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

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

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

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

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

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

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

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

This Technical and Technology Review from the European Society of Gastrointestinal Endoscopy (ESGE) represents an update of the previous document on the technical aspects of endoscopic ultrasound (EUS)-guided sampling in gastroenterology, including the available types of needle, technical aspects of tissue sampling, new devices, and specimen handling and processing. Among the most important new recommendations are:ESGE recommends end-cutting fine-needle biopsy (FNB) needles over reverse-bevel FNB or fine-needle aspiration (FNA) needles for tissue sampling of solid pancreatic lesions; FNA may still have a role when rapid on-site evaluation (ROSE) is available.ESGE recommends EUS-FNB or mucosal incision-assisted biopsy (MIAB) equally for tissue sampling of subepithelial lesions ≥20 mm in size. MIAB could represent the first choice for smaller lesions (<20 mm) if proper expertise is available.ESGE does not recommend the use of antibiotic prophylaxis before EUS-guided tissue sampling of solid masses and EUS-FNA of pancreatic cystic lesions.

Advancements in diagnostic technology have led to the improved detection of pancreatic neuroendocrine tumors (PNETs) and thus to an increase in the number of reported cases. Endoscopic ultrasound (EUS) technology, including in combination with contrast-enhanced harmonic imaging, aids in distinguishing PNETs from other tumors, while EUS-guided fine-needle aspiration or biopsy has improved the histological diagnosis and grading of tumors. The recent introduction of EUS-guided ablation using ethanol injection or radiofrequency ablation has offered an alternative to surgery in the management of PNETs. Comparisons with surgery have shown similar outcomes but fewer adverse effects. Although standardized protocols and prospective studies with long-term follow-up are still needed, EUS-based methods are promising approaches that can contribute to a better quality of life for PNET patients.

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

Insulinoma is a rare pancreatic neuroendocrine neoplasm caused by pancreatic beta cell tumor or beta cell proliferation resulting in excessive insulin secretion. Due to its rarity, surgical analysis and summary studies on patients with insulinoma are few and the sample size is limited.

In this study, we retrospective the cumulative experiences including demographics, clinical characteristics, detailed surgical reports and postoperative outcome of 76 patients diagnosed with insulinoma from 2010 to 2020 at the First Affiliated Hospital of Xi'an Jiaotong University.

Our cohort consisted of 48 females and 28 males with an average diagnosis age of 52 years. Loss of consciousness (68 %), sweating (59 %), vertigo (56 %) are three most shown symptoms. The average time from symptom onset to diagnosis of insulinoma was 33.4 month. When CT combined with MRI was used, the diagnostic rate was as high as 96.87 %. Of the 76 patients, 48.68 % of preoperative tumors were in the head/neck, and the remaining 51.32 % were in the body/tail. Most of the patients received surgery for enucleation (65.79 %). The duration of surgery was 216 ± 105 min. The incidence of postoperative pancreatic fistula was 53.95 %. Postoperative pancreatic hemorrhage occurred in 6 patients (7.89 %), all of whom were pancreatic head/neck surgery patients. The incidence of pancreatic fistula, bleeding and major complications after the operation of pancreatic head/neck insulinoma was higher than that of pancreatic body/tail insulinoma.

CT combined with MRI can localize insulinoma in most patients. As a parenchyma-sparing pancreatectomy, enucleation is the procedure of choice if possible. The incidence of postoperative hemorrhage should be more vigilant after the surgery of pancreatic head/neck insulinoma. The intraoperative suture of high-risk vessels prone to bleeding should be performed if necessary.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a highly sensitive and accurate method for identifying pancreatic neuroendocrine tumors (PanNETs). However, research on grading and assessing the Ki67 proliferation index in FNA samples is limited.

This study analyzed 335 EUS-FNA cases performed between 2016 and 2022, of which 12 cases of PanNET were further evaluated. The morphology, Ki-67 index, and grading (G) of cell blocks (CBs) obtained from the PanNET aspirations were compared to those of the resected material.

Out of 12 PanNET's with rapid on-site evaluation (ROSE), in FNA samples and CB, 7 (58.3%) cases were G1, while 5 (41.7%) cases were G2. On the other hand, on resection of these cases, 6 (50%) were diagnosed as G1, 5 (41.7%) cases were G2, and 1 case (8.3%) was G3. The average Ki-67 index in CB was 2.92 (min: 1 - max: 10), while in resections it was 4.67 (min: 1 - max: 22). Only 2 (16.6%) showed a discordance between grade and Ki-67, resulting in an overall concordance of over 80%. On average, 1.83 needle passes were made (range: 1-3), while the average number of slides and CBs were 9.33 (range: 1-24) and 2.17 (range: 1-6), respectively. There were no significant differences in the number of passes, slides, or CBs between the consistent and discordant groups.

Optimal counting techniques and sensitivity for Ki67 are crucial in grading PanNETs in both aspiration and resection materials. The grade and Ki-67 index demonstrated high concordance when comparing CB and resection. However, in low-volume centers, ROSE support can be beneficial in obtaining sufficient slides and CB for an adequate diagnosis.

Introduction: Neuroendocrine tumors are a diverse group of tumors predominantly found in the gastrointestinal tract or respiratory system. Methods: This retrospective study aimed to measure the serum concentrations of LRP6 (low-density lipoprotein receptor-related protein 6), SFRP3 (secreted frizzled-related protein 3), and DVL1 (segment polarity protein dishevelled homolog) using the ELISA method in patients with NETs (N = 80) and a control group (N = 62). We evaluated the results against various demographic, clinicopathological, and biochemical characteristics. Results: Our analyses revealed that the concentration of SFRP3 in patients with neuroendocrine tumors was significantly elevated (p < 0.001) compared to the control group. Additionally, DVL1 concentrations were significantly higher (p < 0.01) in patients with BP-NETs compared to GEP-NETs. Furthermore, DVL1 analysis showed a moderate negative correlation with chromogranin A (p < 0.001) and weak negative correlations with serotonin (p < 0.05) and 5-HIAA (p < 0.05). Significant negative correlations were also observed between DVL1 and age in the control group (p < 0.01), and between LRP6 and Ki-67 in the study group. Conclusions: These results suggest that changes in the SFRP3 and DVL1 pathways play a key role in NET development. Elevated levels of these proteins highlight their importance in tumor biology, with SFRP3 and DVL1 potentially being crucial in NET molecular mechanisms. Further research is needed to explore their roles and potential in diagnosis and treatment.

Evidence-based treatment decisions for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) require individualized patient-centered decision-making that accounts for patient and cancer characteristics.

To create an accessible guidance document to educate clinicians and patients on biomarkers informing prognosis and treatment in unresectable or metastatic GEP-NENs.

A multidisciplinary panel in-person workshop was convened to define methods. English language articles published from January 2016 to January 2023 in PubMed (MEDLINE) and relevant conference abstracts were reviewed to investigate prognostic and treatment-informing features in unresectable or metastatic GEP-NENs. Data from included studies were used to form evidence-based recommendations. Quality of evidence and strength of recommendations were determined using the Grading of Recommendations, Assessment, Development and Evaluations framework. Consensus was reached via electronic survey following a modified Delphi method.

A total of 131 publications were identified, including 8 systematic reviews and meta-analyses, 6 randomized clinical trials, 29 prospective studies, and 88 retrospective cohort studies. After 2 rounds of surveys, 24 recommendations and 5 good clinical practice statements were developed, with full consensus among panelists. Recommendations focused on tumor and functional imaging characteristics, blood-based biomarkers, and carcinoid heart disease. A single strong recommendation was made for symptomatic carcinoid syndrome informing treatment in midgut neuroendocrine tumors. Conditional recommendations were made to use grade, morphology, primary site, and urinary 5-hydroxyindoleacetic levels to inform treatment. The guidance document was endorsed by the Commonwealth Neuroendocrine Tumour Collaboration and the North American Neuroendocrine Tumor Society.

The study results suggest that select factors have sufficient evidence to inform care in GEP-NENs, but the evidence for most biomarkers is weak. This article may help guide management and identify gaps for future research to advance personalized medicine and improve outcomes for patients with GEP-NENs.

Esophageal subepithelial lesions (ESELs) encompass a variety of diseases, including leiomyoma, granular cell tumors, hemangioma, lipoma, stromal tumors, leiomyosarcoma, schwannoma, neuroendocrine tumors and more. These lesions often present asymptomatically, leading to a generally low clinical diagnosis rate. Common imaging techniques for diagnosing ESELs include conventional endoscopy, spiral computed tomography, and endoscopic ultrasound (EUS). Among these, EUS is currently regarded as one of the most accurate methods for diagnosing ESELs. In recent years, EUS has increasingly been combined with advanced technologies such as artificial intelligence, submucosal saline injection, high-frequency impedance measurement, and enhanced imaging to improve diagnostic accuracy and reduce missed diagnoses. This article reviews the application and recent advancements of EUS in diagnosing esophageal submucosal lesions.

A majority of pancreatic malignancies are unresectable at the time of presentation and require EUS-guided fine-needle aspiration or fine-needle biopsy (EUS-FNA/FNB) for diagnosis. With the advent of precision therapy, there is an increasing need to use EUS-FNA/FNB sample for genetic analysis. Next-generation sequencing (NGS) is a preferred technology to detect genetic mutations with high sensitivity in small specimens. We performed a meta-analysis to evaluate the adequacy of EUS-FNA/FNB for NGS in pancreatic malignancies.

PubMed, Embase, Cochrane Library, and Web of Science were searched from database inception to November 11, 2023. The primary outcome was the proportion of sufficient sample acquired by EUS-FNA/FNB in pancreatic malignancies for NGS. Secondary outcomes were the proportion of sufficient sample for NGS in pancreatic ductal adenocarcinoma (PDAC) and the detection rates of mutations in KRAS, TP53, CDKN2A, and SMAD4 and actionable mutations in PDAC. The pooled proportions were calculated using a random-effects model. Potential sources of heterogeneity were investigated with subgroup analyses and meta-regression.

Twenty studies with 881 samples were included. The pooled adequacy of EUS-FNA/FNB sample for NGS was 89.9% (95% CI, 80.8%-96.7%) in pancreatic malignancies and 92.0% (95% CI, 81.3%-98.8%) in PDAC. Screening sample suitability before NGS testing was associated with lower adequacy in subgroup analysis (79.7% vs. 98.4%, P = 0.001). The pooled prevalences of mutations in KRAS, TP53, CDKN2A, and SMAD4 in PDAC were 87.4% (95% CI, 83.2%-91.2%), 62.6% (95% CI, 53.2%-71.7%), 20.6% (95% CI, 11.9%-30.8%), and 19.4% (95% CI, 11.2%-29.1%), respectively. The pooled prevalence of potentially actionable mutations in PDAC was 14.5% (95% CI, 8.2%-22.0%).

In the majority of cases, EUS-FNA/FNB can acquire adequate sample for NGS and identify tumor-specific mutations in patients with pancreatic malignancies. Strict pre-analysis screening criteria may negatively impact the sample adequacy and the success rate for NGS.

Same-session endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) is an attractive policy for patients with distal malignant biliary obstruction (DMBO) requiring fine-needle biopsy (FNB) and biliary drainage. However, scanty and conflicting data exists regarding safety and efficacy when comparing these two procedures performed in same versus separate sessions.

Single-center, retrospective, propensity score-matched study including patients with DMBO who underwent EUS-FNB followed by ERCP during the same or separate sessions. The primary outcome was the safety of the procedure [number of patients experiencing adverse events (AEs), overall AEs, its severity, post-ERCP pancreatitis (PEP)]. Secondary outcomes were successful ERCP, use of advanced cannulation techniques, EUS-FNB adequacy, length of hospital stay, overall procedure time, and time to recurrent biliary obstruction.

After propensity matching, 87 patients were allocated to each group. AEs developed in 23 (26.4%) vs. 17 (19.5%) patients in the same and separate sessions group, respectively (p = 0.280). The overall number, the severity of AEs, and the rate of PEP were similar in the two groups. Secondary outcome parameters were also comparable in the 2 groups.

Same-session EUS-FNB followed by ERCP with biliary drainage is safe and does not impair technical outcomes of tissue adequacy and biliary cannulation.

The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness.

A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002-2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse).

A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001).

Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment.

Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs.

In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort.

In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate.

NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Neuroendocrine neoplasms (NENs) represent a complex group of tumors arising from neuroendocrine cells, characterized by heterogeneous behavior and challenging diagnostics. Despite advancements in medical technology, NENs present a major challenge in early detection, often leading to delayed diagnosis and variable outcomes. This review aims to provide an in-depth analysis of current diagnostic methods as well as the evolving and future directions of diagnostic strategies for NENs.

The review extensively covers the evolution of diagnostic tools for NENs, from traditional imaging and biochemical tests to advanced genomic profiling and next-generation sequencing. The emerging role of technologies such as artificial intelligence, machine learning, and liquid biopsies could improve diagnostic precision, as could the integration of imaging modalities such as positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrids and innovative radiotracers.

Despite progress, there is still a significant gap in the early diagnosis of NENs. Bridging this diagnostic gap and integrating advanced technologies and precision medicine are crucial to improving patient outcomes. However, challenges such as low clinical awareness, limited possibility of noninvasive diagnostic tools and funding limitations for rare diseases like NENs are acknowledged.

We aimed to assess the diagnostic utility of an immunohistochemical panel including calcium-binding protein P, p53, Ki-67, and SMAD family member 4 and K-ras mutation for diagnosing pancreatic solid lesion specimens obtained by endoscopic ultrasound-guided fine-needle biopsy and to confirm their usefulness in histologically inconclusive cases.

Immunohistochemistry and peptide nucleic acid-clamping polymerase chain reaction for K-ras mutation were performed on 96 endoscopic ultrasound-guided fine-needle biopsy specimens. The diagnostic efficacy of each marker and the combination of markers was calculated. The diagnostic performances of these markers were evaluated in 27 endoscopic ultrasound-guided fine-needle biopsy specimens with histologically inconclusive diagnoses. A classification tree was constructed.

K-ras mutation showed the highest accuracy and consistency. Positivity in more than two or three of the five markers showed high diagnostic accuracy (94.6 % and 93.6 %, respectively), and positivity for more than three markers showed the highest accuracy for inconclusive cases (92.0 %). A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 showed high diagnostic performance, with only two misclassifications in inconclusive cases.

K-ras mutation detection via peptide nucleic acid-clamping polymerase chain reaction is a stable and accurate method for distinguishing between pancreatic ductal adenocarcinoma and non-pancreatic ductal adenocarcinoma lesions. A classification tree using K-ras mutation, Ki-67, S100P, and SMAD4 helps increase the diagnostic accuracy of cases that are histologically difficult to diagnose.

To develop and validate various ultrasomics models based on endoscopic ultrasonography (EUS) for retrospective differentiating pancreatic neuroendocrine tumors (PNET) from pancreatic cancer.

A total of 231 patients, comprising 127 with pancreatic cancer and 104 with PNET, were retrospectively enrolled. These patients were randomly divided into either a training or test cohort at a ratio of 7:3. Ultrasomics features were extracted from conventional EUS images, focusing on delineating the region of interest (ROI) for pancreatic lesions. Subsequently, dimensionality reduction of the ultrasomics features was performed by applying the Mann-Whitney test and least absolute shrinkage and selection operator (LASSO) algorithm. Eight machine learning algorithms, namely logistic regression (LR), light gradient boosting machine (LightGBM), multilayer perceptron (MLP), random forest (RF), extra trees, k nearest neighbors (KNN), support vector machine (SVM), and extreme gradient boosting (XGBoost), were employed to train prediction models using nonzero coefficient features. The optimal ultrasomics model was determined using a ROC curve and utilized for subsequent analysis. Clinical-ultrasonic features were assessed using both univariate and multivariate logistic regression. An ultrasomics nomogram model, integrating both ultrasomics and clinical-ultrasonic features, was developed.

A total of 107 EUS-based ultrasomics features were extracted, and 6 features with nonzero coefficients were ultimately retained. Among the eight ultrasomics models based on machine learning algorithms, the RF model exhibited superior performance with an AUC= 0.999 (95% CI 0.9977 - 1.0000) in the training cohort and an AUC= 0.649 (95% CI 0.5215 - 0.7760) in the test cohort. A clinical-ultrasonic model was established and evaluated, yielding an AUC of 0.999 (95% CI 0.9961 - 1.0000) in the training cohort and 0.847 (95% CI 0.7543 - 0.9391) in the test cohort. Subsequently, the ultrasomics nomogram demonstrated a significant improvement in prediction accuracy in the test cohort, as evidenced by an AUC of 0.884 (95% CI 0.8047 - 0.9635) and confirmed by the Delong test. The calibration curve and decision curve analysis (DCA) depicted this ultrasomics nomogram demonstrated superior accuracy. They also yielded the highest net benefit for clinical decision-making compared to alternative models.

A novel ultrasomics nomogram was proposed and validated, that integrated clinical-ultrasonic and ultrasomics features obtained through EUS, aiming to accurately and efficiently identify pancreatic cancer and PNET.

Background and study aims The optimal number of needle passes during endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) is not yet established. We aimed to perform a per-pass analysis of the diagnostic accuracy of EUS-FNB of solid pancreatic lesions using a 22G Franseen needle. Patients and methods Consecutive patients with solid pancreatic lesions referred to 11 Italian centers were prospectively enrolled. Three needle passes were performed; specimens were collected after each pass and processed individually as standard histology following macroscopic on-site evaluation (MOSE) by the endoscopist. The primary endpoint was diagnostic accuracy of each sequential pass. Final diagnosis was established based on surgical pathology or a clinical course of at least 6 months. Secondary endpoints were specimen adequacy, MOSE reliability, factors impacting diagnostic accuracy, and procedure-related adverse events. Results A total of 504 samples from 168 patients were evaluated. Diagnostic accuracy was 90.5% (85.0%-94.1%) after one pass and 97.6% (94.1%-99.3%) after two passes ( P =0.01). Similarly, diagnostic sensitivity and sample adequacy were significantly higher adding the second needle pass (90.2%, 84.6%-94.3% vs 97.5%, 93.8%-99.3%, P =0.009 and 91.1%, 85.7%-94.9% vs 98.2%, 95.8%-99.3%, P =0.009, one pass vs two passes, respectively). Accuracy, sensitivity, and adequacy remained the same after the third pass. The concordance between MOSE and histological evaluation was 89.9%. The number of passes was the only factor associated with accuracy. One case of mild acute pancreatitis (0.6%) was managed conservatively. Conclusions At least two passes should be performed for the diagnosis of solid pancreatic lesions. MOSE is a reliable tool to predict the histological adequacy of specimens.

Pancreatic Neuroendocrine Neoplasms (PanNENs) are characterized by a highly heterogeneous clinical and biological behavior, making their diagnosis challenging. PanNENs diagnostic work-up mainly relies on biochemical markers, pathological examination, and imaging evaluation. The latter includes radiological imaging (i.e. computed tomography [CT] and magnetic resonance imaging [MRI]), functional imaging (i.e. 68Gallium [68 Ga]Ga-DOTA-peptide PET/CT and Fluorine-18 fluorodeoxyglucose [18F]FDG PET/CT), and endoscopic ultrasound (EUS) with its associated procedures.

This review provides a comprehensive assessment of the recent advancements in the PanNENs diagnostic field. PubMed and Embase databases were used for the research, performed from inception to October 2023.

A deeper understanding of PanNENs biology, recent technological improvements in imaging modalities, as well as progresses achieved in molecular and cytological assays, are fundamental players for the achievement of early diagnosis and enhanced preoperative characterization of PanNENs. A multimodal diagnostic approach is required for a thorough disease assessment.

To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to predict the pathological grade of pancreatic neuroendocrine tumors (pNETs) in a non-invasive manner.

Patients with pNETs who underwent contrast-enhanced abdominal CT between 2010 and 2022 were included in this retrospective study. Radiomics features were extracted, and five radiomics-based ML models, namely logistic regression (LR), random forest (RF), support vector machine (SVM), XGBoost, and GaussianNB, were developed. The performance of these models was evaluated using a time-independent testing set, and metrics such as sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were calculated. The accuracy of the radiomics model was compared to that of needle biopsy. The Shapley Additive Explanation (SHAP) tool and the correlation between radiomics and biological features were employed to explore the interpretability of the model.

A total of 122 patients (mean age: 50 ± 14 years; 53 male) were included in the training set, whereas 100 patients (mean age: 48 ± 13 years; 50 male) were included in the testing set. The AUCs for LR, SVM, RF, XGBoost, and GaussianNB were 0.758, 0.742, 0.779, 0.744, and 0.745, respectively, with corresponding accuracies of 73.0%, 70.0%, 77.0%, 71.9%, and 72.9%. The SHAP tool identified two features of the venous phase as the most significant, which showed significant differences among the Ki-67 index or mitotic count subgroups (p < 0.001).

An interpretable radiomics-based RF model can effectively differentiate between G1 and G2/3 of pNETs, demonstrating favorable interpretability.

The radiomics-based interpretable model developed in this study has significant clinical relevance as it offers a non-invasive method for assessing the pathological grade of pancreatic neuroendocrine tumors and holds promise as an important complementary tool to traditional tissue biopsy.

• A radiomics-based interpretable model was developed to predict the pathological grade of pNETs and compared with preoperative needle biopsy in terms of accuracy. • The model, based on CT radiomics, demonstrated favorable interpretability. • The radiomics model holds potential as a valuable complementary technique to preoperative needle biopsy; however, it should not be considered a replacement for biopsy.

Gallbladder (GB) disease is classified into two broad categories: GB wall-thickening and protuberant lesions, which include various lesions, such as adenomyomatosis, cholecystitis, GB polyps, and GB carcinoma. This review summarizes recent advances in the differential diagnosis of GB lesions, focusing primarily on endoscopic ultrasound (EUS) and related technologies. Fundamental B-mode EUS and contrast-enhanced harmonic EUS (CH-EUS) have been reported to be useful for the diagnosis of GB diseases because they can evaluate the thickening of the GB wall and protuberant lesions in detail. We also outline the current status of EUS-guided fine-needle aspiration (EUS-FNA) for GB lesions, as there have been scattered reports on EUS-FNA in recent years. Furthermore, artificial intelligence (AI) technologies, ranging from machine learning to deep learning, have become popular in healthcare for disease diagnosis, drug discovery, drug development, and patient risk identification. In this review, we outline the current status of AI in the diagnosis of GB.

Insulinomas are the most common functional pancreatic neuroendocrine tumors (PNETs) that lead to incapacitating hypoglycemia. Guidelines recommend surgical resection as the mainstay of management. However, surgery is fraught with complications, causing significant peri/post-operative morbidity. Since insulinomas are usually benign, solitary, small (<2 cm), and do not need lymphadenectomy, hence, in this regard, endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is now being increasingly performed, to circumvent these adverse events and impairment of pancreatic function.

A comprehensive literature search was undertaken across various databases (PubMed/MEDLINE, Embase, Scopus), with no language restriction, for relevant articles (case series, reviews, case reports) pertaining to EUS-RFA for insulinoma and PNETs, till October 2023. In this review, we have explicated the role of EUS-RFA for insulinoma management, detailing thoroughly its mechanism of action, EUS-RFA devices with data on its safety and efficacy, and an algorithmic approach for its management.

EUS-RFA is being advocated as a 'mini-invasive' option with the potential to replace surgery as a first-line approach for benign, sporadic, solitary, and small (<2 cm) insulinomas. Under real-time guidance, EUS-RFA has immense precision, is safe, predictable, with acceptable safety profile. Presently, it is being frequently performed for high-risk or inoperable candidates. Current need-of-the-hour is a randomized controlled trial to substantiate its role in the therapeutic algorithm for insulinoma management.

Due to their aspecific macroscopic appearance, uncommon pancreatic cystic lesions (PCLs) are often misdiagnosed as mucinous lesions and improperly resected. We aimed to evaluate the endoscopic ultrasound (EUS)-guided through-the-needle biopsy (TTNB) capacity of the preoperative diagnosis of uncommon PCLs. Overall, 136 patients with PCLs who underwent EUS-TTNB between 2016 and 2022 were retrospectively identified. Common histotypes (e.g., IPMN, serous cystadenoma, and mucinous cystadenoma) were excluded and 26 (19.1%) patients (15 female, mean age 52.9 ± 10.4) were analyzed. The EUS findings, adverse events (AEs), and TTNB outcomes in uncommon PCLs were evaluated. The cysts histotype was accurately diagnosed by TTNB in 24/26 (92.3%) cases (seven cystic neuroendocrine tumors, four squamoid cysts, three acinar cells cystadenomas, two lymphoepithelial cysts, two mucinous non-neoplastic cysts, two bronchogenic cysts, two cystic lymphangiomas, one solid-pseudopapillary neoplasm, and one schwannoma). In the remaining two cases, lymphangioma was eventually diagnosed after resection. Surgery was performed in 15/26 (57.7%) patients. The mean follow-up of non-surgical patients was 32.5 months. One severe acute case of pancreatitis (3.8%) that required surgery occurred after EUS-TTNB. Uncommon pancreatic/peripancreatic lesions represent the 19.1% of PCLs in our series, with mainly benign histotypes. TTNB demonstrated a high diagnostic performance with a low rate of AEs in this setting, representing a reliable tool with which to avoid useless surgery.

Neuroendocrine neoplasms (NENs) are a group of neoplasms arising from neuroendocrine cells. The worldwide incidence and prevalence of the NENs are estimated to be 6/100,000 and 35/100,000, respectively. Those numbers are increasing every decade, requiring higher and higher diagnosis and treatment costs. Radioligand therapy (RLT) using beta-emitting radioisotopes is an efficient and relatively safe method of treatment, typically used as a second-line treatment. RLT tolerability is higher than other available pharmacotherapies (chemotherapy or tyrosine kinase inhibitors). Recent studies show an increase in overall survival among patients treated with RLT. The present study aimed to learn the epidemiology of NENs in Poland and assess the effectiveness of RLT in a high-reference center. A prospective analysis of 167 patients treated with RLT in one of Poland's highest-reference NEN centers was performed. The analysis covered 66 months of observation (1 December 2017-30 May 2023), during which 479 RLT single administrations of radioisotope were given. The standard procedure was to give four courses of [177Lu]Lu-DOTA-TATE alone, or tandem therapy-[177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE. Grading analysis showed that most patients had non-functioning G2 NEN with a mean Ki-67 of 6.05% (SD ± 6.41). The most common primary tumor location was the pancreas. Over two-thirds of patients did undergo surgery due to primary tumors or distant metastases. The majority of patients were using lanreotide as a chronically injected somatostatin analog. Median progression-free survival (PFS) on somatostatin analogs was 21.0 (IQR = 29.0) months. Directly after the last course of RLT, disease stabilization was noted in 69.46% of patients, partial regression was noted in 20.36% of patients, complete regression was noted in 0.60% of patients, and progression was noted in 9.58% of patients. In long-term follow-up, the median observation time among patients who underwent four treatment cycles (n = 108) was 29.8 (IQR = 23.9) months. Stabilization of the disease was observed in 55.56% of the patients and progression was observed in 26.85% of the patients, while 17.59% of patients died. Median PFS was 29.3 (IQR 23.9), and the median OS was 34.0 months (IQR 16.0). The mean age of NEN diagnosis is the sixth decade of life. It takes almost three years from NEN diagnosis to the start of RLT. In long-term observation, RLT leads to disease stabilization in over half of the patients with progressive disease. No differences in PFS or OS depend on the radioisotope used for RLT. In Poland, organized coordination of NEN treatment in high-reference centers ensures the continuity of patient care.

Pancreatic vasoactive intestinal peptide-producing tumor (VIPoma) is a rare functional neuroendocrine tumor most commonly presenting with watery diarrhea and electrolyte abnormalities that include hypokalemia, hypercalcemia and metabolic acidosis. This type of tumor has usually insidious clinical behavior that is characterized by chronic secretory diarrhea, lasting usually from months to years before diagnosis, not responsive to usual medical or dietary treatment approaches. Given the resemblance of VIPoma with other more common causes of chronic watery diarrhea, the final diagnosis is often delayed and the tumors are usually large and metastatic at the time of detection. Our case of pancreatic VIPoma demonstrates an unusual clinical course for this type of tumor with acute refractory diarrhea and rapid deterioration of patient's clinical and biochemical status that required emergent in-hospital diagnosis and treatment. Our patient is a 45-year-old woman who presented with abrupt, watery diarrhea during the past 24 h before admission accompanied with severe hypokalemia as well as hyponatremia, hyperglycemia and hypercalcemia. Despite aggressive management with fluid administration and electrolyte replenishment, no significant improvement in patient's symptoms and electrolyte imbalance was observed. After exclusion of other causes of acute diarrhea from the medical history and the laboratory tests, the clinical suspicion of a functional neuroendocrine tumor was raised. After the establishment of final diagnosis of pancreatic VIPoma with biochemical tests and magnetic resonance imaging (MRI), somatostatin analogues were prescribed and the patient underwent distal pancreatectomy and splenectomy with no signs of lymph node and splenic metastases. Few days after the surgical resection of the tumor, the patient readmitted to our hospital with tarry stools and severe anemia. The abdominal computed tomography (CT) revealed a retroperitoneal cystic lesion. The gastrointestinal bleeding gradually recessed after endoscopic hemostasis of duodenal ulcer lesions whereas the cystic lesion (postoperative lymphocele) was successfully drained under CT-guidance before discharge. After almost 10 years postoperatively, the patient is still asymptomatic with no signs of relapse or metastasis of the disease in the periodic laboratory and imaging follow-up. In conclusion, pancreatic VIPoma can sometimes manifest symptoms of abrupt onset and rapid progression that require high clinical suspicion, appropriate diagnostic workup and aggressive management.

Neuroendocrine neoplasms (NENs), also called neuroendocrine tumors (NETs), are relatively uncommon, heterogenous tumors primarily originating in the gastrointestinal tract. With the improvement in technology and increasing use of cross-sectional imaging and endoscopy, they are being discovered with increasing frequency. Although traditionally considered indolent tumors with good prognoses, some NENs exhibit aggressive behavior. Timely diagnosis, risk stratification, and management can often be a challenge. In general, small NENs without local invasion or lymphovascular involvement can often be managed using minimally invasive advanced endoscopic techniques, while larger lesions and those with evidence of lymphovascular invasion require surgery, systemic therapy, or a combination thereof. Ideal management requires a comprehensive and accurate understanding of the stage and grade of the tumor. With the recent advancements, a therapeutic advanced endoscopist can play a pivotal role in diagnosing, staging, and managing this rare condition. High-definition white light imaging and digital image enhancing technologies like narrow band imaging (NBI) in the newer endoscopes have improved the diagnostic accuracy of traditional endoscopy. The refinement of endoscopic ultrasound (EUS) over the past decade has revolutionized the role of endoscopy in diagnosing and managing various pathologies, including NENs. In addition to EUS-directed diagnostic biopsies, it also offers the ability to precisely assess the depth of invasion and lymphovascular involvement and thus stage NENs accurately. EUS-directed locoregional ablative therapies are increasingly recognized as highly effective, minimally invasive treatment modalities for NENs, particularly pancreatic NENs. Advanced endoscopic resection techniques like endoscopic submucosal dissection (ESD), endoscopic submucosal resection (EMR), and endoscopic full-thickness resection (EFTR) have been increasingly used over the past decade with excellent results in achieving curative resection of various early-stage gastrointestinal luminal lesions including NENs. In this article, we aim to delineate NENs of the different segments of the gastrointestinal (GI) tract (esophagus, gastric, pancreatic, and small and large intestine) and their management with emphasis on the endoscopic management of these tumors.

The purpose of this study was to compare the sonographic features of primary hepatic neuroendocrine tumors (PHNETs) to those of non-hepatitis B and non-hepatitis C hepatocellular carcinoma (NBNC-HCC) on contrast-enhanced ultrasound (CEUS).

Fourteen patients with a mean age of 56.9 ± 12.2 (SD) years with histopathologically confirmed PHNET were included in the study. Twenty-eight patients with a mean age of 58.5 ± 10.4 years with histopathologically confirmed NBNC-HCC were randomly selected as the control group. The clinical data, conventional ultrasound and CEUS features were retrospectively analyzed between PHNET and NBNC-HCC.

PHNET was more common in women (57.1%, 8/14 cases), and NBNC-HCC was more common in men (75.0%, 21/28) (P=0.040). No significant differences were observed in etiology, tumor marker, and liver function between the two group (P>0.05). Conventional ultrasound revealed that the tumor size of PHNET (10.1 ± 4.7 cm) was larger than that of NBNC-HCC (5.9 ± 3.8 cm) (P=0.006). NBNC-HCC was predominantly hypoechoic, while the echogenicity of PHNET varied (P=0.001). On CEUS, 57.1% (8/14) of PHNETs showed heterogeneous hyperenhancement, whereas 77.0% (21/28) of NBNC-HCC presented homogeneous hyperenhancement (P=0.015). Furthermore, 35.7% (5/14) of PHNETs showed early washout (onset of washout <60 s), which was significantly different from that of NBNC-HCC (3.7%, 1/28) (P=0.005).

CEUS is helpful in discriminating between PHNET and NBNC-HCC. PHNETs mainly present as a single mass with a large size (>10 cm) in the liver. The CEUS showed that most PHNETs exhibited heterogeneous enhancement in the arterial phase, washout in the portal venous and late phases and early washout being more likely than NBNC-HCC. However, more imaging features need to be evaluated in a larger sample.

Death domain-associated protein (DAXX) and/or α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes mutations and alternative lengthening of telomeres (ALT) activation are associated with more aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PanNETs). We aimed to evaluate the reliability of such markers on endoscopic-ultrasound fine-needle biopsy (EUS-FNB) specimens.

Patients who underwent EUS-FNB and subsequent surgical resection for PanNETs between January 2017 and December 2019 were retrospectively identified. Immunohistochemistry (IHC) to evaluate DAXX/ATRX expression and fluorescence in situ hybridization (FISH) for ALT status were performed. Primary outcome was the concordance rate of markers expression between EUS-FNB and surgical specimens. Secondary aims were association between markers and lesion aggressiveness, their diagnostic performance in predicting aggressiveness, and agreement of preoperative and post-surgical Ki67-based grading.

Forty-one NF-PanNETs (mean diameter 36.1 ± 26.5 mm) were included. Twenty-four showed features of lesion aggressiveness. Concordance of expressions of DAXX, ATRX, and ALT status between EUS-FNB and surgical specimens were 95.1% (κ = 0.828; p < 0.001), 92.7% (κ = 0.626; p < 0.001), and 100% (κ = 1; p < 0.001), respectively. DAXX/ATRX loss and ALT-positivity were significantly (p < 0.05) associated with metastatic lymphnodes and lymphovascular invasion. The combination of all tumor markers (DAXX/ATRX loss + ALT-positivity + grade 2) reached an accuracy of 73.2% (95%CI 57.1-85.8) in identifying aggressive lesions. Pre- and post-operative ki-67-based grading was concordant in 80.5% of cases (k = 0.573; p < 0.001).

DAXX/ATRX expression and ALT status can be accurately evaluated in a preoperative setting on EUS-FNB samples, potentially improving the identification of patients with increased risk and poorer prognosis.

Gastrointestinal Stromal Tumors (GISTs) are subepithelial lesions (SELs) that commonly develop in the gastrointestinal tract. GISTs, unlike other SELs, can exhibit malignant behavior, so differential diagnosis is critical to the decision-making process. Endoscopic ultrasound (EUS) is considered the most accurate imaging method for diagnosing and differentiating SELs in the gastrointestinal tract by assessing the lesions precisely and evaluating their malignant risk. Due to their overlapping imaging characteristics, endosonographers may have difficulty distinguishing GISTs from other SELs using conventional EUS alone, and the collection of tissue samples from these lesions may be technically challenging. Even though it appears to be less effective in the case of smaller lesions, histology is now the gold standard for achieving a final diagnosis and avoiding unnecessary and invasive treatment for benign SELs. The use of enhanced EUS modalities and elastography has improved the diagnostic ability of EUS. Furthermore, recent advancements in artificial intelligence systems that use EUS images have allowed them to distinguish GISTs from other SELs, thereby improving their diagnostic accuracy.

Introduction: The development of dedicated endoscopes and the technical evolution of endoscopic ultrasound (EUS) have allowed a direct approach to pancreatic neoplastic lesions both for diagnosis and treatment. Among the more promising targets are pancreatic neuroendocrine tumors (Pan-NETs). Aim: to describe the evolution of endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) with particular attention to the treatment of PanNETs, focusing on safety and clinical efficacy of the technique. Methods: MEDLINE, Scopus, and Cochrane Library databases were searched for studies reporting about EUS-RFA for the treatment of PanNETs. Studies with outcomes of interest were selected and results were reported to describe clinical success, complications, fol-low-ups, and electrodes used. Clinical success was defined as the disappearance of clinical symp-toms for functional (F-) PanNETs and as complete ablation per nonfunctional (NF)-PanNETs. The pooled data were analyzed by a random-effects model. Results: Nineteen studies were selected, including 183 patients (82 males, 44.8%) with 196 lesions (101 F-PanNETs and 95 NF-PanNETs). Pooled estimates for the overall AE rates for the clinical efficacy were 17.8% (95% CI 9.1-26.4%) and 95.1% (95% CI 91.2-98.9%) for F-PanNETs and 24.6% (95% CI 7.4-41.8%) and 93.4% (95% CI 88.4-98.4%) for NF-PanNETs. Conclusions: EUS-RFA appears to be a mini-invasive technique with a good safety and efficacy profile for the treatment of F- and NF-PanNETs. EUS-RFA could be of-fered as possible alternative to surgery for the treatment of low-grade NF- or F-PanNETs, especially for those patients that are not eligible or are at high-risk for surgery.

We retrospectively aimed to assess the prognostic significance of somatostatin receptor (SSTR) standardized uptake value (SUVmax_sstr), SSTR representative tumor volume (RTV_sstr) and total lesion SSTR expression (TL_sstr) obtained by [⁶⁸Ga]Ga-edotreotide PET/CT ([⁶⁸Ga]Ga-SSTR PET/CT) in patients with primary gastroenteropancreatic neuroendocrine tumors (GEP-NET) before surgery.

We analyzed patients who underwent [⁶⁸Ga]Ga-SSTR PET/CT 3-6 weeks before surgery from February 2020 to April 2022. The mean SUVmax_sstr value, the RTV_sstr (cm3; 42% threshold) and the TL_sstr (g) were registered. Thereafter the patients were followed up 10.3 months (range 3-27). The PET/CT results were compared to the event free survival (EFS).

Forty-two patients (61 ± 13 years) have been enrolled. At multivariate analysis only RTV_sstr values were predictive. The Kaplan-Meier survival analysis for RTV_sstr showed a significant better EFS in patients presenting lower values as compared to those having greater (P = .003, log-rank test). SUVmax_sstr was not suitable for predicting EFS, TL_sstr mildly.

RTV_sstr represents a valuable volumetric parameter able to predict the outcome in GEP-NET patients who underwent surgery. The magnitude of the SSTR representative tumor burden holds a predominant value for determining the response to therapy in GEP-NET patients before surgery, rather than the maximal SSTR representation at single voxel.

The objective of this study was to determine the prognostic value of lymph node (LN) involvement and the LN ratio (LNR) and their effect on recurrence rates and survival in patients with pancreatic neuroendocrine tumors (PNETs) undergoing surgery. This single-center retrospective study reviewed the medical records of 95 consecutive patients diagnosed with PNETs who underwent surgery at our medical center between 1997 and 2017. The retrieved information included patient demographics, pathology reports, treatments, and oncological outcomes. Results: 95 consecutive potentially suitable patients were identified. The 78 patients with PNETs who underwent surgery and for whom there was adequate data were included in the analysis. Their mean ± standard deviation age at diagnosis was 57.4 ± 13.4 years (range 20-82), and there were 50 males (64%) and 28 females (36%). 23 patients (30%) had LN metastases (N1). The 2.5- and 5-year disease-free survival (DFS) rates for the entire cohort were 79.5% and 71.8%, respectively, and their 2- and 5-year overall survival (OS) rates were 85.9% and 82.1%, respectively. The optimal value of the LNR was 0.1603, which correlated with the outcome (2-year OS p = 0.002 HR = 13.4 and 5-year DFS p = 0.016 HR = 7.2, respectively, and 5-year OS and 5-year DFS p = 0.004 HR = 9 and p = 0.001 HR = 10.6, respectively). However, the multivariate analysis failed to show that the LNR was an independent prognostic factor in PNETs. Patients with PNETs grade and stage are known key prognostic factors influencing OS and DFS. According to our results, LNR failed to be an independent prognostic factor.

Objective: To investigate whether the dynamic contrast-enhanced ultrasound (DCE-US) analysis and quantitative parameters could be helpful for predicting histopathologic grades of pancreatic neuroendocrine tumors (pNETs). Methods: This retrospective study conducted a comprehensive review of the CEUS database between March 2017 and November 2021 in Zhongshan Hospital, Fudan University. Ultrasound examinations were performed by an ACUSON Sequioa unit equipped with a 3.5 MHz 6C−1 convex array transducer, and an ACUSON OXANA2 unit equipped with a 3.5 MHz 5C−1 convex array transducer. SonoVue® (Bracco Inc., Milan, Italy) was used for all CEUS examinations. Time intensity curves (TICs) and quantitative parameters of DCE-US were created by Vuebox® software (Bracco, Italy). Inclusion criteria were: patients with histopathologically proved pNETs, patients who underwent pancreatic B-mode ultrasounds (BMUS) and CEUS scans one week before surgery or biopsy and had DCE-US imaging documented for more than 2 min, patients with solid or predominantly solid lesions and patients with definite diagnosis of histopathological grades of pNETs. Based on their prognosis, patients were categorized into two groups: pNETs G1/G2 group and pNETs G3/pNECs group. Results: A total of 42 patients who underwent surgery (n = 38) or biopsy (n = 4) and had histopathologically confirmed pNETs were included. According to the WHO 2019 criteria, all pNETs were classified into grade 1 (G1, n = 10), grade 2 (G2, n = 21), or grade 3 (G3)/pancreatic neuroendocrine carcinomas (pNECs) (n = 11), based on the Ki−67 proliferation index and the mitotic activity. The majority of the TICs (27/31) of pNETs G1/G2 were above or equal to those of pancreatic parenchyma in the arterial phase, but most (7/11) pNETs G3/pNECs had TICs below those of pancreatic parenchyma from arterial phase to late phase (p < 0.05). Among all the CEUS quantitative parameters of DCE-US, values of relative rise time (rPE), relative mean transit time (rmTT) and relative area under the curve (rAUC) were significantly higher in pNETs G1/G2 group than those in pNETs G3/pNECs group (p < 0.05). Taking an rPE below 1.09 as the optimal cut-off value, the sensitivity, specificity and accuracy for prediction of pNETs G3/pNECs from G1/G2 were 90.91% [58.70% to 99.80%], 67.64% [48.61% to 83.32%] and 85.78% [74.14% to 97.42%], respectively. Taking rAUC below 0.855 as the optimal cut-off value, the sensitivity, specificity and accuracy for prediction of pNETs G3/pNECs from G1/G2 were 90.91% [66.26% to 99.53%], 83.87% [67.37% to 92.91%] and 94.72% [88.30% to 100.00%], respectively. Conclusions: Dynamic contrast-enhanced ultrasound analysis might be helpful for predicting the pathological grades of pNETs. Among all quantitative parameters, rPE, rmTT and rAUC are potentially useful parameters for predicting G3/pNECs with aggressive behavior.

Pancreatic neuroendocrine tumor (PNET) behavior assessment is a daily challenge for physicians. Modern PNET management varies from a watch-and-wait strategy to surgery depending on tumor aggressiveness. Therefore, the aggressiveness definition plays a pivotal role in the PNET work-up. The aggressiveness of PNETs is mainly based on the dimensions and histological grading, with sometimes a lack of specificity and sensibility. In the last twenty years, EUS has become a cornerstone in the diagnostic phase of PNET management for its high diagnostic yield and the possibility of obtaining a histological specimen. The number of EUS applications in the PNET work-up has been rapidly increasing with new and powerful possibilities. The application of contrast has led to an important step in PNET detection; in recent years, it has been gaining interesting applications in aggressiveness assessment. In this review, we underline the latest experiences and opportunities in the behavior assessment of PNETs using contact-enhanced EUS and contested enhanced harmonic EUS with a particular focus on the future application and possibility that these techniques could provide.

Pancreatic neuroendocrine neoplasms (PNETs) are rare but can be associated with significant morbidity and mortality. PNETs can be difficult to diagnose and have a propensity for metastasis before their diagnosis is established. To this end, many PNETs do not become apparent until late in their clinical course. Endoscopic ultrasound (EUS) has become the modality of choice for detecting these lesions due to its high tumor detection rate. Additionally, therapeutic techniques have arisen from EUS which allow for the treatment of PNETs. Overall, EUS has become a powerful diagnostic and therapeutic modality for addressing pancreatic lesions such as PNETs. In this perspective article, we provide an overview of the therapeutic potentials of EUS in the management of PNETs.