Al[18F]F-NOTA-Octreotide Is Comparable to [68Ga]Ga-DOTA-TATE for PET/CT Imaging of Neuroendocrine Tumours in the Latin-American Population.

PET imaging of neuroendocrine tumours (NET) is well established for staging and therapy follow-up. The short half-life, increasing costs, and regulatory issues significantly limit the availability of approved imaging agents, such as [68Ga]Ga-DOTA-TATE. Al[18F]F-NOTA-Octreotide provides a similar biodistribution and tumour uptake, can be produced on a large scale and may improve access to precision imaging. Here we prospectively compared the clinical utility of [68Ga]Ga-DOTA-TATE and Al[18F]F-NOTA-Octreotide in the Latin-American population. Our results showed that in patients with stage IV NETs [68Ga]Ga-DOTA-TATE presents higher physiological uptake than Al[18F]F-NOTA-Octreotide in the liver, hypophysis, salivary glands, adrenal glands (all p < 0.001), pancreatic uncinated process, kidneys, and small intestine (all p < 0.05). Nevertheless, despite the lower background uptake of Al[18F]F-NOTA-Octreotide, comparative analysis of tumour-to-liver (TLR) and tumour-to-spleen (TSR) showed no statistically significant difference for lesions in the liver, bone, lymph nodes, and other tissues. Only three discordant lesions in highly-metastases livers were detected by [68Ga]Ga-DOTA-TATE but not by Al[18F]F-NOTA-Octreotide and only one discordant lesion was detected by Al[18F]F-NOTA-Octreotide but not by [68Ga]Ga-DOTA-TATE. Non-inferiority analysis showed that Al[18F]F-NOTA-Octreotide is comparable to [68Ga]Ga-DOTA-TATE. Hence, our results demonstrate that Al[18F]F-NOTA-Octreotide provided excellent image quality, visualized NET lesions with high sensitivity and represents a highly promising, clinical alternative to [68Ga]Ga-DOTA-TATE.

TGF-ß1/Smad2/3 signaling pathway modulates octreotide antisecretory and antiproliferative effects in pituitary somatotroph tumor cells.

Octreotide (OCT) is used to inhibit hormone secretion and growth in somatotroph tumors, although a significant percentage of patients are resistant. It has also been tested in nonfunctioning (NF) tumors but with poor results, with these outcomes having been associated with SSTR2 levels and impaired signaling. We investigated whether OCT inhibitory effects can be improved by TGF-ß1 in functioning and nonfunctioning somatotroph tumor cells. OCT effects on hormone secretion and proliferation were analyzed in the presence of TGF-ß1 in WT and SSTR2-overexpressing secreting GH3 and silent somatotroph tumor cells. The mechanism underlying these effects was assessed by studying SSTR and TGFßR signaling pathways mediators. In addition, we analyzed the effects of OCT/TGF-ß1 treatment on tumor growth and cell proliferation in vivo. The inhibitory effects of OCT on GH- and PRL-secretion and proliferation were improved in the presence of TGF-ß1, as well as by SSTR2 overexpression. The OCT/TGF-ß1 treatment induced downregulation of pERK1/2 and pAkt, upregulation of pSmad3, and inhibition of cyclin D1. In vivo experiments showed that OCT in the presence of TGF-ß1 blocked tumor volume growth, decreased cell proliferation, and increased tumor necrosis. These results indicate that SSTR2 levels and the stimulation of TGF-ß1/TGFßR/Smad2/3 pathway are important for strengthening the antiproliferative and antisecretory effects of OCT.

Evaluation of 68Ga-DOTATATE uptake at the pituitary region and the biochemical response to somatostatin analogs in acromegaly.

PURPOSE: Acromegaly is associated with many comorbidities and increased mortality. The first-line treatment is transsphenoidal surgery. However, many patients also need adjuvant drug treatment after surgery. Somatostatin analog (SSA), which suppresses GH secretion by somatotrophs by binding to the SSTR2 receptor, is the first choice. Nevertheless, 50% of patients are partially or totally resistant to SSA, so predictive factors of response are helpful to individualize drug treatment. 68GaDOTATATE PET/CT has emerged as the gold-standard method in the diagnosis and follow-up of gastroenteropancreatic neuroendocrine tumors, which also express SSTR. Our objective was to evaluate whether 68Ga-DOTATATE uptake (SUV max) at the pituitary region of patients on SSA therapy would be useful as a drug response predictor without the need of tumoral tissue. METHODS: Fifteen acromegalics patients on SSA treatment for at least 6 months were underwent to 68Ga-DOTATATE PET/CT at the nuclear medicine service. There was an SSA complete response group (n = 5), defined as GH < 1 µg/L and IFG-1 in the normal range for gender and age, and a group that did not meet these criteria (n = 10). RESULTS: As a result, we did not find out a significantly higher SUV max in the complete response group (p = 0.0576) to SSA. However, we found a significant inverse relationship between postoperative GH values and the SUVmax at the sella turcica (p = 0.0188), probably reflecting tumor SSTR2 expression. CONCLUSION: Thus, after this initial evaluation, 68GaDOTATATE PET/CT should be better studied to assess its usefulness in the follow-up of acromegalic patients.

Somatostatin receptor subtype 1 might be a predictor of better response to therapy in medullary thyroid carcinoma.

PURPOSE: Medullary thyroid carcinoma (MTC) is a malignant neoplasm of parafollicular cells. Because it is a neuroendocrine tumor, it has known somatostatin receptors (SSTRs). The actual frequencies of the SSTR subtypes and their potential influences (by binding with endogenous somatostatin) on MTC cell proliferation have not been fully elucidated to date. The present study evaluated the occurrence of SSTR subtypes 1, 2, 3 and 5 as well as the possible role that each subtype plays in the clinical evolution of patients with MTC. METHODS: This retrospective, longitudinal study analyzed thyroid surgical material from 42 patients with MTC. Immunohistochemical staining was performed with monoclonal antibodies against subtypes 1, 2, 3 and 5 of SSTR. The histological material was classified as negative, focal positive or diffuse positive, in relation to each of the SSTR subtypes. The initial response to treatment, clinical course and patient mortality rate were assessed and related to the presence of SSTR subtypes. RESULTS: The most prevalent SSTR subtype was SSTR 3, which was found in 81% of the patients, when considering any pattern of positivity. However, subtype 2 had the lowest number of positive patients, with 28.6% demonstrating any positive pattern. Subtypes 1 and 5 had an intermediate prevalence of positivity, with subtype 1 present in 45.2% of the patients and subtype 5 positive in 54.8% of the patients, when considering any pattern of positivity. The presence of STR 1, in the form of diffuse positivity, independently predicted a better response to the initial therapy, with a hazard ratio (HR) of 4.80 (p = 0.03). CONCLUSION: This is the first study to show the correlation of the presence of SSTR1, detected by monoclonal immunohistochemical techniques, and better response to initial treatment and possibly better long-term clinical response in patients with MTC. In addition, these patients had low positivity rates for SSTR2, which might explain the low sensitivity of diagnostic and limited therapeutic response to octrotide based radioisotopes.

Association between methylation of SHP-1 isoform I and SSTR2A promoter regions with breast and prostate carcinoma development.

Methylation pattern is presented here for first time as a potential molecular marker of changes on SSTR2A and SHP-1(I) gene promoter related to breast and prostate carcinoma. Our results have shown low concordances with SSTR2A and methylated state in prostate cancer and moderate relationship with unmethylated CpG-27 in breast cancer. We found significant concordances for both cancers and SHP-1(I) unmethylation, and increased HER2 expression and SSTR2A methylation in breast cancer. Moreover, we found a correlation between methylation patterns of two genes in normal breast tissue. These data might assist to select subgroups of patients for the administration of alternative therapies.