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International Journal of Molecular... Mar 2024Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels...
Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, < 0.001 vs. basal, = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, < 0.001 vs. basal, = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.
Topics: Humans; Antimitotic Agents; Neuroendocrine Tumors; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin
PubMed: 38612419
DOI: 10.3390/ijms25073606 -
Case Reports in Gastroenterology 2024Ampullary neuroendocrine tumors (NETs) are usually diagnosed in the 5th-6th decades of life, and no cases were reported in <20 years of age. We report a rare case,...
INTRODUCTION
Ampullary neuroendocrine tumors (NETs) are usually diagnosed in the 5th-6th decades of life, and no cases were reported in <20 years of age. We report a rare case, presenting at a very young age, of well-differentiated NET involving the ampulla of Vater with lymph node metastasis.
CASE PRESENTATION
An 18-year-old man presented with a 3-month history of upper abdominal pain and jaundice. Abdominal ultrasound showed a dilated common bile duct, and endoscopic retrograde cholangiopancreatography revealed two duodenal polypoid lesions, one of them overlying the ampulla of Vater, with an erythematous and ulcerated surface. Histopathological examination confirmed the diagnosis of NET grade 1. Octreotide scan revealed 2 para-aortic lymph nodes with intense radiotracer uptake. The patient had undergone Whipple surgery with para-aortic lymph node dissection. Histopathological examination of the surgical specimens was confirmatory of NET grade 2 and paraganglioma in a few of the dissected lymph nodes. Postoperatively, the patient was kept on monthly intramuscular octreotide. Follow-up gallium-68 DOTATATE is unremarkable apart from an avid left para-aortic lymph node which is showing stability over 12 months of follow-up.
CONCLUSION
This case demonstrates that NETs of the ampulla of Vater can present at a very young age. Radical surgical excision with extended lymph node dissection and postoperative octreotide is associated with better patient outcomes and survival.
PubMed: 38590835
DOI: 10.1159/000538260 -
Clinical Case Reports Apr 2024Treatment of congenital chyloperitoneum is a challenge. Conservative methods may be ineffective. Preoperative visualization of the site of lymphatic leakage is crucial,...
Treatment of congenital chyloperitoneum is a challenge. Conservative methods may be ineffective. Preoperative visualization of the site of lymphatic leakage is crucial, but radiological imaging is technically complicated and may not provide sufficient information, especially in small patients. To ease the detection of lymphatic leakage during surgery, preoperative feeding with fat-rich formula with Sudan Black has been recommended. However, administration of Sudan Black may result in life-threatening methemoglobinemia and liver damage without any advantage of revealing leakage during surgery. We recommend preoperative feeding with pure fat-rich formula.
PubMed: 38585587
DOI: 10.1002/ccr3.8676 -
Current Oncology Reports May 2024This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with... (Review)
Review
PURPOSE OF REVIEW
This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT).
RECENT FINDINGS
Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.
Topics: Humans; Neuroendocrine Tumors; Radiopharmaceuticals; Octreotide; Positron-Emission Tomography; Receptors, Peptide; Theranostic Nanomedicine; Radioisotopes; Organometallic Compounds
PubMed: 38581469
DOI: 10.1007/s11912-024-01526-5 -
Molecular Medicine Reports Jun 2024The intestinal mucosal barrier is of great importance for maintaining the stability of the internal environment, which is closely related to the occurrence and...
The intestinal mucosal barrier is of great importance for maintaining the stability of the internal environment, which is closely related to the occurrence and development of intestinal inflammation. Octreotide (OCT) has potential applicable clinical value for treating intestinal injury according to previous studies, but the underlying molecular mechanisms have remained elusive. This article is based on a cell model of inflammation induced by lipopolysaccharide (LPS), aiming to explore the effects of OCT in protecting intestinal mucosal barrier function. A Cell Counting Kit‑8 assay was used to determine cell viability and evaluate the effectiveness of OCT. Gene silencing technology was used to reveal the mediated effect of somatostatin receptor 2 (SSTR2). The changes in intestinal permeability were detected through trans‑epithelial electrical resistance and fluorescein isothiocyanate‑dextran 4 experiments, and the alterations in tight junction proteins were detected using immunoblotting and reverse transcription fluorescence‑quantitative PCR technology. Autophagosomes were observed by electron microscopy and the dynamic changes of the autophagy process were characterized by light chain (LC)3‑II/LC3‑I conversion and autophagic flow. The results indicated that SSTR2‑dependent OCT can prevent the decrease in cell activity. After LPS treatment, the permeability of monolayer cells decreased and intercellular tight junctions were disrupted, resulting in a decrease in tight junction protein zona occludens 1 in cells. The level of autophagy‑related protein LC3 was altered to varying degrees at different times. These abnormal changes gradually returned to normal levels after the combined application of LPS and SSTR2‑dependent OCT, confirming the role of OCT in protecting intestinal barrier function. These experimental results suggest that OCT maintains basal autophagy and cell activity mediated by SSTR2 in intestinal epithelial cells, thereby preventing the intestinal barrier dysfunction in inflammation injury.
Topics: Humans; Caco-2 Cells; Octreotide; Lipopolysaccharides; Intestinal Mucosa; Tight Junction Proteins; Autophagy; Inflammation; Tight Junctions; Permeability
PubMed: 38577927
DOI: 10.3892/mmr.2024.13214 -
World Journal of Gastrointestinal... Mar 2024Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, often diagnosed in an advanced stage when curative treatment is impossible and grueling...
BACKGROUND
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors, often diagnosed in an advanced stage when curative treatment is impossible and grueling symptoms related to vasoactive substance release by tumor cells affect patients' quality of life. Cardiovascular complications of GEP-NENs, primarily tricuspid and pulmonary valve disease, and right-sided heart failure, are the leading cause of death, even compared to metastatic disease.
CASE SUMMARY
We present a case of a 35-year-old patient with progressive dyspnea, back pain, polyneuropathic leg pain, and nocturnal diarrhea lasting for a decade before the diagnosis of neuroendocrine carcinoma of unknown primary with extensive liver metastases. During the initial presentation, serum biomarkers were not evaluated, and the patient received five cycles of doxorubicin, which he did not tolerate well, so he refused further therapy and was lost to follow-up. After 10 years, he presented to the emergency room with signs and symptoms of right-sided heart failure. Panneuroendocrine markers, serum chromogranin A, and urinary 5-hydroxyindoleacetic acid were extremely elevated (900 ng/mL and 2178 µmol/L), and transabdominal ultrasound confirmed hepatic metastases. Computed tomography (CT) showed liver metastases up to 6 cm in diameter and metastases in mesenteric lymph nodes and pelvis. Furthermore, an Octreoscan showed lesions in the heart, thoracic spine, duodenum, and ascendent colon. A standard transthoracic echocardiogram confirmed findings of carcinoid heart disease. The patient was not a candidate for valve replacement. He started octreotide acetate treatment, and the dose escalated to 80 mg IM monthly. Although biochemical response and symptomatic improvement were noted, the patient died.
CONCLUSION
Carcinoid heart disease occurs with carcinoid syndrome related to advanced neuroendocrine tumors, usually with liver metastases, which manifests as right-sided heart valve dysfunction leading to right-sided heart failure. Carcinoid heart disease and tumor burden are major prognostic factors of poor survival. Therefore, they must be actively sought by available biochemical markers and imaging techniques. Moreover, imaging techniques aiding tumor detection and staging, somatostatin receptor positron emission tomography/CT, and CT or magnetic resonance imaging, should be performed at the time of diagnosis and in 3- to 6-mo intervals to determine tumor growth rate and assess the possibility of locoregional therapy and/or palliative surgery. Valve replacement at the onset of symptoms or right ventricular dysfunction may be considered, while any delay can worsen right-sided ventricular failure.
PubMed: 38577438
DOI: 10.4251/wjgo.v16.i3.1076 -
Best Practice & Research. Clinical... Mar 2024Although predictors of response to first-generation somatostatin receptor ligands (fg-SRLs), and to a lesser extent to pasireotide, have been studied in acromegaly for... (Review)
Review
Although predictors of response to first-generation somatostatin receptor ligands (fg-SRLs), and to a lesser extent to pasireotide, have been studied in acromegaly for many years, their use is still not recommended in clinical guidelines. Is there insufficient evidence to use them? Numerous biomarkers including various clinical, functional, radiological and molecular markers have been identified. The first ones are applicable pre-surgery, while the molecular predictors are utilized for patients not cured after surgery. In this regard, factors predicting a good response to fg-SRLs are specifically: low basal GH, a low GH nadir in the acute octreotide test, T2 MRI hypointensity, a densely granulated pattern, high immunohistochemistry staining for somatostatin receptor 2 (SSTR2), and E-cadherin. However, there is still a lack of consensus regarding which of these biomarkers is more useful or how to integrate them into clinical practice. With classical statistical methods, it is complex to define reliable and generalizable cut-off values for a single biomarker. The potential solution to the limitations of traditional methods involves combining systems biology with artificial intelligence, which is currently providing answers to such long-standing questions that may eventually be finally included into the clinical guidelines and make personalized medicine a reality. The aim of this review is to describe the current knowledge of the main fg-SRLs and pasireotide response predictors, discuss their current usefulness, and point to future directions in the research of this field.
PubMed: 38575404
DOI: 10.1016/j.beem.2024.101893 -
Oman Medical Journal Jan 2024To estimate the incidence of pituitary adenomas (PA) in adult Omani patients and describe its epidemiological, clinical, and radiological characteristics.
OBJECTIVES
To estimate the incidence of pituitary adenomas (PA) in adult Omani patients and describe its epidemiological, clinical, and radiological characteristics.
METHODS
In this longitudinal, descriptive study, we reviewed the records of all PA patients from January 2015 to January 2020 who presented at the endocrinology facilities at Sultan Qaboos University Hospital, Muscat.
RESULTS
The participants comprised of 112 Omani patients with PA. The incidence of PA among all adult patients at Sultan Qaboos University Hospital (inpatient and outpatient) over five years (2015-2020) was 0.23%. The cohort had a mean age of 41.0±15.0 years. Of the 112 patients included in this study, 79 (70.5%) were women. Nearly half (51; 45.5%) of adenomas were prolactinomas while 46 (41.1%) were non-functioning adenomas, and seven (6.3%) were growth hormone-secreting adenomas while six (5.4%) were adrenocorticotropic hormone secreting adenomas. Headache was present in 67 (59.8%) patients, followed by visual field defects (40; 35.7%), galactorrhea (26; 23.2%), and fatigue (19; 17.0%). The majority of women (45/79; 57.0%) presented with menstrual cycle abnormalities. Radiological appearances were nearly equally distributed between micro- and macroadenomas. Most cases (58/112; 52.0%) of PA were treated medically by cabergoline, octreotide, and replacement therapies such as hydrocortisone and thyroxin, 38 (33.9%) were treated surgically (mainly by trans-sphenoidal pituitary resection), and the remaining 10 (8.9%) cases were subjected to radiotherapy. Medical treatment combined with surgery was employed for 15 (13.4%) patients.
CONCLUSIONS
In our investigation, PA was primarily prevalent among Omani female patients, and the most common subtype of pituitary tumors was prolactinomas. The most common presentation symptom was headaches; most female patients had menstrual irregularities. Medical treatment was the primary approach for the applicable types of PAs, while surgery and radiotherapy were found to be secondary and tertiary treatment options, respectively.
PubMed: 38567166
DOI: 10.5001/omj.2024.44 -
ACG Case Reports Journal Apr 2024Chylous ascites is a rare manifestation of decompensated cirrhosis that is associated with increased short-term mortality. Exclusion of other etiologies must be...
Chylous ascites is a rare manifestation of decompensated cirrhosis that is associated with increased short-term mortality. Exclusion of other etiologies must be performed to allow for appropriate management, which itself can be a challenge in the setting of decompensated cirrhosis. We report a case of chylous ascites in a patient with decompensated cirrhosis that was successfully managed with octreotide before liver transplantation.
PubMed: 38560017
DOI: 10.14309/crj.0000000000001322 -
Nuclear Medicine and Biology 2024DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors...
Investigation of imaging the somatostatin receptor by opening the blood-brain barrier with melittin - A feasibility study using positron emission tomography and [Cu]Cu-DOTATATE.
DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors are found naturally in the intestines, pancreas, lungs, and brain (mainly cortex). In vivo measurement of the somatostatin receptors in the cortex has been challenging because available tracers cannot cross the blood-brain barrier (BBB) due to their intrinsic polarity. A peptide called melittin, a main component of honeybee venom, has been shown to disrupt plasma membranes and increase the permeability of biological membranes. In this study, we assessed the feasibility of using melittin to facilitate the passage of [Cu]Cu-DOTATATE through the BBB and its binding to somatostatin receptors in the cortex. Evaluation included in vitro autoradiography on Long Evans rat brains to estimate the binding affinity of [Cu]Cu-DOTATATE to the somatostatin receptors in the cortex and an in vivo evaluation of [Cu]Cu-DOTATATE binding in NMRI mice after injection of melittin. This study found an in vitro B = 89 ± 4 nM and K = 4.5 ± 0.6 nM in the cortex, resulting in a theoretical binding potential (BP) calculated as B/K ≈ 20, which is believed suitable for in vivo brain PET imaging. However, the in vivo results showed no significant difference between the control and melittin injected mice, indicating that the honeybee venom failed to open the BBB. Additional experiments, potentially involving faster injection rates are required to verify that melittin can increase brain uptake of non-BBB permeable PET tracers. Furthermore, an evaluation of whether a venom with a narrow therapeutic range can be used for clinical purposes needs to be considered.
Topics: Animals; Receptors, Somatostatin; Melitten; Rats; Feasibility Studies; Positron-Emission Tomography; Organometallic Compounds; Blood-Brain Barrier; Male; Mice; Copper Radioisotopes; Octreotide
PubMed: 38555651
DOI: 10.1016/j.nucmedbio.2024.108905