Pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous tumors arising from neuroendocrine cells, representing approximately 10 % of all Gastro-Entero-Pancreatic neuroendocrine neoplasms. While most pNENs are sporadic, a subset is associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel-Lindau disease (VHL). pNENs are further classified into functioning and non-functioning tumors, with distinct clinical behaviors, prognoses, and treatment approaches. This review explores genetic and environmental biomarkers that influence the risk, prognosis, and therapeutic responses in pNENs. The epidemiology of pNENs reveals an increasing incidence, primarily due to advancements in imaging techniques. Genetic factors play a pivotal role, with germline mutations in MEN1, VHL, and other genes contributing to familial pNENs. Somatic mutations, including alterations in the mTOR pathway and DNA maintenance genes such as DAXX and ATRX, are critical in sporadic pNENs. These mutations, along with epigenetic dysregulation and transcriptomic alterations, underpin the diverse clinical and molecular phenotypes of pNENs. Emerging evidence suggests that epigenetic changes, including DNA methylation profiles, can stratify pNEN subtypes and predict disease progression. Environmental and lifestyle factors, such as diabetes, smoking, and chronic pancreatitis, have been linked to an increased risk of sporadic pNENs. While the association between these factors and tumor progression is still under investigation, their potential role in influencing therapeutic outcomes warrants further study. Advances in systemic therapies, including somatostatin analogs, mTOR inhibitors, and tyrosine kinase inhibitors, have improved disease management. Biomarkers such as Ki-67, somatostatin receptor expression, and O6-methylguanine-DNA methyltransferase (MGMT) status are being evaluated for their predictive value. Novel approaches, including the use of circulating biomarkers (NETest, circulating tumor cells, and ctDNA) and polygenic risk scores, offer promising avenues for non-invasive diagnosis and monitoring. Despite these advancements, challenges remain, including the need for large, well-annotated datasets and validated biomarkers. Future research should integrate multi-omics approaches and leverage liquid biopsy technologies to refine diagnostic, prognostic, and therapeutic strategies. Interdisciplinary collaborations and global consortia are crucial for overcoming current limitations and translating research findings into clinical practice. These insights hold promise for improving prevention, early detection, and tailored treatments, ultimately enhancing patient outcomes.

This study aimed to evaluate the clinical characteristics, diagnostic approaches, and treatment outcomes of insulinoma patients from diverse regions across the country. We conducted a retrospective analysis of medical records from 76 adult patients diagnosed with insulinoma between 2018 and 2023 at 15 medical centres. Data collected included demographics, presenting symptoms, laboratory and imaging results, surgical reports, pathology findings, and clinical follow-up information.

Multi-centre retrospective study.

The study revealed that key factors such as age, BMI, symptom duration, tumour size, and follow-up period were similar across genders. The majority of patients experienced neuroglycopenic symptoms, particularly during fasting. Insulinoma was typically diagnosed either during fasting or spontaneously, with no significant gender differences in glucose and insulin levels during hypoglycemia. However, men exhibited higher C-peptide levels (p < 0.05). Common comorbidities included hypertension, hypothyroidism, and cardiovascular conditions, and some patients had been using antiepileptics or antidepressants before their diagnosis.

Preoperative tumour diagnoses were largely accurate, with endoscopic ultrasound (EUS) being the most effective method. Most tumours were small ( < 2 cm) and located in the pancreas body, with the majority being solitary. Surgical treatments primarily involved enucleation or distal pancreatectomy. Follow-up data indicated high remission rates, with low rates of nonremission and mortality.

This study emphasises that early diagnosis and intervention, particularly in patients with a history of neurological or psychiatric issues, postprandial symptoms, or rapid symptom improvement after treatment, can lead to significantly better outcomes.

Pancreatic neuroendocrine carcinoma (PNEC) is a rare, aggressive malignancy with limited therapeutic options and a dismal prognosis, particularly in young patients. Approximately 85% of PNEC cases eventually progress to metastatic cancer. Despite advances in oncology, optimal management strategies for metastatic PNEC remain undefined, especially in chemotherapy-ineligible cases.

An 18-year-old male patient, reporting anorexia with associated weight loss (15 kg weight loss over 3 months) and significant abdominal distension.

The results of whole abdominal computed tomography, histopathology, immunohistochemistry, and laboratory examination were consistent with pancreatic neuroendocrine carcinoma with liver metastasis.

Due to the family refusal of chemotherapy, and immunohistochemistry revealed programmed death-1 ligand positivity. The patient received penpulimab (anti-programmed death-1) combined with anlotinib capsules and then changed to penpulimab combined with sorafenib capsules after progression.

Initial therapy achieved 13 months of progression-free survival, demonstrating durable disease control. Subsequent progression highlighted challenges of acquired resistance, with no severe treatment-related toxicity. The patient was still alive at the time of follow-up in July 2024.

Pancreatic neuroendocrine cancer is rare. There are various treatment options available. However, the best treatment plan still needs further exploration. This case underscores that programmed death-1 ligand + PNEC may respond to immunotherapy/antiangiogenic combinations, offering alternatives for chemotherapy-ineligible patients. In addition, young patients with aggressive PNEC represent an understudied population, necessitating tailored strategies.

Current guidelines lack clarity regarding the appropriate use of preoperative ultrasound-guided (EUS) biopsy and receptor positron emission tomography (SSTR PET) imaging for pancreatic neuroendocrine tumors (PNETs). This study aims to reach expert consensus on the optimal sequencing of SSTR PET and EUS biopsy in the diagnostic workup and management of patients with suspected PNETs.

A three-round modified Delphi process was used. A multidisciplinary panel of experts was recruited via snowball sampling. A set of 22 baseline statements pertaining to diagnostic workup, imaging, and biopsy was developed based on literature review and feedback obtained through a focus group. Survey rounds were conducted electronically and anonymously. A panel of international experts was asked to indicate whether they agreed, disagreed, or lacked the appropriate background to answer each statement. Of the 55 experts invited, 38 (69%) accepted to participate. Consensus was achieved with > 80% agreement.

Response rates were 97%, 100%, and 100% in rounds 1, 2, and 3, respectively. Following rounds 1 and 2, 29 final statements achieved consensus in the following three domains: diagnostic workup (15 statements), imaging (nine statements), and tissue sampling (five statements). Cronbach's alpha value, a measure of internal consistency, was 0.91 and 0.85 for rounds 1 and 2, respectively. The final set of statements achieved a 95% approval rate in round 3.

This international Delphi study provides expert consensus-based guidance on the appropriate use of EUS biopsy in the diagnostic workup of PNETs in the era of SSTR PET imaging.

This study represents the first interim report from a phase 2 clinical trial. Accurate localization of insulinomas remains a clinical challenge despite the availability of various imaging modalities.

The current study aimed to evaluate the efficacy of positron emission tomography/computed tomography (PET/CT) using [18F]FB(ePEG12)12-exendin-4 (18F-exendin-4), a novel 18F-labeled PEGylated glucagon-like peptide 1 (GLP-1) receptor-targeted imaging probe, for the noninvasive detection of insulinomas.

This prospective single-center study enrolled patients with biochemically confirmed hyperinsulinemic hypoglycemia suggestive of insulinoma. All patients underwent 18F-exendin-4 PET/CT, with scans performed at 60 and 120 minutes after injection. The findings of 18F-exendin-4 PET/CT were then compared with those of conventional imaging modalities performed before and after 18F-exendin-4 PET/CT in actual clinical settings, with all findings being verified through surgical and pathological findings.

18F-exendin-4 PET/CT successfully identified insulinomas in all 12 patients (100% sensitivity), showing significantly higher uptake in tumor tissues than in the surrounding pancreatic tissues and organs. The detection rate of 18F-exendin-4 PET/CT exceeded that of the conventional imaging modalities (CT, 83%; magnetic resonance imaging, 63%; endoscopic ultrasonography, 90%; selective arterial calcium stimulation, 89%). All identified lesions were surgically confirmed to be insulinomas, with complete clinical resolution of hypoglycemia after resection.

18F-exendin-4 PET/CT demonstrated effective sensitivity for noninvasive insulinoma detection, offering a reliable and practical diagnostic alternative to invasive procedures for precise and prompt preoperative localization with functional evaluation. This novel imaging approach may therefore improve the management of patients with suspected insulinomas.

There is no consensus on managing non-functioning pancreatic neuroendocrine tumors smaller than 2 cm (NF-PANNETs < 2 cm). Therefore, their treatment remains controversial. The aim of this study, by literature review and meta-analysis, is to establish the best management of NF-PANNETs < 2 cm based on overall survival (OS) and cancer-specific survival (CSS).

An extensive online search was conducted using the MEDLINE, EMBASE, Google Scholar, Scopus, Web of Science, and Cochrane Central databases. All retrospective and prospective studies were included in this study, comparing the outcomes of surgical management vs. conservative management in patients with NF-PANNETs < 2 cm. The pooled odds ratio and 95% CI for survival were calculated.

Six studies were included in the quantitative analysis, with 2708 patients managed operatively and 985 managed conservatively. A pooled analysis of all the data demonstrated increased OS in patients managed operatively compared with those managed conservatively at five years (OR = 1.77, 95% CI: 0.96 to 2.58; p = 0.002). In contrast, the meta-analysis did not demonstrate increased CSS in patients undergoing surgical resection compared with conservative management (OR = 1.01, 95% CI: -5.25 to 7.27; p = 0.56). Furthermore, analysis demonstrated a high heterogeneity for OS (Q = 43.98, p < 0.001, tau2 = 0.46, I2 = 88.63%) and for CSS (Q = 22.81, p < 0.0001, tau2 = 1.72, I2 = 91.23%).

This systematic review and meta-analysis indicated that surgical management of NF-PANNETs < 2 cm improves overall survival (OS) but does not significantly enhance cancer-specific survival (CSS). There is variability in outcomes among studies, and while surgery may help some patients, the lack of clear CSS benefits and associated risks call for individualized decision-making. Therefore, a conservative approach with active surveillance may be more suitable for low-risk patients.

Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies that consist of two major subtypes: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Glucagon-like peptide-1 receptor agonists (GLP-1Ra) have demonstrated favorable results in preclinical studies, but their impact on NEN outcomes remains unexplored. Methods: Using the TriNetX US Research Network, we identified adult patients with NEN and either diabetes or obesity. After 1:1 propensity score matching based on demographics, comorbidities, procedures, and medication use, we compared survival outcomes between patients who received GLP-1Ra after NEN diagnosis and those who did not. Results: Among 32,464 eligible patients, 3139 received GLP-1Ra and 29,325 did not. After propensity matching, each cohort included 3043 patients with well-balanced baseline characteristics. During follow-up periods extending up to 15 years, all-cause mortality occurred in 356 (11.7%) GLP-1Ra users versus 753 (24.7%) non-users, representing a 13.0% absolute risk reduction (p < 0.001). GLP-1Ra use was associated with significantly improved survival (HR = 0.56, 95%CI = 0.49-0.63, p < 0.001). Both well-differentiated (HR = 0.52) and poorly differentiated tumors (HR = 0.56) showed significant improvement. Among primary sites, lung NENs demonstrated the most pronounced benefit (HR = 0.42). Tirzepatide showed the strongest association with reduced mortality (HR = 0.16), followed by semaglutide (HR = 0.27) and dulaglutide (HR = 0.52). Results: In this large propensity-matched study, GLP-1Ra use was associated with a 44.3% reduction in mortality risk among NEN patients with diabetes or obesity. The magnitude of the observed benefit suggests a potential role for GLP-1Ra as adjunctive therapy in this patient population. Prospective clinical trials are warranted to confirm these findings and explore underlying mechanisms.

Pancreatic neuroendocrine tumors (PNETs) are comparatively rare pancreatic malignancies that exhibit diverse biologic behavior, ranging from indolent tumors to widely metastatic cancers, with up to 15 % secreting hormones that cause symptoms. As a consequence, the management of PNETs is highly individualized and can include active surveillance of small (1-2 cm) and very small (< 1 cm) nonfunctioning tumors without worrisome features, parenchymal-sparing resection of appropriately located tumors, anatomic pancreatectomy and, in select cases, debulking of metastatic disease, particularly in the liver. This review synthesizes society recommendations and contemporary evidence guiding the surgical management of PNETs. Innovations in molecular profiling and systemic therapies hold promise to refine surgical algorithms for this heterogeneous tumor.

Accurate preoperative localization is imperative for the treatment of insulinomas. Glucagon-like peptide-1 receptor (GLP-1R) imaging has demonstrated remarkable efficacy in localization of insulinomas. The aim of this study was to assess the diagnostic performance of GLP-1R PET/CT with 68Ga-exendin-4 in localization of insulinoma, and to provide evidence for clinical practice from a real-world study.

This is a retrospective analysis of our prospective cohort study of 68Ga-exendin-4 PET/CT in insulinoma (NCT02560376). Patients with endogenous hyperinsulinemic hypoglycemia and definite final diagnosis were enrolled. Results of contrast-enhanced CT (CECT) with pancreatic perfusion scan, MRI, endoscopic ultrasound, and 99mTc-HYNIC-TOC SPECT/CT were collected. The gold standard for diagnosis was histopathology (for insulinoma) or a definite clinical diagnosis of the etiology of hyperinsulinemic hypoglycemia after hospitalization in the endocrinology department (for non-insulinomatous hypoglycemia).

A total of 357 patients (including 296 insulinoma patients and 61 non-insulinoma patients) with were included. The overall sensitivity, specificity, accuracy, PPV, and NPV of 68Ga-exendin-4 PET/CT in localizing insulinoma were 94.93% (95%CI, 91.78%˜97.14%), 100.00% (95%CI, 94.13%˜100%), 95.79% (95%CI, 93.16%˜97.63%), 100.00% (95%CI, 98.32%˜100%), 80.26% (95%CI, 71.29%˜86.94%), respectively. The area under the ROC of 68Ga-exendin-4 PET/CT for diagnosing insulinoma was 0.975 (95%CI, 0.953 ˜ 0.988), which was superior to that of CECT (AUC = 0.873 [95%CI, 0.833 ˜ 0.906]), MRI (AUC = 0.825 [95%CI, 0.773 ˜ 0.869]), EUS (AUC = 0.746 [95%CI, 0.652 ˜ 0.825]) and 99mTc-HYNIC-TOC SPECT/CT (AUC = 0.618 [95%CI, 0.562 ˜ 0.672]). The lesion-based sensitivity of 68Ga-exendin-4 PET/CT in sporadic benign insulinoma was 95.47% (95%CI, 92.22%˜97.64%), and the PPV was 99.61% (95%CI 99.60%˜99.62%). In contrast, the diagnostic efficacy of 68Ga-exendin-4 PET/CT was found to be less effective in cases of sporadic malignant insulinoma or inherited syndromes, yielding a lesion-based detection rate of 66.43% and 68.04%, respectively.

68Ga-exendin-4 PET/CT is a preferred imaging modality in diagnosing insulinoma, particularly in sporadic benign insulinomas.

EUS is sensitive in detecting pancreatic neuroendocrine neoplasm (pNEN). However, the endoscopic diagnosis of pNEN is operator-dependent and time-consuming because pNEN mimics normal pancreas and other pancreatic lesions. We intended to develop a convolutional neural network (CNN)-based system, named iEUS, for identifying pNEN and multiple types of pancreatic lesions using EUS.

Retrospective data of 12,200 EUS images obtained from pNEN and non-pNEN pancreatic lesions, including pancreatic ductal adenocarcinoma (PDAC), autoimmune pancreatitis (AIP), and pancreatic cystic neoplasm (PCN), were used to develop iEUS, which was composed of a 2-category (pNEN or non-pNEN pancreatic lesions) classification model (CNN1) and a 4-category (pNEN, PDAC, AIP, or PCN) classification model (CNN2). Videos from consecutive patients were prospectively collected for a human-iEUS contest to evaluate the performance of iEUS.

Five hundred seventy-three patients were enrolled in this study. In the human-iEUS contest containing 203 videos, CNN1 and CNN2 showed an accuracy of 84.2% and 88.2% for diagnosing pNEN, respectively, which were significantly higher than that of novices (75.4%) and comparable with intermediate endosonographers (85.5%) and experts (85.5%). In addition, CNN2 showed an accuracy of 86.2%, 97.0%, and 97.0% for diagnosing PDAC, AIP, and PCN, respectively. With the assistance of iEUS, the sensitivity of endosonographers at all 3 levels in diagnosing pNEN has significantly improved (64.6% vs 44.8%, 87.5% vs 71.9%, and 74.0% vs 57.6%, respectively).

The iEUS precisely diagnosed pNEN and other confusing pancreatic lesions and thus can assist endosonographers in achieving more accessible and accurate endoscopic diagnoses with EUS. (Clinical trial registration number: ChiCTR2100049697.).

Pancreatic neuroendocrine neoplasms (pNENs) exhibit significant heterogeneity, and the effectiveness of traditional classification methods in predicting tumor biological behavior and patient prognosis is limited. This study aims to reveal potential biomarkers to predict the prognosis of pNENs and explore the underlying mechanisms. Four mRNA sequencing datasets of pNENs were included in the study. CEP55, TPX2, and BIRC2 were identified as overlapping DEGs and were significantly associated with the clinical characteristics and prognosis of pNENs. The nomogram, which incorporated independent prognostic risk factors such as CEP55 expression, tumor grade, and TNM stage, demonstrated higher predictive efficiency than traditional methods. We found that knockdown of CEP55 resulted in the inhibition of proliferation, migration, and invasion in pNENs cells, while a reverse trend was observed in CEP55-overexpressing cells. Furthermore, CEP55 was found to enhance the PI3K/AKT/mTOR pathway in pNENs through its interaction with PI3K-p110. Everolimus, an mTOR inhibitor, was shown to counteract the effects of CEP55 overexpression both in vivo and in vitro. In conclusion, CEP55 may enhance the proliferation, invasion, and migration of pNENs by activating the PI3K/AKT/mTOR pathway through its interaction with PI3K. It may serve as a valuable prognostic marker and a promising therapeutic target.

This position statement addressed the limited scientific literature on the management of diabetes mellitus secondary to endocrinopathies, despite its frequent occurrence in hormonal diseases such as acromegaly, Cushing's syndrome, primary hyperaldosteronism, pheochromocytoma, hyperthyroidism, and neuroendocrine tumors. The aim was to review the pathophysiological mechanisms, clinical features, and management strategies, focusing on nutritional and pharmacological approaches.

A comprehensive review of existing literature was conducted regarding studies on diabetes secondary to endocrinopathies and the effects of treatments for these conditions, such as somatostatin analogues and pancreatic surgery. Particular emphasis was placed on understanding glucose metabolism derangements and the interplay between endocrine excess and therapeutic interventions.

Secondary diabetes arises not only from hormone excess but also as a consequence of treatments for endocrine disorders. For instance, somatostatin analogues, while effective in resolving hormone hypersecretion, impair glucose metabolism by inhibiting pancreatic insulin secretion. Similarly, pancreatic surgery for neuroendocrine tumors often exacerbates glycemic disturbances. The management of secondary diabetes requires a multidisciplinary approach that includes treating the underlying endocrine disorder, tailoring antidiabetic therapy, and optimizing nutritional strategies to mitigate metabolic disruptions.

Diabetes secondary to endocrinopathies presents unique challenges due to its complex etiology and the metabolic effects of treatments. This position statement underscores the importance of an integrated management approach, offering guidance for clinicians in addressing this multifaceted condition. Further research is needed to develop evidence-based guidelines for optimal care.

Peptide Receptor Radionuclide Therapy (PRRT) is approved for patients with inoperable, progressive and/or metastatic well-differentiated NETs. Before the approval of Lutathera®, locally manufactured 177Lu-HA-DOTATATE was used on a regular basis in clinical routine. The aim of this study was (1) to compare the hematotoxicity of locally manufactured 177Lu-HA-DOTATATE with Lutathera® in GEP-NET patients and (2) to compare the recommended treatment interval of 8 weeks between each cycle to a prolonged scheme of up to 11 weeks for both 177Lu-HA-DOTATATE and Lutathera®.

The included patients with GEP NETs (n = 46) received four cycles of PRRT, either 177Lu-HA-DOTATATE or Lutathera®, and were divided into four subgroups. The subgroups were treated with either locally manufactured 177Lu-HA-DOTATATE or Lutathera® and were stratified into a mean application interval of 8 (HA8weeks, n = 10/Lutathera8weeks, n = 16) or 11 weeks (HAadapted, n = 10/Lutatheraadapted, n = 10). To evaluate therapy associated hemato- and nephrotoxicity, patients underwent two laboratory follow-up examinations (follow-up 1-between 2./3. therapy cycle; follow-up 2-after the termination of the 4. therapy cycle) and were then compared to pre-PRRT laboratory results. To assess hematological and renal recovery trends, blood values and parameters of kidney function were collected up to 58.9 weeks after PRRT completion. Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) were used for grading hematological parameters.

The occurrence of high-grade adverse events (CTCAE grade 3/4) after PRRT was moderate, with 1/10 (10%) grade 4 lymphocytopenia in the Lutatheraadapted group, while overall, 20/46 (43.5%) patients had grade 3 lymphocytopenia. Grade 3 thrombocytopenia occurred in 1/10 (10%) patients of the HAadapted group. Absolute and percentage changes in the kidney function (creatinine, TER) remained constant during PRRT in all subgroups. All four subgroups showed a significant decrease in absolute blood value changes for PLT counts, WBC counts, neutrophil granulocytes and lymphocytes between, prior to and after PRRT (p < 0.05, each). Regarding percentage changes in laboratory parameters, only the HAadapted and the HA8weeks groups had significant decreases in WBC (p < 0.03, each) and PLT counts (p < 0.04, each) while there was no significant degradation of any other hematological parameter in any of the subgroups. Only patients with longer treatment intervals under 177Lu-HA-DOTATATE therapy showed a statistically significant correlation in the long-term recovery analysis concerning the PLT counts (r = 0.6, p < 0.0001). Other blood and kidney values showed no significant correlation in the long-term analysis in the other subgroups.

Comparing the hematotoxicity in patients that were treated with locally manufactured 177Lu-HA-DOTATATE with patients that were treated with Lutathera® and assessing different treatment intervals in both groups (8 vs. 11 weeks), revealed that there is overall a low to moderate incidence of significant changes in hematological and renal parameters directly after PRRT. Recovery trends of hematological and renal parameters after 1 year suggest that patients treated with locally manufactured 177Lu-HA-DOTATATE might benefit from a longer treatment interval of 11 weeks regarding their PLT counts. Given the risk of developing hematological diseases such as therapy-related myeloid neoplasms years after PRRT, longer observational periods after PRRT will be crucial.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-inherited syndrome involving multiple endocrine tumors. It is characterized by multiple mutations in the tumor suppressor gene MEN1, which is located on chromosome 11q13. As main etiology of MEN1 is genetic mutations, clinical symptoms may vary. In this editorial, we comment on the article by Yuan et al. This article describes a case of (MEN1) characterized by low incidence and diagnostic complexity. MEN1 commonly presents as parathyroid, pancreatic, and pituitary tumors. Diagnosis requires a combination of serologic tests, magnetic resonance imaging, computed tomography, endoscopic ultrasonography, immunologic and pathology. The diagnosis is unique depending on the site of disease. Surgical resection is the treatment of choice for MEN1. The prognosis depends on the site of origin, but early detection and intervention is the most effective.

Background/Objective: Identifying patterns of diagnostic imaging workflow parallel to the influence of certain variables, such as pathology guidelines over time, provides valuable insight for clinical decision making. This study presents a recurring trend of initial imaging orders and follow-ups, up to the diagnosis of pancreatic neuroendocrine tumors (pNETs), across two decades, with scans which led to pathological investigation. Methods: Three readers evaluated common conventional imaging among initial and follow-up studies for lesion detection and localization. Inter-reader and intra-reader analyses were controlled as contributing factors to the imaging diagnostic trend. Results: Our results show that CT was the prominent initial scan in pNET workup, likely due to their wide availability, high spatial resolution, and rapid acquisition, with a sufficient detection rate throughout both decades, regardless of technical advances. However, MRI scans also gained soaring popularity, especially among syndromic patients, likely due to follow-up and anatomical surgery precision. Conclusions: Newer modalities may be eventually useful and only requested for pNETs staging and further treatment.

Non-functioning pancreatic neuroendocrine tumors (NF-pNETs) significantly contribute to the premature death of multiple endocrine neoplasia type 1 (MEN1) patients. Reliable prognostic markers are not yet available. MicroRNAs (miRNA) and long-non-coding (lnc) RNAs, transported by extracellular vesicles, are emerging as new prognostic tools. This study aimed to analyze the clinical characteristics, the exosomal-miRNA 451 (exo-miR451) and the lnc-RNA nuclear paraspeckle assembly transcript 1 (NEAT1_1, 3.7 kB) in the mild and aggressive courses of MEN1-NFpNET disease. Patient characteristics were assessed regarding an aggressive course of disease. In addition, exo-miR451 and exo-lnc-NEAT1_1 expression levels were quantified in serum by RT-qPCR and correlated with clinical data. Immunohistochemistry results of STAT3 (signal transducer and activator of transcription 3), regulated by NEAT1, were performed in NF-pNET tissue and correlated with exo-lnc-NEAT1_1 expression. Among 66 MEN1 patients with NF-pNETs, 13 (20%) had an aggressive disease course. No significant differences in patient characteristics were observed between those with aggressive (n = 13) and mild (n = 53) disease (all p > .5). Exosomal miRNA-451 was dysregulated in 55% (n = 23) of cases, showing a trend toward higher upregulation in the aggressive group (36% vs. 19%), although this difference was not statistically significant (p = .215). Exo-NEAT1_1 was overexpressed in 42% (16/38) of patients, without significant differences between groups (p = .0523). However, exo-NEAT1_1 expression strongly correlated with STAT3 immunohistochemical staining (p = .001). Although no prognostic marker could be identified, we show for the first time that the STAT3-NEAT1 pathway plays a role in MEN1-associated NF-pNET tumorigenesis.

Pancreatic resections for pancreatic neuroendocrine tumors (pNET) may experience a higher complication rate than for pancreatic ductal adenocarcinoma (PDAC). This study aimed to determine the rate of the novel composite "Ideal Outcome" measure after resection for pNET, using PDAC as reference.

This observational cohort study included all consecutive patients after pancreatic resection for pNET and PDAC using the nationwide Dutch Pancreatic Cancer Audit (2014-2021). The primary outcome was Ideal Outcome; absence of postoperative mortality, postoperative pancreatic fistulas (POPF) grade B/C, other major complications, prolonged length of stay, reoperations and readmissions.

In total, 524 pNET and 2851 PDAC resections were included. The rate of Ideal Outcome was lower after resection for pNET (47.7% versus 55.7%; P<0.001) as compared to PDAC. This difference was driven by a lower rate of Ideal Outcome after pancreatoduodenectomy for pNET (37.7% versus 56.3%; P<0.001), with no difference after left pancreatectomy (54.5% versus 52.5%; P=0.598). Among the individual components of Ideal Outcome after pancreatoduodenectomy, the largest difference was a four times higher rate of POPF (32.1% versus 7.9%; P<0.001) after resection of pNET.

Patients undergoing pancreatoduodenectomy for pNET have a reduced Ideal Outcome rate compared to patients with PDAC, related to a fourfold increased risk of POPF. This highlights the value of pNET-specific patient counseling and the need for effective POPF mitigation strategies.

Neuroendocrine neoplasms (NEN) are rare tumors arising from neuroendocrine cells most commonly in the gastrointestinal-tract. In recent years, advancements in therapeutics have increased survival rates in patients with NEN leading to a greater clinical burden compared to the general population.

The aim of this single-center case-control study was to investigate the incidence of low bone mass and changes in body composition in adult patients diagnosed with gastroenteropancreatic neuroendocrine tumors (GEPNET). Enrolled participants underwent measurements of bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN), and total hip (TH) and body composition analysis with calculation of total fat-mass (TFM) and relative skeletal mass index (RSMI), by dual X-ray absorptiometry.

Ninety GEPNET patients (28 with Pancreatic-NET, 20 with small-intestine-NET, 42 with gastric-NET), and 50 age and sex-matched controls were enrolled. The mean disease duration was 5±4.4 years, the majority of patients (54/90) was classified as stage-1, and were not receiving systemic-treatment (76/90). The incidence of osteoporosis/osteopenia was threefold higher in the patients' cohort, compared to controls (OR: 3.17 95% CI 1.16-7.8, p < 0.001). Among NEN patients, gastric-NET had the lowest bone mass, especially in LS. In addition, GEPNET patients demonstrated significantly lower TFM and RSMI, compared to controls (TFM: 31.6 ± 9.6 kg vs. 38.6 ± 6.4 kg, respectively, p = 0.03; RSMI: 6.4 ± 1.1 vs. 8.2 ± 0.6, respectively, p < 0.001). Within our patients' cohort, RSMI was significantly associated with LS-BMD (rho = 0.49, p < 0.001) and TH-BMD (rho = 0.58, p < 0.001), and TFM was associated with TH-BMD (rho = 0.31, p = 0.004).

Patients with GEPNET even at an early stage exhibit significantly lower bone, muscle and fat mass compared to the non-NET population, highlighting the importance of continuous monitoring of the musculoskeletal system in these patients.

The aim of this meta-analysis was to assess the diagnostic performance of EUS-FNA/B in patients with panNETs.

We conducted a computerized search of the MEDLINE and Embase databases to identify relevant articles. The primary outcomes involved grading concordance rate, diagnostic rate, and correlation coefficient (Cohen's κ) for FNA/B samples compared with surgical specimens. Secondary outcomes included sample adequacy, mean number of passes, and adverse events.

Forty-five studies involving 2978 patients were finally included. The pooled concordance rate between EUS-FNA/B and surgical grading was 0.77 (95% CI: 0.73-0.80; I2 =48.2%). A significantly higher level of concordance was observed in G1 subgroup (0.88, 95% CI: 0.84-0.91), whereas the G2 subgroup revealed the lowest level of agreement (0.59, 95% CI: 0.52-0.65; P < 0.001). Pooled diagnostic rate for FNA/B sampling was 0.83 (95% CI: 0.79-0.86; I2 =63.3%). In addition, FNB outperformed FNA in terms of sample adequacy (0.93 for FNB vs. 0.81 for FNA; P =0.007) and number of needle passes required (2.53 for FNB vs. 3.32 for FNA; P =0.013). Moreover, the overall level of agreement for grading was moderate (κ=0.59, 95% CI: 0.49-0.68; I2 =84.5%). There were a limited number of adverse events that had minor influence on patient outcomes (0.03, 95% CI: 0.02-0.05; I2 =19.2%).

EUS-FNA/B is a reliable approach for the diagnosis and preoperative grading of panNET, with FNB demonstrating superior performance compared with FNA.

Lymph node dissection is required for many pancreatic neuroendocrine neoplasms. However, the need for such dissection has rarely been examined in detail by the tumor size, tumor location, or World Health Organization grading. The objective is to determine which characteristics of pancreatic neuroendocrine neoplasms require lymph node dissection, and to what extent lymph node dissection should be performed.

A retrospective review was performed of patients who had undergone pancreatectomy with lymph node dissection between 2000 and 2022. Frequency of lymph node metastases stratified by tumor size and grade, and efficacy index (calculated by multiplying the frequency of metastasis to the lymph node station by the 5-year overall survival rate of patients with metastasis to that station) for each lymph node station were evaluated.

Among 130 patients, 29 (22.3%) had lymph node metastases. Tumors larger than 2 cm had a 33.3% lymph node metastasis rate, whereas grade 1 and grade 2 neuroendocrine tumors had rates of 2.4% and 31.8%, respectively. In grade 1 neuroendocrine tumor, for pancreatic head tumor, only peripancreatic head lymph node had an efficacy index of 5.0. Pancreatic body and tail tumor had no lymph node metastases. In grade 2 neuroendocrine tumor, for pancreatic head tumor, peripancreatic and superior mesenteric artery lymph nodes had efficacy indexes of 29.2 and 14.3, respectively. For pancreatic body tumor, peridistal pancreatic lymph node had an efficacy index of 27.3, whereas for pancreatic tail tumor, peridistal pancreatic lymph node and splenic hilum lymph node had an efficacy index of 27.8 and 7.1, respectively.

The optimal extent of lymph node dissection for pancreatic neuroendocrine neoplasms should be determined by considering both the tumor size and grade for each tumor location.

Pancreatic neuroendocrine tumors are a heterogeneous group of rare clinical tumors, which can be classified into functional pancreatic neuroendocrine tumor (insulinoma is the most common) and noninsulinoma. Insulinoma and noninsulinoma have different mutation profiles. In noninsulinoma, ATRX/DAXX mutation is associated with alternative lengthening of telomeres-positive phenotype and positively correlated with poor prognosis. Copy number variation is also a prognostic marker for a high risk of recurrence. Scholars have used epigenetics as well as a multiomics approach (combining epigenetics, metabolomics, proteomics, etc) to molecularly type noninsulinoma, and there are huge differences in molecular expression and patient prognosis between different groups. In this manuscript, we summarize the published studies that utilized genome, epigenome, transcriptome, and proteome data to classify noninsulinoma.

This document presents the findings of the American Association of Clinical Endocrinology (AACE) on the diagnosis, management, and surveillance of patients with multiple endocrine neoplasia type 1 (MEN1) and associated tumors. The task force included a diverse group of experts in endocrinology, oncology, genetics, surgery, and patient representation. A comprehensive literature review was conducted to address key issues related to the evaluation, surveillance, and treatment of MEN1-related tumors.

The task force, comprised of 9 members with expertise in endocrinology, surgery, medical oncology, genetics, and patient advocacy, collaborated to develop guidance for the evaluation, surveillance, and management of MEN1-associated tumors. Consensus was defined as ≤1 dissenting vote and significant majority as ≥75%. Relevant studies were identified through a literature review process, and consensus statements were based on the available evidence.

The task force deliberated on the surveillance, evaluation, and management of MEN1-related tumors including parathyroid, pituitary, and gastroenteropancreatic neuroendocrine tumors and other tumors of relevance. The document also addresses the indications for MEN1 genetic testing.

This consensus statement aims to offer evidence-informed guidance for health care providers involved in the care of patients with MEN1 and associated tumors. It provides guidance on diagnostic tools, genetic testing criteria, imaging techniques, surgical interventions, and posttreatment monitoring. The practical, patient-centered approach outlined in this document is intended to improve outcomes for individuals with MEN1 and other high-risk endocrine tumors.

Surgery is the primary treatment for pancreatic neuroendocrine carcinoma (PNEC), however, the optimal surgical approach remains undetermined. We aimed to compare long-term survival outcomes between patients who received local resection (LR) and radical resection (RR) for PNEC without distant metastasis. Patients diagnosed with PNEC between 2000 and 2020 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Selection bias was minimized by using propensity score matching (PSM). The Kaplan-Meier method and multivariate Cox proportional hazards models were utilized to evaluate overall survival (OS) and cancer-specific survival (CSS). A total of 1331 patients were enrolled in the study, with 678 receiving LR and 653 undergoing RR. The RR group exhibited a poorer grade, larger tumor size, and TN stage compared to the LR group (P <  0.05). After PSM, 450 matched pairs of patients were compared, with no significant differences in demographic and clinical characteristics observed. No significant differences were observed in long-term OS (P =  0.746) or CSS (P =  0.634) between the two groups. Subgroup analyses also demonstrated comparable OS and CSS between the LR and RR groups (P >  0.05). Multivariate Cox analysis revealed age, AJCC stage, N stage, and chemotherapy as independent prognostic risk factors for OS, while AJCC stage and N stage were identified as independent prognostic risk factors for CSS. Our study demonstrated that in patients with PNEC without distant metastasis, LR and RR exhibit similar prognoses, suggesting that LR may be adequate as a treatment option for these patients.

This study aimed to evaluate potential difference in clinicopathological characteristics, prognosis as well as the genetic bases between insulinomas and non-functional pancreatic neuroendocrine neoplasms (NF-PNENs).

We analyzed data from 241 patients who underwent resection for PNENs measuring 1-2 ​cm at West China Hospital between 2002 and 2020.

NF-PNENs were more likely to show lymph node involvement (P ​< ​0.001), perineural invasion (P ​= ​0.025), and a more advanced tumor grade (P ​< ​0.001). In multivariate analysis, NF-PNENs, when combined with lymph node metastasis and WHO G2/G3 grading, independently decreased recurrence-free survival [hazard ratio (HR), 4.72; P ​= ​0.014]. Whole exome sequencing revealed that most of the top 20 somatic mutated genes (90 ​%, 36/40) between insulinomas and NF-PNENs are different. Besides, all copy number variant (CNV) patterns were present in NF-PNENs, whereas insulinomas were more likely to exhibit CNV amplification.

Insulinomas and small NF-PNENs exhibit distinct tumor biology, prognosis, and genetic backgrounds, which may inform changes in surgical management and postoperative follow-up strategies for these patients.

Despite the well-known prognostic role of lymph node metastasis (LNM) in pNETs, less is known about the importance of lymphovascular invasion (LVI) among patients with these tumors.

Patients undergoing pancreatectomy for pNET between 2002 and 2020 were identified in the US Neuroendocrine Tumor Study Group database. Cox regression analysis was utilized to identify the impact of LVI on recurrence-free survival (RFS) among patients with node-negative pNET.

Among 853 patients who underwent resection for pNET, 214 patients (25.1%) had LNM, while 116 (13.6%) and 523 individuals (61.3%) were LVI + N0 and LVI - N0, respectively. The overall incidence of LVI among patients with N0 pNET was 18.1%; the incidence of LVI increased with increasing tumor size and Ki-67 levels (size < 2 cm and Ki-67 < 3%: 5.5%; size < 2 cm and Ki-67 ≥ 3%: 17.2%; size ≥ 2 cm and Ki-67 < 3%: 22.2%; size ≥ 2 cm and Ki-67 ≥ 3%: 43.1%, p < 0.001). Five-year RFS was highest among patients with LVI - N0 disease followed by individuals with LVI + N0 and N+ pNETs (92.8% vs. 61.6% vs. 58.3%, p < 0.001). On multivariable analysis, the presence of LVI on pathology remained independently associated with almost 2.5 times higher hazards of recurrence (HR 2.47, 05% CI 1.44-4.24) among individuals with N0 pNETs.

The incidence of LVI varied according to tumor size and Ki-67. LVI was associated with a higher likelihood of recurrence among individuals who underwent formal pancreatic resection for N0 pNETs. LVI is an important prognostic indicator among patients with node-negative pNETs.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for both oncological and hormone control and is a widely accepted standard of care treatment for patients with neuroendocrine neoplasms (NEN). Its use is anticipated to increase significantly, and this demands accurate tools and paradigms to assess treatment response post PRRT. This article outlines the current role and future developments of anatomical, molecular imaging and biomarkers for response assessment to PRRT, highlighting the challenges and provides perspectives for the need to focus on a multimodality, multidisciplinary and individualised approach for patients with this complex heterogeneous disease.

18F-labelled somatostatin receptor tracers have recently gained popularity due to their better spatial resolution, longer half-life and lower costs compared to 68Ga-labeled tracers. The aim of this study was to evaluate the impact and limitations of reduced administered activities of [18F]SiTATE on image quality, lesion detectability and quantitative PET parameters in a long axial field-of-view (LAFOV) PET/CT scanner.

Twenty-four patients with histologically confirmed neuroendocrine tumor, who underwent clinically indicated [18F]SiTATE PET/CT examination (3.0 MBq/kg, 5 min PET scan time) on a Siemens Biograph Vision Quadra LAFOV PET/CT, were included retrospectively in this study. PET list-mode data were rebinned for shorter frame durations to simulate 5 min scans with lower activities of injected radiotracer. A comparison of image reconstruction in high sensitivity (HS) and ultra-high sensitivity mode (UHS) mode was performed. Subjective image quality, noise and lesion detectability of n = 122 lesions were rated using a 5-point Likert scale. The molecular tumor volume (MTV), signal-to-noise ratio (SNR), tumor-to-liver activity concentration ratio (TLR) and standardized uptake values (SUV) were analyzed.

Subjective image quality decreased with simulated reduction of injected activity with generally superior ratings in the UHS mode compared to the HS mode. Despite a reduction to 1 MBq/kg of [18F]SiTATE all lesions were still detected while at 0.25 MBq/kg lesion detectability decreased to 70% (HS) and 93% (UHS). Only minor changes in SUVmean and TLR were detected with reduced activity. However, reduced activities led to an increase in SUVSD, which in turn caused a decrease in SNR (at 1 MBq/kg: 7.3 in HS and 9.0 in UHS mode and an increase in deviation of the MTV.

Reducing the administered activity of injected [18F]SiTATE by 66% to 1 MBq/kg (HS & UHS) is feasible in a LAFOV PET/CT scanner, maintaining clinically diagnostic image quality without statistically significant deviations in PET uptake parameters and MTV. Furthermore, in low activity [18F]SiTATE PET/CT, the UHS mode improves image quality and noise as well as lesion detectability compared to HS mode, further reinforcing the clinical benefits of this recently introduced reconstruction mode.

Pancreatic neuroendocrine neoplasms (pNENs) diagnosed in childhood are very rare, with few data available. The aim was to describe the clinical presentation and behavior of children with pNENs at a national level.

National multicenter retrospective study of all patients, aged from 0 to 17 years at diagnosis, treated from 2011 to 2020 for a pNEN and registered in the French National Registry of Childhood Cancers or FRACTURE database.

Fifteen patients, 13 well-differentiated pancreatic neuroendocrine tumors (pNETs) and two neuroendocrine carcinomas (pNECs), were selected. Median age at diagnosis was 14 years (range, 7-17). Eight patients, all with localized disease, had a cancer predisposition syndrome (CPS), including five cases diagnosed during systematic screening. Five (31%) had metastatic disease at diagnosis: three grade 2 pNETs and two pNECs. First line therapy included exclusive pancreatectomy (seven cases, all M0), active surveillance (three cases, all M0), medical therapies (somatostatin analogues, chemotherapy; four cases, all M1), and surgery with medical therapy (one M1 case). Three-year progression-free survival was 57% (confidence interval [CI] 95%: 27-78) and was significantly better for patients with low-grade well differentiated (73 vs. 0%; p < 10-4) and localized (76 vs. 20%; p = .02) tumors. The two patients with pNECs died. Three-year overall survival was 92% (CI95%: 59-99) and was significantly better in patients with low-grade tumor (100 vs. 50%; p = 10-4).

Childhood pNENs occur more frequently in adolescents with CPS. Localized low-grade pNETs in children have a very good prognosis, whereas the treatment of high-grade and metastatic pNETs/pNECs should be better defined.

Pancreatic neuroendocrine tumors (PNETs) are the leading cause of death related to multiple endocrine neoplasia type 1 (MEN1). Previous studies have linked certain mutations in the MEN1 gene and loss of interactions with MENIN's functional partners to the mortality or aggressiveness of PNETs. This study aimed to evaluate the genotype-phenotype correlations of MEN1-related PNETs in Korean patients and to summarize the treatment outcomes comprehensively.

We retrospectively analyzed 72 patients diagnosed with MEN1 at a tertiary care center in Korea between January 2003 and September 2022. MEN1 mutations were analyzed using direct or next-generation sequencing.

Among 40 families with MEN1, 10 had exon 2 mutations, which were the most frequently observed. Of these, 50 (69.4 %) were diagnosed with PNETs; 20 underwent pancreatic resection. Patients with truncating mutations showed a significant difference in age-related penetrance of PNET (p = 0.029). No distinct genotype was associated with malignant transformation (lymph node or distant metastasis) in MEN1-related PNETs. In the subgroup Cox model, mutations in exons 3 or 10 showed significant differences in tumor progression in the observation group (adjusted hazard ratio: 8.164,(95 % CI: 1.648-40.436), p = 0.010, HR: 8.300, (95 % CI: 1.808-38.113), p = 0.007).

PNETs in Korean patients with MEN1 exhibit a stable prognosis. An individualized follow-up strategy may be necessary, particularly for young patients with truncating mutation in the MEN1 gene. In addition, those with mutations in exons 3 or 10 may require more active surveillance to decrease the risk of progression.

Neuroendocrine tumors (NETs), although rare, are considered one of the most common gastrointestinal and bronchopulmonary pediatric neoplasms. We aimed to determine the incidence, tumor characteristics, management, and outcome of NETs and explore the role of genetic predisposition, focusing on low and intermediate grade tumors.

Using the Danish National Pathology Registry, we conducted a nationwide retrospective study including all Danish children aged ≤18 years diagnosed with a pathology-proven NET between 1995 and 2020.

We identified 220 patients, with a 1.89:1 female to male ratio. The yearly incidence was 6.84 per 1 million children, with no significant change in incidence throughout the observation period. NETs were located in the appendix (93.2%), the pulmonary system (4.5%), and pancreas (2.3%). One recurrence was noted in the pancreas in a genetically predisposed patient with multiple neuroendocrine neoplasia type 1 (MEN1), resulting in an overall recurrence rate of 0.5% (0% in appendiceal NETs; 0% in bronchopulmonary NETs; 20.0% in pancreatic NETs). No NET-related mortality was registered. Four patients had a known predisposing genetic condition, one appendiceal NET associated with neurofibromatosis type 1, and three pancreatic NETs associated with MEN1. Postsurgical surveillance regimes, choice of tumor markers, and imaging modality varied throughout the study period.

We confirmed a stable incidence of pediatric NETs during the study period. The overall recurrence rate was 0.5% and no NET-related mortality was observed. Known genetic predisposition was present in 1.8% of patients. Future guidelines should consider the apparent indolent nature and excellent prognosis of these tumors.

The incidence and prevalence of pancreatic neuroendocrine neoplasms are steadily increasing. These tumors are highly heterogeneous, with treatment options ranging from observation to surgery, and various medical therapies. The choice of treatment is influenced by factors such as tumor stage, grade (proliferative activity), and the presence of hormone-related syndromes. Endoscopic ultrasound (EUS) is becoming increasingly valuable for assessing pancreatic neuroendocrine neoplasms, offering detailed morphological, vascular, and functional information through techniques such as contrast enhancement and elastography. It also allows biopsies that are useful for both histopathological and molecular analyses. These tumors are highly heterogeneous, with treatment options ranging from observation to various medical therapies and surgery. Recent data suggest that small, non-functioning PanNENs with low proliferation rates may be safely monitored, whereas more aggressive or functioning tumors typically require surgery. EUS-guided ablation is a promising alternative for patients with functional pancreatic neuroendocrine neoplasms who are unsuitable for surgery, although randomized trials are needed. In non-resectable pancreatic neuroendocrine neoplasms, treatment options include somatostatin analogs, targeted therapies (e.g., everolimus, sunitinib), chemotherapy, and radioligand therapy. This review discusses key factors in planning personalized treatment strategies for pancreatic neuroendocrine neoplasms.