pNET Patients Research Articles

National practice patterns in the use of endoscopic ultrasound biopsy for resectable Pancreatic Neuroendocrine Tumors: Insights into the role of DOTATATE PET/CT in diagnosis

IntroductionPancreatic neuroendocrine tumors (PNETs) are typically diagnosed using endoscopic ultrasound-guided (EUS) biopsy, which can be associated with complications. Since 2016, DOTATATE PET/CT has emerged as an effective tool to localize and stage PNETs. MethodsPatients with PNETs who underwent R0 resections were identified from the 2004–2019 National Cancer Database PUF. Joinpoint regression and multivariable logistic regression were used to analyze trends in the use of biopsy. ResultsOf 16,746 R0 resected PNET patients, 44 ​% underwent diagnostic biopsy. Joinpoint regression showed a significant increase in the use of biopsy from 2004 to 2019 (APC 1.80, p ​< ​0.001). A higher percentage of patients diagnosed after DOTATATE approval underwent biopsy compared to those diagnosed before (48 ​% vs. 42 ​%, p ​< ​0.001). Adjusted analysis showed diagnosis after 2016 was associated with increased odds of biopsy (OR ​= ​1.67, p ​< ​0.001). ConclusionsDespite technologic advancement with DOTATATE PET/CT, there has been a significant increase in the proportion of resectable PNETs undergoing preoperative biopsy.

Survival disparities in rural versus urban patients with pancreatic neuroendocrine tumor: A multi-institutional study from the US neuroendocrine tumor study group

BackgroundPancreatic Neuroendocrine Tumors (PNETs) are indolent malignancies that often have a prolonged clinical course. This study assesses disparities in outcomes between PNET patients who live in urban (UA) and rural areas (RA). MethodsA retrospective cohort study was performed using the US Neuroendocrine Tumor Study Group database. PNET patients with a home zip code recorded were included and categorized as RA or UA according to the Federal Office of Rural Health Policy. Overall survival (OS) was analyzed by Kaplan-Meier method, log-rank test, and logistical regression. ResultsOf the 1176 PNET patients in the database, 1126 (96%) had zip code recorded. While 837 (74%) lived in UA, 289 (26%) lived in RA. RA patients had significantly shorter median OS following primary PNET resection (122 vs 149 months, p ​= ​0.01). After controlling for income, local healthcare access, distance from treatment center, ASA class, BMI, and T/N/M stage, living in a RA remained significantly associated with worse OS (HR 1.60, 95%CI 1.08–2.39, p ​= ​0.02). ConclusionRural patients have significantly shorter OS following PNET resection compared to their urban counterparts.

Metformin and pancreatic neuroendocrine tumors: A systematic review and meta-analysis.

Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET. To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET. A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival. A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with I² = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; P < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; P < 0.001). The study heterogeneity was intermediate, with I² = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET. T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Quantitative SSTR-PET/CT for predicting response and survival outcomes in patients with pancreatic neuroendocrine tumors receiving CAPTEM.

This study aimed to evaluate the predictive and monitoring role of somatostatin receptor (SSTR) positron emission tomography-computed tomography (PET/CT) and clinical parameters in patients with neuroendocrine liver metastases (NELM) from pancreatic neuroendocrine tumors (pNET) receiving capecitabine and temozolomide (CAPTEM). This retrospective study included twenty-two patients with pNET and NELM receiving CAPTEM who underwent pre- and post-therapeutic 68Ga-DOTATATE/-TOC PET/CT. Imaging (including standardized uptake value [SUV] of target lesions [NELM and pNET], normal spleen and liver) and clinical (Chromogranin A [CgA], Ki-67) parameters were assessed. Treatment outcome was evaluated as response according to RECIST 1.1, progression free survival (PFS) and overall survival (OS). The median PFS (mPFS) was 7 months. Responders had a significantly longer mPFS compared to non-responders (10 vs. 4 months p = 0.022). Median OS (mOS) was 33 months (mOS: responders = 80 months, non-responders = 24 months p = 0.182). Baseline imaging showed higher SUV in responders, including absolute SUV, tumor-to-spleen (T/S), and tumor-to-liver (T/L) ratios (p < 0.02). All SUV parameters changed only in the responders during follow-up. Univariable Cox regression analysis identified baseline Tmax/Smean ratio and percentage change in size of pNETs as significant factors associated with PFS. A baseline Tmax/Smean ratio < 1.5 was associated with a shorter mPFS (10 vs. 4 months, (p < 0.05)). Prognostic factors for OS included age, percentage change in CgA and in T/S ratios in univariable Cox regression. SSTR-PET/CT can be useful for predicting response and survival outcomes in pNET patients receiving CAPTEM: Higher baseline SUV values, particularly Tmax/Smean ratios of liver metastases were associated with better response and prolonged PFS.

Pancreatic neuroendocrine tumor: prediction of tumor grades by radiomics models based on ultrasound images.

We aimed to investigate whether the radiomics analysis based on B-mode ultrasound (BMUS) images could predict histopathological tumor grades in pancreatic neuroendocrine tumors (pNETs). A total of 64 patients with surgery and histopathologically confirmed pNETs were retrospectively included (34 male and 30 female, mean age 52.4 ± 12.2 years). Patients were divided into training cohort (n = 44) and validation cohort (n = 20). All pNETs were classified into Grade 1 (G1), Grade 2 (G2), and Grade 3 (G3) tumors based on the Ki-67 proliferation index and the mitotic activity according to WHO 2017 criteria. Maximum relevance minimum redundancy, least absolute shrinkage and selection operator were used for feature selection. Receiver operating characteristic curve analysis was used to evaluate the model performance. Finally, 18 G1 pNETs, 35 G2 pNETs, and 11 G3 pNETs patients were included. The radiomic score derived from BMUS images to predict G2/G3 from G1 displayed a good performance with an area under the receiver operating characteristic curve of 0.844 in the training cohort, and 0.833 in the testing cohort. The radiomic score achieved an accuracy of 81.8% in the training cohort and 80.0% in the testing cohort, a sensitivity of 0.750 and 0.786, a specificity of 0.833 and 0.833 in the training/testing cohorts. Clinical benefit of the score also exhibited superior usefulness of the radiomic score, as shown by the decision curve analysis. Radiomic data constructed from BMUS images have the potential for predicting histopathological tumor grades in patients with pNETs. The radiomic model constructed from BMUS images has the potential for predicting histopathological tumor grades and Ki-67 proliferation indexes in patients with pNETs.

Two machine learning-based nomogram to predict risk and prognostic factors for liver metastasis from pancreatic neuroendocrine tumors: a multicenter study

BackgroundPancreatic 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.MethodsWe 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.ResultsOf 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.ConclusionWe developed two clinically significant predictive models to aid physicians in personalized clinical decision-makings.

Real world sequence of peptide receptor radionucleotide therapy (PRRT) and chemotherapy in patients with metastatic pancreatic neuroendocrine tumors (pNETs).

e16237 Background: Peptide Receptor Radionuclide Therapy (PRRT) is an effective therapy for advanced pNETs but carries long-term risks of myeloid neoplasia. Early data from United States centres may suggest a higher risk of myelodysplasia and leukemia in patients treated with temozolomide prior to PRRT. The objective of this study is to characterize the sequence of PRRT and chemotherapy at two Canadian pNET treatment centres, distinguished by the availability of PRRT. Methods: This is a multicentre retrospective cohort study involving The Ottawa Hospital Cancer Centre (TOHCC; PRRT non-treatment centre (PRRT-NTC)) and London Regional Cancer Centre (LRCC; PRRT treatment centre (PRRT-TC). Patients with histologically confirmed pNETs between January 2010 – June 2021 over the age 18 (n=226), with metastatic disease (n=177) were included. Demographic, clinical and cancer treatments were collected. Descriptive statistics were used to evaluate the sequence of systemic therapy. Results: 177 patients with metastatic pNET were identified. Systemic therapies included octreotide (n=59, 40%), lanreotide (n=47, 32%), targeted agents (n=40, 27%), chemotherapy (n=48, 33%) and PRRT (n=47, 32%). Of patients receiving chemotherapy, 22 (46%) received temozolomide-containing regimens. The most frequent first line therapies were somatostatin analogues (SSAs, n=76, 43%), chemotherapy (n=23, 13%) and observation (n=18, 10%), second-line were PRRT (n=24, 14%), targeted therapy (n=26, 15%) and SSA (n=13, 7%), and third-line were PRRT (n=15, 9%), chemotherapy (n=11, 6%) and targeted therapy (n=8, 5%). There were 83 (47%) patients treated at the PRRT-TC, of which 33 (40%) received PRRT prior to chemotherapy and 7 (8%) received temozolomide-containing therapy prior to PRRT. In comparison, 94 (53%) patients were treated at the PRRT-NTC, of which 1 (1%) received PRRT prior to chemotherapy and 0 (0%) received PRRT prior to temozolomide-containing therapy. Conclusions: In this large cohort of metastatic pNET patients, the sequence of chemotherapy and PRRT showed centre-to-centre variability with patients treated at a PRRT-TC being more likely to receive chemotherapy, including temozolomide, prior to PRRT. This may be explained in-part by referral/practice patterns, and PRRT availability. These findings suggest an opportunity to evaluate and optimize the sequence of systemic therapy with the increasing availability of PRRT.

Response to Commentary on '"Long-Term Outcomes of Parenchyma-Sparing and Oncologic Resections in Patients With Nonfunctional Pancreatic Neuroendocrine Tumors

Response to Commentary on '"Long-Term Outcomes of Parenchyma-Sparing and Oncologic Resections in Patients With Nonfunctional Pancreatic Neuroendocrine Tumors <3 cm in a Large Multicenter Cohort".

Construction and validation of a nomogram for patients with pancreatic neuroendocrine tumors: A population study of 5,927 patients

BackgroundPancreatic neuroendocrine tumors (pNETs) are a group of uncommon tumors derived from peptide neurons and neuroendocrine cells, and account for roughly 2% to 4% of all pancreatic neoplasms. This study aimed to construct and validate a nomogram for predicting the prognosis of patients with pNETs. Our data came from the SEER database.MethodsA total of 5927 pNETs patients between 2004 and 2018 were included in this study. The nomogram was constructed base on eight prognostic factors and validated by C-index, ROC curve and calibration curves. A nomogram based on eight independent prognostic factors (patient age, sex, race, tumor grade, AJCC T, AJCC N, AJCC M, surgery, radiation, chemotherapy, tumor function and marital status) was developed for the prediction of CSS at 3 and 5 years.ResultsThe C-index and AUCs of the nomogram demonstrated that its superiority in discrimination over AJCC staging system. The calibration plots showed the good consistency between predictions and actual observations.ConclusionsIn conclusion, our nomogram could better predict the prognosis of pNETs patients than AJCC staging system. The nomogram could be improved by integrating more important factors other than SEER database.

Quantitative contrast-enhanced endoscopic ultrasound in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors: can we predict survival using perfusion parameters? A pilot study.

Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) parameters may be used to predict prognosis of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET). The aim of this study was to investigate the association between several perfusion parameters on CEH-EUS performed before treatment and survival outcome in patients with PDAC or pNET. Thirty patients with PDAC or pNET who underwent CEH-EUS and EUS-guided fine needle aspiration (EUS-FNA) were included. Quantitative analysis of tumor vascularity was performed using time-intensity curve (TIC) analysis-derived parameters, obtained from processing CEH-EUS recordings with a commercially available software (VueBox). Cox proportional hazards models were used to determine associations with survival outcome. Median overall survival (OS) for PDAC patients was 9.61 months (95% CI: 0.1-38.7) while the median OS for pNET patients was 15.81 months (95% CI: 5.8-24.75. In a multivariate model for OS, a lower peak enhancement (HR=1.76, p=0.02) and a lower wash-in area under the curve (HR=1.06, p=0.001) were associated with worse survival outcome for patients with PDAC. CEH-EUS parameters may be used as a surrogate to predict PDAC aggressiveness and survival before treatment. After validation by large-scale studies, CEH-EUS perfusion parameters have the potential to be used in pretreatment risk stratification of patients with PDAC and in evidence-based clinical decision support.

Clinical characteristics of 662 patients with pancreatic neuroendocrine tumors receiving antitumoral therapy

Pancreatic neuroendocrine neoplasia constitute an important subentity of the gastroenteropancreatic neuroendocrine neoplasms accounting for up to 15% of all neuroendocrine neoplasm. Prognosis and oncological behavior of pancreatic neuroendocrine tumors (pNETs) is extremely heterogenous and dependent on the specific tumor stage and differentiation. However, systematic data on the specific epidemiology of pNET are scarce. We identified 662 patients with pNET within the Oncology Dynamics database (IQVIA). Patients were derived from 4 European countries (Germany, France, UK, Spain), 3 Asian countries (Japan, China, South Korea) and 2 South American countries (Mexico and Brazil) and with regard to major patient and tumor related characteristics including patients' age, sex, tumor stage, tumor grading, and differentiation. The mean age of the study cohort was 62 years (SD 12 years) with 53.9.1% of all patients being male. The majority of patients had an Eastern co-operative of Oncology Group 1 performance status (63.3%). The most common Union international contre le cancer tumor stage was stage IV (85%) with liver metastases (89.0%) representing the most common site of extra-pancreatic tumor manifestation. The majority of all patients displayed well or moderate tumor differentiation (9.6% of patients had a Ki-67 expression below 2%. 67.6% of pNET patients had a Ki-67 expression between 2 and 20% and 22.8% of patients showed an expression above 20%). At time point of diagnoses, 93.1% of patients were classified as inoperable. Of note, 93.9 % of patients received systemic anti-tumoral therapy in palliative intention, while treatment was administered in 1.4 % of cases in neoadjuvant and in 4.7% of cases in in an adjuvant setting. Biological therapy was applied to 39.4% of patients, followed by targeted therapies (31.4%) and chemotherapy. Pancreatic neuroendocrine neoplasia are diagnosed in advanced tumor stages, globally. Systemic treatment was the most commonly used treatment modality. Such data may help to better understand the specific epidemiology of pNET worldwide.

The incidence, prevalence, and survival analysis of pancreatic neuroendocrine tumors in the United States.

The incidence of pancreatic neuroendocrine tumors (pNETs) was increasing. The main purpose of this study was to statistically analyze the incidence and prevalence of pNETs and the main risk factors for the prognosis. Based on the Surveillance, Epidemiology, and End Results (SEER) database, with three registries integrated, this study comprehensively displayed the annual age adjust incidence of pNETs from 1975 to 2018, the estimated 20-year limited-duration prevalence, and conducted the univariate and multivariate survival analysis. The incidence of pNETs has increased to about 1.5 per 100,000 population, and the prevalence has reached about 0.008% with the aged, Grade 1 and nonfunctional tumors accounting for the majority. The average median overall survival (OS), 5-year survival rate, and median disease-free survival (DFS) of pNETs patients from 1975 to 2018 were 85months, 57.55%, and 220months, respectively. From 2000 to 2018, the median OS was 94months, and the 5-year survival rate was 59.94%. In multivariate survival analysis, the greatest risk factor was Grade 3&4 with HR = 3.62 (3.10-4.28), followed by distant stage with HR = 2.77 (2.28-3.36), and aged over 80years old with HR = 2.26 (1.33-3.83). Surgery was a protective prognostic factor with HR = 0.34 (0.29-0.40). The incidence and prevalence of pNETs were still increasing, but the trend was gradual and aging in recent years. The survival time of pNETs was longer but has not changed much in recent years. The degrees of malignancy, stage, and operation were the most important prognosis factors.

Patients with non-functional metastatic G2 pancreatic neuroendocrine tumor benefit from palliative surgery: A 20-year single-center retrospective analysis.

Pancreatic neuroendocrine tumor (pNET) is the most common subset (31.5%) of gastroenteropancreatic neuroendocrine tumor in China. Based on real-world data from a single center, the present study aimed to evaluate the influence of clinical characteristics, medical treatment and surgery on the survival of non-functional metastatic G2 pNET. In total, 114 metastatic non-functional G2 pNET patients, who were treated and followed up in the Department of Medical Oncology, Peking Union Medical College Hospital (PUMCH) from 2001 until 2019, were analyzed retrospectively. The primary endpoint, overall survival (OS), was calculated from the date of diagnosis to the date of death. The second endpoint, progression-free survival (PFS), was calculated from the date of diagnosis to the date of disease progression. Statistical data were analyzed to evaluate the effects of a clinical characteristic, medical treatment and surgery on OS and PFS. Sixty-nine (60.5%) patients were male and 87 (76.3%) were aged < 60 years. The liver was the most common metastatic organ, with a total of 84 cases (73.7%). With respect to surgery, 32 (28.1%) patients underwentradical surgery and 37 (32.5%) underwent palliative surgery. Survival analysis showed that the 5-year and 10-year survival rates were 79.36% and 70.0%, respectively. Univariate and multivariate Cox regression analyses suggested that both radical (p < .001/.003) and palliative surgery (p < .001/.002) significantly prolonged OS, as revealed by the Kaplan-Meier test (p < .001). Subgroup analysis showed that palliative resection also significantly improves the prognosis in patients with multiple liver metastases. However, the first-line systemic anti-tumor therapy option showed no statistical differences in the present study. Overall, patients with non-functional metastatic G2 pNET receiving palliative or radical surgery demonstrated significantly better survival. Prospective clinical trials are suggested to validate our findings.

Multimodality imaging differentiation of pancreatic neuroendocrine tumors and solid pseudopapillary tumors with a nomogram model: A large single-center study.

BackgroundPancreatic neuroendocrine tumors (pNETs) and solid pseudopapillary tumors (SPTs) are two of the most common pancreatic neoplasms with different treatment procedures. However, the broad heterogeneity of pNETs and SPTs in clinical manifestations and radiological features often confuse the presurgical discrimination in clinical practice, and the clinical and molecular differentiation of the two tumors remains elusive to date. We presume that a large and comprehensive study into the multimodality features of pNETs and SPTs is necessary for precise clinical management.MethodsWe collected and analyzed the clinicopathological information and multimodality features of nonfunctional pNET and SPT patients, for a total of 631 cases from 2006 to 2021. Univariate analysis of imaging features, including contrast-enhanced computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound (EUS) and nuclear medicine imaging, and clinical characteristics was performed, and CT features and clinical information were integrated to establish a nomogram model.ResultsWe recruited 354 nonfunctional pNET and 277 SPT patients in our cohort. Regarding demographic information, pNET patients had a lower female percentage (55.4% vs. 72.9%), smaller tumor size (2.8 vs. 4.8 cm), and older age (53.4 vs. 35.3 years). In CT imaging and EUS, pNETs tended to appear as solid and homogenous lesions with strong enhancement intensity. Multifocal lesions, duct dilation, and lymph node (LN) enlargement were more likely to be observed in pNETs, while calcification was more common in SPT lesions. On positron emission tomography (PET)/CT, pNETs exhibited significant sensitivity to somatostatin receptor scintigraphy (SRS), with positive rates of 81.4% and 95% on 99mTc-HYNIC-TOC and 68Ga-DOTATATE PET/CT, respectively, while SPTs were all negative on SRS. Multivariate analysis identifies tumor size, age, enhancement intensity, calcification, and LN enlargement as statistically significant variables.ConclusionsCompared to SPT patients, pNET patients exhibit an older age and smaller tumor size. CT manifestations of strong intensity, LN enlargement, and no calcification could indicate a higher possibility of pNET. Meanwhile, the similarity in the immunohistochemical profile indicates that the two tumors could potentially develop from the same origin.

Disparities in overall survival (OS) outcomes based on treating facility volume in pancreatic neuroendocrine tumors.

150 Background: Pancreatic neuroendocrine tumors (pNETs) comprise less than 5% of all pancreatic tumors and 7% of all neuroendocrine tumors (NETs). There has been considerable progress in understanding the biology of pNETs and numerous therapeutic options emerged, especially with the collaboration of various specialties in the multidisciplinary setting. In this this study, we sought to analyze the association of facility volume, treatment modalities offered, and different risk adjusted outcomes in pNETs. Methods: We extracted data from National Cancer Data Base (NCDB) that covers 70% of all newly diagnosed cancer cases in the U.S and Puerto Rico. Patients with pNETs diagnosed between 2004 &amp; 2017 were included and classified into tertiles based on hospital volume. Volume–outcome relationship was determined by using Cox regression adjusting for patient demographics, comorbidities, tumor characteristics, insurance type and therapy received. Kaplan Meier estimates of OS were compared with log-rank test. The primary predictor of interest was the facility volume defined as number of pNETs treated/year. A total of 7202 patients with pathologically confirmed pNETS were treated at 840 facilities. The median annual facility volume was 5patients/year. Facilities were classified into (T:mean cases/year) T1: &lt; 3; T2:4-8; T3:≥9 cases/year. Results: A total of 7202 pNET patients were treated at 840 facilities. The median annual facility volume was 5 patients/year. Facilities were classified into (T: mean cases/year) T1:&lt;3; T2:4-8; T3:≥9 cases/year. The unadjusted median OS by facility volume was: T1: 71 months (m), T2: 136 m, and T3: not-reached (p &lt; 0.001). On multivariable analysis, compared with patients treated at T3 facilities, patients treated at lower-tertile facilities had higher risk of death [T2 hazard ratio (HR), 1.17 (95% CI, 1.03-1.33); T1 HR, 1.45 (CI, 1.30-1.67), p &lt; 0.0001] and such a difference in OS was more pronounced in stage IV disease (Table). Patients at T3 facilities (vs T1) were more likely to receive surgical resection of the primary tumor (75 vs 49%), lymph node dissection performed at the time of surgery (70 vs 42%), and a better R0 resection (72 vs 46%) (p &lt; 0.01). Conclusions: Patients who were treated for pNETs at high-volume centers (&gt; 9cases/year) had significantly higher OS and were more likely to receive surgical resection along with lymph node dissection and R0 resection. There was a 45% increased risk of death in patients treated at low volume centers (&lt; 3/year) as compared to high-volume centers (&gt; 9/year). While OS difference was noticed in all stages, the difference was more pronounced in stage IV disease demonstrating the importance of multi-disciplinary approach in pNETs management and incorporating such quality measures in low-volume facilities.[Table: see text]

Abstract 6162: Histone deacetylase inhibitor modulates T cell recruitment to metastatic pancreatic neuroendocrine tumors by CCR5 regulation

Abstract Pancreatic neuroendocrine tumors (PNETS) represent the second most common pancreatic neoplasm with surgical resection serving as the mainstay of treatment for localized PNETs (lPNETs) &amp;gt; 2 cm in size; however, therapeutic options for managing metastatic PNETs (mPNETs) remain limited. Recently, immunotherapy with checkpoint inhibitors has emerged as effective therapy across a range of malignancies but has shown limited efficacy in PNET patients partly due to what has been reported as a “cold” tumor microenvironment (TME). Here, we aimed to characterize the TME among both localized and mPNETs and identify mechanisms to increase tumor immunogenicity and T cell recruitment among these patients. We analyzed tumor-infiltrating and peripheral T cells from patients with lPNETs and mPNETs by flow cytometry and found higher expression of CD69+ (activation), CCR5+ (recruitment), and PD1+ (exhaustion) in T cells isolated from TME compared to peripheral blood. Further, we identified a more profound degree of CD3+ and CD8+ T cell infiltration among mPNETs compared to lPNETs by immunohistochemistry analysis, suggesting that mPNETs are at least moderately enriched with activated T cells. RNA-sequencing performed on 22 sporadic, well-differentiated primary PNETs revealed distinct transcriptional signatures dependent upon metastatic potential. These divergent transcriptomes were analyzed by an L1000 computational algorithm, which classifies landmark gene signatures perturbed by drug treatments. We identified the histone deacetylase inhibitor vorinostat as the drug most likely to perturb the PNET gene signature. A KEGG pathway analysis revealed that these vorinostat-target genes were commonly involved in both Th1, Th2, and Th17 cell differentiation and in the NF-κB pathway. Vorinostat treatment of patient-derived mPNET resulted in increased T cell migration towards metastatic tumors across a semi-permeable membrane; cotreatment with a competitive CCR5 antagonist abrogated this effect. In addition, vorinostat treatment of BON-1 and QGP-1, two PNET cell lines, elevated both NF-κB activity and CCR5 expression, with induction reduced following inhibition of NF-κB nuclear localization. Our study demonstrates that T cell recruitment toward mPNET tissue is dependent upon CCR5 expression. These results reveal that PNET TME is regulatable by vorinostat and opens an avenue of potential sensitization to immune checkpoint blockade among patients with PNETs. Citation Format: Jacques A. Greenberg, Jessica N. Limberg, Akanksha Verma, David Kim, Maureen D. Moore, Timothy M. Ullmann, Jessica W. Thiesmeyer, Zachary Loewenstein, Kevin J. Chen, Caitlin E. Egan, Dessislava I. Stefanova, Rohan Bareja, Rasa Zarnegar, Brendan M. Finnerty, Theresa Scognamiglio, Olivier Elemento, Thomas J. Fahey, Irene M. Min. Histone deacetylase inhibitor modulates T cell recruitment to metastatic pancreatic neuroendocrine tumors by CCR5 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6162.

Value of lymphadenectomy in patients with surgically resected pancreatic neuroendocrine tumors

BackgroundAlthough some factors that predict the prognosis in pancreatic neuroendocrine tumor (pNET) have been confirmed, the predictive value of lymph node metastasis (LNM) in the prognosis of pNETs remains conflicting and it is not clear whether regional lymphadenectomy should be performed in all grades of tumors.MethodsWe included pNET patients undergoing surgery in Shanghai pancreatic cancer institute (SHPCI). The risk factors for survival were investigated by the Kaplan–Meier method and Cox regression model. We evaluated the predictors of LNM using Logistic regression.ResultsFor 206 patients in the SHPCI series, LNM was an independent prognostic factor for entire cohort suggested by multivariate Cox regression analysis. LNM (P = 0.002) predicted poorer overall survival (OS) in grade 2/3 cohort, but there is no significant association between LNM and OS in grade 1 cohort. Grade (P < 0.001) and size (P = 0.049) predicted LNM in entire cohort. Grade (P = 0.002) predicted LNM while regardless of size in grade 2/3 cohort.ConclusionsBased on our own retrospective data obtained from a single center series, LNM seems to be associated with poorer outcome for patients with grade 2/3 and/or grade 1 > 4 cm tumors. On the other way, LNM was seems to be not associated with prognosis in patients with grade 1 tumors less than 4 cm. Moreover, tumor grade and tumor size seem to act as independent predictors of LNM. Thus, regional lymphadenectomy should be performed in grade 2/3 patients but was not mandatory in grade 1 tumors < 4 cm. It is reasonable to perform functional sparing surgery for grade 1 patients or propose a clinical-radiological monitoring.

Prognostic Nomogram Based on the Metastatic Lymph Node Ratio for T1-4N0-1M0 Pancreatic Neuroendocrine Tumors After Surgery

PurposeThis study aimed to investigate the prognostic significance of the metastatic lymph node ratio (LNR) in patients with pancreatic neuroendocrine tumors (pNETs) and to develop and validate nomograms to predict 5-, 7-, and 10-year overall survival (OS) and cancer-specific survival (CSS) rates for pNETs after surgical resection.MethodsThe demographics and clinicopathological information of T1-4N0-1M0 pNET patients between 2004 and 2018 were extracted from the Surveillance, Epidemiology and End Results database. X-tile software was used to determine the best cutoff value for the LNR. Patients were randomly divided into the training and the validation groups. A Cox regression model was used in the training group to obtain independent prognostic factors to develop nomograms for predicting OS and CSS. The concordance index (C-index), calibration curves, area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to assess the nomograms. Patients were divided into four groups according to the model scores, and their survival curves were generated by the Kaplan–Meier method.ResultsA total of 806 patients were included in this study. The best cutoff value for the LNR was 0.16. The LNR was negatively correlated with both OS and CSS. Age, sex, marital status, primary site, grade, the LNR and radiotherapy were used to construct OS and CSS nomograms. In the training group, the C-index was 0.771 for OS and 0.778 for CSS. In the validation group, the C-index was 0.737 for OS and 0.727 for CSS. The calibration curves and AUC also indicated their good predictability. DCA demonstrated that the nomograms displayed better performance than the American Joint Committee on Cancer (AJCC) TNM staging system (8th edition). Risk stratification indicated that patients with higher risk had a worse prognosis.ConclusionsThe LNR is an independent negative prognostic factor for pNETs. The nomograms we built can accurately predict long-term survival for pNETs after surgery.

Incidental nonfunctioning pancreatic neuroendocrine tumors: Contrast enhanced ultrasound features in diagnosis1.

Preoperative suspicion of malignancy in nonfunctioning pancreatic neuroendocrine tumors (pNETs) is mostly based on tumor size. We retrospectively analyzed the contrast enhanced ultrasound (CEUS) features of a series of histopathologically proved nonfunctioning pNETs. In this retrospective study, 37 surgery and histologically proved nonfunctioning pNETs were included. All pNETs lesions were incidentally detected by transabdominal ultrasound. B mode ultrasound (BMUS) and CEUS features were reviewed and analyzed. 52 histopathologically proved pancreatic ductal adenocarcinoma (PDACs) lesions were included as a control group. All nonfunctioning pNETs patients showed no typical clinical symptoms. No significant differences were observed in size, echogenicity or internal color flow imaging signal between pNETs and PDAC patients (P > 0.05). Most of nonfunctioning pNETs showed a well-defined tumor margin. The presence of pancreatic duct dilatation was less frequently observed in nonfunctioning pNETs patients (P < 0.05). After injection of ultrasound contrast agents, homogeneous enhancement was more commonly observed in nonfunctioning pNETs group (P < 0.05). During arterial phase of CEUS, most of nonfunctioning pNETs were hyper- or isoenhanced (32/37, 86.5%), whereas most of PDACs were hypoenhanced (34/52, 65.4%) (P < 0.05). Nonenhanced necrosis area was more commonly detected in PDACs (P = 0.012). CEUS features are helpful for preoperative non-invasive differential diagnosis of nonfunctioning pNETs, assisting further clinical decision-making process.

Survival and Incidence Patterns of Pancreatic Neuroendocrine Tumors Over the Last 2 Decades: A SEER Database Analysis.

BackgroundPancreatic neuroendocrine tumors (pNETs) are rare cancers with outcomes determined by multiple factors including grade, stage, and clinical presentation. In this study, we aimed to determine the prognosis of patients with pNETs using a large population-based database.Materials and MethodsIn this population-based study, we identified patients with pNETs from the SEER 18 registry (2000-2016) using a combination of ICD-O-3 and histology codes. We calculated age-adjusted incidence rates using SEER*Stat 8.3.5. In addition, we analyzed overall survival (OS) using the Kaplan-Meier method, and investigated prognostic factors using a multivariable Cox proportional hazards model.ResultsA total of 8944 pNETs patients were identified. Annual incidence rates increased from 0.27 to 1.00 per 100 000. This was largely explained by an increase in number of patients diagnosed with localized disease in more recent years (2012-2016). Median OS was 68 months (95% CI [64, 73]) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for patients diagnosed between 2009 and 2016 (median OS 85 months) compared with those diagnosed between 2000 and 2008 (median OS 46 months) (HR 0.66; 95% CI [0.62, 0.70]). This improvement in OS was consistent across all stages.Conclusions and RelevanceThis study shows a steady increase pNETs incidence with notable stage migration to earlier stages in recent years. This increase in incidence is accompanied by a significant improvement in survival across different disease stages.