Although pancreatic neuroendocrine tumors (PanNETs) are less common than other pancreatic tumors, they show significant differences in clinical behavior, genetics, and treatment responses. The understanding of the molecular pathways of PanNETs has gradually improved with advances in sequencing technology. Mutations in MEN1 (the most frequently varied gene) may result in the deletion of the tumor suppressor menin, affecting gene regulation, DNA repair, and chromatin modification. Changes in ATRX and DAXX involve chromatin remodeling, telomere stability and are associated with the alternative lengthening of telomeres (ALT) pathway and aggressive tumors. VHL mutations emphasize the roles of hypoxia and angiogenesis. Mutations in PTEN, TSC1/TSC2, and AKT1-3 often disrupt the mTOR pathway, complicating the genetic landscape of PanNETs. Understanding these genetic alterations and their impact on the PI3K/AKT/mTOR axis help to investigate new targeted therapies, which in turn can improve patient prognosis. This review aims to clarify PanNET pathogenesis through key mutations and their clinical relevance.

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.

Persistent hypoglycemia is a life-threatening complication in insulinoma patients. When tumor excision is not possible, medical treatments are the main option. Pasireotide has shown promise in managing refractory hypoglycemia, but its use has been reported only in case series and reports.

This work aimed to assess the efficacy and safety of pasireotide in treating insulinoma-associated hypoglycemia.

We conducted a systematic review on using pasireotide to treat insulinoma-associated hypoglycemia, following a predeveloped protocol. We searched MEDLINE, Scopus, Google Scholar, and references forward and backward from database inception to March 30, 2024.

Of 490 identified studies, 137 were reviewed, and 17 cases from 13 studies met the inclusion criteria. Patients' ages ranged from 52 to 71 years (9 women). Five patients (30%) underwent surgical tumor resection. Pasireotide was never the initial treatment. The most common doses were 40 to 60 mg/month for pasireotide long-acting release and 0.6 mg/12 h for short-acting pasireotide. Six patients (35%) showed no improvement, 4 (23%) had partial improvement, and 7 (41%) had complete resolution. Patients with aggressive insulinomas had a lower response rate, with 55% showing no improvement compared to 16% in indolent cases. Larger tumors were significantly associated with poorer response (P = .043). Hyperglycemia was the most common side effect (n = 3).

Pasireotide effectively restored glucose levels in insulinoma patients who failed prior treatments. However, its efficacy was lower in aggressive insulinomas, emphasizing the need for alternative or combinatory strategies in metastatic cases. Given that pasireotide was never used as a first-line therapy in the reviewed cases, earlier administration in selected patients may improve outcomes.

To prospectively investigate the pancreatic stiffness (c) and fluidity (φ) of pancreatic neuroendocrine neoplasms (pNENs), measured using multifrequency magnetic resonance elastography (MRE), and evaluate their performance in predicting pNENs pathological grade.

This study included 96 untreated patients with pathologically confirmed pNENs who underwent multifrequency MRE within 2 weeks before surgery between September 2021 and November 2023. Independent predictors of pathological grade were identified using multivariate regression analysis, and predictive performance was assessed using receiver operating characteristic curves.

The study included 76 patients with low-grade pNENs (45 men; mean age: 48.7 ± 14.0 years; Grade 1: 34 patients, Grade 2: 42 patients) and 20 patients with high-grade pNENs (10 men; mean age: 54.4 ± 13.8 years; Grade 3: 15 patients, neuroendocrine carcinoma: 5 patients). The two radiologists showed substantial or near-perfect interobserver agreement in evaluating the quantitative parameters. The multivariate regression analysis identified c and relative enhancement in the portal venous phase (V) as independent predictors of pathological grade. The combined model (V + c) had the best predictive performance (area under the curve (AUC) = 0.930; sensitivity: 95.0%; specificity: 82.9%) and outperformed V (AUC = 0.806, p = 0.010), c (AUC = 0.847, p = 0.021), and φ (AUC = 0.709, p = 0.003) alone, as well as other clinical and conventional MRI parameters (all p < 0.05) in Delong's test.

Tumour stiffness quantified via multifrequency MRE improved the predictive performance for the pathological grade of pNENs when combined with conventional MRI parameters.

Tumour stiffness quantified using multifrequency magnetic resonance elastography provides a non-invasive, preoperative method for predicting the pathological grade of pancreatic neuroendocrine neoplasms. Predictive performance improves when combined with conventional MRI parameters, facilitating clinical decision-making and prognostic prediction.

Multifrequency magnetic resonance elastography (MRE) can indicate stiffness and fluidity of pancreatic neuroendocrine neoplasms (pNENs). Tumour stiffness combined with conventional MRI parameters can independently predict pNENs pathological grade. Multifrequency MRE can serve as a biomarker for the prediction of pNENs pathological grade.

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) represent a rare and varied class of neoplasms, characterized by diverse clinical presentations and prognostic trajectories. Accurate and prompt diagnosis is vital to inform and optimize therapeutic decisions. Ultrasound, including standard B-mode imaging and advanced methods such as contrast-enhanced ultrasound (CEUS) and endoscopic ultrasound (EUS), serves as a key component in the diagnostic evaluation of these tumors. B-mode US and CEUS provide non-invasive, accessible methods for early detection and characterization. On B-mode imaging, GEP-NETs typically present as well-defined, hyperechoic, or iso-echoic lesions, while CEUS highlights their characteristic vascularity, marked by arterial-phase hyperenhancement and venous-phase washout. Compared to CT and MRI, ultrasound offers real-time, dynamic imaging without ionizing radiation or nephrotoxic contrast agents, making it particularly advantageous for patients requiring frequent monitoring or with contraindications to other imaging modalities. CT and MRI are widely regarded as the preferred methods for staging and surgical planning due to their detailed anatomical visualization. However, ultrasound, especially CEUS, provides a significant adjunctive role in both early detection and the follow-up on GEP-NETs. This analysis delves into the strengths, challenges, and innovations in ultrasound technology for diagnosing pancreatic NETs, focusing on its contribution to comprehensive imaging strategies and its impact on patient care decisions.

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.

Metastatic neuroendocrine neoplasms (mNEN) require new treatment options. Intralesional (IL) PV-10 is an autolytic chemotherapy that may elicit an adaptive immune response.

This phase 1 study evaluated IL PV-10 administered percutaneously to hepatic lesions in patients with progressive mNEN. IL PV-10 was injected in a single lesion per treatment cycle. A treatment cycle could be repeated after ≥ 6 weeks if multiple targetable lesions were present. The primary endpoint was safety.

Twelve patients were enrolled with a median age of 66 years (range 47-79). All patients had progressive disease at enrolment and received prior somatostatin analogues; 10 patients had peptide receptor radionuclide therapy (PRRT) treatment. One lesion was injected per cycle for all 12 patients. Reported grade 3 side effects were photosensitivity (1 patient), face oedema (1 patient), elevated transaminases (1 patient), hypertension (2 patients). Response rate was 42% of injected lesions with patient-level disease control of 84%, PFS 9.4 months and median OS 24.0 months.

IL PV-10 elicited no safety concerns. Encouraging evidence of local and systemic disease control was seen in a heavily pre-treated, progressing mNEN population.

NCT02693067.

Pancreatic neuroendocrine tumors (PNETs) are a rare subset of pancreatic neoplasms with diverse biological behavior and clinical presentations. Traditional treatment approaches, such as surgery and targeted therapies, have significantly improved outcomes. However, advancements in molecular biology, immunotherapy, and minimally invasive techniques have ushered in a new era of treatment possibilities. This manuscript explores the emerging modalities in PNET management, emphasizing the need for a multidisciplinary approach tailored to individual patient profiles.

To develop a clinical practice guideline and recommendations for symptom management of patients with well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors.

ASCO convened an Expert Panel to develop a clinical practice guideline by reviewing the literature for relevant guidelines, systematic reviews, randomized controlled trials (RCTs), and observational studies to develop recommendations for clinical practice.

The literature review identified eight guidelines, 19 systematic reviews, and three RCTs that informed the development of guideline recommendations.

Recommendations are included for carcinoid syndrome, carcinoid heart disease and carcinoid crisis, and functional pancreatic neuroendocrine tumor syndromes. Recommendations are provided for surgical management, liver-directed therapy, and systemic therapy options, as well as palliative care. Limited guidance is provided for sequencing of interventions.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

The biology of metastatic pancreatic neuroendocrine tumors (panNET) may alter over time. It remains to be defined if, how, and when this patient group should be recommended to re-evaluate the characteristics of their disease. This prospective single-center, longitudinal cohort study at Uppsala University Hospital, Sweden (NCT03130205), included metastatic panNET patients with progressive disease to participate in a standardized re-characterization protocol: clinical and biochemical analyses, core-needle biopsy, and dual-positron emission tomography/computed tomography (PET/CT) (18F-fluorodeoxyglucose (18F-FDG) and Gallium-68 DOTATOC (68Ga-DOTATOC)) with NETPET score assessments. At further disease progression, a second re-characterization was offered. The proportion of patients with a clinically significant change is reported and defined as information that could lead to a change in the therapeutic algorithm proposed in the European Neuroendocrine Tumor Society (ENETS) guidelines. Between 2017 and 2021, 21 patients with progressive metastatic panNETs were included. Before inclusion, 19 tumors were grade (G) 1 or 2, and two were G3. Sixteen patients underwent biopsy with collection of adequate tumor material, of whom 81.3% (n = 13/16) displayed an increase in the Ki-67 index, with transition from G2 to G3 in 50% (n = 8/16). Twelve and 15 patients were positive on 18F-FDG- and 68Ga-DOTATOC-positron emission tomography (PET), respectively. This corresponded to NETPET grades P1 (n = 2), P2b (n = 12), and P3b (n = 1). A clinically significant change was noted among 62% (n = 13/21) of patients at first re-characterization, leading to therapy change in 7 positron emission tomography/computed tomography (PET/CT) patients. After the second re-characterization, a significant clinical change occurred in 43% (n = 3/7) with a shift in therapy for one patient. This study shows that a considerable number of progressive metastatic panNETs experience significant changes in their disease characteristics over time. This may result in a revised treatment plan and highlights the need to re-evaluate all relevant aspects of panNET disease. Such comprehensive re-characterization is particularly crucial in the context of clinical trial inclusion.

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.

Pancreatic neuroendocrine tumours (pNETs) are rapidly increasing. Their management implies considerable resources. Multidisciplinary discussion of tumours has become a cornerstone in clinical oncology but no studies demonstrate a clear clinical benefit. The aim of the present study is to evaluate whether the systematic discussion of patients with pNET in multidisciplinary meeting (MM) has changed their management.

This retrospective single-centre study was held from 2004 to 2023. Since 2018 all patients were discussed in MM; thus, they were divided into two groups (board and no board) to evaluate clinical and surgical outcomes and whether multidisciplinary discussion improved adherence to guidelines.

A total of 128 patients were enrolled (55 board group and 73 no board). Groups were comparable for gender (36.4% female vs. 45.2%), mean age (60.3 vs. 61.7 years), mean American Society of Anesthesiologists score (2.66 vs. 2.71), Charlson Comorbidity Index (CCI) (CCI < 6, 80 vs. 79.45%), rate of functioning tumours (7.3 vs. 16.4%, P = 0.2), and pre/postoperative grading. Endoscopic ultrasound (EUS) was used more in board vs. no board (EUS: 90.9 vs. 71.2%, P = 0.005, EUS with fine-needle aspiration 89.1 vs. 65.8%, P = 0.002). More patients underwent surgery in no board (78.1 vs. 61.8%, P = 0.045). Postoperative complications were comparable as well as mortality (9.1 vs. 9.6%) and adherence to guidelines (board vs no board adherents: 90.3 vs. 87.6%, P = 0.9).

Systematic multidisciplinary discussion does not result in significant clinical impact in terms of surgical complications, recurrences, and reinterventions. A selective approach in multidisciplinary discussion would be worth considering.

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.

Accurate preoperative localization is particularly important for surgical treatment of insulinomas. Current imaging methods, including 18F-FDG (FDG) PET/CT, 68Ga-DOTATATE (TATE) PET/CT, CE-CT, and CE-MRI, have limitations. This prospective study provides a direct comparison of 68Ga-NOTA-Exendin-4 (Ex4) PET/CT with other imaging techniques.

47 patients with biochemically proven endogenous hyperinsulinemic hypoglycemia underwent Ex4 PET/CT and other imaging methods. Sensitivity and accuracy of all imaging procedures for localizing insulinoma were calculated at the patient level and lesion level. Both clinical (>10 years experience) and junior (< 2 years experience) nuclear medicine physician readings were used to assess the diagnostic efficacy. We compared the SUVmax and tumor-to-background ratio (TBR) of three tracers and analyzed the values with Ki-67, maximum tumor diameter, and glucose metabolism indicators.

In patient level, the sensitivity and accuracy of Ex4 PET/CT (94.11% and 95.74%) were higher than TATE PET/CT (70.59%, p = 0.026; 78.72%, p = 0.030), FDG PET/CT (50.00%, p < 0.001; 63.83%, p < 0.001), CE-CT (77.77%, p = 0.135; 72.22%, p = 0.007), and CE-MRI (63.64%, p = 0.135; 43.75%, p < 0.001), respectively. Interobserver agreement was higher for Ex4 PET/CT than TATE PET/CT and FDG PET/CT (Cohen κ, 0.839 vs. 0.707 and 0.784, respectively). SUVmax and TBR of Ex4 and TATE PET/CT were significantly higher than FDG PET/CT (p < 0.01). Negative correlations of tumor Ki-67 with TATE PET/CT were observed with SUVmax (r = -0.637, p < 0.001). SUVmax and TBR of three molecular imaging methods had positive correlations with the maximum tumor diameter (p < 0.05), except TBR of FDG PET/CT. Semi-quantitative values of the three tracers showed no correlation with the lowest blood glucose level, corresponding insulin, and C-peptide level. TBR of TATE PET/CT showed a positive correlation with C-peptide (r = 0.393, p = 0.043).

Ex4 PET/CT showed superior characteristics in localization compared to routine imaging modalities in benign insulinomas. Ex4 PET/CT demonstrates better imaging quality and interpretability than FDG PET/CT and TATE PET/CT. Combined Ex4 and TATE PET/CT could provide a comprehensive evaluation/localization of insulinoma.

The trial was retrospectively registered at ClinitalTrial.gov (NCT06690957 and NCT06725693) on November 14, 2024 and December 5, 2024.

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.

Peptide receptor radionuclide therapy (PRRT) is a well-established treatment option for neuroendocrine tumors (NET), yet randomized controlled trials have not provided data on its impact on overall survival. The real-world efficacy of PRRT and its association with tumor functionality and grading in pancreatic neuroendocrine tumors (PanNET) remains underexplored.

A retrospective analysis of 166 patients with histologically confirmed metastatic PanNET was performed. Subgroup analyses examined progression-free survival (PFS) and overall survival (OS) following PRRT cycles, stratified by tumor grading, tumor functionality and bone metastases.

Of 166 patients, 100 (60.2%) received PRRT with a median of four cycles. In the PRRT cohort, 68% of patients had deceased. PFS after four and eight consecutive cycles was 20 and 18 months, respectively (p=0.4). OS for the entire cohort was 79 months, with patients receiving 4+ cycles of PRRT having an OS of 87 months and those receiving 5+ cycles achieving an OS of 100 months. Patients with grade 1 or 2 tumors had a significantly longer median OS of 97 months compared to 74.5 months for grade 3 tumors (p = 0.0055). There was no significant difference in OS between functioning and non-functioning tumors after PRRT. Patients with bone metastases who received PRRT had a significantly shorter OS than those without (74 vs. 89 months, p = 0.013). In 19% of patients who received PRRT, therapy was discontinued due to progressive disease, toxicity or death.

Patients receiving extended cycles of PRRT showed improved survival outcomes in metastatic PanNET, particularly in patients with lower tumor grades and without bone metastases. No survival difference was seen between functioning and non-functioning PanNET, while patients with grade 3 tumors and bone metastases had significantly shorter survival despite PRRT.

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.

Functioning neuroendocrine tumors (f-NETs) represent a minority of all NETs, however their management is challenging due to the impact on patients' survival and quality of life. In addition to f-NETs, paraneoplastic syndromes (PNS) are due to substances that are not related to the primary anatomical site, they can develop in different phases of NETs evolution, and might complicate the patient's clinical course. Dedicated guidelines are still scanty. We aim to review available literature on f-NETs to propose a useful tool for clinicians in order to improve the diagnostic process and the management.

Narrative review focused on f-NETs.

The most common f-NETs include insulinomas, gastrinomas and carcinoid syndrome (CS)- associated NETs. Symptoms related to hormone production may overlap with other common endocrine and gastrointestinal disorders, highlighting the pivotal role of multidisciplinary management. Somatostatin analogs (SSAs) represent the gold standard first-line treatment of most f-NETs, often followed by or combined with other treatments (surgery, liver-directed therapies, targeted therapies, peptide receptor radionuclide therapy). Paraneoplastic syndromes can develop in different phases of NET evolution and might complicate the patient's clinical course and response to therapy.

The management of hormonal syndromes is challenging and must be based on the multidisciplinary approach. Herein, we pointed out the minimal requirements for a NET specialist in the diagnosis and treatment of f-NETs. Efforts should be made to improve the awareness of functioning forms, to understand their pathogenesis and to improve their management.

Survival rates after a diagnosis of cancer are improving. Poorly managed gastrointestinal (GI) side effects can interfere with delivery of curative cancer treatment. Long-term physical side effects of cancer therapy impinge on quality of life in up to 25% of those treated for cancer, and GI side effects are the most common and troublesome.

To provide comprehensive, practical guidance on the management of acute and chronic luminal gastrointestinal symptoms arising during and after treatment for cancer METHODS: A multidisciplinary expert group including patients treated for cancer, divided into working parties to identify, and synthesise recommendations for the optimal assessment, diagnosis and appropriate interventions for luminal GI side effects of systemic and local cancer therapies. Recommendations were developed using the principles of the BMJ AGREE II reporting.

103 recommendations were agreed. The importance of the patient perspective and what can be done to support patients are emphasised. Key physiological principles underlying the development of GI toxicity arising from cancer therapy are outlined. Individual symptoms or symptom clusters are poor at distinguishing the underlying cause(s), and investigations are required if empirical therapy does not lead rapidly to significant benefits. Patients frequently have multiple GI causes for symptoms; all need to be diagnosed and optimally treated to achieve resolution. Investigations and management approaches now known to be ineffective or of questionable benefit are highlighted.

The physical, emotional and financial costs to individuals, their families and society from cancer therapy can be considerable. Identifying and signposting affected patients who require specialist services is the role of all clinicians. Progress in the treatment of cancer increasingly means that patients require expert, multidisciplinary supportive care providing effective and safe treatment at every stage of the cancer journey. Development of such expertise should be prioritised as should the education of health professionals and the public in what, when and how acute and chronic gastrointestinal symptoms and complications should be managed.

Metabolic flexibility, a key hallmark of cancer, reflects aberrant tumour changes associated with metabolites. The metabolic plasticity of pancreatic neuroendocrine tumours (pNETs) remains largely unexplored. Notably, the heterogeneity of pNETs complicates their diagnosis, prognosis, and therapeutic management.

Here, we compared the plasma metabolomic profiles of patients with pNET and non-cancerous individuals to understand metabolic dysregulation.

Plasma metabolic profiles of 76 patients with pNETs and 38 non-cancerous individuals were analyzed using LC-MS/MS and FIA-MS/MS (Biocrates AbsoluteIDQ p180 kit). Statistical analyses, including univariate and multivariate methods, were performed along with the generation of receiver operating characteristic (ROC) curves for metabolomic signature identification.

Compared with non-cancerous individuals, patients with pNET exhibited elevated levels of phosphoglyceride metabolites and reduced acylcarnitine levels, indicating an upregulation of fatty acid oxidation (FAO), which is crucial for the energy metabolism of pNET cells and one-carbon metabolism metabolites. Elevated glutamate levels and decreased lipid metabolite levels have been observed in patients with metastatic pNETs. Patients with the germline MEN1 mutations showed lower amino acid metabolites and FAO, with increased metabolites related to leucine catabolism and lipid metabolism, compared to non-MEN1 mutated patients. The highest area under the ROC curve was observed in patients with pNET harbouring MEN1 mutations.

This study highlights the distinct plasma metabolic signatures of pNETs, including the critical role of FAO and elevated glutamate levels in metastasis, supporting the energy and biosynthetic needs of rapidly proliferating tumour cells. Mapping of these dysregulated metabolites may facilitate the identification of new therapeutic targets for pNETs management.

A 90-year-old male was admitted to the hospital due to recurrent symptomatic hypoglycemia. After ruling out the most common outpatient causes of hypoglycemia, endogenous hyperinsulinism was confirmed. An abdominal computed tomography (CT) scan revealed a 15 mm solid nodular lesion in the pancreatic tail. The (68)Ga-DOTA-TOC PET-CT findings led to the diagnosis of insulinoma. A multidisciplinary committee considered the patient unfit for surgery. The treatment was started with a low dose of diazoxide; however, side effects appeared as the dose was gradually increased. Consequently, a dietary approach was prioritized, incorporating modified cornstarch (Glycosade®) in fractionated doses administered under the guidance of continuous glucose monitoring. This strategy allowed for a reduction in the diazoxide dosage and effectively prevented further hypoglycemic episodes without additional side effects. Since the initial medical treatment was successful, the patient and his family preferred to avoid other possible minimally invasive treatments unless pharmacological and dietary approaches failed.

To establish a preoperative prediction model for pathological grade of PanNETs based on computed tomography (CT), magnetic resonance imaging (MRI) and endoscopic ultrasonography (EUS).

Clinical data of 58 patients with pathologically confirmed PanNETs were included in this retrospectively study and they were divided into grade 1 and grade 2/3. CT, MRI and EUS images were collected within one week before surgery. A clinical predictive model based on the independent clinical risk factors and significant radiological features was established. The area under receiver operating characteristic curve (AUC) was performed to assess the model.

Gender, pancreatic duct dilatation (PDD) and portal enhancement ratio (PER) were the independent predictors for PanNETs grading (P < 0.05). PanNETs grade 1 and grade 2/3 had statistical difference in elastography score (P = 0.001). The combination of gender, PDD and PER had better predictive efficiency than each of these three predictors alone, with a high AUC of 0.925. The elastography score also achieved an AUC of 0.838.

We proposed a comprehensive model based on preoperative CT, MRI and EUS to predict grade 1 and grade 2/3 of PanNETs and better informs clinicians on individualized diagnosis and treatment of patients with PanNETs.

Multimodal interventions in neuroendocrine tumors appear to have a beneficial impact on survival. Metastatic insulinoma is associated with hypoglycemia and, historically, a shortened life expectancy.

The authors retrospectively analyzed the clinical outcomes of patients with metastatic insulinomas treated at a tertiary care center between 2006 and 2023.

Clinical data on 14 patients with metastatic insulinoma (metastases to the liver, skeleton, and lung) were reviewed in this descriptive study. The patients underwent various treatments including surgery; liver directed therapies (embolization, selective internal radiotherapy), somatostatin analogs; targeted agents (everolimus); systemic chemotherapy (capecitabine/temozolomide; carboplatin/etoposide); external beam radiation; and peptide receptor radiotherapy. Seven subjects died during follow-up. The time of the 7 deaths ranged from 2.5 to 10.4 years (median time to death was 8.2 years). This compares to previous reports of median survival of about 2 years. Seven subjects are alive 1.2-12.3 years after diagnosis. Hypoglycemia was well-controlled and did not cause the deaths.

Multimodal interventions in metastatic insulinoma can be effective in managing hypoglycemia. The patients on multimodal treatments also lived a long time when considering previous published reports of median survival of just 2 years. Our findings challenge previous assumptions regarding clinical outcomes in this patient population.

This study aimed to develop and validate intratumoral, peritumoral, and combined radiomic models based on endoscopic ultrasonography (EUS) for retrospectively differentiating pancreatic neuroendocrine tumors (PNETs) from pancreatic cancer.

A total of 257 patients, including 151 with pancreatic cancer and 106 with PNETs, were retroactively enrolled after confirmation through pathological examination. These patients were randomized to either the training or test cohort in a ratio of 7:3. Radiomic features were extracted from the intratumoral and peritumoral regions from conventional EUS images. Following this, the radiomic features underwent dimensionality reduction through the utilization of the least absolute shrinkage and selection operator (LASSO) algorithm. Six machine learning algorithms were utilized to train prediction models employing features with nonzero coefficients. The optimum intratumoral radiomic model was identified and subsequently employed for further analysis. Furthermore, a combined radiomic model integrating both intratumoral and peritumoral radiomic features was established and assessed based on the same machine learning algorithm. Finally, a nomogram was constructed, integrating clinical signature and combined radiomics model.

107 radiomic features were extracted from EUS and only those with nonzero coefficients were kept. Among the six radiomic models, the support vector machine (SVM) model had the highest performance with AUCs of 0.853 in the training cohort and 0.755 in the test cohort. A peritumoral radiomic model was developed and assessed, achieving an AUC of 0.841 in the training and 0.785 in the test cohorts. The amalgamated model, incorporating intratumoral and peritumoral radiomic features, exhibited superior predictive accuracy in both the training (AUC=0.861) and test (AUC=0.822) cohorts. These findings were validated using the Delong test. The calibration and decision curve analyses (DCA) of the combined radiomic model displayed exceptional accuracy and provided the greatest net benefit for clinical decision-making when compared to other models. Finally, the nomogram also achieved an excellent performance.

An efficient and accurate EUS-based radiomic model incorporating intratumoral and peritumoral radiomic features was proposed and validated to accurately distinguish PNETs from pancreatic cancer. This research has the potential to offer novel perspectives on enhancing the clinical utility of EUS in the prediction of PNETs.

Peptide receptor radionuclide therapy (PRRT) using [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) represents an established treatment modality for somatostatin receptor-positive, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumours (GEP NET) of grade 1 or 2. The studies have demonstrated that four cycles of PRRT with 177Lu-DOTATATE prolongs progression-free survival and preserves quality of life, in patients with grade 1 and 2 advanced GEP NET. Notably, first-line PRRT using 177Lu-DOTATATE in grade 2 and 3 GEP NET patients has also shown efficacy and safety. Furthermore, PRRT can ameliorate symptoms in patients with NET-associated functioning syndromes. Although various studies have explored alternative radionuclides for PRRT, none currently meet the criteria for routine clinical implementation. Ongoing research aims to further enhance PRRT, and the results from large clinical trials comparing PRRT with other NET treatments are anticipated, potentially leading to significant modifications in NET treatment strategies and PRRT protocols. The results of these studies are likely to help address existing knowledge gaps in the coming years. This review describes the clinical practice, recent developments and future treatment options of PRRT in patients with grade 1 and 2 GEP NET.

Digestive neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumors with varying prognoses and clinical behaviors. Grade 2 (G2) tumors, defined by a Ki-67 index between 3% and 20%, are particularly challenging to manage due to their intermediate and variable biological behavior. Evidence suggests a distinct prognosis between G2 digestive NENs with a Ki-67 index < 10% and those with a Ki-67 index ≥ 10%.

To investigate the clinical and biological heterogeneity between Grade 1 (G1) and G2 digestive NENs, and within G2 tumors, with a focus on the prognostic significance of a 10% Ki-67 index cutoff.

This study involved a combined retrospective and prospective analysis of patients with low-grade G1 and G2 digestive NENs managed at IRCCS San Gerardo Hospital in Monza, Italy, between January 2000 and May 2024. Data on patient demographics, tumor characteristics, treatment modalities, and survival outcomes were collected and potential differences were analyzed between G1, G2 with Ki-67 index < 10% and G2 with Ki-67 index ≥ 10%.

Out of a total of 113 enrolled patients, 69 (61%) had G1 tumors, and 44 (39%) had G2 tumors. Median tumor size at diagnosis was 19 mm (IQR: 12-25 mm), with primary lesions mainly localized in the pancreas (57% among G1 and 45% among G2). Most G1 tumors were diagnosed at stage I (29 patients, 42%), while the majority of G2 tumors were metastatic at diagnosis (24 patients, 54.5%). Patients with G1 tumors exhibited a slightly higher 5-year OS rate compared to G2 tumors (98.1% vs. 92.8% respectively, though not statistically significant), and a significantly longer median PFS (141 vs. 22 months, p = 0.0003). Within the G2 group, 31 patients (70%) had a Ki-67 index < 10%, while 13 (30%) had a Ki-67 index ≥ 10%, with comparable baseline characteristics. A Ki-67 index < 10% was associated with a significantly better median PFS (38 vs. 8 months for tumors with Ki-67 index ≥ 10% G2 tumors, p = 0.002). PFS after first-line medical therapy was significantly longer in patients with a Ki-67 index < 10%, compared to those with ≥ 10% (undefined vs. 16 months, p = 0.0085), as well as median post-surgical PFS (84 vs. 10.5 months, p < 0.0001). Multivariate analysis identified higher tumor grade, advanced stage at diagnosis, and absence of PRRT as independent predictors of worse outcomes.

The findings highlight the significant clinical heterogeneity within G2 digestive NENs. A Ki-67 index cutoff of 10% within G2 tumors may serve as a critical prognostic marker, with patients with a Ki-67 index < 10% exhibiting significantly better outcomes in terms of PFS. These results suggest that the Ki-67 index could play an essential role in guiding treatment strategies, emphasizing the need for personalized approaches in managing G2 digestive NENs.

Pancreatic neuroendocrine neoplasms (pNENs) represent approximately 2% of all solid pancreatic tumors. The incidence of pNENs has been increasing in the last decade. The clinical manifestations of pNENs range from hormone secretion syndromes in functioning neoplasms (F-pNENs) to local infiltration or distant metastases in late-stage diagnoses or incidental findings in small non-functioning neoplasms (NF-pNENs). While surgery is the gold-standard treatment for larger and more aggressive tumors, small and low-grade tumors (G1) may be followed-up due to the indolent course of disease. Recently, endoscopic ultrasound (EUS)-guided ablative techniques, such as ethanol injection (EUS-EI) and radiofrequency ablation (EUS-RFA), have emerged as promising options for loco-regional ablations in selected cases. Despite promising safety profile and efficacy, high-quality evidence is needed to support their widespread adoption. This article reviews the current state of EUS-guided locoregional therapies, patient selection criteria, procedural details, and associated risks.

Functioning pancreatic neuroendocrine tumors (PanNETs) represent a subset of PanNETs that cause symptoms due to hormonal activity. Insulinoma is the most common functioning PanNET type. Mutations in the alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) genes result in genomic instability. ATRX/DAXX mutations and associated alternative lengthening of telomeres (ALT) are common in non-functioning PanNETs and associated with aggressive tumor behavior. Recent reports have shown that ATRX/DAXX mutations and ALT are also present in functioning PanNETs. In this review, we summarize the literature addressing ATRX/DAXX mutations and ALT in functioning PanNETs and discuss the clinical relevance with regard to distinguishing aggressive and indolent functioning tumors. ATRX/DAXX gene mutations and/or ALT have been reported in insulinoma, glucagonoma, gastrinoma, VIPoma and calcitoninoma. In insulinoma, the presence of ATRX/DAXX mutations and ALT are associated with aggressive behavior and could therefore be used as prognostic biomarkers. Although ATRX/DAXX mutation and ALT assessment may currently not be the standard of care in routine diagnostic pathology practice, the use of DAXX/ATRX immunohistochemistry at least can be encouraged not only for non-functioning but also for functioning PanNETs.

Autoimmune pancreatitis (AIP) is a rare chronic pancreatitis subtype that often mimics pancreatic cancer due to the overlapping clinical and radiological features, posing significant diagnostic challenges. Similarly, distinguishing AIP from pancreatic neuroendocrine neoplasms (PanNENs), which present with nonspecific symptoms, adds complexity to clinical evaluations. We present the case of a 46-year-old male with recurrent acute idiopathic pancreatitis. Abdominal computed tomography (CT) revealed a 25 mm hypodense mass in the pancreatic tail with mild arterial contrast enhancement. Magnetic resonance imaging (MRI) showed the mass to be hypointense on T2-weighted sequences, with no diffusion restriction and an enhancement pattern akin to normal pancreatic tissue. The endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) was inconclusive. Gallium-68 DOTATATE positron emission tomography-CT (Ga-68 DOTATATE PET-CT) showed an increased tracer uptake, leading to a distal pancreatectomy with a splenectomy. Histopathology demonstrated chronic sclerotic pancreatitis with inflammatory infiltrates. Elevated serum IgG4 levels confirmed the diagnosis of type 1 AIP Differentiating AIP from pancreatic malignancies, including PanNENs, is both critical and complex. This case highlights a misdiagnosis of PanNENs in a patient with focal AIP, where neuroendocrine hyperplasia and islet cell clusters within fibrotic areas mimicked PanNENs, even on Ga-68 PET-CT. The findings emphasize the potential for false positives with Ga-68 DOTATATE PET-CT and the importance of integrating clinical, radiological, and histological data for an accurate diagnosis.

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.

Endocrine surgery in multimorbid, frail and geriatric patients is increasing, is often urgent and characterized by special risk constellations. Successful parathyroid gland surgery nearly always results in a marked improvement, irrespective of the specific risk profile of the patient. Except for critical intubation and mediastinal interventions in the risk profile, surgery of the thyroid glands is predominantly beneficial and justifiable even in frail patients. For surgery of the adrenal glands and for gastroenteropancreatic neuroendocrine tumors (GEP-NET), the expected extension of resection, the underlying disease or the grading are decisive for whether alternative treatment measures or surveillance appear to be more beneficial for patients at risk.

Somatostatin analogs (SSAs) were developed as antisecretory agents to palliate hormonal symptoms in patients with functioning neuroendocrine tumors (NETs). Their antiproliferative activity has been established in the phase 3 PROMID and CLARINET trials. SSAs currently represent the standard first-line therapy for the majority of well-differentiated G1/G2 gastroenteropancreatic NETs as well as for pulmonary NETs.

An update on the clinical applications of established SSAs for the treatment of NETs is provided. Perspectives on emerging nonpeptide SSAs such as paltusotine and innovative formulations of octreotide (CAM2029) are included.

SSAs represent the cornerstone of treatment for both functioning and nonfunctioning NETs. While standard-dose SSAs have a defined place in the therapeutic algorithm of well-differentiated NETs, uncertainties remain on how to best integrate above-label doses of SSAs in the treatment sequence, particularly when tumor control is the goal. Octreotide and lanreotide appear to be clinically interchangeable, and no signs of superiority of one agent over the other has been observed so far. Whether SSAs may be exploited in the maintenance setting following more aggressive treatments, whether continuing SSAs beyond-progression after first-line therapy could be an effective treatment strategy, and whether new-generation SSAs such as pasireotide could overcome resistance to established SSAs are key areas of investigation.

Neuroendocrine tumours (NET) are rare entities arising from hormone producing cells in the gastroentero-pancreatic (GEP) tract. Surgery is the most common treatment of GEP-NETs.

Improvements in surgical techniques allow for more locally advanced and metastasised GEP-NETs to be resected. Laparoscopic and robotically--assisted approaches are increasingly being utilised in the resection of selected GEP-NETs and are facilitated by novel intraoperative tumour localisation tools and parenchyma-sparing methods. At the same time, some authors suggest that indications for formal resections of small well differentiated non-functioning pancreatic NETs and appendiceal NETs should be more restrictive. Advancements in surgery allows for tissue-sparing resections of GEP-NETs. Indications for surgical resection and the extent of the procedure are highly dependent on GEP-NET size, localisation and grading. Robotically assisted surgeries with intraoperative ultrasound and visualisation methods as well as vessel-sparing radical retrograde lymphadenectomies for small intestinal NETs seem to be the future of GEP-NET surgery.

Background: Hypoglycemia in the case of persons without diabetes is a rare event, being usually, initially misinterpreted based on the symptoms that can mimic various diseases, especially of a neuro-psychiatric nature. In the case of the identification of insulin-mediated hypoglycemia, the evaluation of pancreatic neuroendocrine tumors, which represent the most common and worrisome causes of non-diabetic insulin-mediated hypoglycemia, must be considered. Case Report: We present the case of a 57-year-old patient, hospitalized for a history of approximately one month of recurrent episodes of symptoms suggestive for severe hypoglycemia. The biological evaluation performed during an episode of hypoglycemia showed a plasma glucose value of 44 mg/dL, insulinemia 16.3 µU/mL, C peptide 3.72 ng/mL, HbA1c 4.99%, absence of urinary ketone bodies and anti-insulin antibodies <0.03 U/mL. The CT and MRI examination showed a 15.3/15 mm rounded tumor in the pancreatic corporeo-caudal region. The pancreatic tumor formation was enucleated and the histopathological and immunohistochemical analysis confirmed the diagnosis of the pancreatic neuroendocrine tumor with a positive reaction for chromogranin A, synaptophysin and insulin, without malignancy features (Ki 67 positive in 1% of the tumor cells). The postoperative evolution was favorable, without episodes of hypoglycemia, the fasting insulinemia one day after surgery being 4.1 µU/mL and HbA1c at three weeks postoperatively being 5.51%. Conclusions: The management of patients with hyperinsulinemic hypoglycemia secondary to insulinoma involves multidisciplinary collaboration with an important role in recognizing symptoms suggestive of hypoglycemia in a person without diabetes, initiating biological and imaging evaluation, establishing the optimal therapeutic option and histopathological confirmation.