Somatostatin Receptor Expression Research Articles

Efficacy and tolerability of somatostatin analogues according to gender in patients with neuroendocrine tumors.

As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life.

Changes in tumor-to-blood ratio as a prognostic marker for progression-free survival and overall survival in neuroendocrine tumor patients undergoing PRRT

BackgroundHistorically, patient selection for peptide receptor radionuclide therapy (PRRT) has been performed by virtue of somatostatin receptor scintigraphy (SRS). In recent years, somatostatin receptor positron emission tomography (SSTR-PET) has gradually replaced SRS because of its improved diagnostic capacity, creating an unmet need for SSTR-PET-based selection criteria for PRRT. Tumor-to-blood ratio (TBR) measurements have shown high correlation with the net influx rate Ki, reflecting the tumor somatostatin receptor expression, to a higher degree than standardized uptake value (SUV) measurements. TBR may therefore predict treatment response to PRRT. In addition, changes in semiquantitative SSTR-PET parameters have been shown to predate morphological changes, making them a suitable metric for response assessment.MethodsThe institutional database of the Department of Nuclear Medicine (University Hospital Essen) was searched for NET patients undergoing ≥ 2 PRRT cycles with available baseline and follow-up SSTR-PET. Two blinded independent readers reported the occurrence of new lesions quantified tumor uptake of up to nine lesions per patient using SUV and TBR. The association between baseline TBR and changes in uptake/occurrence of new lesions with progression-free survival (PFS) and overall survival (OS) was tested by use of a Cox regression model and log-rank test.ResultsPatients with baseline TBR in the 1st quartile had a shorter PFS (14.4 months) than those in the 3rd (23.7 months; p = 0.03) and 4th (24.1 months; p = 0.02) quartile. Similarly, these patients had significantly shorter OS (32.5 months) than those with baseline TBR in the 2nd (41.8 months; p = 0.03), 3rd (69.2 months; p < 0.01), and 4th (42.7 months; p = 0.03) quartile. Baseline to follow-up increases in TBR were independently associated with shorter PFS when accounting for prognostic markers, e.g., RECIST response (hazard ratio = 2.91 [95%CI = 1.54–5.50]; p = 0.01). This was confirmed with regard to OS (hazard ratio = 1.64 [95%CI = 1.03–2.62]; p = 0.04). Changes in SUVmean were not associated with PFS or OS.ConclusionsBaseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

Impact of the PI3K-alpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model.

The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). However, after initial disease stabilisation, most patients develop resistance within 1 year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3K-alpha inhibitor alpelisib in an everolimus-resistant orthotopic pancreatic neuroendocrine carcinoma xenograft mouse model. Female SCID mice underwent laparoscopic pancreatic transplantation of everolimus-sensitive (BON1KDMSO) or everolimus-resistant (BON1RR2) NET cells. Both groups were further divided into four treatment groups: placebo, everolimus, alpelisib, and everolimus + alpelisib (combination). Oral treatment was started at a tumour volume of approximately 140 mm3 and continued until 1900-2000 mm3, validated by weekly MRI. Somatostatin receptor expression and tumour viability were analysed by 68Ga-DOTATOC and 18F-FDG PET/CT. Everolimus resistance of the BON1RR2 tumours was confirmed. In the everolimus-sensitive group, everolimus alone, alpelisib alone, and combination treatment significantly prolonged survival, compared to placebo, while in the BON1RR2 group, only combination treatment significantly prolonged survival compared to placebo, but neither everolimus nor alpelisib alone. Placebo-treated everolimus-sensitive tumours grew more rapidly (median survival 45 days), compared to placebo-treated everolimus-resistant tumours (60 days). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 days). Of all groups, the everolimus-resistant combination-treated group survived longest (69 days). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.

Effect of paclitaxel octreotide conjugate on human ovarian paclitaxel-resistant cell xenograft tumor model and the mechanism underlying reversal of paclitaxel resistance

Purpose: To determine the effect of paclitaxel octreotide conjugate (POC) on human ovarian paclitaxelresistant cell xenograft tumor model and the mechanism underlying reversal of paclitaxel resistance.&#x0D; Methods: Forty female BALB/c-nu/nu mice were subcutaneously inoculated with 106 paclitaxel-resistant cells (a2780/taxol) per mouse during the logarithmic growth phase of ovarian cancer. They were randomly divided into four groups (control, octreotide, paclitaxel and POC). Immunohistochemical streptavidin-peroxidase (SP) method was used to determine expression of nuclear proliferation antigen (PCNA) while TUNEL method was used to assess apoptosis of human ovarian cancer metastasis. Realtime polymerase chain reaction (PCR) was used to assay mRNA expression levels of somatostatin receptor 2 (SSTR2), multidrug-resistant gene (MDR1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and acetylated tubulin (α-tubulin and β-III-tubulin), while the corresponding protein expressions were assayed using western blotting.&#x0D; Results: Immunohistochemical SP showed significantly lower PCNA levels in octreotide, paclitaxel and POC groups than in control mice, but that of POC mice was significantly reduced, relative to those of octreotide and paclitaxel groups (p &lt; 0.05). There were significantly higher expression levels of SSTR2 mRNA and protein in octreotide, paclitaxel and POC groups than in control mice, but they were significantly higher in POC group than in octreotide and paclitaxel groups (p &lt; 0.05). The mRNA and protein expressions of other factors in POC mice were significantly lower than those in both octreotide and paclitaxel groups (p &lt; 0.05).&#x0D; Conclusion: Paclitaxel-octreotide conjugate effectively inhibits the growth of a2780/taxol xenografts in nude mice, induces tumor cell apoptosis, and suppresses tumor cell growth via mechanism involving enhancement of SSTR2 expression, and decreases in levels of acetylated tubulin, matrix metalloproteinase-9, and vascular endothelial growth factor.

Sstr2 Defines the Cone Differentiation-Competent Late-Stage Retinal Progenitor Cells in the Developing Mouse Retina.

Cone cell death is a characteristic shared by various retinal degenerative disorders, such as cone-rod dystrophy, Stargardt disease, achromatopsia, and retinitis pigmentosa. This leads to conditions like color blindness and permanently impaired visual acuity. Stem cell therapy focused on photoreceptor replacement holds promise for addressing these conditions. However, identifying surface markers that aid in enriching retinal progenitor cells (RPCs) capable of differentiating into cones remains a complex task. In this study, we employed single-cell RNA sequencing to scrutinize the transcriptome of developing retinas in C57BL/6J mice. This revealed the distinctive expression of somatostatin receptor 2 (Sstr2), a surface protein, in late-stage RPCs exhibiting the potential for photoreceptor differentiation. In vivo lineage tracing experiments verified that Sstr2+ cells within the late embryonic retina gave rise to cones, amacrine and horizontal cells during the developmental process. Furthermore, Sstr2+ cells that were isolated from the late embryonic mouse retina displayed RPC markers and exhibited the capability to differentiate into cones in vitro. Upon subretinal transplantation into both wild-type and retinal degeneration 10 (rd10) mice, Sstr2+ cells survived and expressed cone-specific markers. This study underscores the ability of Sstr2 to enrich late-stage RPCs primed for cone differentiation to a large extent. It proposes the utility of Sstr2 as a biomarker for RPCs capable of generating cones for transplantation purposes.

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly.

We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) . A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively. In all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01). The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.

177Lu-DOTATATE (Lutathera) Therapy in 68Ga-DOTATATE PET/CT-Negative Liver Metastases of a Neuroendocrine Tumor.

A 73-year-old man with metastatic pancreatic neuroendocrine tumor was evaluated with 68Ga-DOTATATE PET/CT for peptide receptor radionuclide therapy. Both PET-positive and negative lesions were seen in the liver, along with extrahepatic metastases. Histopathology was obtained from one of the PET-negative liver lesions to exclude secondary malignancy. Histology confirmed a well-differentiated (G2) metastasis of pNET with high somatostatin receptor expression. We initiated peptide receptor radionuclide therapy with close monitoring of the PET-negative liver metastases. We present a rare case, where posttherapeutic scintigraphy revealed vigorous uptake of 177Lu-DOTATATE even in the 68Ga-DOTATATE PET-negative liver metastases. Follow-up PET/CT showed a partial response to therapy.

A Prospective Registry Study of 68Ga-DOTATATE PET/CT Incorporation Into Treatment Planning of Intracranial Meningiomas

IntroductionThe current standard for meningioma treatment planning involves MRI-based image guidance. SSTR ligands such as 68Ga-DOTATATE are being explored for meningioma treatment planning due to near-universal expression of somatostatin receptor 1/2 in meningioma tissue. We hypothesize that 68Ga-DOTATATE PET-guided treatment management for meningioma patients will be safe, effective, and identify which patients benefit most from adjuvant radiotherapy. MethodsA single institution prospective registry study was created and included intracranial meningioma patients who received a 68Ga-DOTATATE PET scan to assist with radiation oncologist decision-making. Patients who received a PET scan from 1/1/2018-2/25/2022 were eligible for inclusion. Results60 patients were treated in this registry. 40%, 47%, and 5% of patients had WHO Grades 1, 2, and 3 meningiomas. 5 cases (8%) did not have a grade assigned. 22%, 72%, and 7% were categorized as RTOG 0539 high, intermediate, and low-risk, respectively. After completing their PET scan, 48, 11, and 1 patient(s) proceeded with RT, observation, or redo craniotomy. The median follow-up for the entire cohort was 19.5 months. 3 patients (5%) experienced local failure (LF) between 9.2-28.5 months after diagnosis. 2 patients with LF had PET-avid disease in their post-operative cavity and elected for observation prior to recurrence, and 1 high-risk patient with multifocal disease experienced LF 2 years after a second radiation course and multiple previous recurrences. Notably, 5 patients did not have any local PET uptake and were observed; none of these patients experienced recurrence. There was only one Grade 3 toxicity attributed to PET-guided radiation. ConclusionThis is one of the largest known population of intracranial meningioma patients followed by physicians who utilized 68Ga-DOTATATE PET guided therapy. Incorporating 68Ga-DOTATATE PET into future trials may assist with clinician decision-making and improve patient outcomes.

Immunological role and prognostic value of somatostatin receptor family members in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is among the most prevalent cancers worldwide, ranking as the third most prevalent malignancy in incidence and mortality. The somatostatin receptor (SSTR) family comprises G-protein-coupled receptors (GPCRs), which couple to inhibitory G proteins (Gi and Go) upon binding to somatostatin (SST) analogs. GPCRs are involved in hormone release, neurotransmission, cell growth inhibition, and cancer suppression. However, their roles in COAD remain unclear. This study used bioinformatics to investigate the expression, prognosis, gene alterations, functional enrichment, and immunoregulatory effects of the SSTR family members in COAD. SSTR1-4 are differentially downregulated in COAD, and low SSTR2 expression indicates poor survival. Biological processes and gene expression enrichment of the SSTR family in COAD were further analyzed using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology. A strong correlation was observed between SSTR expression and immune cell infiltration. We also quantified SSTR2 expression in 25 COAD samples and adjacent normal tissues using quantitative real-time polymerase chain reaction. We analyzed its correlation with the dendritic cell-integrin subunit alpha X marker gene. The biomarker exploration of the solid tumors portal was used to confirm the correlation between SSTR2 with immunomodulators and immunotherapy responses. Our results identify SSTR2 as a promising target for COAD immunotherapy. Our findings provide new insights into the biological functions of the SSTR family and their implications for the prognosis of COAD.

Correlation of the apparent diffusion coefficient with the standardized uptake value in meningioma of the skull plane using [68]Ga-DOTATOC PET/MRI.

To evaluate a correlation between an MRI-specific marker for cellular density [apparent diffusion coefficient (ADC)] and the expression of Somatostatin Receptors (SSTR) in patients with meningioma of the skull plane and orbital space. 68 Ga-DOTATOC PET/MR imaging was performed in 60 Patients with suspected or diagnosed meningiomas of the skull base and eye socket. Analysis of ADC values succeeded in 32 patients. ADC values (ADC mean and ADC min ) were analyzed using a polygonal region of interest. Tracer-uptake of target lesions was assessed according to corresponding maximal (SUV max ) and mean (SUV mean ) values. Correlations between assessed parameters were evaluated using the Pearson correlation coefficient. One out of 32 patients (3%) was diagnosed with lymphoma by histopathological examination and therefore excluded from further analysis. Median ADC mean amounted to 822 × 10 -5 mm²/s -1 (95% CI: 570-1497) and median ADC min was 493 × 10 -5 mm 2 /s -1 (95% CI: 162-783). There were no significant correlations between SUV max and ADC min (r = 0.60; P = 0.76) or ADC mean (r = -0.52; P = 0.79), respectively. However, Pearson's test showed a weak, inverse but insignificant correlation between ADC mean and SUV mean (r = -0.33; P = 0.07). The presented data displays no relevant correlations between increased SSTR expression and cellularity in patients with meningioma of the skull base. SSTR-PET and DWI thus may offer complementary information on tumor characteristics of meningioma.

Somatostatin Receptor Expression in Lung Neuroendocrine Tumors: An Analysis of DOTATATE PET Scans.

Somatostatin receptor (SSTR) expression in metastatic lung neuroendocrine tumors (NETs) has not been well characterized using PET imaging. Understanding the degree and uniformity of SSTR expression is important to establish the role of SSTR-targeted treatments in lung NETs. Methods: A retrospective institutional review of patients with metastatic lung NETs who underwent DOTATATE PET imaging from March 2017 to February 2023 was performed. Results: In total, 48 patients with metastatic lung NETs who underwent 68Ga- or 64Cu-DOTATATE PET imaging were identified. Four had completely negative SSTR expression, and 10 had very weak expression (less than in a normal liver). Among the remaining 34 patients, 21 had uniformly positive DOTATATE PET scans, and 13 had heterogeneous expression. Only 44% had uniformly positive receptor expression, identifying them as candidates for peptide receptor radionuclide therapy. Conclusion: Most metastatic lung NETs lack uniform SSTR expression and are thus suboptimal candidates for SSTR-targeted therapy. SSTR imaging in lung NETs should be evaluated carefully for uniformity of expression.

THU511 Somatostatin Analogs Or Active Surveillance In Sporadic And MEN1 Associated Non-functioning Pancreatic Neuroendocrine Tumors

Abstract Disclosure: S. Raia: None. S. Chiloiro: None. M. Maratta: None. B. Maiorano: None. E. Rossi: None. M. Brizi: None. V. Rufini: None. L. De Marinis: None. G. Rindi: None. G. Schinzari: None. A. Pontecorvi: None. G. Tortora: None. A. Bianchi: None. Introduction: Non-functioning (NF), sporadic and MEN1 associated, G1-G2 pancreatic neuroendocrine tumors (PanNETs) usually display an indolent course. Surgery is the first-choice treatment for localized tumors &amp;gt;2 cm. Unresectable or metastatic PanNETs expressing somatostatin receptors (SSTRs) are treated with somatostatin analogs (SSAs). The standard treatment for patients with PanNETs ≤2cm is active surveillance (AS). Yet no evidence of the value of SSA treatment exist in such patient population. Aim(s): To assess the clinical value of SSAs in patients with PanNETs ≤2cm. Material and methods: Data from patients (pts) NF, G1-G2 PanNETs≤2cm were retrospectively collected. Median progression-free survival (mPFS) and response rate (RR) were analyzed in SSA group and AS group. Results: From June 2007 to June 2022, data from 46 pts were considered: 29 pts, who declined an AS program but had not indication for surgery, entered in the SSA group (21 sporadic and 8 MEN1 associatd PanNET) and 17 in the AS group. At a median follow-up of 64.8 months for sporadic and of 63.9 for MEN1 associated PanNET, no disease progression (PD) was reported in the SSA group, without differences between sporadic and MEN1 associated PanNET. While the PD rate was 23.5 % in the AS group, with a mPFS of 36.2 months. Conclusion: SSAs therapy showed significant antiproliferative activity in patients with both sporadic and MEN1 associated NF, G1-G2 PanNETs ≤2cm. SSAs treatment delay tumor progression and distant spread in small lesions that sometimes may reveal an unpredictable aggressiveness. Presentation: Thursday, June 15, 2023

SAT610 Multiple Endocrine Neoplasia Type 1 - The First Reported Case In An Indigenous Australian

Abstract Disclosure: E. Mignone: None. K. Neal: None. Background: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare and under recognised syndrome. It has not been previously reported in Indigenous Australians for this reason. Clinical Case: A 48-year-old Indigenous Australian female was consulted on by an inpatient endocrine team in March 2020 for persistent hypercalcaemia on a background of a parathyroidectomy in 2011 for primary hyperparathyroidism (PHPTH). She was admitted to a remote Australian hospital for investigation and management of acute on chronic abdominal pain. Relevant medical history included a parathyroidectomy at age 40, multiple PE/DVT, MI, AF, CTEPH, right heart failure, HTLV-1 and recurrent abdominal pain presumed secondary to GORD. Gastroscopy from 2013 revealed chronic gastritis with hundreds of gastric polyps discovered on subsequent gastroscopy in 2015. The young age of PHPTH combined with her chronic gastritis and polyps prompted neuroendocrine tumour (NET) screening, including MEN1. At time of consult in 2020, laboratory studies were consistent with recurrence of PHPTH with a corrected calcium of 2.9 mmol/L (2.15-2.57mmol/L), serum PTH level 31.5 pmol/L (1-7pmol/L), vitamin D level 30 nmol/L, 24-hour urinary calcium variable between low and high. NET markers were markedly elevated with a gastrin level of 14042 ng/L (&amp;lt;100 ng/L), pancreatic polypeptide 2905 pmol/L (&amp;lt;55 pmol/L), urine 5HIAA ratio 8 mmol/L (&amp;lt;4 mmol/L), vasoactive intestinal peptide and glucagon levels normal. Pituitary studies, serum calcitonin, plasma metanephrines and PTH related protein levels were within normal limits. A CT of the abdomen showed thickened gastric folds, and persistent liver and IVC lesions from 2018. A diagnosis of Zollinger Ellison Syndrome (ZES) was made. Eventually, genetic testing was positive for a rare heterozygous variant of c.207dupC in exon 2 of MEN1 gene. A 68-gallium-DOTATATE PET/CT showed multiple avid pancreatic, gastric, nodal and liver lesions with high somatostatin receptor expression, suggestive of a neuroendocrine malignancy. Treatment was based largely on symptom control due to poor overall prognosis from underlying cardiorespiratory comorbidities. Abdominal pain from ZES was managed with a high dose PPI, H2 receptor antagonist and subcutaneous somatostatin analogue were trialled. Hypercalcaemia was treated with IV bisphosphonate therapy. Calcimimetic analogues were considered however patient declined. Genetic counselling was attempted however many cultural and logistical barriers were identified and family declined further testing. Unfortunately, our patient died in 2021 from presumed multifactorial respiratory failure. Conclusion: High index of suspicion is required to diagnose MEN1. This is particularly true within the Indigenous Australian population, with no prior documented cases reported. Presentation: Saturday, June 17, 2023

FRI368 Thyroid Paraganglioma: A Rare Manifestation Of Paraganglioma Syndrome Associated With SDHD Mutation

Abstract Disclosure: K. Samuel: None. C. McMullen: None. C. Veloski: None. S. Kushchayev: None. J.E. Hallanger-Johnson: None. J. Hernandez Prera: None. J. Muzaffar: None. G.Q. Yang: None. V. Tarasova: None. Background: Thyroid paragangliomas (TP) are exceptionally rare, representing 0.5% of all paragangliomas (PGL) with total of less than 70 cases reported to date. We report a case of a TP presenting with an indeterminate thyroid nodule, as a first manifestation of multifocal head and neck PGL, associated with succinate dehydrogenase complex subunit D (SDHD) mutation. Clinical case: A 59-year female was initially seen at the tertiary referral center for an indeterminate thyroid nodule discovered incidentally on neck ultrasound (US) ordered for evaluation of a palpable posterior left neck mass. Neck/thyroid US showed multiple nonspecific bilateral lymph nodes measuring up to 1.2 cm and a 1.7 cm right interpolar markedly hypoechoic and hypervascular solid thyroid nodule (TR5). Clinically, the patient did not have symptoms related to the thyroid nodules or lymph nodes in the neck. Thyroid function tests were within normal range. An US-guided FNA biopsy was nondiagnostic. Core biopsy was suspicious for papillary thyroid carcinoma (hypercellular thyroid parenchyma with some follicular cells with nuclear irregularity, grooves, and hyperchromasia). Pathology slides review at the tertiary center showed nondiagnostic sample (Bethesda I) on cytopathology and neuroendocrine neoplasm consistent with PGL on core biopsy (immunohistochemical stains showed tumor cells positive for synaptophysin, chromogranin and GATA3. TTF1, TG, calcitonin, CEA and AE1/3 negative). US of the neck/thyroid 4 months later showed stable disease. Calcitonin and 24-h urinary catecholamines, metanephrines were within normal limits. There was no family history of pheochromocytoma or PGL. Genetic testing showed germline SDHD mutation (p.P81L(c.242c&amp;gt;5). 68Ga-DOTATATE PET/CT revealed multifocal areas of increased somatostatin receptor expression from the skull base to the left thoracic inlet, which included right and left skull base lesions, left neck level IIA lymph node, right and left level III lymph nodes, right thyroid lobe lesion, and left prevascular superior mediastinal lesion. An MRI of the brain and neck with and without contrast showed 1.7 cm right jugular, 0.6 cm right carotid, and 0.6 cm left vagal PGL, 1.3 cm right thyroid nodule, left level II 1.1x.6 cm lymphadenopathy, and 0.4 cm left superior mediastinal nodule. A CT of the neck w/contrast showed multiple areas likely representing bilateral carotid body tumors, left vagal PGL, right glomus jugular, and thyroid PGL stable over 6 months. MIBG nuclear medicine scan revealed no radiotracer accumulation in the lesions. EBRT therapy is planned to the skull base lesion. Conclusions: TP should be considered in the differential diagnosis of hypervascular thyroid nodules in patients with SDH-related pheochromocytoma-PGL syndromes. This case illustrates the importance of experienced multidisciplinary team evaluation and management of complex and rare PRG cases. Presentation: Friday, June 16, 2023

SSTR2 positively associates with EGFR and predicts poor prognosis in nasopharyngeal carcinoma.

Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinases family and overexpression of EGFR has been linked to poor prognosis and cancer progression. Somatostatin receptor 2 (SSTR2) is a G-protein-coupled receptor (GPCR) with diverse biological functions in humans, and it is upregulated through the NF-KB signalling pathway in nasopharyngeal carcinomas (NPC). However, no studies have examined the EGFR and SSTR2 in NPC. This study aimed to investigate whether SSTR2 is associated with EGFR and clinicopathological features in NPC. Bioinformatics analysis was performed to assess the correlation between EGFR and SSTR2 based on the GEO database. The expression of SSTR2 and EGFR was evaluated by immunohistochemistry (IHC) in 491 cases of NPC and 50 cases of non-cancerous nasopharyngeal epithelium. The bioinformatics analysis and IHC showed a positive correlation between SSTR2 and EGFR in NPC. High expression of SSTR2 and EGFR was significantly increased in NPC patients compared with non-cancerous nasopharyngeal epithelium. High expression of SSTR2 and/or EGFR was associated with a worse outcome and a higher risk of progression. The study found that patients receiving chemoradiotherapy (CR) with high expression of SSTR2, high expression of EGFR, and high coexpression of SSTR2 and EGFR had a poorer prognosis in both progression-free survival (PFS) and overall survival (OS). Interestingly, NPC patients with high expression of SSTR2, high expression of EGFR, high coexpression of EGFR and SSTR2, and EGFR/SSTR2 anyone high expression had a better prognosis with CR combined with targeted therapy. Cox multivariate analysis identified SSTR2 and EGFR as independent poor predictors of PFS. Our study is the first to shed light on the intricate relationship between SSTR2 and EGFR in NPC and provides new insights into the potential benefits of EGFR targeted therapy for patients with high SSTR2 expression. Additionally, SSTR2 has potential as a new biomarker for poor prognosis in NPC patients.

Somatostatin receptor expression and clinical outcome of multilineage pituitary tumours expressing PIT1 and SF1.

The application of transcription factor immunohistochemistry to pituitary neuroendocrine tumour (PitNET) assessment has allowed identification of tumours that do not conform to a single lineage. Multilineage pituitary transcription factor 1 (PIT1) and steroidogenic factor 1 (SF1) PitNETs are a rare and relatively newly described tumour subtype. These tumours express both transcription factors and may also express combinations of hormones corresponding to both lineages. Histological and clinical characteristics can vary, and overall clinical behaviour and prognosis is not known. We describe the clinical outcomes and somatostatin receptor status (SSTR) of a series of nine cases identified from our cohort of pituitary tumours at Westmead Hospital. Eight PitNETs (88.9%) expressed growth hormone and caused acromegaly at presentation. Of the seven macrotumours that caused acromegaly, one had cavernous sinus invasion. The Ki-67 labeling index score ranged from 0.6% to 3.6%. About 88% of tumours that secreted excess growth hormone exhibited strong immunostaining for SSTR 2 and all tumours displayed weak immunoreactivity for SSTR5. In 62.5% of patients with acromegaly, cure was achieved after surgical resection. Somatostatin receptor ligands resulted in clinical remission in cases where medical treatment was initiated. There was no new tumour recurrence or regrowth over an overall mean follow-up period of 62.5 months.

Predictors of long-term remission in acromegaly – an updated review

Abstract Acromegaly is a rare chronic disorder due to growth hormone (GH) - secreting pituitary tumor. The first-line treatment of acromegaly is a transsphenoidal adenomectomy. Surgical remission rates range from 30-50% for macroadenomas to 70-90% for microadenomas. Thus in patients with active acromegaly after surgery, medical treatment is recommended. Treatment outcome on medical therapy differs a lot depending on medications. The aim of this paper is to summerize the current knowledge of factors predicting acromegaly remission after surgery and biochemical control on medical treatment. Factors affecting treatment outcome, not related to the patient and the tumor, are neurosurgeon’s experience and visualisation tools used during surgery. Younger patients, as well as women tend to achieve acromegaly remission after surgery less often. Patients with lower GH and insulin-like growth factor-1 (IGF-1) concentrations at diagnosis, in oral glucose tolerance test (OGTT) and postoperatively have a greater chance of surgical remission. However, some publications do not confirm that. Patients presenting with larger and more invasive tumors achieve surgical remisson less often. Hypointensive tumors on T2-weighted magnetic resonance imaging (MRI) scans are associated with better response to first-generation somatostatin receptor ligands (SRLs) and to pasireotide. Pathologic factors increasing the chance of acromegaly remission are densely granulated tumors, lower Ki-67 index, high expression of somatostatin receptors (SSTRs) and high expression of E-cadherin. A thorough analysis of the abovementioned factors predicting the treatment outcome in acromegaly may be helpful for selecting the best treatment option for each patient.

Abstract PO-016: SSTR2 use and molecular profile in EBV-positive nasopharyngeal carcinoma: A single institution experience

Abstract Background: Nasopharyngeal carcinoma (NPC) is a rare malignancy endemic in Southeast Asia. EBV infection is recognized as a major risk factor playing important roles in oncogenic pathways. Somatostatin receptor 2 (SSTR2) is a marker used in neuroendocrine tumors and appears to demonstrate high prevalence in EBV+ NPCs. Methods: We identified a total of 16 patients with biopsy-proven WHO type 3 EBV+ (via EBER) NPC in which SSTR2 expression via immunohistochemistry (IHC) was analyzed in either primary or metastatic lesions. Additionally, risk factors (smoking or alcohol), P16 via IHC, PD-L1 via IHC, tumor mutation burden (TMB), microsatellite instability (MSI), genomic alterations via Next Generation Sequencing (NGS), and time to progression (TTP) in months were reported. Results: Mean age of diagnosis was 60 years old, 14 were male, 13 were locally advanced and 37.5% former or heavy smokers. Ten patients were Asian with the rest being Latino (4), European (1) and unknown (1). Fourteen out of sixteen patients (87.5%) had SSTR2 expression either in primary lesions or metastatic lesions. P16 was measured in seven cases, all of them being negative. PDL1 was measured in 11 cases, 9 had high expression (≥ 20 CPS), 2 had expression (1-19 CPS) and 5 was not measured. In 10 cases TMB was evaluated, seven had low TMB and three intermediate TMB. From the TMB intermediate cases, all of them were MSI stable and two high PDL1 expression. From the 10 patients with MSI status all of them were stable. Out of the 16 patients, 11 patients had NGS performed from which 9 patients had clinically significant alterations. 4 out of 9 patients (44.4%) had an 11q13.2-13.3 amplification followed by 33.3% having a 9p21 loss and 22.2% TP53 mutation. Survival, median survival was not reached and median TTP was 23 months with the most common site being the liver. Conclusions: Given the high prevalence of SSTR2 in EBV+ NPCs (87.5%) in our cohort, SSTR2 via IHC may be a good screening tool for EBV + NPCs with potential diagnostic and therapeutic implications. 11q amplifications being present in 44.4% of our cohort might also be of diagnostic significance in NPC. Prognostic and clinical implications warrant further investigation. Citation Format: Juan J. Juarez-Vignon Whaley, Michelle Afkhami, Mykola Onyshchenko, Thomas Gernon, Robert Kang, Ellie Maghami, Sagus Sampath, Arya Amini, Diana Bell, Victoria M. Villaflor. SSTR2 use and molecular profile in EBV-positive nasopharyngeal carcinoma: A single institution experience [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-016.

AI-based quantification of whole-body tumour burden on somatostatin receptor PET/CT

BackgroundSegmenting the whole-body somatostatin receptor-expressing tumour volume (SRETVwb) on positron emission tomography/computed tomography (PET/CT) images is highly time-consuming but has shown value as an independent prognostic factor for survival. An automatic method to measure SRETVwb could improve disease status assessment and provide a tool for prognostication. This study aimed to develop an artificial intelligence (AI)-based method to detect and quantify SRETVwb and total lesion somatostatin receptor expression (TLSREwb) from [68Ga]Ga-DOTA-TOC/TATE PET/CT images.MethodsA UNet3D convolutional neural network (CNN) was used to train an AI model with [68Ga]Ga-DOTA-TOC/TATE PET/CT images, where all tumours were manually segmented with a semi-automatic method. The training set consisted of 148 patients, of which 108 had PET-positive tumours. The test group consisted of 30 patients, of which 25 had PET-positive tumours. Two physicians segmented tumours in the test group for comparison with the AI model.ResultsThere were good correlations between the segmented SRETVwb and TLSREwb by the AI model and the physicians, with Spearman rank correlation coefficients of r = 0.78 and r = 0.73, respectively, for SRETVwb and r = 0.83 and r = 0.81, respectively, for TLSREwb. The sensitivity on a lesion detection level was 80% and 79%, and the positive predictive value was 83% and 84% when comparing the AI model with the two physicians.ConclusionIt was possible to develop an AI model to segment SRETVwb and TLSREwb with high performance. A fully automated method makes quantification of tumour burden achievable and has the potential to be more widely used when assessing PET/CT images.

Somatostatin receptor expression in Merkel cell carcinoma: correlation with clinical data

Background Merkel cell carcinoma (MCC) is a rare, high-grade neuroendocrine neoplasm (NEN) of the skin. Somatostatin receptors (SSTRs) are G protein-linked receptors that regulate cell proliferation and growth. SSTRs are expressed in many NENs; however, scant information is available on their expression in MCCs or their association with clinical parameters and patient outcomes. Material and methods This retrospective study was conducted at Helsinki University Hospital and the University of Helsinki. Using a tissue microarray, we investigated SSTR1-5 expression by immunohistochemistry in 99 MCC tissue samples. Samples were collected between 1983 and 2017 and coupled with the patients’ clinical data. Results SSTR2-SSTR5 were detected in 69%, 6%, 4%, and 1% of the tumours, respectively. However, SSTR1 expression was not observed. Cytoplasmic SSTR2 positivity was associated with metastatic disease at the time of diagnosis (p = 0.009), but it did not correlate with disease-specificity or overall survival. Conclusion SSTR2-5 expression was observed in MCCs. In particular, SSTR2 expression is clinically valid because it is associated with metastatic disease at the time of diagnosis and can thus serve as a prognostic marker. Moreover, SSTR2 overexpression provides a molecular basis for tumour imaging and treatment with somatostatin analogues.