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Journal of Gastrointestinal Cancer Jun 2024The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic....
INTRODUCTION
The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied.
MATERIALS AND METHODS
Retrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS).
RESULTS
Of the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017).
CONCLUSION
A higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.
PubMed: 38874852
DOI: 10.1007/s12029-024-01077-9 -
Theranostics 2024Somatostatin receptor imaging with F-AlF-NOTA-octreotide (F-AlF-OC) has shown promising performance in neuroendocrine neoplasms (NENs). In this study, we aim to...
Somatostatin receptor imaging with F-AlF-NOTA-octreotide (F-AlF-OC) has shown promising performance in neuroendocrine neoplasms (NENs). In this study, we aim to investigate the diagnostic performance and clinical impact of F-AlF-OC in a large prospective cohort of patients with NEN. Between January 2023 and November 2023, a total of 219 patients with confirmed or suspected NEN were enrolled prospectively and underwent F-AlF-OC PET/CT at 2 h post-injection. The primary endpoint was the diagnostic performance, including sensitivity, specificity, and accuracy. An additional primary endpoint was the impact of F-AlF-OC on clinical management. The reference standard was based on the results of histopathology or radiological follow-up. 205 patients were included in the final analysis. The patient-level sensitivity, specificity, and accuracy of F-AlF-OC PET/CT compared with contrast-enhanced CT/MRI were 90.5% vs. 81.8%, 93.1% vs. 71.1%, and 91.2% vs. 79.4%, respectively. 26 patients had tiny gastrointestinal NENs (smaller than 1 cm in diameter). The patient-based sensitivity of F-AlF-OC PET/CT and contrast-enhanced CT/MRI were 61.5% (16/26) and 37.5% (9/24), respectively. The smallest diameter of gastrointestinal NEN detected by F-AlF-OC PET/CT was 0.6 cm in the rectum, 0.3 cm in the stomach, and 0.5 cm in the duodenum. F-AlF-OC PET/CT results led to changes in clinical management in 19.5% of patients (40/205), owing mainly to new or unexpected findings compared to contrast-enhanced CT/MRI. F-AlF-OC PET/CT demonstrated great diagnostic performance in patients with NEN, particularly for detecting tiny gastrointestinal NEN. Furthermore, F-AlF-OC PET/CT impacted the therapeutic management in 19.5% of patients. Our results further validate the role of F-AlF-OC as a somatostatin receptor imaging tracer in clinical practice.
Topics: Humans; Neuroendocrine Tumors; Male; Female; Middle Aged; Prospective Studies; Positron Emission Tomography Computed Tomography; Octreotide; Aged; Adult; Sensitivity and Specificity; Radiopharmaceuticals; Heterocyclic Compounds, 1-Ring; Receptors, Somatostatin; Fluorine Radioisotopes; Magnetic Resonance Imaging; Aged, 80 and over; Heterocyclic Compounds
PubMed: 38855183
DOI: 10.7150/thno.96762 -
Endocrine Jun 2024Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young...
PURPOSE
Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese.
METHODS
The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants.
RESULTS
Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs).
CONCLUSION
Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.
PubMed: 38851643
DOI: 10.1007/s12020-024-03898-x -
Lancet (London, England) Jun 2024There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine... (Randomized Controlled Trial)
Randomized Controlled Trial
[Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study.
BACKGROUND
There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [Lu]Lu-DOTA-TATE (Lu-Dotatate) treatment.
METHODS
NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting.
FINDINGS
Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period.
INTERPRETATION
First-line Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. Lu-Dotatate should be considered a new standard of care in first-line therapy in this population.
FUNDING
Advanced Accelerator Applications, a Novartis Company.
Topics: Humans; Octreotide; Pancreatic Neoplasms; Male; Neuroendocrine Tumors; Female; Middle Aged; Organometallic Compounds; Stomach Neoplasms; Aged; Intestinal Neoplasms; Adult; Radiopharmaceuticals; Treatment Outcome; Neoplasm Grading; Progression-Free Survival
PubMed: 38851203
DOI: 10.1016/S0140-6736(24)00701-3 -
The American Journal of Pathology Jun 2024A group of genetic diseases known as polycystic liver disease (PLD) are distinguished by the gradual development of fluid-filled hepatic cysts formed from cholangiocytes...
A group of genetic diseases known as polycystic liver disease (PLD) are distinguished by the gradual development of fluid-filled hepatic cysts formed from cholangiocytes and commonly related to primary cilia defects. The NAD salvage pathway, which sustains cellular bioenergetics and supplies a required substrate for tasks important to rapidly multiplying cells, has a rate-limiting phase that is mediated by nicotinamide phosphoribosyltransferase (NAMPT). In this study, the efficacy and mechanisms of action of FK866, a novel, high-potency NAMPT inhibitor with a good toxicity profile, were assessed. NAMPT-siRNA and FK866 reduced NAD levels and inhibited the proliferation of PLD cells in a dose-dependent manner. Notably, this pharmacologic and siRNA-mediated suppression of NAMPT was less effective in normal cells at the same concentrations. The addition of nicotinamide mononucleotide (NMN), a byproduct of NAMPT that restores NAD concentration, rescued the cellular viability of PLD cells and verified the on-target action of FK866. In FK866-treated PLD cells, mitochondrial respiration and ATP production were impaired and reactive oxygen species production was induced. Importantly, FK866 treatment was associated with improved effects of octreotide, a drug used for PLD treatment. As a result, the use of NAMPT inhibitors, including FK866 therapy, offers the possibility of a further targeted strategy for the therapeutic treatment of PLD.
PubMed: 38849029
DOI: 10.1016/j.ajpath.2024.04.010 -
Expert Opinion on Drug Safety Jun 2024Neuroendocrine neoplasms (NENs) are a rare group of tumors originating from neuroendocrine cells in various organs. They include neuroendocrine tumors (NETs) and... (Review)
Review
INTRODUCTION
Neuroendocrine neoplasms (NENs) are a rare group of tumors originating from neuroendocrine cells in various organs. They include neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which differ in biological behavior and prognosis. NETs are usually well-differentiated and slow-growing, while NECs are poorly differentiated and more aggressive. Management of NETs often involves somatostatin analogs like octreotide and lanreotide to control tumor growth and alleviate symptoms, especially in well-differentiated NETs. Lanreotide is used to control tumor growth, and both lanreotide and octreotide alleviate symptoms. Treatment approaches may vary depending on the specific type and grade of the neuroendocrine neoplasm.
AREAS COVERED
This review provides an update on the safety of lanreotide autogel in treating patients with NETs, through a comprehensive review of clinical trials, post-marketing surveillance, real-world evidence, and its safety profile. Specific adverse events, side effects, and potential risks associated with lanreotide autogel are discussed, along with risk mitigation strategies and recommendations for patient monitoring.
EXPERT OPINION
The findings highlight the overall safety of lanreotide autogel in managing NETs, focusing on its efficacy in controlling hormone secretion, tumor progression, and symptom management. New safety concerns and precautions are also addressed to help healthcare providers make informed decisions when prescribing lanreotide autogel.
PubMed: 38847075
DOI: 10.1080/14740338.2024.2365823 -
Annals of Surgical Oncology Jun 2024
PubMed: 38844630
DOI: 10.1245/s10434-024-15455-x -
Expert Review of Endocrinology &... Jul 2024Acromegaly is a rare endocrine disorder usually caused by a benign growth hormone‒secreting pituitary adenoma. Surgical adenoma resection is typically the first line... (Review)
Review
INTRODUCTION
Acromegaly is a rare endocrine disorder usually caused by a benign growth hormone‒secreting pituitary adenoma. Surgical adenoma resection is typically the first line of treatment, and medical therapy is used for patients with persistent disease following surgery, for adenoma recurrence, or for patients ineligible for, or declining, surgery. Approved somatostatin receptor ligands (SRLs) have been limited to injectable options, until recently. Oral octreotide capsules (OOC) are the first approved oral SRL for patients with acromegaly.
AREAS COVERED
We review published reports and provide case study examples demonstrating practical considerations on the use of OOC. Using two hypothetical case scenarios, we discuss current treatment patterns, breakthrough symptoms and quality of life (QoL), efficacy of SRLs, OOC dose titration, evaluation of OOC treatment response, and incidence and management of adverse events.
EXPERT OPINION
OOC are an option for patients with acromegaly including those who experience breakthrough symptoms, who have preference for oral therapies, or other reasons for declining injectable SRLs. OOC have been associated with improved patient-reported QoL measures compared with those reported for lanreotide and octreotide. Continued real-world experience will determine whether OOC, alone or in combination with other therapies, provides further advantages over current injectable acromegaly treatments.
Topics: Humans; Acromegaly; Octreotide; Administration, Oral; Antineoplastic Agents, Hormonal; Quality of Life; Capsules; Adenoma; Growth Hormone-Secreting Pituitary Adenoma; Clinical Trials as Topic; Treatment Outcome
PubMed: 38842362
DOI: 10.1080/17446651.2024.2363540 -
Journal of Neuroendocrinology Jun 2024[F]AlF-NOTA-octreotide ([F]AlF-OC) is a promising alternative for [Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the...
[F]AlF-NOTA-octreotide ([F]AlF-OC) is a promising alternative for [Ga]Ga-DOTA-somatostatin analogs (SSAs) in positron emission tomography (PET) imaging of the somatostatin receptor (SSTR). Our aim is to assess changes in TNM staging and differences in patient management between [F]AlF-OC PET/CT and [Ga]Ga-DOTA-SSA PET/CT in the work-up of neuroendocrine tumor (NET) patients. Patients who underwent both [F]AlF-OC and [Ga]Ga-DOTA-TATE or [Ga]Ga-DOTA-NOC PET/CT in our multicenter study (Pauwels et al., J Nucl Med.2023;63:632-638) with a NET were included for analysis. TNM staging was determined and compared for both tracers. For each patient, the blinded [Ga]Ga-DOTA-SSA or [F]AlF-OC PET/CT images were presented in random order at a multidisciplinary team board. The images were presented together with clinical information and compared with previous SSTR and [F]FDG PET/CT imaging. After a consensus decision for patient management was recorded, the board was presented with the PET/CT images from the other SSTR tracer and a decision was made for the second tracer. Differences in management were classified as major if it entailed an intermodality change and minor if it led to an intramodality change. Compared with [Ga]Ga-DOTA-SSA, the use of [F]AlF-OC led to a change in 16/75 patients: TNM staging changes in 10/75 patients (13.3%; downstaging in 3/10, upstaging in 7/10) and differences in clinical management were seen in 10/75 patients (13.3%), leading to a major difference in 7/10 cases and a minor change in 3/10 cases. All 10 cases with a difference in patient management between both PET tracers were caused by additional lesion detection by [F]AlF-OC. The use of [F]AlF-OC did not impact TNM staging or clinical management in the large majority of the patients (86.7%), further validating the potential for routine clinical use of [F]AlF-OC PET/CT as an alternative for [Ga]Ga-DOTA-SSA PET/CT. The trial is registered under ClinicalTrials.gov identifier NCT04552847 and EudraCT 2020-000549-15.
PubMed: 38837825
DOI: 10.1111/jne.13420