Dijkum, Els J.�M. Nieveen van

Abstract Pancreatic neuroendocrine tumors (PanNETs) have an age-adjusted incidence of 1.5 per 100,000 people, with a notable rise in the incidence of small (≤2 cm) non-functional PanNETs (NF-PanNETs) in recent decades. While surgery is traditionally the preferred treatment for localized NF-PanNETs, active surveillance is now an accepted management strategy for tumors smaller than 2 cm due to their relatively benign behavior. However, this approach has not yet been fully integrated into routine clinical practice. There is considerable histopathological heterogeneity observed in NF-PanNETs, which results in significant variability in clinical presentation, behavior and treatment outcomes. Hence, tumor size alone does not provide sufficient certainty regarding a benign clinical course for decision-making. Although studies advocate for incorporating WHO grade into clinical prognostic assessments, this marker also has limitations. Several established tissue-based markers, such as ATRX and DAXX alterations, alternative lengthening of telomeres, and copy number variations, can be used for PanNET subtyping and correlate with metastatic risk. Combining these markers with traditional histopathological parameters may yield a more comprehensive and accurate prognostic assessment. This review discusses the advantages and limitations of current prognostication methods for small NF-PanNETs and highlights recently established prognostic markers, along with the requirements for their implementation into routine clinical practice. It also proposes practical solutions to address the challenges associated with the immediate integration of these biomarkers into routine care.

Background: A potential downside of robotic pancreatoduodenectomy (RPD) is the lack of tactile feedback when tying sutures, which could be especially perilous during pancreatic anastomosis. Near-infrared fluorescence imaging with indocyanine green (NIRF-ICG) could detect transpancreatic-suture-induced hypoperfusion of the pancreatic stump during RPD, which may be related to postoperative pancreatic fistula (POPF) grade B/C, but studies are lacking. Methods: This prospective study included 37 patients undergoing RPD to assess the relation between pancreatic stump hypoperfusion as objectified with NIRF-ICG using Firefly and the rate of POPF grade B/C. In 27 patients, NIRF-ICG was performed after tying down the transpancreatic U-sutures. In 10 ‘negative control’ patients, NIRF-ICG was performed before tying these sutures. Results: Pancreatic stump hypoperfusion was detected using NIRF-ICG in 9/27 patients (33%) during RPD. Hypoperfusion was associated with POPF grade B/C (67% [6/9 patients] versus 17% [3/18 patients], P = 0.026). No hypoperfusion was objectified in 10 ‘negative controls’. Conclusions: Transpancreatic-suture-induced pancreatic stump hypoperfusion can be detected using NIRF-ICG during RPD and was associated with POPF grade B/C. Surgeons could use NIRF-ICG to adapt their suturing approach during robotic pancreatico-jejunostomy. Further larger prospective studies are needed to validate the association between transpancreatic-suture-induced hypoperfusion and POPF.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.