Dermot O'TOole

Management of Zollinger–Ellison syndrome (ZES) in patients with multiple endocrine neoplasia type 1 (MEN1) remains controversial, particularly in non‐metastatic disease where the role of surgery is debated. In contrast, treatment of metastatic disease is guided by established systemic approaches. We aimed to evaluate stage‐dependent clinical decision‐making in MEN1‐related ZES using standardized clinical vignettes across ENETS Centers of Excellence (CoEs). A questionnaire‐based study using two clinical vignettes was conducted by the ENETS MEN1 Task Force across all 68 ENETS CoEs, with a predefined participation target of 70%. Additional non‐ENETS expert centers were also invited. Dedicated multidisciplinary teams provided institutional consensus responses. Scenarios included non‐metastatic disease, locally metastatic disease, and distant metastatic disease. Centers were stratified by volume using a cutoff of 30 MEN1 patients in active care. Data were analyzed descriptively, comparing management strategies between low‐ and high‐volume centers. Fifty‐seven centers participated (52 of 68 ENETS CoEs [76.5%] and 5 additional non‐ENETS expert centers). All 57 centers completed the questionnaire in full. All cases received symptomatic therapy with proton pump inhibitors. In non‐metastatic disease, management was heterogeneous, with 56.1% recommending surgery. Centre volume strongly influenced decisions (73.1% vs. 41.9% surgery in low‐ vs. high‐volume centers, p = .018). Preferred surgical approaches included duodenotomy with regional lymphadenectomy (43.9%) and the Thompson procedure (left pancreatectomy, duodenal exploration with excision of tumors and node dissection, enucleation of pancreatic head lesions; 26.3%). In locally metastatic disease, surgical management increased to 78.9%, with a shift toward more extensive procedures including pancreaticoduodenectomy (35.1%). In distant metastatic disease, somatostatin analogues were the systemic therapy of choice (50.9%), followed by curative‐intent surgery with pancreaticoduodenectomy or duodenotomy with regional lymphadenectomy combined with liver resection or thermal ablation of liver lesions (35.1%), while no other systemic treatments were selected by any center. A liver biopsy was recommended by 43.9% of centers. Management of MEN1‐related ZES demonstrates stage‐dependent convergence. In early disease, decision‐making—particularly regarding surgical versus medical management—is highly variable and influenced by center experience, whereas advanced disease shows more consistent, guideline‐aligned treatment patterns. The high participation rate across ENETS CoEs suggests that these findings are likely to be relevant to expert neuroendocrine tumor practice.

INTRODUCTION: Type 1 gastric neuroendocrine tumors (T1g-NETs) are well-differentiated lesions with excellent survival but frequent recurrence. Tumor size is the main prognostic factor, yet optimal management for tumors >1 cm remains uncertain. This study aimed to evaluate treatment strategies and outcomes in patients with T1g-NETs>1 cm. METHODS: We conducted a retrospective multicenter study including 106 adults with T1g-NETs >1 cm. Clinicopathologic and management data were collected. The primary outcome event was a composite unfavorable outcome, defined as recurrence or progression, used to analyze progression-free survival (PFS) as the main time-to-event outcome. Analyses included multinomial logistic regression, Cox models, and Kaplan–Meier curves ( P < 0.05). RESULTS: Among 106 patients (58.5% female; median age 59), median tumor size was 15 mm. Most tumors were Grade 1 (61.4%) or Grade 2 (37.7%), with median Ki-67 of 2%. Endoscopic resection was performed in 76 patients (71.7%), surgery in 33 (31.1%, including 13 initially treated endoscopically), and 10 (9.4%) were surveilled. Over a median 61-month follow-up, 24 patients (22.6%) recurred, 8 (7.5%) progressed; only 2 deaths (1.9%) were tumor-related. Larger tumors were associated with unfavorable outcome ( P = 0.005), with lesions ≥24 mm predicting shorter PFS (hazard ratio 3.93; P < 0.001). Endoscopic submucosal dissection and modified-endoscopic mucosal resection were associated with a significantly longer PFS ( P = 0.004). R0 resection showed a borderline protective effect. Five-year overall survival approached 95%. DISCUSSION: T1g-NETs > 1 cm frequently recur and may exhibit aggressive potential, particularly when lesions are larger. When endoscopic resection is feasible, endoscopic submucosal dissection or modified-endoscopic mucosal resection should be preferred to optimize outcomes.

Multiple Endocrine Neoplasia type 1 (MEN1) Clinical Practice Guidelines (2012) are predominantly based on expert opinion due to limited available evidence at the time, leaving room for interpretation and variation in practices. Evidence on the natural course of MEN1‐related neuroendocrine tumours (NET) and the value of screening programs has increased and new imaging techniques have emerged. The aim of this study is to provide insight in the current practices of screening and surveillance for MEN1‐related NETs in ENETS Centers of Excellence (CoEs). A clinical practice questionnaire was distributed among all 65 ENETS CoEs. Response rate was 91% (59/65). In 14% of CoEs 100 patients with MEN1 are seen. Practices with regard to screening and surveillance of NETs were markedly heterogeneous. Differences between countries were noted in the use of gut hormones for biochemical screening and the choice for imaging modality for screening/surveillance of pancreatic NETs (PanNETs). Magnetic resonance imaging (MRI) is the preferred modality for screening and surveillance of PanNETs, whereas this is computed tomography (CT) for thoracic NETs. Practices regarding screening for thoracic NETs were more homogeneous among larger volume CoEs, with longer screening intervals. The majority of CoEs tailored the surveillance of small pancreatic and lung NETs to observed growth rate. 68% of CoEs advise patients with clinical MEN1 with negative genetic testing to undergo periodic screening like mutation‐positive patients. In conclusion, there is still marked heterogeneity in practice, although there are also common trends. Differences were sometimes associated with volume or country, but often no association was found. This underscores the need for clear and evidence‐based practice recommendations.

Purpose of Review This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. Recent Findings In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Summary Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.

Introduction Real-world data evaluating patients’ injection experiences using the latest devices/formulations of the long-acting (LA) somatostatin analogs (SSAs) lanreotide Autogel/Depot (LAN; Somatuline®) and octreotide LA release (OCT; Sandostatin®) are limited. Methods PRESTO 2 was a 2020/2021 e-survey comparing injection experience of adults with neuroendocrine tumors (NETs) or acromegaly treated with LAN prefilled syringe versus OCT syringe for > 3 months in Canada, Ireland, the UK and the USA (planned sample size, 304). Primary endpoint: the proportion of patients with injection-site pain lasting > 2 days after their most recent injection, analyzed using a multivariate logistic regression model. Secondary endpoints included interference with daily life due to injection-site pain and technical injection problems in patients with current SSA use for ≥ 6 months. Results There were 304 respondents (acromegaly, n = 85; NETs, n = 219; LAN, n = 168; OCT, n = 136; 69.2% female; mean age, 59.6 years). Fewer patients had injection-site pain lasting > 2 days after the most recent injection with LAN (6.0%) than OCT (22.8%); the odds of pain lasting > 2 days were significantly lower for LAN than OCT, adjusted for disease subgroup and occurrence of injection-site reactions (odds ratio [95% confidence interval]: 0.13 [0.06–0.30]; p < 0.0001). Injection-site pain interfered with daily life “a little bit” or “quite a bit” in 37.2% and 3.8% (LAN) versus 52.5% and 7.5% (OCT) of patients, respectively. Among patients with ≥ 6 months’ experience with current SSA (92.4% of patients), technical injection problems never occurred in 76.8% (LAN) and 42.9% (OCT) of patients. Conclusions Compared with OCT, significantly fewer patients using LAN had injection-site pain lasting > 2 days after their most recent injection. Also, fewer LAN-treated patients experienced technical problems during injection. These findings demonstrate the importance of injection modality for overall LA SSA injection experience for patients with acromegaly or NETs. Graphical abstract

Objectives: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) occurs due to abnormal proliferation of pulmonary neuroendocrine cells. We hypothesized that performing a quantitative analysis of airway features on chest CT may reveal differences to matched controls, which could ultimately help provide an imaging biomarker. Methods: A retrospective quantitative analysis of chest CTs in patients with DIPNECH and age matched controls was carried out using semi-automated post-processing software. Paired segmental airway and artery diameters were measured for each bronchopulmonary segment, and the airway:artery (AA) ratio, airway wall thickness:artery ratio (AWTA ratio) and wall area percentage (WAP) calculated. Nodule number, size, shape and location was recorded. Correlation between CT measurements and pulmonary function testing was performed. Results: 16 DIPNECH and 16 control subjects were analysed (all female, mean age 61.7 +/− 11.8 years), a combined total of 425 bronchopulmonary segments. The mean AwtA ratio, AA ratio and WAP for the DIPNECH group was 0.57, 1.18 and 68.8%, respectively, compared with 0.38, 1.03 and 58.3% in controls (p < 0.001, p = 0.03). AA ratio correlated with FVC (R2 = 0.47, p = 0.02). A multivariable model incorporating nodule number, AA ratio and AWTA-ratio demonstrated good performance for discriminating DIPNECH and controls (AUC 0.971; 95% CI: 0.925–1.0). Conclusions: Quantitative CT airway analysis in patients with DIPNECH demonstrates increased airway wall thickness and airway:artery ratio compared to controls. Advances in knowledge: Quantitative CT measurement of airway wall thickening offers a potential imaging biomarker for treatment response.

Background: Current guidance for type 1 gastric neuroendocrine neoplasms (gNENs) recommends either resection of all visible lesions or selective resection of gNENs >10 mm. We adopt a selective strategy targeting lesions approaching 10 mm for endoscopic mucosal resection (EMR) and provide surveillance for smaller lesions. Objectives: This study aimed to describe the incidence of type 1 gNENs requiring endoscopic/surgical resection and the risk of disease progression (both considered significant disease) on endoscopic surveillance. The secondary objective was to assess the risk factors for disease progression during surveillance and the incidence of gastric dysplasia/adenoma/adenocarcinoma. Methods: We collected consecutive patients with type 1 gNENs and obtained demographic and clinical data through the electronic patient record. Results: In our cohort of 57 patients, 12 patients had EMR at index gastroscopy; 7 patients had surgery (4: large/multiple gNENs and 3: nodal metastases) (5.2% [3/57] risk of nodal metastases); and a patient with nodal and liver metastases (1.8% [1/57] risk of distant metastases). The prevalence of gastric adenocarcinoma in our study was 3.5% with an incidence rate of 9.59 per 1,000 persons per year. For patients undergoing surveillance, 29.5% (13/44) of patients progressed requiring resection. Serum gastrin was significantly higher in patients who progressed to resection (p value = 0.023). Conclusion: We concluded that up to a third of patients with type 1 gNENs have significant disease requiring resection. Hence, endoscopic surveillance and resect strategy would benefit patients.