BACKGROUND: We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival.
METHODS: Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined.
RESULTS: Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05).
CONCLUSIONS: Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.

OBJECTIVE: To explore the potential of radiomics features to predict the histologic grade of nonfunctioning pancreatic neuroendocrine tumor (NF-PNET) patients using non-contrast sequence based on MRI.
METHODS: Two hundred twenty-eight patients with NF-PNETs undergoing MRI at 5 centers were retrospectively analyzed. Data from center 1 (n = 115) constituted the training cohort, and data from centers 2-5 (n = 113) constituted the testing cohort. Radiomics features were extracted from T2-weighted images and the apparent diffusion coefficient. The least absolute shrinkage and selection operator was applied to select the most important features and to develop radiomics signatures. The area under receiver operating characteristic curve (AUC) was performed to assess models.
RESULTS: Tumor boundary, enhancement homogeneity, and vascular invasion were used to construct the radiological model to stratify NF-PNET patients into grade 1 and 2/3 groups, which yielded AUC of 0.884 and 0.684 in the training and testing groups. A radiomics model including 4 features was constructed, with an AUC of 0.941 and 0.871 in the training and testing cohorts. The fusion model combining the radiomics signature and radiological characteristics showed good performance in the training set (AUC = 0.956) and in the testing set (AUC = 0.864), respectively.
CONCLUSIONS: The developed model that integrates radiomics features with radiological characteristics could be used as a non-invasive, dependable, and accurate tool for the preoperative prediction of grade in NF-PNETs.
CONCLUSIONS: Our study revealed that the fusion model based on a non-contrast MR sequence can be used to predict the histologic grade before operation. The radiomics model may be a new and effective biological marker in NF-PNETs.
CONCLUSIONS: The diagnostic performance of the radiomics model and fusion model was better than that of the model based on clinical information and radiological features in predicting grade 1 and 2/3 of nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs). Good performance of the model in the four external testing cohorts indicated that the radiomics model and fusion model for predicting the grades of NF-PNETs were robust and reliable, indicating the two models could be used in the clinical setting and facilitate the surgeons\' decision on risk stratification. The radiomics features were selected from non-contrast T2-weighted images (T2WI) and diffusion-weighted imaging (DWI) sequence, which means that the administration of contrast agent was not needed in grading the NF-PNETs.

The potential benefits of surgical resection for small non-functional pancreatic neuroendocrine tumors (NF-PNETs) in terms of survival remain uncertain. This study aimed to evaluate the impact of surgical treatment on patients with NF-PNETs. Using SEER data, we identified 1102 patients from 2004 to 2015 with well and moderately differentiated pancreatic neuroendocrine tumors (PNETs). The associations between continuous variables and receipt of surgery were assessed using Wilcoxon rank-sum tests. Kaplan-Meier survival curves for OS were compared using the log-rank test. We compared outcomes in patients who received surgical resection with those in patients who did not, using a univariable Cox model with inverse probability weighting according to the propensity score and propensity-score matching. Among the cohort of 1102 patients, a majority of 965 individuals (87%) underwent surgical intervention. Upon conducting univariate analysis, we observed that surgical treatment significantly prolonged patients\' survival [HR = 0.41, 95% CI [0.26-0.65] P < 0.001]. However, the old [HR = 3.27, 95% CI (2.24-4.76), P 0.001], male gender [HR = 1.82, 95% CI (1.23-2.68), P = 0.003], and moderately well-differentiated factors [HR = 1.71, 95% CI (1.04-2.80), P = 0.034] were found to potentially decrease patients\' survival time. In the multivariate analysis, male gender [HR = 1.73, 95% CI (1.15-2.61), P = 0.009] and the old factor [HR = 3.52, 95% CI (2.33-5.31), P < 0.001] emerged as influential predictors with higher hazard ratios. Notably, surgical treatment remained a significant factor associated with improved overall survival [HR = 0.53, 95% CI (0.33-0.84), P = 0.007]. Propensity-score matching and inverse probability weighting were employed as analytical techniques. The univariate analysis results showed favorable outcomes in the weight group [HR = 0.48, 95% CI (0.29-0.78), P = 0.003] and matched group [HR = 0.44, 95% CI (0.22-0.85), P = 0.015], respectively. Survival analysis further confirmed that surgical treatment contributed to increased overall survival (log rank, P < 0.05) in both the matching and weight groups. Patients diagnosed with small, non-functioning pancreatic neuroendocrine tumors who undergo surgical intervention exhibit improved overall survival (OS) outcomes. Therefore, surgery is strongly recommended for this patient population.

Surgical resection is the standard of care for the treatment of pancreatic neuro-endocrine tumors (pNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1). However, surgery can cause significant short- and long-term morbidity. Magnetic resonance-guided radiotherapy (MRgRT) is a potential effective treatment with little side effects. With traditional radiotherapy techniques, irradiation of pancreatic tumors to high dose levels was hampered by poor visibility of the tumor during treatment. MRgRT uses onboard MRI to guide the treatment, thereby enabling delivery of ablative irradiation doses to the tumor, while sparing surrounding tissues. In this study, we describe results from a systematic review assessing efficacy of radiotherapy in pNET and present the protocol of the PRIME study.
PubMed, Embase and Cochrane Library were searched for articles assessing efficacy and side effects of radiotherapy for the treatment of pNETs. Risk of bias was assessed using the ROBINS-I Risk of Bias Tool for observational studies. Descriptive statistics were used to describe results of included trials.
Four studies comprising of 33 patients treated by conventional radiotherapy were included. Despite the heterogeneity of studies, radiotherapy appeared to be effective for the treatment of pNETs with most patients responding (45.5%) or stabilizing (42.4%) in tumor size.
Due to the limited literature available and concerns about damage to surrounding tissue, conventional radiotherapy is currently little used for pNETs. The PRIME study is a phase I-II trial with a single arm prospective cohort study design, investigating the efficacy of MRgRT in MEN1 patients with pNET. MEN1 patients with growing pNETs with a size between 1.0 and 3.0 cm without malignant features are eligible for inclusion. Patients are treated with 40 Gy in 5 fractions on the pNET, using online adaptive MRgRT on a 1.5T MR-linac. The primary endpoint is the change in tumor size at MRI 12 months follow-up. Secondary endpoints include radiotoxicity, quality of life, endocrine and exocrine pancreas function, resection rate, metastatic free and overall survival. When MRgRT is found effective with low radiotoxicity, it could reduce the need for surgery for pNET and preserve quality of life.
PROSPERO https://clinicaltrials.gov/, (CRD42022325542).

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are one of the most common endocrine tumors, and liver metastasis (LMs) are the most common location of metastasis from PNETS; However, there is no valid nomogram to predict the diagnosis and prognosis of liver metastasis (LMs) from PNETs. Therefore, we aimed to develop a valid predictive model to aid physicians in making better clinical decisions.
METHODS: We screened patients in the Surveillance, Epidemiology, and End Results (SEER) database from 2010-2016. Feature selection was performed by machine learning algorithms and then models were constructed. Two nomograms were constructed based on the feature selection algorithm to predict the prognosis and risk of LMs from PNETs. We then used the area under the curve (AUC), receiver operating characteristic (ROC) curve, calibration plot and consistency index (C-index) to evaluate the discrimination and accuracy of the nomograms. Kaplan-Meier (K-M) survival curves and decision curve analysis (DCA) were also used further to validate the clinical efficacy of the nomograms. In the external validation set, the same validation is performed.
RESULTS: Of the 1998 patients screened from the SEER database with a pathological diagnosis of PNET, 343 (17.2%) had LMs at the time of diagnosis. The independent risk factors for the occurrence of LMs in PNET patients included histological grade, N stage, surgery, chemotherapy, tumor size and bone metastasis. According to Cox regression analysis, we found that histological subtype, histological grade, surgery, age, and brain metastasis were independent prognostic factors for PNET patients with LMs. Based on these factors, the two nomograms demonstrated good performance in model evaluation.
CONCLUSIONS: We developed two clinically significant predictive models to aid physicians in personalized clinical decision-makings.

The purpose of this study was to examine trends in the incidence and incidence-based (IB) mortality of functional pancreatic neuroendocrine tumors(F-PNETs), and to identify factors associated with survival times.
Data were obtained from the Surveillance, Epidemiology, and End Results database from 2000 to 2017. Trends in the age-adjusted incidence of F-PNETs and IB mortality were examined using the Joinpoint Regression Program. Statistical analyses were run using chi-square tests, Kaplan-Meier curves, and the Cox proportional hazards model. Multiple imputation was used to deal with missing data.
A total of 142 patients with F-PNETs met the study inclusion criteria. It was found that the incidence of F-PNETs decreased over the study period, with an annual percent change (APC) of -2. 5% (95% CI [-4. 3, -0. 5], P<0. 05). This decrease was found to be significant for women, and also when limited to cases with distant disease or rare F-PNETs, with APCs of -4. 2% (95% CI [-7. 4, -0. 9], P<0. 05), -6. 7% (95% CI [-10. 4, -2. 8], P<0. 05), and -9. 1% (95% CI [-13. 5, -4. 4], P<0. 05), respectively. The Cox regression analysis revealed that the tumor size, tumor stage, tumor type, and surgical resection were associated with F-PNETs mortality.
This was the first population-based epidemiological study of F-PNETs and we found a continual decrease in the incidence of F-PNETs from 2000 to 2017. The prognosis and survival times were closely related to the calendar year at diagnosis, tumor stage, and tumor size.

Surufatinib, is a potent inhibitor of vascular endothelial growth factor receptors 1-3; fibroblast growth factor receptor-1; colony-stimulating factor 1 receptor. This Phase 1/1b escalation/expansion study in US patients with solid tumors evaluated 5 once daily (QD) surufatinib doses (3 + 3 design) to identify maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate safety and efficacy at the RP2D in 4 disease-specific expansion cohorts including pancreatic neuroendocrine tumors [pNET] and extrapancreatic NETs [epNET]. MTD and RP2D were 300 mg QD (escalation [n = 35]); 5 patients (15.6%) (Dose Limiting Toxicity [DLT] Evaluable Set [n = 32]) had DLTs. Pharmacokinetics were dose proportional. Estimated progression-free survival (PFS) rates at 11 months were 57.4% (95% confidence interval [CI]: 28.7, 78.2) and 51.1% (95% CI: 12.8, 80.3) for pNET and epNET expansion cohorts, respectively. Median PFS was 15.2 (95% CI: 5.2, not evaluable) and 11.5 (95% CI: 6.5,11.5) months. Response rates were 18.8% and 6.3%. The most frequent treatment-emergent adverse events (both cohorts) were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%). Pharmacokinetics, safety, and antitumor efficacy of 300 mg QD oral surufatinib in US patients with pNETs and epNETs are consistent with previously reported studies in China and may support applicability of earlier surufatinib studies in US patients. Clinical trial registration: Clinicaltrials.gov NCT02549937.

Molecular analyses have shown that tumours diagnosed as supratentorial primitive neuro-ectodermal tumours of the central nervous system (CNS-PNETs) in the past represent a heterogenous group of rare childhood tumours including high-grade gliomas (HGG), ependymomas, atypical teratoid/rhabdoid tumours (AT/RT), CNS neuroblastoma with forkhead box R2 (FOXR2) activation and embryonal tumour with multi-layered rosettes (ETMR). All these tumour types are rare and long-term clinical follow-up data are sparse. We retrospectively re-evaluated all children (0-18 years old) diagnosed with a CNS-PNET in Sweden during 1984-2015 and collected clinical data.
In total, 88 supratentorial CNS-PNETs were identified in the Swedish Childhood Cancer Registry and from these formalin-fixed paraffin-embedded tumour material was available for 71 patients. These tumours were histopathologically re-evaluated and, in addition, analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier.
The most frequent tumour types, after histopathological re-evaluation, were HGG (35%) followed by AT/RT (11%), CNS NB-FOXR2 (10%) and ETMR (8%). DNA methylation profiling could further divide the tumours into specific subtypes and with a high accuracy classify these rare embryonal tumours. The 5 and 10-year overall survival (OS) for the whole CNS-PNET cohort was 45% ± 12% and 42% ± 12%, respectively. However, the different groups of tumour types identified after re-evaluation displayed very variable survival patterns, with a poor outcome for HGG and ETMR patients with 5-year OS 20% ± 16% and 33% ± 35%, respectively. On the contrary, high PFS and OS was observed for patients with CNS NB-FOXR2 (5-year 100% for both). Survival rates remained stable even after 15-years of follow-up.
Our findings demonstrate, in a national based setting, the molecular heterogeneity of these tumours and show that DNA methylation profiling of these tumours provides an indispensable tool in distinguishing these rare tumours. Long-term follow-up data confirms previous findings with a favourable outcome for CNS NB-FOXR2 tumours and poor chances of survival for ETMR and HGG.

To evaluate the immediate results of enucleation of pancreatic neuroendocrine tumors (pNETs).
The results of enucleation of pancreatic neuroendocrine tumors (pNETs) were analyzed in 95 patients between 2016 and 2021. Functioning tumors (mean size 16.8 mm) were found in 70 patients, non-functioning (mean size 25 mm) - in 25 patients. Intraparenchymal tumors were found in 48 people, extraorganic lesion - in 47 patients.
There were 262 patients with pNETs who underwent various surgeries between 2016 and 2021. Various resections were performed in 167 (63.8%) cases, enucleations - in 95 (36.2%) patients. Traditional surgical approach was used in 65 patients. Pancreatic fistula occurred in 21 patients (type B - 17, type C - 4), while arrosive bleeding occurred in 6 patients with unfavorable outcomes in 2 cases. Minimally invasive surgeries were performed in 30 patients. Eight patients with intraparenchymal tumors required conversion to open surgery. Type B pancreatic fistula occurred in 5 patients that led to arrosive bleeding in 2 cases (hemostasis was provided by endovascular method). Comparison of intraparenchymal and extraorgan tumors regarding the incidence of pancreatic fistula revealed odds ratio 5.26 (95% CI 1.5355; 18.0323, p=0.0041). Postoperative mortality was 2.1%.
Enucleation is advisable for highly differentiated pancreatic neuroendocrine tumors up to 2 cm. Minimally invasive enucleation is indicated for extraorgan tumors. Intraparenchymal tumors significantly increase the risk of postoperative complications.
Оценка ближайших результатов энуклеации нейроэндокринных опухолей (НЭО) поджелудочной железы (ПЖ), выполненной в различных панкреатологических клиниках России.
Изучены результаты энуклеации НЭО ПЖ у 95 больных, оперированных в 2016—2021 гг. Функционирующие опухоли (средний размер 16,8 мм) были у 70 пациентов, нефункционирующие (средний размер 18 мм) — у 25, интрапаренхиматозное расположение опухоли — у 48, экстраорганное — у 47.
В клиниках за указанный период оперированы 262 пациента с НЭО ПЖ, различные резекционные операции выполнены у 167 (63,8%) из них, энуклеации — у 95 (36,2%). Традиционным доступом произведено 65 операций. Панкреатический свищ (ПС) возник у 21 (тип B у 17, тип C у 4) больного, аррозионное кровотечение при этом зарегистрировано у 6 пациентов, которое привело к смерти 2 больных. Миниинвазивные операции предприняты у 30 больных. Конверсия на открытое оперативное вмешательство потребовалась при интрапаренхиматозном расположении опухоли у 8 пациентов. ПС тип B возник у 5 больных, что привело к аррозионному кровотечению в 2 случаях (гемостаз обеспечен эндоваскулярным методом). При сравнении влияния интрапаренхиматозного и экстраорганного расположения опухоли на частоту ПС отношение шансов в двух группах составило 5,26 (95% ДИ 1,5355; 18,0323; p=0,0041). Послеоперационная летальность составила 2,1%.
Энуклеация является оправданной операцией при высокодифференцированных НЭО ПЖ размером до 2 см. Миниинвазивные варианты энуклеации показаны при экстраорганном расположении опухоли. Интрапаренхиматозная локализация опухоли статистически значимо увеличивает вероятность послеоперационных осложнений.

In the absence of rapid on-site evaluation (ROSE), it is not clear which method of tissue preparation is best to process tissue obtained from EUS guidance. Cytological smearing (CS), cell block (CB), and direct histology (DH) are the available techniques.
OBJECTIVE: To compare the diagnostic yield of three techniques of tissue preparation for EUS-guided tissue acquisition without ROSE.
METHODS: Patients who were referred for EUS-FNA of peri-gastrointestinal masses were recruited. Without ROSE, each lesion was biopsied with three needle passes, and the order in which tissue is prepared was randomized to either (i) CS + CB, (ii) CB only, or (iii) DH only. The prepared specimens were reviewed.
RESULTS: A total of 243 specimens were taken from 81 patients. Tissue diagnosis was achieved in 78/81 (96.3%) of patients, including 63 neoplasms (PDAC [n = 45], pancreatic neuroendocrine tumors [PNET; n = 4], cholangiocarcinoma [n = 5], metastatic disease [n = 4], lymphoma [n = 1], linitis plastica [n = 2], leiomyoma [n = 2]) and 15 benign pathologies (chronic pancreatitis [n = 8], reactive nodes [n = 5], inflammatory biliary stricture [n = 1], and pancreatic rest [n = 1]). The three non-diagnostic cases were found to be PDAC (n = 2) and PNET (n = 1). Sensitivity and diagnostic accuracy was highest with DH (94 and 95%), which was significantly better than that by CS + CB (43 and 54%; P = 0.0001) and CB-only preparations (32 and 48.6%; P < 0.0001). There was no significant difference between the CS + CB and CB-only arms (P > 0.22).
CONCLUSIONS: Without ROSE, our findings suggest that with just a single pass, DH should be the tissue preparation method of choice given its significantly higher diagnostic accuracy compared with CS and/or CB techniques.