was administered, followed by dynamic PET scans. Custom MatLab scripts generated voxel-by-voxel gas volume and strain maps from CT slices at para-diaphragmatic (Para-D) and mid-thoracic (Mid-T) levels. Analysis of regional Voxel-associated Normal Strain (VoStrain) and [68Ga]Ga-DOTA-TATE uptake was performed and a measure of the statistical correlation between these two variables was quantified using the linear mutual information (LMI) method.ResultsCompared to controls, the VILI group exhibited statistically significant higher VoStrain and Standardized Uptake Value Ratios (SUVR) both at Para-D and Mid-T levels. Both VoStrain and SUVR increased along the gravitational axis with an increment described by statistically different regression lines between VILI and healthy controls and reaching the peak in the dependent regions of the lung (for strain in VILI vs. control was at Para-D: 760 ± 210 vs. 449 ± 106; at Mid-T level 497 ± 373 vs. 193 ± 160; for SUVR, in VILI vs. control was at Para-D: 2.2 ± 1.3 vs. 1.3 ± 0.1; at Mid-T level 1.3 ± 1.0 vs. 0.6 ± 0.03). LMI in both Para-D and Mid-T was statistically significantly higher in VILI than in controls.ConclusionsIn this porcine model of VILI, we found a topographical correlation between lung strain and [68Ga]Ga-DOTA-TATE uptake at voxel level, suggesting that mechanical alteration and specific activation of inflammatory cells are strongly linked in VILI. This study represents the first voxel-by-voxel examination of this relationship in a multi-modal imaging analysis.

Agonists, Antagonists and Receptors of Somatostatin: Pathophysiological and Therapeutical Implications in Neoplasias.

Somatostatin is a peptide that plays a variety of roles such as neurotransmitter and endocrine regulator; its actions as a cell regulator in various tissues of the human body are represented mainly by inhibitory effects, and it shows potent activity despite its physiological low concentrations. Somatostatin binds to specific receptors, called somatostatin receptors (SSTRs), which have different tissue distributions and associated signaling pathways. The expression of SSTRs can be altered in various conditions, including tumors; therefore, they can be used as biomarkers for cancer cell susceptibility to certain pharmacological agents and can provide prognostic information regarding disease evolution. Moreover, based on the affinity of somatostatin analogs for the different types of SSTRs, the therapeutic range includes conditions such as tumors, acromegaly, post-prandial hypotension, hyperinsulinism, and many more. On the other hand, a number of somatostatin antagonists may prove useful in certain medical settings, based on their differential affinity for SSTRs. The aim of this review is to present in detail the principal characteristics of all five SSTRs and to provide an overview of the associated therapeutic potential in neoplasias.

Alterations of pleiotropic neuropeptide-receptor gene couples in Cetacea

BackgroundHabitat transitions have considerable consequences in organism homeostasis, as they require the adjustment of several concurrent physiological compartments to maintain stability and adapt to a changing environment. Within the range of molecules with a crucial role in the regulation of different physiological processes, neuropeptides are key agents. Here, we examined the coding status of several neuropeptides and their receptors with pleiotropic activity in Cetacea.ResultsAnalysis of 202 mammalian genomes, including 41 species of Cetacea, exposed an intricate mutational landscape compatible with gene sequence modification and loss. Specifically for Cetacea, in the 12 genes analysed we have determined patterns of loss ranging from species-specific disruptive mutations (e.g. neuropeptide FF-amide peptide precursor; NPFF) to complete erosion of the gene across the cetacean stem lineage (e.g. somatostatin receptor 4; SSTR4).ConclusionsImpairment of some of these neuromodulators may have contributed to the unique energetic metabolism, circadian rhythmicity and diving response displayed by this group of iconic mammals.

685TiP A phase I, multicenter trial (“KinLET”) of [177Lu]Lu-edotreotide for treatment of somatostatin receptor positive solid tumors or lymphoma, in patients two to less than 18 years of age

685TiP A phase I, multicenter trial (“KinLET”) of [177Lu]Lu-edotreotide for treatment of somatostatin receptor positive solid tumors or lymphoma, in patients two to less than 18 years of age

P050 PITFALLS IN ESTABLISHING THE DIAGNOSIS OF PHEOCHROMOCYTOMA ILLUSTRATED BY THREE CASE REPORTS

Background and Objective: Pheochromocytoma is a rare cause of secondary hypertension. Because of the low incidence, any diagnostic test has a low positive predictive value. Methods: We report three example cases with diagnostic pitfalls. Results: First case: A 72-year old Caucasian women was admitted for the evaluation of a right adrenal mass, measuring 4 cm. The patient was asymptomatic, never hypertensive. Standard endocrinological evaluation of the adrenal mass revealed significantly elevated plasma and urine normetanephrine (>2 fold upper normal range) and metanephrine levels (>10 fold upper normal range). Subsequent functional imaging with MIBG SPECT/CT confirmed catecholamine storage in the left adrenal mass. After pretreatment with phenoxybenzamine (causing hypotension) the mass was removed surgically and a pheochromcytoma confirmed histologically. Second case: A 59-year old Caucasian women with repetitive hypertensive crises for several years was screened for pheochromocytoma and significantly elevated plasma and urine normetanephrine levels (> 5 fold upper normal range) were observed. MRI demonstrated a small left adrenal mass of 2 cm. Although no relevant tracer uptake was observed on MIBG SPECT/CT, subsequent somatostatin receptor imaging with DOTA-TATE PET/CT suggested adrenal pheochromocytoma (Fig.). After pretreatment with doxazosine the mass was removed surgically and a pheochromocytoma confirmed histologically, blood pressure normalized after surgery. Third case: A 67 year old Asian woman was admitted for the evaluation of a large left adrenal mass measuring 7.5 cm. She had well controlled hypertension with dual antihypertensive medication and did not suffer from paroxysmal hypertensive crises. Plasma normetanephrine levels were substantially elevated (>20 fold upper normal range). MIBG SPECT/CT confirmed catecholamine storage in the adrenal mass that was partly necrotic. After pretreatment with doxazosine the mass was removed surgically, a largely necrotic pheochromocytoma was confirmed histologically. No further antihypertensive treatment was necessary. Conclusions: These cases demonstrate that a pheochromocytoma may be asymptomatic, any adrenal mass needs standard endocrinological workup. Standard functional imaging has a limited sensitivity, additional approaches have to be considered.