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Introduction Insulinomas represent the most common functional pancreatic neuroendocrine tumors. Following preoperative localization, surgical excision is the curative treatment. It may be difficult to confirm a complete resection of insulinoma. We used intermittently scanned continuous glucose monitoring (isCGM) to record the fluctuation of interstitial glucose throughout surgery to help verify the tumor’s complete surgical excision. Materials and methods In five individuals with insulinoma undergoing laparoscopic surgery we used the isCGM system (Freestyle Libre 2 Abbott) during tumor removal in order for the surgeon to understand “in real-time” the extent of tumor removal. Results Two patients received no preoperative treatment, while three patients received medical treatment with either lanreotide (2 patients) or diazoxide (1 patient). In the non-treated patients, following tumor resection, there was a rapid interstitial glucose increase along with stabilized glucose levels thoroughly documented by intraoperative isCGM. Lanreotide treatment, on the other hand, resulted in only a minor increase in interstitial glucose. Finally, diazoxide-treated patients had a response that was intermediate between lanreotide-treated and non-treated patients. Conclusion Our findings suggest that isCGM is a useful tool to monitor the outcome of surgery during pancreatic insulinoma excision, assisting the surgical team in successfully removing the tumor. Despite the limited sample size, the results are promising, and, if validated in larger studies, they make us believe that the use of CGM systems has a definite benefit for becoming a standard in the surgical treatment of insulinomas.

IntroductionThe surgical intervention approach to insulinomas in proximity to the main pancreatic duct remains controversial. Standard pancreatic resection is recommended by several guidelines; however, enucleation (EN) still attracts surgeons with less risk of late exocrine/endocrine insufficiency, despite a higher postoperative pancreatic fistula (POPF) rate. Recently, the efficacy and safety of preoperative pancreatic stent placement before the EN have been demonstrated. Thus, a multicentre open-label study is being conducted to evaluate the efficacy and safety of stent placement in improving the outcome of EN of insulinomas in proximity to the main pancreatic duct.Methods and analysisThis is a prospective, randomised, open-label, superiority clinical trial conducted at multiple tertiary centres in China. The major eligibility criterion is the presence of insulinoma located in the head and neck of the pancreas in proximity (≤2 mm) to the main pancreatic duct. Blocked randomisation will be performed to allocate patients into the stent EN group and the direct EN group. Patients in the stent EN group will go through stent placement by the endoscopist within 24 hours before the EN surgery, whereas other patients will receive EN surgery directly. The primary outcome is the assessment of the superiority of stent placement in reducing POPF rate measured by the International Study Group of Pancreatic Surgery standard. Both interventions will be performed in an inpatient setting and regular follow-up will be performed. The primary outcome (POPF rate) will be tested for superiority with the Χ2 test. The difference in secondary outcomes between the two groups will be analysed using appropriate tests.Ethics and disseminationThe study has been approved by the Peking Union Medical College Hospital Institutional Review Board (K23C0195), Ruijin Hospital Ethics Committee (2023-314), Peking University First Hospital Ethics Committee (2024033-001), Institutional Review Board of Xuanwu Hospital of Capital Medical University (2023223-002), Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University (XJTU1AF2023LSK-473), Institutional Review Board of Tongji Medical College Tongji Hospital (TJ-IRB202402059), Ethics Committee of Tongji Medical College Union Hospital (2023-0929) and Shanghai Cancer Center Institutional Review Board (2309282-16). The results of the study will be published in an international peer-reviewed journal.Trial registration numberNCT05523778.

Abstract Context Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is rapidly emerging as feasible therapy for patients with pancreatic neuroendocrine tumors (pNETs) in selected cases, as a result of its favorable safety profile. Objective To assess the feasibility, safety, and efficacy of EUS-RFA in a cohort of patients with functional and nonfunctional pNETs (NF-pNETs). Design Data on pNET patients treated with EUS-RFA between March 2017 and October 2018 at two tertiary centers was retrospectively analyzed. Results The cohort included 18 adults (eight women, 10 men), aged 60.4 ± 14.4 years (mean ± SD), seven insulinoma patients, and 11 patients with NF-pNETs. Twenty-seven lesions with a mean diameter of 14.3 ± 7.3 mm (range 4.5 to 30) were treated. Technical success defined as typical postablative changes on a surveillance imaging was achieved in 26 out of 27 lesions. Clinical response with normalization of glucose levels was observed in all (seven of seven) insulinoma cases within 24 hours of treatment. Overall, there were no major complications 48 hours postprocedure. No clinically significant recurrences were observed during mean follow-up of 8.7 ± 4.6 months (range 2 to 21 months). Conclusions EUS-guided RFA of pNETs is a minimally invasive, safe, and technically feasible procedure for selected patients. The initial experience with endoscopic ultrasound-guided radiofrequency ablation for functional and nonfunctional pancreatic neuroendocrine tumors was found to be a safe and feasible therapeutic modality in a selected cohort of patients with small tumors.

Introduction Due to the rarity of malignant insulinoma, a lack of the literature describing factors affecting outcomes exists. Our aim was to review malignant insulinoma incidence, characteristics and survival trends. Methods We identified all patients with malignant insulinoma in the SEER registries from 1973 to 2015. Incidence, neoplasm characteristics and factors affecting cancer-specific survival (CSS) were described. Results A total of 121 patients were identified. The crude annual overall incidence was low (range 0.0–0.27 cases per million person years). The largest proportion had localized disease (40%), while 16% had regional disease, 39% distant metastatic disease, and stage was unreported in 5%. Most neoplasms were in the body/tail of the pancreas, followed by the head of the pancreas. Grade was reported in 40% of patients; only a single patient reported as having grade IV with the remainder all grades I/II. Surgical resection was performed in 64% of patients. Within surgical patients, the median primary neoplasm size was 1.8 cm. Regional lymph nodes were examined in 57.1% of surgical patients, while 34% of examined nodes were positive. The median CSS was 183 months. On multivariable analysis, surgical resection, male sex and absence of metastatic disease were associated with superior survival. Conclusion While the greatest proportion of patients with malignant insulinoma present with localized disease, regional lymph node involvement was found in 34% of whose nodes were tested. Further studies are needed to assess the role of lymph node dissection in improving survival and preventing recurrence given the observed frequency of lymph node involvement.

The aim of this study was to evaluate the use of cathepsin-activated intraoperative near-infrared (NIR) imaging to detect insulinomas in dogs, a spontaneous large animal model for human disease. A prospective, pilot clinical trial was performed on dogs with naturally occurring insulinomas undergoing exploratory laparotomy. Each dog underwent routine preoperative diagnostic assessment, and a cathepsin-activated fluorophore (VGT-309) was administered intravenously 1-2 days preoperatively. All intraoperative findings with visible light and NIR imaging were recorded and mean NIR fluorescence intensity of tumors and grossly normal pancreas were quantified. Excision of any identified primary tumor and suspected metastatic lesions was performed. All excised tissues underwent histologic evaluation and immunohistochemistry (IHC) for cathepsin B expression. Descriptive statistics were calculated, and differential fluorescence intensity and cathepsin B expression between the pancreatic mass and adjacent grossly normal pancreatic tissue were assessed for statistical significance via paired t tests with p < 0.05 used for significance. Six dogs were enrolled. No adverse events occurred secondary to administration of the imaging agent. In situ, insulinomas had significantly greater mean fluorescence intensities than the surrounding pancreas, and the median tumor to background ratio was 1.906 (range 1.286-2.556). One dog had an occult pancreatic mass that was identified intraoperatively with NIR guidance. Background fluorescence of liver and lymph nodes was observed in all cases, and one dog was diagnosed with nodal and hepatic metastasis. Histologic tumor margins correlated with margins of NIR fluorescence. Cathepsin B expression was determined to be significantly greater in the pancreatic tumor compared to adjacent non-neoplastic pancreas via IHC, and there was no overlap in the range of median IHC-positive proportion values for these tissues. However, there was overlap in the range of IHC-positive proportion values for neoplastic pancreatic samples and lymph node and liver tissues. The findings of this pilot study support further investigation of cathepsin-activated NIR imaging to enhance intraoperative canine insulinoma localization and margin evaluation. Future studies are needed to further characterize and optimize the utility of targeted NIR imaging, particularly to identify metastatic lesions, for canine insulinoma, which may serve as an effective translational model for humans with pancreatic neuroendocrine tumors.

This study aimed to evaluate potential difference in clinicopathological characteristics, prognosis as well as the genetic bases between insulinomas and non-functional pancreatic neuroendocrine neoplasms (NF-PNENs). We analyzed data from 241 patients who underwent resection for PNENs measuring 1–2 ​cm at West China Hospital between 2002 and 2020. NF-PNENs were more likely to show lymph node involvement (P ​< ​0.001), perineural invasion (P ​= ​0.025), and a more advanced tumor grade (P ​< ​0.001). In multivariate analysis, NF-PNENs, when combined with lymph node metastasis and WHO G2/G3 grading, independently decreased recurrence-free survival [hazard ratio (HR), 4.72; P ​= ​0.014]. Whole exome sequencing revealed that most of the top 20 somatic mutated genes (90 ​%, 36/40) between insulinomas and NF-PNENs are different. Besides, all copy number variant (CNV) patterns were present in NF-PNENs, whereas insulinomas were more likely to exhibit CNV amplification. Insulinomas and small NF-PNENs exhibit distinct tumor biology, prognosis, and genetic backgrounds, which may inform changes in surgical management and postoperative follow-up strategies for these patients. •We found that NF-PNENs exhibited more aggressive behavior and worse prognosis compared with insulinomas, even at an early stage.•Whole exome sequencing revealed that the top 20 mutated genes in insulinomas and NF-PNENs were largely distinct.•While all copy number variant patterns were observed in NF-PNENs, insulinomas were more likely to show chromosomal copy number amplification.

Diagnosis and pathological classification of insulinomas are challenging. To characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma. Patients with surgically resected sporadic insulinoma were included. Eighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a. Localization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon.

PurposeMost insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades.MethodsOperated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000–2010 (group 1) and 2011–2020 (group 2).ResultsSixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1–249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease.ConclusionInsulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent.

Background Benign insulinoma is the most common functioning neuroendocrine tumor of the pancreas, and its incidence is estimated at 0.4%. The treatment of choice is organ-preserving resection. The aim of this study was to compare short-term and long-term outcomes of minimally invasive laparoscopic or robotic enucleation (MIC-EN) and open enucleation (O-EN) for sporadic benign insulinoma. Methods A retrospective bi-institutional analysis of 71 patients who underwent an enucleation for sporadic benign insulinoma between 2003 and 2016 was performed. Patients were analyzed according to intention-to-treat principle. Results Fifteen (21%) patients underwent MIC-EN (three robotic and 12 laparoscopic) and 56 (79%) patients O-EN. In all MIC-EN patients, the insulinoma was localized by preoperative imaging compared to only 62.5% (35 of 56) patients in the O-EN group ( p  = 0.005). Three of the MIC-EN patients (20%) with insulinomas in the pancreatic head had to undergo a conversion. Excluding conversions, MIC-EN procedures were shorter (145 vs 180, p  = 0.036) compared to O-EN surgery. Late complications and pathological data did not differ between groups, excluding margin status R1 MIC-EN (26.7%) compared to O-EN (10.7%, p  = 0.115). After a median follow-up of 75 (range 1–151) months, all patients were alive, but four (5.6%) patients (one after MIC-EN and three after O-EN) developed a functional recurrence. No patient with a R1 resection had a disease recurrence. Conclusions MIC-EN for benign sporadic insulinoma is a safe procedure with at least similar short-term and long-term postoperative outcomes as the open technique. Thus, preoperatively localized benign insulinoma should be approached laparoscopically, if technically feasible.