Somatostatin Receptor Analogs Research Articles

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.

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. 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 120min 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. [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. [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. ClinicalTrials.gov identifier NCT06056362.

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

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. 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. 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 5days, there was a significantly higher bloodpool activity than at longer intervals. 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 5days after the injection of lanreotide.

FRI318 A Case Of Mixed Growth Hormone And Prolactin-secreting Giant Pituitary Macroadenoma

Abstract Disclosure: A. Khan: None. I. Alpertunga: None. V. Kantorovich: None. Introduction Co-secretion of prolactin (PRL) and growth hormone (GH) from a single pituitary adenoma is an established entity in the medical literature and present in about 5% of the cases. Guidelines recommend to obtain an insulin-like growth factor-1 (IGF-1) in patients with prolactinoma at the time of initial diagnosis. Our case describes the management of a giant pituitary macroadenoma co-secreting PRL and GH. Case A 20-year-old male with history significant for schizophrenia presented with visual disturbances and discharge from his left nipple. His prolactin level (PRL) was noted to be elevated at 12,396 (4.0-15.2) ng/ml on work-up during recent prior investigation. On physical exam, he had bilateral temporal visual field deficit as well as dysfunction in upward gaze of left eye. Head imaging showed a 7.5 x 6.2 x 5 cm associated with remodeling of the sella turcica and expanding into the suprasellar space and significant mass-effect on the adjacent frontal lobes bilaterally, mild mass-effect on the adjacent optic chiasm with significant surrounding vasogenic edema and compressing the bilateral anterior cerebral arteries. Patient was started on low dose cabergoline in caution of prevention of possibility of rapid response-related significant volume contraction of the tumor with possibility of reactive edema. The dose of cabergoline was rapidly titrated up to 3 mg bi-weekly with minimal prolactin fluctuation of PRL between 12,000 and 16,000 ng/ml. Because of mild atypical acromegalic facial features, patient had GH axis assessment. IGF-1 level came back elevated at 529 (83-456) ng/ml with a high IGF Binding Protein- 3 of 8.9 (2.9-7.2) mg/l. He was started on octreotide titrated up to a dose of 150 mcg three times daily. Repeat MRI brain did not show tumor shrinkage. Subsequently, patient underwent bifrontal craniotomy for resection/debulking of parasellar tumor. PRL dropped to 931 ng/ml immediately after surgery. At the time of writing, pathology of the tumor and repeat IGF-1 level is pending. Patient was monitored closely in the ICU with a steroid taper postoperatively. Discussion Dopamine agonists are the first-line therapy for medical treatment of hyperprolactinemia but can also suppress GH and IGF-1 levels. However, in acromegaly, cabergoline is utilized mostly for small adenomas with mild elevation of IGF-1. In our case, we decided to use a combination of cabergoline and somatostatin receptor analog, octreotide. However, given the giant adenoma with very high PRL and IGF-1 levels, patient showed a poor response to medical therapy, and given the impending threat to patient’s vision, he underwent surgical debulking. Our case highlights the management of a giant, mixed hormone-secreting pituitary adenoma. Presentation: Friday, June 16, 2023

Imaging of Small-Bowel Neuroendocrine Neoplasms: AJR Expert Panel Narrative Review.

Neuroendocrine neoplasms (NENs) of the small bowel are typically slow-growing lesions that remain asymptomatic until reaching an advanced stage. Imaging modalities for lesion detection, staging, and follow-up in patients with known or suspected NEN include CT enterography, MR enterography, and PET/CT using a somatostatin receptor analog. FDG PET/CT may have a role in the evaluation of poorly differentiated NENs. Liver MRI, ideally with a hepatocyte-specific contrast agent, should be used in the evaluation of hepatic metastases. Imaging informs decisions regarding both surgical approaches and systematic therapy (specifically, peptide receptor radionuclide therapy). This AJR Expert Panel Narrative Review describes the multimodality imaging features of small-bowel NENs; explores the optimal imaging modalities for their diagnosis, staging, and follow-up; and discusses how imaging may be used to guide therapy.

Is Nuclear Imaging Important in the Management of Head and Neck Paragangliomas?

Nuclear medical imaging is indicated in most, but not all, patients with suspected paragangliomas of the head and neck. Advances in technology and somatostatin receptor analogs have improved the selectivity and sensitivity of this imaging.

Clinical significance of atypical 68Ga-DOTATOC prostatic uptake on PET/CT: A ten-year review.

Gallium-68-DOTA-D-Phe1-Try3-Octreotide (68Ga-DOTATOC) is a radiolabeled somatostatin receptor (SSTR) analog that is widely used in the imaging of neuroendocrine tumors (NET). Benign and malignant prostate tumors have been observed to express SSTR. Diffuse symmetric DOTATOC uptake in the prostate is a normal positron emission tomography (PET) finding. The aim of this study was to evaluate the frequency and clinical significance of incidental atypical prostatic uptake in men undergoing 68Ga-DOTATOC PET/computed tomography(CT). A retrospective review of consecutive male patients who underwent 68Ga-DOTATOC PET/CT studies at Aalborg University Hospital, Denmark, from November 2010 to April 2020 was performed. Positron emission tomography/CT reports were searched for text words or phrases indicating incidental atypical prostatic uptake. In the resulting cohort, PET/CT were re-evaluated, and DOTATOC uptake in the prostate gland was categorized as focal, diffuse or mixed. The intensity of the uptake was visually graded using the Krenning visual score. Follow-up was based on all available clinical, biochemical, imaging, and pathology follow-up. A total of 178 male patients underwent 193 68Ga-DOTATOC PET/CT scans. Incidental atypical uptake of 68Ga-DOTATOC on PET/CT in the prostatic bed was observed in eight patients (4.5%) (mean age 67 years, range 58-85 years). Six patients (75%) had diffuse uptake; two (25%) patients had focal uptake. Four patients out of eight with incidental findings (50%) had uptake less than or equal to that of the liver (Krenning score 2); four patients (50%) had uptake greater than that of the liver (score 3). All patients had measurements of serum prostate-specific antigen and were referred for urological evaluation. Five patients (62%) underwent a transrectal ultrasound, and three required a biopsy of the prostate. No cases of prostate malignancy (including prostatic cancer) were diagnosed. During a 10-year period, we found that 4.5% of men exhibited prostate incidentalomas on 68Ga-DOTATOC PET/CT. No malignancy was found in the prostate in this population. Our data indicate absent malignancy among incidental 68Ga-DOTATOC findings in the prostate.

PMON105 Giant Growth Hormone (GH)-Secreting Pituitary Tumor with Massive Sphenoid Sinus Invasion and Spontaneous Cerebrospinal Fluid (CSF) Leak: A Case Report

Abstract Introduction Giant pituitary tumor, defined as &amp;gt;4cm, comprise 6-10% of all pituitary tumors. Giant GH-secreting pituitary tumors are rare and difficult to treat. They typically invade surrounding structures ​such as the cavernous sinus, making ​complete resection challenging or impossible. This report highlights a case of giant GH-secreting pituitary tumor with an unusual clinical presentation.CLINICAL CASE: A 56 Y/O male with hypertension, cardiomyopathy, obesity, and OSA presented to the ER with stroke-like symptoms. Brain CT and MRI revealed small acute to subacute infarcts within the left occipital, left frontal, right frontal, right parietal areas, and right cerebellum. An incidental finding was a 4.3 cm T2 hyperintense enhancing mass centered within the skull base with involvement of the sella, extension into bilateral cavernous sinuses, clivus, encasement of bilateral carotid arteries, and invasion through the sphenoid sinus into the nasopharyngeal space resulting in a preoperative CSF. He was overtly acromegalic with coarse facial features, prominent frontal bossing, early prognathism, and macroglossia. Hands and feet were enlarged, but non-edematous. Visual field testing was normal. Laboratory values: IGF-1, 317 ng/mL (NL &amp;lt;170): GH, 4 ng/ml (NL&amp;lt;10); prolactin, 17.6 ng/mL (NL 2.5-17.4); total testosterone, 11 ng/dL (NL 130-810); free testosterone, 2 pg/dL (NL 36-146). ACTH stimulation produced a normal cortisol response. Test for AIP gene mutation was negative. Emergent packing of the CSF leak site was done. He underwent trans-sphenoidal (TSS) debulking of the tumor along with reconstruction of the ​skull base and repair of CSF leak. Postoperatively, IGF-1 level decreased to 216 ng/mL. Immunohistochemical stains of the tumor were strongly positive for GH and somatostatin receptor type2 (SSTR2). Three weeks postoperatively, IGF-1 increased to 482 ng/mL. IGF-1 level decreased to 326 ng/mL after 3 doses of lanreotide 90 mg/month. He will be now monitored on 120 mg/month. Currently, he requires only testosterone replacement. Conclusion This patient had the unique presentation of florid acromegaly and CSF leak mainly related to his delay in seeking medical care. Absence of visual defects has been noted in only 15% of reported patients with giant GH-secreting adenomas. Massive replacement of the sphenoid sinus by a giant pituitary tumor causing a CSF leak with invasion into the ​cavernous sinuses and clivus has been rarely reported. Trans-sphenoidal resection is the preferred first-line treatment for patients with acromegaly. The remission rate decreases and can reach almost 0% for giant GH-secreting tumors. Somatostatin receptor analogs (SRA) are the preferred first-line pharmacological treatment as an adjuvant therapy for residual tumor. Our patient likely will need continued SRA and potentially other modalities to control acromegaly due to unresectable tumor anatomy. This case also highlights the complications of delayed detection and benefits of extensive TSS surgical resection with the goal to enhance his response to SRA. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON115 Long term follow-up of patient with gigantism harboring an exon 2 deletion in the AIP gene

Abstract Introduction Pituitary gigantism is a rare endocrinopathy that has been linked to inactivating germline mutations in AIP gene with a prevalence of 30%. AIP is a tumor suppressor gene associated with high predisposition to pituitary adenoma. Thus, the genetic screening of AIP mutations has been recommended to cases with sporadic young-onset pituitary adenoma. Even with a phenotype suggesting gigantism the diagnosis could be delayed, making the treatment more complex, due the large pituitary tumor. Here we describe a giant patient with deletion of exon 2 of the AIP gene detected by Multiplex Ligation-dependent Probe Amplification assay (MLPA) 33 years after the diagnosis. Material and Methods In 1988, a 13-year-old afro-descendent boy with no history of familial pituitary adenoma, presented with seizures and tall stature. On exam he showed signs of gigantism and hypopituitarism: height 2.05 m (SD: + 7), target height was 1.65 (SD: -1), weight 75 kg (SD: + 3.2), no signs of puberty and impaired vision field. Basal GH was &amp;gt; 40 ng/mL, IGF-1: &amp;gt; 1200 ng/mL (ULN: +4). MRI revealed an invasive macroadenoma (Knosp IV). He underwent pituitary surgery twice with an adenoma GH/PRL positive with no remission. He did not respond to the treatment with somatostatin receptor analogue presenting remission only after radiotherapy, developing permanent deficiency of ACTH/TSH/LH/FSH/GH and diabetes insipidus. Peripheral blood was collected to genetic analysis in 2021. Results The genetic analysis supported by Sanger sequencing resulted negative to pathogenic germline variants in intron-exon frontiers and coding areas of the AIP and MEN1 genes. Thus, MLPA was performed using the SALSA MLPA kit P244 designed to detect large deletions or amplifications in AIP, CDKN1B and MEN1 genes (MRC-Holland, Amsterdam, The Netherlands). Once the exon 2 heterozygous deletion from the AIP gene was found via MLPA the confirmation was carried out through long-range PCR covering full open reading frame of the AIP gene. By agarose gel electrophoresis, the presence of two bands of different sizes confirmed this deletion. Discussion More than 130 AIP mutations have been described over the last decade and most of them, 70% generate truncated proteins (including insertions/deletions). However, gross AIP deletions were exceptionally reported so far (13 cases only: 11 had gigantism or acromegaly). Despite rarity, the present case reinforces the importance of investigate large AIP deletions, especially in gigantism. Cases harboring AIP mutations are associated with more aggressive tumors, lesser response to somatostatin receptor analogues needing, frequently, of an extensive multidisciplinary approach. It was also suggested that cases harboring truncated AIP mutations may develop pituitary adenoma in younger age than patients with non-truncated mutations. Thus, the characterization of genotype could help to refine making-decision on management of this complex disorder in an earlier stage avoiding multimodal treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

OR12-6 Rocking Around the Cortex and Medulla

Abstract Introduction Pituitary gigantism is a rare endocrinopathy that has been linked to inactivating germline mutations in AIP gene with a prevalence of 30%. AIP is a tumor suppressor gene associated with high predisposition to pituitary adenoma. Thus, the genetic screening of AIP mutations has been recommended to cases with sporadic young-onset pituitary adenoma. Even with a phenotype suggesting gigantism the diagnosis could be delayed, making the treatment more complex, due the large pituitary tumor. Here we describe a giant patient with deletion of exon 2 of the AIP gene detected by Multiplex Ligation-dependent Probe Amplification assay (MLPA) 33 years after the diagnosis. Material and Methods In 1988, a 13-year-old afro-descendent boy with no history of familial pituitary adenoma, presented with seizures and tall stature. On exam he showed signs of gigantism and hypopituitarism: height 2. 05 m (SD: + 7), target height was 1.65 (SD: -1), weight 75 kg (SD: + 3.2), no signs of puberty and impaired vision field. Basal GH was &amp;gt; 40 ng/mL, IGF-1: &amp;gt; 1200 ng/mL (ULN: +4). MRI revealed an invasive macroadenoma (Knosp IV). He underwent pituitary surgery twice with an adenoma GH/PRL positive with no remission. He did not respond to the treatment with somatostatin receptor analogue presenting remission only after radiotherapy, developing permanent deficiency of ACTH/TSH/LH/FSH/GH and diabetes insipidus. Peripheral blood was collected to genetic analysis in 2021. Results The genetic analysis supported by Sanger sequencing resulted negative to pathogenic germline variants in intron-exon frontiers and coding areas of the AIP and MEN1 genes. Thus, MLPA was performed using the SALSA MLPA kit P244 designed to detect large deletions or amplifications in AIP, CDKN1B and MEN1 genes (MRC-Holland, Amsterdam, The Netherlands). Once the exon 2 heterozygous deletion from the AIP gene was found via MLPA the confirmation was carried out through long-range PCR covering full open reading frame of the AIP gene. By agarose gel electrophoresis, the presence of two bands of different sizes confirmed this deletion. Discussion More than 130 AIP mutations have been described over the last decade and most of them, 70% generate truncated proteins (including insertions/deletions). However, gross AIP deletions were exceptionally reported so far (13 cases only: 11 had gigantism or acromegaly). Despite rarity, the present case reinforces the importance of investigate large AIP deletions, especially in gigantism. Cases harboring AIP mutations are associated with more aggressive tumors, lesser response to somatostatin receptor analogues needing, frequently, of an extensive multidisciplinary approach. It was also suggested that cases harboring truncated AIP mutations may develop pituitary adenoma in younger age than patients with non-truncated mutations. Thus, the characterization of genotype could help to refine making-decision on management of this complex disorder in an earlier stage avoiding multimodal treatment. Presentation: Sunday, June 12, 2022 11:00 a.m. - 12:30 p.m.

68Ga-DOTATOC Embolus Manifestation and Spontaneous Resolution by PET/CT.

68Ga-labeled somatostatin receptor analogs physiologic distribution patterns have become recognizable among nuclear medicine physicians because of the increasing routine clinical use of this modality in the work-up of neuroendocrine tumors. Some pitfalls during 68Ga-labeled somatostatin receptor PET/CT have recently been reported as causes of misdiagnoses. Iatrogenic microembolism as a cause of 18F-FDG embolus is well-established; however, 68Ga-DOTATOC embolus is not well documented in the literature. In the current case, the presence and the spontaneous resolution of the 68Ga-labeled somatostatin receptoranalogs embolus during sequential PET/CT are nicely demonstrated. Awareness of this incidental finding would avoid misdiagnosis and unnecessary investigations.

Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism-The UK Perspective.

ContextIn focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery.ObjectiveWe describe surgical and nonsurgical outcomes of focal CHI in a national cohort.MethodsPatients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018.ResultsOf 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose.ConclusionDespite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management.

Evaluation of Liver and Renal Toxicity in Peptide Receptor Radionuclide Therapy for Somatostatin Receptor Expressing Tumors: A 2-Year Follow-Up.

BackgroundPeptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin receptor (SSR) analogs is now an established systemic treatment for neuroendocrine tumors (NET). However, more short- and long-term data about renal and hepatotoxicity is needed. Here we present our experience in this clinical scenario.MethodsEighty-six patients with progressive SSR-expressing malignancies underwent PRRT with Lu-177 Dotatate and were followed up for up to 2 years. Laboratory tests were done 1 week before each cycle and every 2 months at follow-up. Hepatic and renal toxicity was determined based on NCI CTCAE V5.0.Results55/86 (64%) patients completed all 4 cycles of PRRT; 18/86 (20.9%) are currently being treated; 13/86 (15.1%) had to discontinue PRRT: 4/13 (31%) due to hematologic toxicity, 9/13 (69%) due to non-PRRT-related comorbidities. Out of the patients who finished treatment, only transient grade 2 toxicities were observed during PRRT: hypoalbuminemia in 5.5% (3/55), and renal toxicity (serum creatinine and estimated glomerular filtration rate) in 1.8% (1/55). No grade 3 or 4 liver and renal toxicity occurred. Patients presenting with impaired liver or renal function prior to PRRT, either improved or had stable findings. No deterioration was observed.ConclusionPeptide receptor radionuclide therapy does not have a negative impact on liver and renal function, even in patients with pre-existing impaired parameters. No grade 3 or 4 hepatic or renal toxicity was identified. Only transient grade 2 hypoalbuminemia in 5.5% and nephrotoxicity in 1.8% of patients were seen during PRRT.

Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors.

Simple SummaryNeuroendocrine neoplasms (NENs) are rare and heterogeneous tumors, presenting in often challenging clinical scenarios, and require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for imaging well-differentiated neuroendocrine tumors NETs, and labelled with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and criteria for peptide receptor radionuclide therapy (PRRT) eligibility of based on somatostatin receptor (SSTR) expression. The present paper is an overview of currently employed radiolabeled SSTR analogues used for both diagnosis and therapy of NENs. Further emerging radiopharmaceuticals targeting SSTRs (e.g., fluorinated SSTR agonists, radiolabeled SSTR antagonists) as well as strategies to improve PRRT efficacy (by means of implementation of personalized treatment schemes, dosimetry, amelioration of response assessment strategies, and optimization of treatment sequencing) are also discussed. Finally, although very preliminary, some studies employing radiomic features in various kinds of NET are reported.Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors that require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for diagnosis and with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and as a criteria for peptide receptor radionuclide therapy (PRRT) eligibility based on somatostatin receptor (SSTR) expression. On the diagnostic side, [68Ga]Ga-DOTA peptides PET/CT (SSTR PET/CT) is the gold standard for imaging well-differentiated SSTR-expressing neuroendocrine tumors (NETs). [18F]FDG PET/CT is useful in higher grade NENs (NET G2 with Ki-67 > 10% and NET G3; NEC) for more accurate disease characterization and prognostication. Promising emerging radiopharmaceuticals include somatostatin analogues labelled with 18F (to overcome the limits imposed by 68Ga), and SSTR antagonists (for both diagnosis and therapy). On the therapeutic side, the evidence gathered over the past two decades indicates that PRRT is to be considered as an effective and safe treatment option for SSTR-expressing NETs, and is currently included in the therapeutic algorithms of the main scientific societies. The positioning of PRRT in the treatment sequence, as well as treatment personalization (e.g., tailored dosimetry, re-treatment, selection criteria, and combination with other alternative treatment options), is warranted in order to improve its efficacy while reducing toxicity. Although very preliminary (being mostly hampered by lack of methodological standardization, especially regarding feature selection/extraction) and often including small patient cohorts, radiomic studies in NETs are also presented. To date, the implementation of radiomics in clinical practice is still unclear. The purpose of this review is to offer an overview of radiolabeled SSTR analogues for theranostic use in NENs.

Role of Ga-68 DOTANOC Positron Emission Tomography/ Computed Tomography Scan in Clinical Management of Patients with Neuroendocrine Tumors and its Correlation with Conventional Imaging- Experience in a Tertiary Care Center in India.

Purpose of Study:Aim of the study was to evaluate the role of 68Gallium-DOTANOC positron emission tomography/computed tomography (68Ga-DOTANOC PET/CT), a pan somatostatin receptor (SSTR) analog in the clinical management of patients with neuroendocrine tumors (NETs) and its correlation with conventional imaging.Materials and Methods:We retrospectively evaluated 69 patients of known/suspected NETs who underwent 68Ga-DOTANOC PET/CT scan for tumor localization (n = 15), stage modification (primary staging, n = 26 and restaging, n = 25) and therapy monitoring (n = 3). We also compared PET scan with conventional imaging as reference standard and evaluated the impact of PET/CT in the clinical management of patients.Results:The concordant findings on 68Ga-DOTANOC PET/CT and conventional imaging seen in 33 and discordant in 36 patients. Among discordant group, disease was upstaged in 32 patients; down staged in 3 patients; no stage change in one patient. PET/CT localized primary tumor in 4 patients. Among patients with raised tumor markers (39/69), PET was positive in 29 and negative in 10 patients. Patients were followed for mean duration of 27 months to assess management. We found strong agreement between positive PET and raised tumor markers (Kappa value = 0.8). Sensitivity and specificity of PET/CT for primary tumor localization, stage modification, and therapy monitoring was >90% (P < 0.05).Conclusions:Study shows that DOTANOC, a broad spectrum SSTRs binding peptide labeled with Ga-68 in PET/CT scan is an excellent modality in the management of NETs patients.

Probable alterations in fecal bacterial microbiota by somatostatin receptor analogs in acromegaly

Abstract Objective Data on bacterial diversity and microbiota alterations in acromegaly are currently lacking. The effects of somatostatin receptor analogs on gut microbiota remain unknown. The objective of this study was to determine microbiota alterations in patients with acromegaly and to assess the effects of somatostatin receptor analogs on gut microbiota. Methods The study was designed as a cross-sectional case-control research and three cohorts, comprising individuals with acromegaly without medical therapy (n=5), acromegaly receiving octreotide acetate (OCT) (n=8) and healthy controls (n=5), were evaluated. Results No statistically-supported changes in Bacteroidetes, Firmicutes, Proteobacteria and Actinobacteria abundance were observed. Bacteroidaceae, Odoribacteraceae, Porphyromonadaceae, Prevotellaceae and Alistipes families of Bacteroidetes and Bifidobacterium genus of the Actinobacteria phyla were detected, without overt differences. Variations in Clostridia, Erysipelotrichaceae and Veillonellaceae were not significant, while Lactobacillales were increased in individuals receiving OCT. Moreover, Akkermansia mucinophila was present in patients under OCT treatment. Conclusion Our preliminary results suggest that the bacterial community profile under OCT treatment may facilitate a colonic microenvironment for improved glucose metabolism. Alterations in the gut microbiota may be a factor affecting diabetes development during somatostatin analog treatment in acromegalic patients.

Positron Emission Tomography and Molecular Imaging of Head and Neck Malignancies

Metabolic reprogramming and avid fluorodeoxyglucose (FDG) uptake in locally advanced head and neck squamous cell carcinomas and other cancers of the upper aerodigestive tract lead to favorable sensitivity and diagnostic accuracy of FDG PET/CT or PET/MR compared to conventional imaging. Meanwhile, the role of non-FDG PET in head and neck malignancies is rapidly expanding. Accurate staging, identifying a clinically occult primary, or detection of distant metastasis or a synchronous malignancy on FDG PET significantly impacts management. FDG uptake after definitive therapy is an invaluable biomarker for surveillance. Patients with metabolic resolution can be spared from neck dissection, whereas FDG avid refractory disease or distant metastasis could necessitate surgical or systemic therapy. PET tracers targeting amino acid transport or fibroblast activation hold promise for improved specificity and better delineation of tumor prior to radiation therapy given their low physiologic or inflammatory uptake in head and neck compared to FDG. Tracers for hypoxia or cellular proliferation provide complementary information to FDG after radiation therapy for assessment of residual malignant cells that could lead to treatment failure. FDG remains the primary tracer for imaging lymphoma and other pediatric head and neck malignancies. Several other PET tracers such as gallium-68-labeled somatostatin receptor analogs and fluorodopa are being increasingly used for detection and characterization of head and neck paragangliomas and certain other cancers. FDG and other PET radiopharmaceuticals are increasingly being exploited in guiding clinical management of various head and neck malignancies and significantly impact patient outcomes.

Multimodal Imaging of 2-Cycle PRRT with 177Lu-DOTA-JR11 and 177Lu-DOTATOC in an Orthotopic Neuroendocrine Xenograft Tumor Mouse Model.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) analogs is a common approach in advanced neuroendocrine neoplasms. Recently, SSTR antagonists have shown promising results for imaging and therapy due to a higher number of binding sites than in commonly used agonists. We evaluated PRRT with SSTR agonist 177Lu-DOTATOC and antagonist 177Lu-DOTA-JR11 longitudinally in an orthotopic murine pancreatic neuroendocrine neoplasm model expressing human SSTR2. Morphologic and metabolic changes during treatment were assessed using multimodal imaging, including hybrid PET/MRI and SPECT/CT. Methods: In vitro radioligand binding and internalization assays and cell-cycle analysis were performed. SSTR2-transfected BON cells (BON-SSTR2) were used for in vivo experiments. Tumor-bearing mice received 2 intravenous injections of 100 μL of saline, 30 MBq of 177Lu-DOTATOC, or 20 MBq of 177Lu-DOTA-JR11 with an interval of 3 wk. Weekly T2-weighted MRI was performed for tumor monitoring. Viability of the tumor tissue was assessed by 18F-FDG PET/MRI once after PRRT. Tumor and kidney uptake of the respective radiopharmaceuticals was measured 24 h after injection by SPECT/CT. Results: Compared with 177Lu-DOTATOC, 177Lu-DOTA-JR11 treatment resulted in an increased accumulation of cells in G2/M phase. Animals treated with the SSTR antagonist showed a significant reduction in tumor size (P < 0.001) and an increased median survival (207 d; interquartile range [IQR], 132-228) compared with 177Lu-DOTATOC (126 d; IQR, 118-129). SPECT/CT revealed a 4-fold higher median tumor uptake for the antagonist and a 3-fold higher tumor-to-kidney ratio in the first treatment cycle. During the second therapy cycle, tumor uptake of 177Lu-DOTATOC was significantly lower (P = 0.01) whereas 177Lu-DOTA-JR11 uptake remained stable. Imaging of tumor morphology indicated comparatively larger necrotic fractions for 177Lu-DOTA-JR11 despite further tumor growth. These results were confirmed by 18F-FDG PET, revealing the least amount of viable tumor tissue in 177Lu-DOTA-JR11-treated animals, at 6.2% (IQR, 2%-23%). Conclusion:177Lu-DOTA-JR11 showed a higher tumor-to-kidney ratio and a more pronounced cytotoxic effect than did 177Lu-DOTATOC. Additionally, tumor uptake was more stable over the course of 2 treatment cycles.

Efficacy of monotherapy versus combined GH receptor antagonist therapy in patients with somatostatin receptor analogues resistant acromegaly

Efficacy of monotherapy versus combined GH receptor antagonist therapy in patients with somatostatin receptor analogues resistant acromegaly

Prognostic impact of somatostatin receptor expression in advanced bladder cancer

Introduction and objectivesSomatostatin receptors (SSTR) recently have been identified as potential targets for treatment of solid tumors. Furthermore, they have been shown to be of high relevance for tumor biology and prognosis in various types of cancer. However, there is a lack of clinical data for SSTR in bladder cancer (BC). Aim of this study was to determine the expression of all relevant somatostatin receptor subtypes in benign urothelium and tumor tissue of patients with muscle invasive BC. Furthermore, their potential role as prognostic factor for cancer-specific survival (CSS) and overall survival (OS) was evaluated. MethodsThe collective included BC and benign urothelium tissue of 103 patients (Median age 69; range 32–84, 79 male, 24 female) who underwent a radical cystectomy. A tissue microarray with subsequent immunohistochemical staining was used to assess membranous expression of SSTR1–5. Results were correlated to clinical and histopathological data as well as CSS and OS. ResultsExpressions of SSTR1-4 were significantly decreased in BC compared to benign urothelium (P < 0.002 each), whereas SSTR5 expression was increased (P = 0.0017). Expression of SSTR1 was associated with organ–confined disease (≤pT2) (P = 0.0477). No correlation between SSTR1-5 expression and N- and M-stage was observed. Univariate analyses showed a significantly longer CSS and OS in patients with high expression of SSTR3 (P = 0.0316 and 0.0044). Multivariate analyses confirmed SSTR3 expression as independent marker of improved CSS and OS (P = 0.0324 and 0.0076). ConclusionsThe majority of somatostatin receptor subtypes exhibit decreased expression in BC compared to benign bladder tissue. Expression of SSTR3 is an indicator for favorable prognosis in patients with muscle-invasive BC. These results support preclinical investigations using somatostatin receptor analogues such as octreotide to influence BC growth.

SUN-142 Clinical Characteristics of Patients Diagnosed with Functional Neuroendocrine Tumors Treated at a Tertiary National Referral Center in Mexico

Neuroendocrine tumors (NET) represent up to 0.5% of all new cancers and can be functional or non-functional. Epidemiologic data on NET in Mexico is very limited. To delineate the clinical characteristics of patients with functional NET at a tertiary national referral center in Mexico we performed a retrospective cohort study (January 1987-June 2019). The target study population was adults with functional NET with biochemical and histopathological confirmation. Results: 126 patients with functional NET were included in this study. The median follow-up was 47.4 months (IQR 10.8 to 93.7). Most were female (64.3%). The mean age at diagnosis was 46.3 ± 14.48 years. The most frequent insulinomas (59.5%), followed by (12.7%) carcinoid tumors, gastrinomas (11.1%), ACTHomas (10.3%), VIPomas (2.4%) glucagonomas (2.4%) and PPomas (1.6%). Nineteen subjects (15.1%) had genetic syndromes, mainly MEN1 (89.5%); and 8.7% had other neoplasms, most frequently non-functional gastrointestinal (GI) carcinoids (36.3%) and thyroid cancer (18.8%). The median duration of symptoms prior to diagnosis was 24 months (IQR 7.75 to 48). The most common locations were, the GI tract (86.5%), whereas 7.1% were outside the GI tract and 6.4% were of unknown primary origin. Functional NETs outside GI tract were localized primarily in lungs(66.6%). Functional pancreatic NETs occurred more commonly in the tail (39.6%). 24.6% had locoregional or distant metastasis during follow-up. The most frequent metastatic sites were liver (86.5%), regional lymph nodes (59.8%) and bone (13.5%). The most common treatment was surgery (87.3%, with 13.6% ≥2), followed by 18.3% somatostatin receptor analogues and 11.1% cytotoxic chemotherapy. Most subjects (73%) had complete remission with first line therapy, but 14.1% had recurrence at a median of 50.7 months (IQR 15.4 to 97.6). Subjects with an incomplete remission progressed after a median of 14.85 months (IQR 10 to 38.9). Conclusions: The clinical characteristics of functional NET treated at a tertiary center in Mexico are similar to those in other population and geographic locations described in the literature.