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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 -
Best Practice & Research. Clinical... May 2024Injectable first-generation somatostatin receptor ligands (fg-SRLs) are the standard of care of medical treatment for acromegaly. While fg-SRLs control acromegaly in up... (Review)
Review
Injectable first-generation somatostatin receptor ligands (fg-SRLs) are the standard of care of medical treatment for acromegaly. While fg-SRLs control acromegaly in up to 50 % of patients, they may lead to bothersome injection pain and site reactions. Paltusotine is an investigational, highly selective somatostatin receptor subtype 2 agonist, which is administered orally once a day. To date, phase 2 and 3 clinical trials suggest paltusotine treatment can achieve biochemical and symptom control in acromegaly, with a safety profile comparable to those of the fg-SRLs. Since paltusotine is a once-daily oral drug, it may represent a future treatment option for addressing patient preference or improving quality of life.
PubMed: 38845246
DOI: 10.1016/j.beem.2024.101906 -
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 -
Endocrine Journal Jun 2024Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is...
[F]FB(ePEG12)12-exendin-4 noninvasive imaging of insulinoma negative for insulin immunostaining on specimen from endoscopic ultrasonography-guided fine needle aspiration: a case report with review of literature.
Insulinomas are the most common functional pancreatic neuroendocrine neoplasm; when treatment is delayed, they induce hyperinsulinemic hypoglycemia, which is life-threatening. As surgical resection is the only curative treatment for insulinoma, preoperative localization is crucial; however, localization based on conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging is often inconclusive. Somatostatin receptor-targeted imaging is another option for detecting pancreatic neuroendocrine neoplasms but has low sensitivity and is not specific for insulinoma. The clinical application of other localizing approaches such as selective arterial calcium stimulation and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is limited by their being invasive and/or technically complex. Moreover, an EUS-FNA specimen of an insulinoma may be negative on insulin immunostaining. Thus, a noninvasive and clinically practical insulinoma-specific diagnostic tool to discriminate insulinomas with high accuracy is anticipated. Glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged in the effort to fulfill this need. We recently developed the novel fluorine-18-labeled exendin-4-based probe conjugated with polyethylene glycol, [F]FB(ePEG12)12-exendin-4 (F-exendin-4) for positron emission tomography (PET) imaging and reported its clinical benefit in a case of insulinoma in the pancreatic tail. We report here a case of insulinoma in the pancreatic head in which an EUS-FNA specimen was negative on insulin immunostaining while precise preoperative localization and conclusive evidence for curative enucleation was provided by F-exendin-4 PET/CT (Japan Registry of Clinical Trials; jRCTs051200156).
PubMed: 38839345
DOI: 10.1507/endocrj.EJ24-0187 -
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 -
GE Portuguese Journal of... Jun 2024Pancreatic neuroendocrine neoplasms (panNENs) have been historically regarded as rare, but their incidence has raised more than 6-fold over the last 3 decades, mostly... (Review)
Review
Portuguese Pancreatic Club Perspectives on Pancreatic Neuroendocrine Neoplasms: Diagnosis and Staging, Associated Genetic Syndromes and Particularities of Their Clinical Approach.
Pancreatic neuroendocrine neoplasms (panNENs) have been historically regarded as rare, but their incidence has raised more than 6-fold over the last 3 decades, mostly owing to improvement in the detection of small asymptomatic tumours with imaging. Early detection and proper classification and staging are essential for the prognosis and management of panNENs. Histological evaluation is mandatory in all patients for the diagnosis of panNEN. Regarding localization and staging, multiphasic contrast-enhanced computer tomography is considered the imaging study of choice. Nevertheless, several other diagnostic modalities might present complementary information that can help in diagnosis and staging optimization: magnetic resonance imaging, somatostatin receptor imaging using positron emission tomography in combination with computed tomography (PET/CT), PET/CT with fluorodeoxyglucose (F-FDG), and endoscopic ultrasound. Approximately 10% of panNENs are due to an inherited syndrome, which includes multiple endocrine neoplasia type 1, von Hippel-Lindau disease, neurofibromatosis type 1 (NF-1), tuberous sclerosis complex, and Mahvash disease. In this review, the Portuguese Pancreatic Club summarizes the classification, diagnosis, and staging of panNENs, with a focus on imaging studies. It also summarizes the characteristics and particularities of panNENs associated with inherited syndromes.
PubMed: 38836119
DOI: 10.1159/000534641 -
Pituitary Jun 2024A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their...
PURPOSE
A series of consensus guidelines on medical treatment of acromegaly have been produced in the last two decades. However, little information is available on their application in clinical practice. Furthermore, international standards of acromegaly care have not been published. The aim of our study was to report current standards of care for medical therapy of acromegaly, using results collected through an audit performed to validate criteria for definition of Pituitary Tumor Centers of Excellence (PTCOE).
METHODS
Details of medical treatment approaches to acromegaly were voluntarily provided by nine renowned international centers that participated in this audit. For the period 2018-2020, we assessed overall number of acromegaly patients under medical treatment, distribution of patients on different treatment modalities, overall biochemical control rate with medical therapy, and specific control rates for different medical treatment options.
RESULTS
Median number of total patients and median number of new patients with acromegaly managed annually in the endocrinology units of the centers were 206 and 16.3, respectively. Median percentage of acromegaly patients on medical treatment was 48.9%. Among the patients on medical treatment, first-generation somatostatin receptor ligand (SRL) monotherapy was used with a median rate of 48.7%, followed by combination therapies with a median rate of 29.3%. Cabergoline monotherapy was used in 6.9% of patients. Pegvisomant monotherapy was used in 7 centers and pasireotide monotherapy in 5 centers, with median rates of 7.9% and 6.3%, respectively.
CONCLUSIONS
Current standards of care in PTCOEs include use of first-generation SRLs as the first medical option in about 50% of patients, as recommended by consensus guidelines. However, some patients are kept on this treatment despite inadequate control suggesting that cost-effectiveness, availability, patient preference, side effects, and therapeutic inertia may play a possible role also in PTCOE. Moreover, at odds with consensus guidelines, other monotherapies for acromegaly appear to have a marginal role as compared to combination therapies as extrapolated from PTCOE practice data. Presence of uncontrolled patients in each treatment category suggest that further optimization of medical therapy, as well as use of other therapeutic tools such as radiosurgery may be needed.
PubMed: 38833044
DOI: 10.1007/s11102-024-01397-w -
The Journal of Clinical Endocrinology... Jun 2024Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly.
CONTEXT
Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly.
OBJECTIVE
To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs).
METHODS
This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had insulin-like growth factor I (IGF-I) ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0×ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary (ASD) score, and maintenance of mean 5-sample growth hormone (GH) <1.0 ng/mL.
RESULTS
The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0×ULN (odds ratio: 126.53; 95% CI: 13.73, >999.99; P<.0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (±SE) change in IGF-I of 0.04±0.09×ULN versus 0.83±0.1×ULN (P<.0001); mean (±SE) change in ASD score of -0.6±1.5 versus 4.6±1.6 (P=.02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) versus 5/18 (27.8%) patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P=.0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs.
CONCLUSION
Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated.
PubMed: 38828555
DOI: 10.1210/clinem/dgae385