Nonfunctioning Pancreatic Neuroendocrine Tumors Research Articles

Efficacy and safety of surufatinib in unresectable or metastatic grade 3 pancreatic neuroendocrine tumors (NET G3): Real-world analysis.

657 Background: Currently, there is limited exploration regarding the treatment of NET G3, resulting in restricted treatment options. Therapeutics for NET G1/2 may serve as an alternative. Surufatinib, with its potent targeting of VEGFRs, FGFR1, and CSF-1R, not only exerts inhibitory effects on tumor angiogenesis but also modulates the immune microenvironment. Due to its demonstrated efficacy and manageable safety profile, it has secured approval for the treatment of G1/2 NETs. Methods: This is a multi-center real-world study that retrospectively analyzes the clinical data of pts with NET G3 who received surufatinib-based treatment from December 2021 to February 2024, aiming to assess its efficacy and safety. Eligible pts were unresectable or metastatic p-NET with ki-67>20%. The primary endpoint was PFS, with secondary endpoints were ORR, DCR, and safety. Results: As of September 2024, data from 37 pts were analyzed. The median age was 54 years (range: 32-80), with 59.5% male. The median Ki-67 index was 30% (range: 25-70%), and 94.6% of the cases were non-functional p-NETs, with 89.2% having liver metastases and 35.1% having bone metastases. In terms of prior treatments, 18.9%, 40.5%, and 40.5% of pts had received 0, 1, and ≥2 systemic therapies, respectively. Among them, 81.1% had previously undergone chemotherapy, 35.1% had received interventional therapy of liver metastases, and 13.5% with everolimus or anti-angiogenic agents. 48.6% pts had surufatinib-based combination treatment. The median PFS was 9.30 months (mo, 95% CI: 8.02–13.02), with an ORR of 21.6% and a DCR of 81.1%. First-line (1L) treatment showed a higher ORR (42.9% vs. 16.7%) and a trend of better PFS (9.67 vs. 9.04 mo, p=0.7) compared to ≥2L treatment. Combination therapy improved ORR (33.3% vs. 10.5%) with a similar PFS (9.30 vs. 9.44 mo, p=0.93) compared to surufatinib monotherapy. Liver metastases had limited impact on PFS (9.93 vs 9.30 mo, p=0.55). Common grade ≥3 adverse events included hypertension (8.1%), proteinuria (5.4%), and elevated bilirubin (5.4%). Conclusions: Surufatinib has demonstrated initial efficacy and manageable safety in pts with NET G3, providing a new treatment option for these pts. First-line therapy may be a favorable factor for improving PFS. To delve deeper into these findings, additional subgroup analyses, with a particular emphasis on pts with ep-NET G3 will be conducted in the future.

Efficacy and safety of endoscopic ultrasonography-guided radiofrequency ablation of small pancreatic neuroendocrine neoplasms: A prospective, pilot study.

Endoscopic ultrasonography (EUS)-guided radiofrequency ablation has recently been introduced as one of the management strategies for small pancreatic neuroendocrine neoplasms (PNENs). However, prospective data on its safety and efficacy remain limited. This prospective pilot study was conducted at Okayama University Hospital from May 2023 to December 2024. Patients with grade 1 PNENs ≤15mm, confirmed by EUS-guided fine-needle aspiration, were included. The primary endpoint was safety (adverse events [AEs] evaluated according to the 2010 guidelines of the American Society for Gastrointestinal Endoscopy. Severe AEs were defined as moderate or higher in American Society for Gastrointestinal Endoscopygrading and grade ≥3. Secondary endpoints included efficacy (complete response on contrast-enhanced computed tomography at 1 and 6 months), treatment details, device failure, diabetes mellitus exacerbation, and overall survival at 6 months. Five patients with non-functional PNENs (median age: 64 years; median tumor size: 10mm) were treated. AEs occurred in two patients (40%, 2/5), although none was severe. Both patients developed asymptomatic pseudocysts, one experienced mild pancreatitis, and both resolved with conservative treatment. The complete response rates on contrast-enhanced computed tomography at one and 6 months were 100%. The median procedure time was 16min without any device failure, and the median hospitalization was 5 days. None of the patients developed new-onset or worsening diabetes mellitus. The 6-month overall survival rate was 100%. EUS-guided radiofrequency ablation demonstrated a high complete response rate with no severe AEs in this pilot study, suggesting a minimally invasive option for small, low-grade PNENs (jRCTs062230014).

Novel Surgical Initiatives in Gastroenteropancreatic Neuroendocrine Tumours.

Neuroendocrine tumours (NET) are rare entities arising from hormone producing cells in the gastroentero-pancreatic (GEP) tract. Surgery is the most common treatment of GEP-NETs. Improvements in surgical techniques allow for more locally advanced and metastasised GEP-NETs to be resected. Laparoscopic and robotically--assisted approaches are increasingly being utilised in the resection of selected GEP-NETs and are facilitated by novel intraoperative tumour localisation tools and parenchyma-sparing methods. At the same time, some authors suggest that indications for formal resections of small well differentiated non-functioning pancreatic NETs and appendiceal NETs should be more restrictive. Advancements in surgery allows for tissue-sparing resections of GEP-NETs. Indications for surgical resection and the extent of the procedure are highly dependent on GEP-NET size, localisation and grading. Robotically assisted surgeries with intraoperative ultrasound and visualisation methods as well as vessel-sparing radical retrograde lymphadenectomies for small intestinal NETs seem to be the future of GEP-NET surgery.

Endoscopic-Ultrasound-Guided Radiofrequency Ablation for Pancreatic Tumors.

Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) is a promising minimally invasive technique for the treatment of pancreatic lesions. This review first focuses on the technical aspects in EUS-RFA: the procedure typically employs EUS probes with integrated radiofrequency electrodes, enabling accurate targeting and ablation of pancreatic lesions. Different types of RFA devices, monopolar and bipolar energy delivery systems, are discussed, along with considerations for optimal ablation, including energy settings, procedure time, and pre- and post-procedural management. This paper presents a comprehensive literature review of EUS-RFA applied to both solid and cystic pancreatic lesions, including functioning and non-functioning pancreatic neuroendocrine tumors (pNETs), pancreatic cystic lesions (PCLs), pancreatic ductal adenocarcinoma (PDAC), and pancreatic metastases (PMs), discussing current evidence on safety, efficacy, clinical outcomes, and adverse events (AEs). EUS-RFA is an emerging technique with expanding potential for the treatment of both benign and malignant conditions; however, further studies are needed to better define patient selection criteria, assess long-term benefits, and establish definitive indications for its use.

Predictors Based on the Radiologic Characteristics for Aggressiveness of Small (< 20 mm) Nonfunctioning Pancreatic Neuroendocrine Tumors.

To find the association between preoperative computed tomography (CT) features combined with tumor marker and known high-risk factors of small nonfunctioning pancreatic neuroendocrine tumors (NF-PNETS), thereby selecting appropriate treatment strategy for these patients. One hundred fourteen patients with NF-PNETs< 20 mm who underwent surgical operation were retrospectively analyzed from 2009 to 2023. Univariate and multivariable logistic regression analyses were performed to find the relationship between preoperative clinical psychological and CT features and high-risk factors. The overall survival (OS) rates with and without high-risk factors were compared. Of 114 patients, 29(25%) had at least one of these high-risk factors. Main pancreatic duct dilation (OR, 3.315; 95% CI, 1.079-10.184; p = 0.036), irregular tumor margin (OR, 2.955; 95% CI, 1.021-8.551; p = 0.046), positive tumor marker (OR, 6.047; 95% CI, 1.408-25.963; p = 0.015) were associated with increased odds of having any of these high-risk factors. The time to death differed significantly between patients with and without high-risk factors. Patients combining with high-risk factors were associated with lower 3- and 5-year OS (100% vs. 81.8%, 93.1% vs. 81.8%, respectively; p = 0.035 for both). Main pancreatic duct dilation, irregular tumor margin and positive tumor marker could screen a subset of patients recommended for surgery.

Circulating Chromogranin A is associated with disease extent, progression and recurrence in patients with non-functioning pancreatic neuroendocrine tumor (NF-PNET).

Non-functioning Pancreatic Neuroendocrine Tumors (NF-PNET) are rare tumors with heterogeneous biology. Radiology and serum biomarkers are used for post-resection surveillance; however, no universally established protocol exists. Serum Chromogranin A (CgA) concentration is elevated in NF-PNET, and generally correlates with burden of disease; many CgA studies include mixed gastrointestinal and pancreatic populations. We sought to review the NF-PNET literature with focus on post-resection surveillance and hypothesized that CgA is useful for surveillance after NF-PNET resection. Comprehensive English literature review by PICO criteria (P-human NF-PNET patients; I-pancreatectomy; C- none; O- CgA correlation with disease recurrence). Four studies yielded granular data for resected NF-PNET patients. From 333 patients, 113 recurred and 110 (97%) had elevated CgA. Additional 7 studies with mixed gastro-entero-pancreatic NET included 269 NF-PNET patients. In these patients, CgA uniformly predicted disease extent. Serum Chromogranin A correlates with disease extent in NF-PNET, and is useful for surveillance after resection of NF-PNET.

Preoperative Prediction of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors Using a Combined CT Radiomics-Clinical Model.

PanNETs are a rare group of pancreatic tumors that display heterogeneous histopathological and clinical behavior. Nodal disease has been established as one of the strongest predictors of patient outcomes in PanNETs. Lack of accurate preoperative assessment of nodal disease is a major limitation in the management of these patients, in particular those with small (< 2cm) low-grade tumors. The aim of the study was to evaluate the ability of radiomic features (RF) to preoperatively predict the presence of nodal disease in pancreatic neuroendocrine tumors (PanNETs). An institutional database was used to identify patients with nonfunctional PanNETs undergoing resection. Pancreas protocol computed tomography was obtained, manually segmented, and RF were extracted. These were analyzed using the minimum redundancy maximum relevance analysis for hierarchical feature selection. Youden index was used to identify the optimal cutoff for predicting nodal disease. A random forest prediction model was trained using RF and clinicopathological characteristics and validated internally. Of the 320 patients included in the study, 92 (28.8%) had nodal disease based on histopathological assessment of the surgical specimen. A radiomic signature based on ten selected RF was developed. Clinicopathological characteristics predictive of nodal disease included tumor grade and size. Upon internal validation the combined radiomics and clinical feature model demonstrated adequate performance (AUC 0.80) in identifying nodal disease. The model accurately identified nodal disease in 85% of patients with small tumors (< 2cm). Non-invasive preoperative assessment of nodal disease using RF and clinicopathological characteristics is feasible.

8789 Unraveling Von Hippel Lindau Syndrome: A Comprehensive Analysis of Clinical Manifestations, Age-Related Variations, and Tumor Prevalence in a Specialized Endocrine Center

Abstract Disclosure: K.K. Pasam: None. Y. Gupta: None. A. Goyal: None. N. Tandon: None. Introduction: This study presents a thorough examination of Von Hippel Lindau (VHL) syndromes, focusing on the clinical spectrum and genetic mutations in our population. Methods: The study, conducted at the Department of Endocrinology and Metabolism from 2016 to 2022. Objectives included studying the spectrum of diseases in index patients and asymptomatic family members. Results: In our study, we identified 19 index cases and 12 asymptomatic cases identified on screening. The analysis of 31 VHL patients revealed a mean age of presentation of 24.2±11.1 years. Pancreatic cysts were the most common manifestation in 61% followed by pheochromocytoma in 54%, cerebellar hemangioblastomas in 45%, retinal angiomas in 39% and renal cell carcinoma in 35%. 16% of patients presented with nonfunctioning pancreatic neuroendocrine tumors, and one case featured an endolymphatic sac tumor.Pheochromocytomas in VHL syndrome presented at a remarkably young age, with an average of 23.1±11.4 years. Bilateral pheochromocytomas were observed in 14 (82%) and hormonal evaluation revealed urinary noradrenaline, normetanephrines, and plasma normetanephrine elevations of 5, 6, and 7-fold, respectively.The median size of pheochromocytomas in VHL syndrome was 5.4 cm. Metastatic pheochromocytoma was observed in one patient. Genetic analysis was available for 9 patients with most common mutation in exon 3 of chromosome 3. Discussion:The average age of VHL syndrome presentation in our cohort is younger than in other Indian studies. Males in our study were 45%, deviating from the absence of gender preponderance associated with VHL. Disparities in age of diagnosis and tumor prevalence compared with other international cohorts highlight potential regional and ethnic variations. Multiple pancreatic cysts in our study, with a prevalence of 61%, lower than the South Indian study's 71%. Literature comparisons indicate pancreatic cyst prevalence ranging from 42% to 51.6%. Cerebellar hemangioblastomas and retinal angiomas, typical VHL lesions, displayed prevalence rates of 45% and 39%, respectively.Pheochromocytoma, the second most common tumor in our cohort (54%), exhibited variations in prevalence compared to international studies. Higher rates reported by Fagundes et al. and Dwivedi et al. from Brazil might be attributed to recruitment biases from endocrine centers.The average age of VHL-associated pheochromocytoma presentation in our study contrasts with MEN2, emphasizing the unique features of VHL. Our study, reporting a 16% prevalence of PNETs, aligns with Binderup et al. The mean age of presentation for VHL-associated PNETs (20.8 ± 3.63 years) contrasts with Western literature, suggesting potential ethnic differences. Conclusion: Our study contributes to a nuanced understanding of VHL syndrome, shedding light on age-related variations, gender distribution, and tumor prevalence. Presentation: 6/2/2024

8789 Unraveling Von Hippel Lindau Syndrome: A Comprehensive Analysis Of Clinical Manifestations, Age-Related Variations, And Tumor Prevalence In A Specialized Endocrine Center

Abstract Disclosure: K.K. Pasam: None. Y. Gupta: None. A. Goyal: None. N. Tandon: None. Introduction: This study presents a thorough examination of Von Hippel Lindau (VHL) syndromes, focusing on the clinical spectrum and genetic mutations in our population. Methods: The study, conducted at the Department of Endocrinology and Metabolism from 2016 to 2022. Objectives included studying the spectrum of diseases in index patients and asymptomatic family members. Results: In our study, we identified 19 index cases and 12 asymptomatic cases identified on screening. The analysis of 31 VHL patients revealed a mean age of presentation of 24.2±11.1 years. Pancreatic cysts were the most common manifestation in 61% followed by pheochromocytoma in 54%, cerebellar hemangioblastomas in 45%, retinal angiomas in 39% and renal cell carcinoma in 35%. 16% of patients presented with nonfunctioning pancreatic neuroendocrine tumors, and one case featured an endolymphatic sac tumor.Pheochromocytomas in VHL syndrome presented at a remarkably young age, with an average of 23.1±11.4 years. Bilateral pheochromocytomas were observed in 14 (82%) and hormonal evaluation revealed urinary noradrenaline, normetanephrines, and plasma normetanephrine elevations of 5, 6, and 7-fold, respectively.The median size of pheochromocytomas in VHL syndrome was 5.4 cm. Metastatic pheochromocytoma was observed in one patient. Genetic analysis was available for 9 patients with most common mutation in exon 3 of chromosome 3. Discussion:The average age of VHL syndrome presentation in our cohort is younger than in other Indian studies. Males in our study were 45%, deviating from the absence of gender preponderance associated with VHL. Disparities in age of diagnosis and tumor prevalence compared with other international cohorts highlight potential regional and ethnic variations. Multiple pancreatic cysts in our study, with a prevalence of 61%, lower than the South Indian study's 71%. Literature comparisons indicate pancreatic cyst prevalence ranging from 42% to 51.6%. Cerebellar hemangioblastomas and retinal angiomas, typical VHL lesions, displayed prevalence rates of 45% and 39%, respectively.Pheochromocytoma, the second most common tumor in our cohort (54%), exhibited variations in prevalence compared to international studies. Higher rates reported by Fagundes et al. and Dwivedi et al. from Brazil might be attributed to recruitment biases from endocrine centers.The average age of VHL-associated pheochromocytoma presentation in our study contrasts with MEN2, emphasizing the unique features of VHL. Our study, reporting a 16% prevalence of PNETs, aligns with Binderup et al. The mean age of presentation for VHL-associated PNETs (20.8 ± 3.63 years) contrasts with Western literature, suggesting potential ethnic differences. Conclusion: Our study contributes to a nuanced understanding of VHL syndrome, shedding light on age-related variations, gender distribution, and tumor prevalence. Presentation: 6/2/2024

S2470 Diagnosis of Non-Functional Pancreatic Neuroendocrine Tumor in a Patient with a Transplanted Pancreas: A Case Report

S2470 Diagnosis of Non-Functional Pancreatic Neuroendocrine Tumor in a Patient with a Transplanted Pancreas: A Case Report

Transformation of non-functioning pancreatic neuroendocrine tumours into insulinomas in multiple endocrine neoplasia type 1: a case report

Transformation of non-functioning pancreatic neuroendocrine tumours into insulinomas in multiple endocrine neoplasia type 1: a case report

Neoadjuvant 177Lu-DOTATATE for non-functioning pancreatic neuroendocrine tumours (NEOLUPANET): multicentre phase II study.

Resection of non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) is curative in most patients. The potential benefits of neoadjuvant treatments have, however, never been explored. The primary aim of this study was to evaluate the safety of neoadjuvant 177Lu-labelled DOTA0-octreotate (177Lu-DOTATATE) followed by surgery in patients with NF-PanNETs. NEOLUPANET was a multicentre, single-arm, phase II trial of patients with sporadic, resectable or potentially resectable NF-PanNETs at high-risk of recurrence; those with positive 68Ga-labelled DOTA PET were eligible. All patients were candidates for neoadjuvant 177Lu-DOTATATE followed by surgery. A sample size of 30 patients was calculated to test postoperative complication rates against predefined cut-offs. The primary endpoint was safety, reflected by postoperative morbidity and mortality within 90 days. Secondary endpoints included rate of objective radiological response and quality of life. From March 2020 to February 2023, 31 patients were enrolled, of whom 26 completed 4 cycles of 177Lu-DOTATATE. A partial radiological response was observed in 18 of 31 patients, and 13 patients had stable disease. Disease progression was not observed. Twenty-four R0 resections and 4 R1 resections were performed in 29 patients who underwent surgery. One tumour was unresectable owing to vascular involvement. There was no postoperative death. Postoperative complications occurred in 21 of 29 patients. Severe complications were observed in seven patients. Quality of life remained stable after 177Lu-DOTATATE and decreased after surgery. Neoadjuvant treatment with 177Lu-DOTATATE is safe and effective for patients with NF-PanNETs.

Enucleation for Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors Larger than 2 Centimeters Is Associated with Equivalent Morbidity and Survival Compared to Smaller Tumors: A Multi-Institutional Study

Introduction: Nonfunctioning pancreatic neuroendocrine tumor (NF-PanNET) ≤2 cm can be observed or resected. Surgery remains recommended for NF-PanNET >2 cm but its extent, enucleation (EN) versus formal resection, remains controversial. Methods: Multicentric retrospective cohort of sporadic NF-PanNET patients treated with EN. Short- and long-term outcomes were compared according to tumor size on imaging ≤2 cm versus >2 cm. Results: 131 patients underwent EN for NF-PanNET, including 103 (79.0%) ≤2 cm and 28 (21.0%) >2 cm (extremes, 4–55 mm). Patients’ characteristics were comparable, and tumor characteristics only differed in their diameter. Clavien III-IV complications were similar (18.4% vs. 17.9%, p = 1.00) with one death in NF-PanNET ≤2 cm. Grade B/C pancreatic fistula were comparable (16.5% vs. 10.7%, p = 0.850). In NF-PanNET >2 cm there were more pT2/3 stage tumors (85.7% vs. 21.4%, p < 0.001), similar rates of grade G2/3 tumors (25% vs. 16.5%, p = 0.408) with a median Ki67 of 2 (interquartile range: 1–3), and of lymphovascular and perineural invasions. Lymph node picking was done in 46 (35.1%) patients, with a higher median number of harvested lymph nodes in NF-PanNET >2 cm (4 vs. 3, p = 0.01). All were pN0. R0 resection rate (78.6% vs. 82.5%, respectively; p = 0.670) was equivalent. Five-year overall (100% vs. 99%, p = 0.602) and 10-year disease-free (96% vs. 92%, respectively; p = 0.532) survivals were comparable. Conclusions: EN for selected NF-PanNET >2 cm carries equivalent morbidity, overall and disease-free survivals compared to those observed with NF-PanNET ≤2 cm.

Trends in the Use of Observation for Small Nonfunctional Pancreatic Neuroendocrine Tumors

This study assesses nationwide trends in the use of observation for pancreatic neuroendocrine tumors 2 cm or smaller and to evaluate factors associated with resection.

Comparison among different preclinical models derived from the same patient with a non-functional pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine tumors are the second most common tumors of the pancreas, and approximately half of patients are diagnosed with liver metastases. Currently, the improvement in the efficacy of relevant treatment methods is still limited. Therefore, there is an urgent need for in-depth research on the molecular biological mechanism of pancreatic neuroendocrine tumors. However, due to their relatively inert biology, preclinical models are extremely scarce. Here, the patient-derived organoid, and patient-derived xenograft were successfully constructed. These two models and the previously constructed cell line named SPNE1 all derived from the same patient with a grade 3 non-functional pancreatic neuroendocrine tumor, providing new tumor modeling platforms, and characterized using immunohistochemistry, whole-exome sequencing, and single-cell transcriptome sequencing. Combined with a tumor formation experiment in immunodeficient mice, we selected the model that most closely recapitulated the parental tumor. Overall, the patient-derived xenograft model most closely resembled human tumor tissue.

Critical appraisal of the adequacy of surgical indications for non-functioning pancreatic neuroendocrine tumours.

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.

Prospective study on stereotactic body radiotherapy for small pancreatic neuroendocrine tumors: tolerance and effectiveness analysis.

Surgery is the standard treatment for pancreatic neuroendocrine tumors (pNETs), obtaining favorable results but associating high morbidity and mortality rates. This study assesses stereotactic body radiation therapy (SBRT) as a radical approach for small (< 2cm) nonfunctioning pNETs. From January 2017 to June 2023, 20 patients with small pNETs underwent SBRT in an IRB-approved study. Endpoints included local control, tolerance, progression-free survival, and overall survival (OS). Diagnostic assessments comprised endoscopy, CT scans, OctreScan or PET-Dotatoc, abdominal MRI, and histological confirmatory samples. In a 30-month follow-up of 20 patients (median age 55.5years), SBRT was well-tolerated with no grade > 2 toxicity. 40% showed morphological response, 55% remained stable. Metabolically, 50% achieved significant improvement. With a median OS of 41.5months, all patients were alive without local or distant progression or need for surgical resection. SBRT is a feasible and well-tolerated approach for small neuroendocrine pancreatic tumors, demonstrating effective local control. Further investigations are vital for validation and extension of these findings.

Disease-free survival after pancreatectomy for pancreatic neuroendocrine tumors: A 17-year single-center experience of 223 patients

Metastasis or recurrence of pancreatic neuroendocrine tumors (pNETs) after pancreatectomy is an important source of postsurgical morbidity. This study aimed to define disease-free survival (DFS) in this population. Patients who underwent pancreatectomy for pNETs between January 2005 and January 2022 were included. Clinicopathologic and survival data were collected, and the primary endpoint was DFS. Kaplan-Meier survival analysis and Cox proportional hazards regression modeling were performed. Of the 223 patients, 144 (65%) distal/subtotal/partial pancreatectomies, 71 (32%) pancreaticoduodenectomies, 6 (3%) total pancreatectomies, and 2 (1%) enucleations were performed. Of the 223 patients, 45 (20%) experienced disease recurrence or metastasis after index pancreatectomy during the 17 years of the study. Nonfunctional pNETs (162 [73%]) were more common than hormonally functional subtypes. The 2- and 5-year DFSs were 82% and 76%, respectively. Kaplan-Meier analysis demonstrated that N1 node positive disease, size of ≥4cm, lymphovascular invasion, perineural invasion, Ki-67 of ≥20%, and nonfunctional pNETs are significantly associated with a lower DFS (P<.05). Univariate Cox analysis identified the following predictors to be significantly associated with poorer DFS: larger tumor size (hazard ratio [HR], 1.16; 95% CI, 1.04-1.28), Ki-67 index of ≥20% (HR, 4.93; 95% CI, 2.00-11.44), perineural invasion (HR, 3.23; 95% CI, 1.40-7.89), open surgery (HR, 3.34; 95% CI, 1.03-1.33), node-positive disease (HR, 5.27; 95% CI, 2.28-13.26), and increased body mass index (HR, 1.10; 95% CI, 1.03-1.17) (P<.05). Of note, 1 in 5 patients who underwent resection developed recurrence or metastasis after pancreatectomy. Prognostic predictors of DFS in pNETs could help optimize treatment and enhance follow-up protocols to improve quality and reduce morbidity.

Endoscopic ultrasonography-based intratumoral and peritumoral machine learning radiomics analyses for distinguishing insulinomas from non-functional pancreatic neuroendocrine tumors.

To develop and validate radiomics models utilizing endoscopic ultrasonography (EUS) images to distinguish insulinomas from non-functional pancreatic neuroendocrine tumors (NF-PNETs). A total of 106 patients, comprising 61 with insulinomas and 45 with NF-PNETs, were included in this study. The patients were randomly assigned to either the training or test cohort. Radiomics features were extracted from both the intratumoral and peritumoral regions, respectively. Six machine learning algorithms were utilized to train intratumoral prediction models, using only the nonzero coefficient features. The researchers identified the most effective intratumoral radiomics model and subsequently employed it to develop peritumoral and combined radiomics models. Finally, a predictive nomogram for insulinomas was constructed and assessed. A total of 107 radiomics features were extracted based on EUS, and only features with nonzero coefficients were retained. Among the six intratumoral radiomics models, the light gradient boosting machine (LightGBM) model demonstrated superior performance. Furthermore, a peritumoral radiomics model was established and evaluated. The combined model, integrating both the intratumoral and peritumoral radiomics features, exhibited a comparable performance in the training cohort (AUC=0.876) and achieved the highest accuracy in predicting outcomes in the test cohorts (AUC=0.835). The Delong test, calibration curves, and decision curve analysis (DCA) were employed to validate these findings. Insulinomas exhibited a significantly smaller diameter compared to NF-PNETs. Finally, the nomogram, incorporating diameter and radiomics signature, was constructed and assessed, which owned superior performance in both the training (AUC=0.929) and test (AUC=0.913) cohorts. A novel and impactful radiomics model and nomogram were developed and validated for the accurate differentiation of NF-PNETs and insulinomas utilizing EUS images.

Well-differentiated G1 and G2 pancreatic neuroendocrine tumors: a meta-analysis of published expanded DNA sequencing data.

Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (MEN1). The Knudson hypothesis stated a second, somatic hit in MEN1 as the cause of PNETs of MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs. A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020.A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25th of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the 'maftools' R-package. Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was MEN1, with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in MEN1, VHL, CHEK2, BRCA2, PTEN, CDKN1B, and/or MUTYH) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The MEN1 point mutations/indels were distributed throughout MEN1. Overall, DAXX (16%, 37/225) and ATRX-variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. DAXX mutations occurred more frequently in PNETs with MEN1 mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways. The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).