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.

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.

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.

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.

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.

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.

To retrospectively develop and validate an interpretable deep learning model and nomogram utilizing endoscopic ultrasound (EUS) images to predict pancreatic neuroendocrine tumors (PNETs). Following confirmation via pathological examination, a retrospective analysis was performed on a cohort of 266 patients, comprising 115 individuals diagnosed with PNETs and 151 with pancreatic cancer. These patients were randomly assigned to the training or test group in a 7:3 ratio. The least absolute shrinkage and selection operator algorithm was employed to reduce the dimensionality of deep learning (DL) features extracted from pre-standardized EUS images. The retained nonzero coefficient features were subsequently applied to develop predictive eight DL models based on distinct machine learning algorithms. The optimal DL model was identified and used to establish a clinical signature, which subsequently informed the construction and evaluation of a nomogram. Gradient-weighted Class Activation Mapping (Grad-CAM) and Shapley Additive Explanations (SHAP) were implemented to interpret and visualize the model outputs. A total of 2048 DL features were initially extracted, from which only 27 features with coefficients greater than zero were retained. The support vector machine (SVM) DL model demonstrated exceptional performance, achieving area under the curve (AUC) values of 0.948 and 0.795 in the training and test groups, respectively. Additionally, a nomogram was developed, incorporating both DL and clinical signatures, and was visually represented for practical application. Finally, the calibration curves, decision curve analysis (DCA) plots, and clinical impact curves (CIC) exhibited by the DL model and nomogram indicated high accuracy. The application of Grad-CAM and SHAP enhanced the interpretability of these models. These methodologies contributed substantial net benefits to clinical decision-making processes. A novel interpretable DL model and nomogram were developed and validated using EUS images, cooperating with machine learning algorithms. This approach demonstrates significant potential for enhancing the clinical applicability of EUS in predicting PNETs from pancreatic cancer, thereby offering valuable insights for future research and implementation.

The objective is to develop and validate intratumoral and peritumoral ultrasomics models utilizing endoscopic ultrasonography (EUS) to predict pathological grading in pancreatic neuroendocrine tumors (PNETs).

Eighty-one patients, including 51 with grade 1 PNETs and 30 with grade 2/3 PNETs, were included in this retrospective study after confirmation through pathological examination. The patients were randomly allocated to the training or test group in a 6:4 ratio. Univariate and multivariate logistic regression were used for screening clinical and ultrasonic characteristics. Ultrasomics is ultrasound-based radiomics. Ultrasomics features were extracted from both the intratumoral and peritumoral regions of conventional EUS images. Subsequently, the dimensionality of these radiomics features was reduced using the least absolute shrinkage and selection operator (LASSO) algorithm. A machine learning algorithm, namely multilayer perception (MLP), was employed to construct prediction models using only the nonzero coefficient features and retained clinical features, respectively.

One hundred seven ultrasomics features based on EUS were extracted, and only features with nonzero coefficients were ultimately retained. Among all the models, the combined ultrasomics model achieved the greatest performance, with an AUC of 0.858 (95% CI, 0.7512 - 0.9642) in the training group and 0.842 (95% CI, 0.7061 - 0.9785) in the test group. A calibration curve and a decision curve analysis (DCA) also demonstrated its accuracy and utility.

The integrated model using EUS ultrasomics features from intratumoral and peritumoral tumors accurately predicts PNETs' pathological grades pre-surgery, aiding personalized treatment planning.

ChiCTR2400091906.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by a germline pathogenic variant in the MEN1 tumor suppressor gene. Patients with MEN1 have a high risk for primary hyperparathyroidism (PHPT) with a penetrance of nearly 100%, pituitary adenomas (PitAd) in 40% of patients, and neuroendocrine neoplasms (NEN) of the pancreas (40% of patients), duodenum, lung, and thymus. Increased MEN1-related mortality is mainly related to duodenal-pancreatic and thymic NEN. Management of PHPT differs from that of patients with sporadic disease, as the surgical approach in MEN1-related PHPT includes near-total or total parathyroidectomy because of multigland hyperplasia in most patients and the consequent high risk of recurrence. NEN management also differs from patients with sporadic disease due to multiple synchronous and metasynchronous neoplasms. In addition, the lifelong risk of developing NEN requires special considerations to avoid excessive surgeries and to minimize damage to the patient's function and well-being. This progress report will outline current insights into surveillance and management of the major clinical manifestation of MEN1 syndrome in children and adults with MEN1 diagnosis. In addition, we will discuss MEN1-like clinical presentation with negative MEN1-genetic workup and future clinical and research directions.

Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) is a promising minimally invasive technique for the treatment of pancreatic lesions. This review first focuses on the technical aspects in EUS-RFA: the procedure typically employs EUS probes with integrated radiofrequency electrodes, enabling accurate targeting and ablation of pancreatic lesions. Different types of RFA devices, monopolar and bipolar energy delivery systems, are discussed, along with considerations for optimal ablation, including energy settings, procedure time, and pre- and post-procedural management. This paper presents a comprehensive literature review of EUS-RFA applied to both solid and cystic pancreatic lesions, including functioning and non-functioning pancreatic neuroendocrine tumors (pNETs), pancreatic cystic lesions (PCLs), pancreatic ductal adenocarcinoma (PDAC), and pancreatic metastases (PMs), discussing current evidence on safety, efficacy, clinical outcomes, and adverse events (AEs). EUS-RFA is an emerging technique with expanding potential for the treatment of both benign and malignant conditions; however, further studies are needed to better define patient selection criteria, assess long-term benefits, and establish definitive indications for its use.

Introduction and importance: Even though insulinoma is the most frequent neuroendocrine tumor, it represents only 2% of pancreatic 2% of all pancreatic neoplasms. Diagnosis is relatively simple, and surgery after accurate determination of the tumors location within the pancreas is the cornerstone of its treatment. Case presentation: We herein report 4 patients undergoing various surgeries for benign secreting insulinomas, after extensive radiological and endoscopic exploration. Clinical discussion: Diagnosis is relatively simple relying on clinical and biological criteria, it must be followed by an extensive and accurate preoperative determination of the tumors localization. The laparoscopic tumoral enucleation is the treatment of choice for small isolated tumors, but open surgery still has its indications. Conclusion: Pancreatic insulinoma is a rare neuroendocrine tumor that can be life-threatening due to hypoglycemic manifestations. The diagnosis is based on clinical and biological criteria. echo endoscopy and to a lesser extent radiological exploration can precisely determine the tumors location. Laparoscopic surgical enucleation of the tumor remains the preferred curative treatment.

Evidence on the efficacy and safety of minimally invasive treatment for insulinoma has increased over the past decade to the point of becoming a recommendation in clinical practice guidelines for the management of this type of neuroendocrine tumor.

We describe the case of an elderly male patient with multiple comorbidities and recurrent isolated insulinoma of 3.7 × 3.5 cm involving the uncinate process of the pancreas and contacting the splenomesenteric confluent many years after first resection, in whom, after refusing surgical management, was performed as successful arterial embolization of the pancreatic tumor.

When addressing this pathology, it is common to encounter patients who are not candidates for surgical management, either due to the presence of comorbidities, the location of the tumor in relation to vascular structures, or refusal of the intervention. Therefore, it is important to be aware of the different therapeutic options in localized and metastatic disease.

Minimally invasive procedures are positioned as an effective alternative for the treatment of the hormonal overproduction in patients with insulinoma.

Neuroendocrine neoplasms (NENs) arise from the diffuse endocrine system and have been considered to be rare. However, the incidence and prevalence of these tumours have increased in recent years, and they are being seen in younger patients including women in the reproductive age group. Due to the paucity of data, diagnostic and therapeutic strategies in managing such tumours during pregnancy can be challenging to both treating physicians and patients. This article describes the experience and outcomes of managing pregnant women with NEN at a European Neuroendocrine Tumour Society (ENETS) Centre of Excellence. In this retrospective analysis, we evaluated a total of 22 pregnancies in 18 pregnant women with concurrent diagnoses of NENs who were managed at Royal Free Hospital ENETS Centre of Excellence throughout their pregnancy. These were identified from our tumour registry of 3500 NEN patients between 2015 and 2023. Cross-sectional imaging (computed tomography (CT)/magnetic resonance imaging (MRI)), pre- and post-pregnancy, for each patient was reviewed by an experienced radiologist. Tumour growth rate (TGR) was calculated using the formula: TGR = 100 × [exp (TG) - 1]; TG. [3 × log (D2/D1)]/time (months), where D1 is the tumour size at date 1; D2 is the tumour size at date 2; and time (months) = (Date 2 - Date 1 + 1)/30.44. Tumour growth rate pre-conception (TGRpc) and tumour growth rate post-partum (TGRpp) were calculated for each patient. In a sub-group of patients, positivity for oestrogen and progesterone receptors were analysed on the tumour tissue to evaluate whether the presence of these receptors affected tumour progression during the pregnancy. We also reviewed the pregnancy outcome in patients treated with somatostatin analogues during pregnancy. We analysed the data of a total 22 pregnancy encounters in 18 women: 15 pregnancies (68%) preceded the diagnosis of the NEN, whereas the diagnosis of NEN was made during pregnancy or in the post-partum period in 5 (23%) and 2 (9%) pregnancies respectively. Eight patients (44%) had a diagnosis of a pancreatic NEN, whereas 5 (28%) were diagnosed with mid-gut NENs, and a further 5 at other sites. The majority of the patients (n = 12, 67%) had evidence of metastatic disease at the time of diagnosis. Most pregnancies had a successful outcome (n = 19, 86%), whereas 3 patients (14%) had miscarriages in the 1st trimester. Five patients in total of 6 pregnancies were treated with somatostatin analogues as monotherapy during the pregnancy, and all of them had stable disease after pregnancy. All of them delivered healthy babies without any side effects or complications due to therapy. The average TGRpc was -0.8% (n = 5) and the average TGRpp was +0.96% (n = 6); 2 patients who did not have suitable targets for calculation of TGRpc developed new lesions suggesting disease progression. Moreover, 2 of the 4 patients who have had both pre-conception and post-pregnancy scans showed an increase in TGRpp compared to TGRpc. The management of NENs during pregnancy should be multidisciplinary with an individualised approach to each patient. Somatostatin analogues appear to be safe during pregnancy, though further robust studies are needed. Pregnancy per se may accelerate tumour progression, and patients should be counselled regarding this possibility.

Glucagonomas are functioning pancreatic neuroendocrine tumors (PanNETs) responsible for glucagonoma syndrome. This study aims to shed light on the clinicopathological and molecular features of these neoplasms. Six patients with glucagonomas were identified. All neoplasms were investigated with immunohistochemistry for neuroendocrine markers (Synaptophysin, Chromogranin-A), ATRX, DAXX, ARX, and PDX1 transcription factors. Fluorescent in situ hybridization (FISH) for assessing alternative lengthening of telomeres (ALT), and next-generation sequencing (NGS) for molecular profiling were performed. All cases were large single masses (mean size of 8.2 cm), with necrolytic migratory erythema as the most common symptom (6/6 cases, 100%). All neoplasms were well-differentiated G1 tumors, except one case that was G2. The tumors consistently showed classic/conventional histomorphology, with solid-trabecular and nested architecture. Lymphatic and vascular invasion (6/6, 100%), perineural infiltration (4/6, 66.6%), and nodal metastasis (4/6, 66.6%) were frequently observed. Transcription factors expression showed strong ARX expression in all tumors, and PDX1 expression in 5/6 cases (83.3%), indicating co-occurring alpha- and beta-cell differentiation. NGS showed recurrent somatic MEN1 and ATRX/DAXX biallelic inactivation. Cases with ATRX or DAXX mutations also showed matched loss of ATRX or DAXX protein expression and ALT. One case harbored somatic MUTYH inactivation and showed a high tumor mutational burden (TMB, 41.0 mut/Mb). During follow-up, one patient died of the disease, and four patients developed distant metastasis. Pancreatic glucagonomas are distinct PanNETs with specific clinicopathological and molecular features, including histological aspects of biological aggressiveness, co-occurring alpha- and beta-cell differentiation, MEN1 and DAXX/ATRX mutations enrichment, and the possible presence of high-TMB as an actionable marker.

This review examines the diagnostic and prognostic biomarkers for pancreatic neuroendocrine neoplasms (PanNENs), a heterogeneous group of tumors with expression of neuroendocrine markers. PanNENs include both well-differentiated pancreatic neuroendocrine tumors (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). The diagnosis is confirmed through markers such as chromogranin A, synaptophysin, and INSM1, which establish neuroendocrine differentiation. The World Health Organization classification categorizes PanNENs based on tumor differentiation and proliferative activity (Ki-67 and/or mitotic index) into well-differentiated PanNETs (grade 1 to grade 3) and poorly differentiated PanNECs. In most cases, the morphology and proliferation index are sufficient to distinguish PanNETs from PanNECs. However, distinguishing grade 3 PanNETs from PanNECs can be challenging on the basis of morphology and proliferative activity alone. Additional key diagnostic markers for distinguishing grade 3 PanNET from PanNEC include SSTR2A expression and molecular immunohistochemical markers such as p53, Rb1, menin, ATRX, and DAXX. PanNECs are by definition high-grade tumors with highly aggressive clinical behavior, while PanNETs have a variable prognosis that is difficult to predict using current biomarkers such as tumor grade and size. Several studies have shown that ATRX or DAXX loss is strongly associated with a higher risk of PanNET metastasis and recurrence. They are therefore key prognostic markers in PanNETs. In addition, chromosomal copy number variations can further help assess PanNET aggressiveness and prognosis. Molecular profiling is increasingly important for improving the diagnosis, treatment, and prognosis of PanNENs.

Insulinomas are rare insulin-secreting neuroendocrine neoplasms of the pancreas. First-line treatment is the surgical removal of the tumor, however, the localization with standard imaging techniques is often challenging. With the help of selective intraarterial calcium stimulation the insulinoma's localization can be narrowed down to one third of the pancreas which the selected artery supplies.

We aimed to prove the usefulness of the calcium stimulation test in case of 9 patients treated between 2006 and 2021 diagnosed with endogenous hyperinsulinemic hypoglycemia confirmed by fasting test, where conventional imaging methods, like transabdominal ultrasound, CT or MRI failed to detect the source of hyperinsulinemia.

We performed selective intraarterial calcium stimulation with angiography with calcium gluconate injected to the main supporting arteries of the pancreas (splenic, superior mesenteric and gastroduodenal arteries); blood samples were obtained from the right hepatic vein before, and 30, 60 and 120 seconds after calcium administration.

With selective angiography we found a significant elevation of insulin levels taken from the right hepatic vein in five of the nine cases. On histopathology, the lesions were between 1-2 cm, in one case malignancy was also confirmed. In four patients we found a significant rise of insulin levels obtained from all catheterized sites, which confirmed the diagnosis of nesidioblastosis. In three cases no surgery was performed, and the symptoms relieved with medical treatment.

Selective intraarterial calcium stimulation remains an important tool in localization of the source of insulin excess, especially in cases where other diagnostic modalities fail.

Pancreatic neuroendocrine tumors (NETs) are rare well-differentiated neoplasms with limited therapeutic options and unknown cells of origin. The current classification of pancreatic neuroendocrine tumors is based on proliferative grading, and guides therapeutic strategies, however, tumors within grades exhibit profound heterogeneity in clinical manifestation and outcome. Manifold studies have highlighted intra-patient differences in tumors at the genetic and transcriptomic levels. Molecular classification might become an alternative or complementary basis for treatment decisions and reflect tumor biology, actionable cellular processes. Here, we provide a comprehensive review of genomic, transcriptomic, proteomic and epigenomic studies of pancreatic NETs to elucidate patterns shared between proposed subtypes that could form a foundation for new classification. We denote four NET subtypes with distinct molecular features, which were consistently reproduced using various omics technologies.

Functional neuroendocrine neoplasms (NENs) are those associated with specific symptoms related to the hormonal secretion of the NENs. Although less than 25 % of NENs are functional at diagnosis,1 the associated syndromes significantly increase the patient burden of disease. Management of hormonal NEN symptoms may involve tumor resection or other reduction strategies (e.g., chemotherapy, embolotherapy, etc), but also specific therapies directed at decreasing hormonal synthesis, secretion, or end-organ effects. In this review, we focus on specific symptomatic management of many of the NEN syndromes, which may be pursued in addition to management primarily directed at tumor bulk and growth. A continued focus on symptom management related to the hormonal secretions of NENs, in the context of other efforts to reduce tumor bulk and growth, could significantly improve patient wellbeing.

Neuroendocrine neoplasms (NENs) encompass a heterogeneous spectrum of tumors originating from the diffuse neuroendocrine cell system. Approximately 30% of NEN exhibit functional activity with clinical syndromes through hormone-mediated effects. Synchronous and metachronous functioning syndromes, resulting from the simultaneous release of distinct hormones, are exceptionally rare. Of note, hormonal excess syndromes can have a greater effect on patients' morbidity and mortality than the tumor mass itself. We present the case of a 49-year-old male patient affected by an oligo-metastatic ileal NEN, concurrently demonstrating vasointestinal peptide (VIP) and serotonin excretion, complicated by pulmonary tuberculosis. After the first cycle of Lutetium-177-DOTATATE peptide-radio-receptor therapy, the patient developed a severe watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome, despite receiving high-dose somatostatin analogues, everolimus, and telotristat ethyl, without any surgical options. The WDHA syndrome necessitated intensive-care-unit (ICU) admission with continual intravenous administration of electrolytes and fluids. With limited alternatives, an off-label intervention using the enkephalinase inhibitor racecadotril was initiated. After 5 days of treatment, the WDHA syndrome exhibited sufficient control, facilitating the patient's discharge from the ICU. This case report underscores racecadotril as an individualized, off-label treatment strategy for patients with severe VIPoma and serotonin-driven WDHA syndrome, where conventional therapeutic avenues have been exhausted.

Advancements in somatostatin receptor (SSTR) targeted imaging and treatment of well-differentiated neuroendocrine tumors (NETs) have revolutionized the management of these tumors. This comprehensive review delves into the current practice, discussing the use of the various FDA-approved SSTR-agonist PET tracers and the predictive imaging biomarkers, and elaborating on Lu177-DOTATATE peptide receptor radionuclide therapy (PRRT) including the evolving areas of post-therapy imaging practices, PRRT retreatment, and the potential role of dosimetry in optimizing patient treatments. The future directions sections highlight ongoing research on investigational PET imaging radiotracers, future prospects in alpha particle therapy, and combination therapy strategies.

Pancreatic neuroendocrine tumors (pNET) exhibit a wide spectrum of clinical behavior, which makes their assessment and management quite challenging. The purpose of this study was to comprehensively assess the existing treatment landscape for patients with pNET.

The study was conducted with the support of the ESSO-EYSAC Research Academy in collaboration with the E-AHPBA. An online survey was distributed via email and social media to surgical networks across Europe and beyond (September 1-30, 2023).

Overall, 155 complete responses were obtained. A specialized NET tumor board was present at the institutions of 94 (61 %) of the study participants. The most frequently applied guidelines were from ENETS (n = 97; 63 %), NCCN (n = 74; 48 %), and ESMO (n = 53; 34 %). For resectability, similar criteria as in pancreatic ductal adenocarcinoma were used by 111 (72 %) participants, even though 116 (75 %) participants believed that pNET/pNEC should have their own resectability criteria. Most respondents used somatostatin analogues (n = 126; 81 %) and chemotherapy (n = 85; 55 %) as neoadjuvant treatments, followed by molecularly targeted agents (n = 45; 29 %) and PRRT (n = 37; 24 %). Only 17 (11 %) participants agreed/strongly agreed that the management of pNET/pNEC is sufficiently addressed in surgical education programs.

This international survey highlighted areas for improvement in the care of pNET, namely the lack of pNET-specific resectability criteria and educational programs addressing pNET management.

Insulinomas are rare functional neuroendocrine tumors that are usually indolent and small. Due to their rarity, there is often a delay in disease recognition and diagnosis, and small tumor size makes their localization challenging. Glucose monitoring and dietary modification with or without pharmacotherapy are crucial during diagnostics, and surgery is the only definite treatment. Continuous glucose monitoring (CGM) systems can be a valuable tool in managing insulinoma patients. We present three patients with confirmed endogenous hyperinsulinemic hypoglycemia undergoing tumor localization, medical treatment, and surgery while wearing a CGM system. By accurately depicting glucose fluctuations, CGM can help prevent hypoglycemia, decrease hypoglycemia unawareness, track hypoglycemia frequency, aid in medical therapy dose titration, and confirm a cure after surgery.

Surgery is a cornerstone in the management of pancreatic cancer and precancerous pancreatic lesions. However, many patients are not suitable candidates for surgery at the time of diagnosis for various reasons. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) appears to be a promising treatment option for patients who are ineligible for surgery for management of pancreatic adenocarcinoma (PDAC), and pancreatic neuroendocrine tumors (PNETs), and pancreatic cystic lesions (PCLs).

EUS-RFA may serve as an adjunct to chemotherapy or palliative measures for inoperable cases of PDAC. Given its feasibility and efficacy, EUS-RFA has an evolving niche as a minimally invasive and potentially definitive treatment for PNETs and high-risk PCLs such as intraductal papillary mucinous neoplasms (IPMNs). EUS-RFA is a generally well tolerated procedure, with abdominal pain and acute pancreatitis being the most common adverse effects, though the risk can be mitigated through prophylactic measures.

There is an increasing body of evidence to support the use of EUS-RFA in managing pancreatic lesions, either as definitive, adjunctive, or palliative treatment, depending on lesion type.

Background: Gastrointestinal neuroendocrine neoplasms (GI-NENs) represent a diverse group of tumors, with surgical resection being the gold standard for treatment. Materials and Methods: A retrospective analysis was conducted on 63 patients (32 women, 31 men) who underwent surgery for GI-NENs at the Department of Digestive Tract Surgery from January 2013 to June 2023. Tumors were classified by stage (localized, regionally advanced, metastatic). Results: Clinical symptoms were reported by 42 (66.7%) patients, with abdominal pain being the most common symptom, affecting 28 (44.4%) patients. The majority of tumors (44, 69.8%) originated in the midgut. The most frequently performed surgery was right hemicolectomy, carried out on 33 (52.4%) patients. Radical tumor resection was performed in 35 (55.6%) patients. Postoperative complications occurred in 12 (19%) patients, with male gender identified as an independent predictive factor for complications (p = 0.04). Non-functioning tumors were more common (33, 52.4%), and most tumors were classified as grade 1 histopathologically (49, 77.8%). Distant metastases were present in 29 (46%) patients. The overall two-year survival rate was 94.9%, with a five-year survival rate also estimated at 94.9%. Conclusions: GI-NENs are often diagnosed at advanced stages, frequently with distant or lymph node metastases, and predominantly arise in the midgut. Despite low postoperative morbidity and mortality, male gender may be a predictor of postoperative complications. Overall, the prognosis for GI-NENs is favorable, reflected in high overall survival rates.