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Objective: To construct a CT-based diagnostic nomogram for distinguishing grade 3 pancreatic neuroendocrine tumors (G3 PNETs) from pancreatic ductal adenocarcinomas (PDACs) and assess their respective survival outcomes. Methods: Patients diagnosed with G3 PNETs (n = 30) and PDACs (n = 78) through surgery or biopsy from two medical centers were retrospectively identified. Demographic and radiological information, including age, gender, tumor diameter, shape, margin, dilatation of pancreatic duct, and invasive behavior, were carefully collected. A nomogram was established after univariate and multivariate logistic regression analyses. The Kaplan–Meier survival was performed to analyze their survival outcomes. Results: Factors with a p-value <0.05, including age, CA 19-9, pancreatic duct dilatation, irregular shape, ill-defined margin, pancreatic atrophy, combined pancreatitis, arterial/portal enhancement ratio, were included in the multivariate logistic analysis. The independent predictive factors, including age (OR, 0.91; 95% CI, 0.85–0.98), pancreatic duct dilatation (OR, 0.064; 95% CI, 0.01–0.32), and portal enhancement ratio (OR, 1,178.08; 95% CI, 5.96–232,681.2) were determined to develop a nomogram. The internal calibration curve and decision curve analysis demonstrate that the nomogram exhibits good consistency and discriminative capacity in distinguishing G3 PNETs from PDACs. Patients diagnosed with G3 PNETs exhibited considerably better overall survival outcomes compared to those diagnosed with PDACs (median survival months, 42 vs. 9 months, p < 0.001). Conclusions: The nomogram model based on age, pancreatic duct dilatation, and portal enhancement ratio demonstrates good accuracy and discriminative ability effectively predicting the probability of G3 PNETs from PDACs. Furthermore, patients with G3 PNETs exhibit better prognosis than PDACs. [ABSTRACT FROM AUTHOR]

Purpose: Accurate identification of lymph node (LN) metastases is pivotal for surgical planning of pancreatic neuroendocrine tumours (PanNETs); however, current imaging techniques have sub-optimal diagnostic sensitivity. Aim of this study is to investigate whether [68Ga]Ga-DOTATOC PET radiomics might improve the identification of LN metastases in patients with non-functioning PanNET (NF-PanNET) referred to surgical intervention. Methods: Seventy-two patients who performed preoperative [68Ga]Ga-DOTATOC PET between December 2017 and March 2022 for NF-PanNET. [68Ga]Ga-DOTATOC PET qualitative assessment of LN metastases was measured using diagnostic balanced accuracy (bACC), sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV). SUVmax, SUVmean, Somatostatin receptor density (SRD), total lesion SRD (TLSRD) and IBSI-compliant radiomic features (RFs) were obtained from the primary tumours. To predict LN involvement, these parameters were engineered, selected and used to train different machine learning models. Models were validated using tenfold repeated cross-validation and control models were developed. Models' bACC, SN, SP, PPV and NPV were collected and compared (Kruskal–Wallis, Mann–Whitney). Results: LN metastases were detected in 29/72 patients at histology. [68Ga]Ga-DOTATOC PET qualitative examination of LN involvement provided bACC = 60%, SN = 24%, SP = 95%, PPV = 78% and NPV = 65%. The best-performing radiomic model provided a bACC = 70%, SN = 77%, SP = 61%, PPV = 60% and NPV = 83% (outperforming the control model, p < 0.05*). Conclusion: In this study, [68Ga]Ga-DOTATOC PET radiomics allowed to increase diagnostic sensitivity in detecting LN metastases from 24 to 77% in NF-PanNET patients candidate to surgery. Especially in case of micrometastatic involvement, this approach might assist clinicians in a better patients' stratification. [ABSTRACT FROM AUTHOR]

Introduction: Insulinomas are rare, usually sporadic, and typically benign pancreatic neuroendocrine tumours. Pre-operative localization is challenging and evidence on comparative analysis of anatomic and scintigraphic modalities for pre-operative tumour localization is limited, even in contemporary series. Methods: The current study was designed to study the clinical features and management challenges of insulinomas managed at a tertiary care centre. Clinical features, diagnosis, imaging techniques, surgical procedures, and outcomes details were collated. Pre-operative imaging techniques (CT/MRI, nuclear scintigraphy) were compared with intraoperative and histopathological findings to assess their accuracy of localization. Results: Thirty-seven patients (15 females [42%]; median age 36 years [IQR 28–49]) were included in the study. In four patients (10.8%), the tumour occurred in the setting of multiple endocrine neoplasia type 1 (MEN 1) while the remaining were sporadic. The sensitivity of pre-operative localization was 61.5% (multiphasic CT), 66.6% (multiphasic MRI), 100% (68Ga Exendin-4 PET-CT), and 91.6% (EUS). Three patients with normal multiphasic CT had localization on 68Ga Exendin-4 PET-CT. The positive predictive value (PPV) of both Exendin-PET-CT and EUS was similar at 91.6% and 91.6%, respectively. All patients (except one with nesidioblastosis), who underwent enucleation or partial pancreatic resection, were cured. Conclusion: 68Ga Exendin-4 PET-CT based is a non-invasive imaging modality that has high sensitivity and PPV and can be used as a first-line imaging modality. The overall prognosis of these tumours is good with high cure rates attained following surgical resection.

Introduction: Insulinomas are rare, usually sporadic, and typically benign pancreatic neuroendocrine tumours. Pre-operative localization is challenging and evidence on comparative analysis of anatomic and scintigraphic modalities for pre-operative tumour localization is limited, even in contemporary series. Methods: The current study was designed to study the clinical features and management challenges of insulinomas managed at a tertiary care centre. Clinical features, diagnosis, imaging techniques, surgical procedures, and outcomes details were collated. Pre-operative imaging techniques (CT/MRI, nuclear scintigraphy) were compared with intraoperative and histopathological findings to assess their accuracy of localization. Results: Thirty-seven patients (15 females [42%]; median age 36 years [IQR 28–49]) were included in the study. In four patients (10.8%), the tumour occurred in the setting of multiple endocrine neoplasia type 1 (MEN 1) while the remaining were sporadic. The sensitivity of pre-operative localization was 61.5% (multiphasic CT), 66.6% (multiphasic MRI), 100% (68Ga Exendin-4 PET-CT), and 91.6% (EUS). Three patients with normal multiphasic CT had localization on 68Ga Exendin-4 PET-CT. The positive predictive value (PPV) of both Exendin-PET-CT and EUS was similar at 91.6% and 91.6%, respectively. All patients (except one with nesidioblastosis), who underwent enucleation or partial pancreatic resection, were cured. Conclusion: 68Ga Exendin-4 PET-CT based is a non-invasive imaging modality that has high sensitivity and PPV and can be used as a first-line imaging modality. The overall prognosis of these tumours is good with high cure rates attained following surgical resection. [ABSTRACT FROM AUTHOR]

Background: While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX‐positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1‐positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere‐specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence. Methods: Two hundred fifty‐six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases. Results: ARX reactivity correlated with worse disease‐free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT‐positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT‐negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX‐positive tumours and 7.5% (5/67) of ARX‐negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX‐positive tumours recurred compared to 0 of 33 ARX‐negative tumours and 33.3% (3/9) ALT‐positive tumours showed recurrence versus 4.4% (2/45) ALT‐negative tumours. Conclusion: Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low‐grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention. [ABSTRACT FROM AUTHOR]

Background: Insulinoma is a rare type of pancreatic neuroendocrine tumor with low incidence and low-malignant features. While very few insulinomas present with malignant behaviours, such as lymph node and liver metastasis, only a few studies have focused on this field owing to the limitation of samples. Existing evidence suggests that metastatic insulinoma largely derive from non-functional pancreatic neuroendocrine tumor. However, we found a portion of metastatic insulinomas may derive from non-metastatic insulinomas and explored their clinicopathological signatures and genetic characteristics. Methods: Four metastatic insulinoma patients with synchronous liver metastasis or lymph node metastasis at the Peking Union Medical College Hospital between October 2016 and December 2018 were enrolled, and whole exon and genome sequencing were performed on fresh frozen tissues and peripheral blood samples. Clinicopathological information and genomic sequencing results were collected and matched to explore the characteristics of the metastatic insulinomas. Results: These four metastatic insulinoma patients underwent surgery or interventional therapy, and their blood glucose levels immediately increased and maintained within standard range after treatment. For these four patients, the proinsulin/insulin molar ratio <1 and primary tumors were all present as PDX1+, ARX-, and insulin+, which were similar to non-metastatic insulinomas. However, the liver metastasis showed PDX1+ and ARX+, insulin+. Meanwhile, genomic sequencing data showed no recurrently mutations and typical CNV patterns. However, one patient harboured the YY1 T372R mutation, a recurrently mutated gene in non-metastatic insulinomas. Conclusions: A portion of metastatic insulinomas were largely derived from nonmetastatic insulinomas in hormone secretion and ARX/PDX1 expression patterns. Meanwhile, the accumulation of ARX expression may be involved in the progression of metastatic insulinomas. [ABSTRACT FROM AUTHOR]

Ectopic adrenocorticotropic hormone secretion (EAS) from the pancreatic neuroendocrine tumour (PNET) is rare, aggressive, and challenging to treat. We hereby present a rare case of EAS from PNET presenting with Cushing syndrome diagnosed with endoscopic ultrasound-guided fine-needle aspiration cytology. This case highlights the advanced presentation of EAS from PNET with poor clinical correlation of hypercortisolism and the grade of PNET.

Simple Summary: ATRX and DAXX mutations occur in 30–40% of pancreatic neuroendocrine tumours (PanNETs), and there are no reports in the literature of any genetically engineered mouse model (GEMM) evaluating the effect of Atrx disruption as a putative driver event on PanNET initiation. We created a novel GEMM with Atrx conditional disruption in β cells. We observed that this genetic alteration, per se, was not tumourigenic, but we reported novel roles of Atrx on endocrine function, which resulted in dysglycaemia and the exacerbation of inflammageing (increased pancreatic inflammation and hepatic steatosis). ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events. [ABSTRACT FROM AUTHOR]

Background: The optimal duration of capecitabine combined with temozolomide (CapTem) for metastatic pancreatic neuroendocrine tumours (PanNETs) remains controversial. The present study aimed to assess the activity and safety of prolonged CapTem and Cap maintenance therapy in patients with metastatic PanNETs. Methods: Retrospective real‐world data of 94 patients with metastatic PanNETs were obtained from one cancer centre. Fifteen patients were treated with Cap maintenance therapy after fixed 12–13 cycles of CapTem (group I), 44 patients were treated with prolonged CapTem until disease progression (group II), and 35 patients were treated with fixed 12–13 cycles of CapTem (group III). Results: The mean ± SE follow‐up period was 41.79 ± 26.31 months. The median CapTem treatment duration was 12 months in group I and 14 months in group II. The median time to best partial response was 12 months both in groups I and group II. The objective response rates of groups I and II were significantly higher than those of group III (73.3%, 41.9%, and 20%, respectively, p =.002). The median progression‐free survival (mPFS) of group I and group II was significantly higher than that of group III (35 months, 26 months vs. 19 months, p <.001). Safety analysis of the three groups indicated rare events of grade 3–4 toxicities, with nausea, vomiting, fatigue, and anaemia being the most common adverse effects. Conclusions: Patients with PanNETs who responded well to CapTem treatment may benefit from prolonged CapTem and Cap maintenance therapy after fixed cycles. Prospective studies are encouraged to further explore the prolonged CapTem treatment and maintenance therapy. [ABSTRACT FROM AUTHOR]

Introduction: Neuroendocrine tumours (NETs) are rare tumours with an increasing incidence. While low- and intermediate-grade pancreatic NET (PanNET) and small intestinal NET (siNET) are slow growing, they have a relatively high rate of metastasizing to the liver, leading to substantially worse outcomes. In many solid tumours, the outcome is determined by the quality of the antitumour immune response. However, the quality and significance of antitumour responses in NETs are incompletely understood. This study provides clinico-pathological analyses of the tumour immune microenvironment in PanNET and siNETs. Methods: Formalin-fixed paraffin-embedded tissue from consecutive resected PanNETs (61) and siNETs (131) was used to construct tissue microarrays (TMAs); 1-mm cores were taken from the tumour centre, stroma, tumour edge, and adjacent healthy tissue. TMAs were stained with antibodies against CD8, CD4, CD68, FoxP3, CD20, and NCR1. T-cell counts were compared with counts from lung cancers. Results: For PanNET, median counts were CD8+ 35.4 cells/mm2, CD4+ 7.6 cells/mm2, and CD68+ macrophages 117.7 cells/mm2. For siNET, there were CD8+ 39.2 cells/mm2, CD4+ 24.1 cells/mm2, and CD68+ 139.2 cells/mm2. The CD8+ cell density in the tumour and liver metastases were significantly lower than in the adjacent normal tissues, without evidence of a cell-rich area at the tumour edge that might have suggested immune exclusion. T-cell counts in lung cancer were significantly higher than those in PanNET and siNETs: CD8+ 541 cells/mm2 and CD4+ 861 cells/mm2 (p ≤ 0.0001). Conclusion: PanNETs and siNETs are immune cold with no evidence of T cell exclusion; the low density of immune infiltrates indicates poor antitumour immune responses. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumours (panNET) are heterogeneous neoplasms usually characterised by slow growth and secretion of hormones, which often cause symptoms. The effect of these symptoms on quality of life (QoL) has not previously been examined in detail. EORTC (European Organisation for Research and Treatment of Cancer) guidelines were followed in phases 1–3 to produce a potential module of questions usable for trials in panNET, focusing on three common types of panNET. For two less common types, a list of symptoms was constructed. Following an extensive literature search and phase 1a interviews with patients and healthcare workers, a long list of potential issues (169) was obtained. This list was shown to 12 patients from three countries in phase 1b interviews to check that no items were missed. The list was reduced to 57 issues. The list of issues was converted to questions, mainly from existing validated questions within the EORTC item library. The list of questions was then used in a phase 3 international study in eight countries using seven languages. A provisional module of 24 items is presented for use in nonfunctioning panNET, gastrinoma and insulinoma. This module increases knowledge concerning QoL in this condition and may be a useful adjunct in clinical trials. A phase 4 trial is being considered for validation of this questionnaire. [ABSTRACT FROM AUTHOR]

Focal pancreatic lesions include a heterogeneous group of solid and cystic lesions, with different natures and variable clinical, imagiological, and pathological characteristics. Several endoscopic ultrasound (EUS)-guided ablative techniques have been tested during the last decade for the treatment of these pancreatic lesions, mostly consisting of the injection of ablative agents and, more recently, radiofrequency ablation. The most encouraging EUS-guided ablation outcomes are being reached in the treatment of some pancreatic cystic neoplasms and small (≤2 cm) pancreatic neuroendocrine tumours (pNETs). Data supporting a potential role of ablative therapies in the treatment of pancreatic ductal adenocarcinoma is still lacking. In this article, GRUPUGE presents an updated perspective of the potential role of EUS-guided ablation for the treatment of pancreatic cystic neoplasms and pNETs, addressing the selection criteria and technical issues of different techniques and analysing recent data on their safety and efficacy.

Multiple endocrine neoplasia type 1 (MEN1), an autosomal domina nt disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreati c and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroi dism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore inve stigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic is lets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic backgro und significantly influenced the development of pituitary, adrenal and ovarian tumours, whic h occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/ SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furth ermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/S vEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.

Objective: To construct a CT-based diagnostic nomogram for distinguishing grade 3 pancreatic neuroendocrine tumors (G3 PNETs) from pancreatic ductal adenocarcinomas (PDACs) and assess their respective survival outcomes., Methods: Patients diagnosed with G3 PNETs (n = 30) and PDACs (n = 78) through surgery or biopsy from two medical centers were retrospectively identified. Demographic and radiological information, including age, gender, tumor diameter, shape, margin, dilatation of pancreatic duct, and invasive behavior, were carefully collected. A nomogram was established after univariate and multivariate logistic regression analyses. The Kaplan-Meier survival was performed to analyze their survival outcomes., Results: Factors with a p-value <0.05, including age, CA 19-9, pancreatic duct dilatation, irregular shape, ill-defined margin, pancreatic atrophy, combined pancreatitis, arterial/portal enhancement ratio, were included in the multivariate logistic analysis. The independent predictive factors, including age (OR, 0.91; 95% CI, 0.85-0.98), pancreatic duct dilatation (OR, 0.064; 95% CI, 0.01-0.32), and portal enhancement ratio (OR, 1,178.08; 95% CI, 5.96-232,681.2) were determined to develop a nomogram. The internal calibration curve and decision curve analysis demonstrate that the nomogram exhibits good consistency and discriminative capacity in distinguishing G3 PNETs from PDACs. Patients diagnosed with G3 PNETs exhibited considerably better overall survival outcomes compared to those diagnosed with PDACs (median survival months, 42 vs. 9 months, p < 0.001)., Conclusions: The nomogram model based on age, pancreatic duct dilatation, and portal enhancement ratio demonstrates good accuracy and discriminative ability effectively predicting the probability of G3 PNETs from PDACs. Furthermore, patients with G3 PNETs exhibit better prognosis than PDACs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Lv and Dong.)

Pancreatic neuroendocrine tumours (PNET) is a rare disease and in the absence of metastases, surgical resection is recommended. Key factors affecting survival in PNETs are the stage and grade of the disease, but there is increasing evidence suggesting lymph node involvement is associated with shorter disease-free and overall survival. Ability to predict the likelihood of lymph node involvement at the time of diagnosis would affect surgical decision making in these patients. A systemic inflammatory index such as neutrophil to lymphocyte ratio or platelet to lymphocyte ratio has been associated with poor prognosis in several cancers.Method: This study is a retrospective multi-centre study. The data including pre-operative inflammatory markers such as haemoglobin, neutrophil, lymphocyte counts and pathological data including number of positive lymph nodes, tumour grade and size, are collected to assess the association between inflammatory index and lymph node involvement.Conclusion: This study aims to assess the value of routinely available pre-operative haematological markers in predicting lymph node involvement in non-functioning PNETs.

Background: Owing to the limited prevalence and heterogeneity, it is difficult to predict long‐term survival of non‐functional pancreatic neuroendocrine tumours (NF‐PNETs).This study aimed to evaluate the factors predicting disease‐specific survival (DSS) for well‐differentiated NF‐PNETs. Methods: Data were collected retrospectively from 256 patients with pancreatic neuroendocrine tumours who underwent surgical resection between January 2009 and December at our institution. Of these, 103 NF‐PNETs (40%) were identified for analysis. Results: Of the 103 patients, 54 were male (52%) and the mean age was 52 years (range 21–75 years). Most patients (60/103, 58%) in our series were symptomatic. Seventeen patients (16%) died during follow‐up, with a median period of 47 months. There were 88 patients with well‐differentiated tumours and 10 of them (10/88, 11%) died of tumour progression. Median DSS after primary resection was 58.8 months (range 16–122 months). Multivariate analysis identified age >52 years (P = 0.038) and tumour grade G2 (P = 0.001) as statistically significant predictors of DSS. There was no association between gender, tumour size, symptoms, surgical procedure, severe complications, tumour location, tumour size, resection margin, positive lymph nodes and vascular invasion with DSS. Conclusion: Tumour grade, age, presence of symptoms and distant metastasis were related to poor DSS of NF‐PNETs. Age >52 years and tumour grade G2 might be independent predictors of poor DSS for patients with well‐differentiated NF‐PNETs. [ABSTRACT FROM AUTHOR]

Background: Serine/threonine kinase 33 (STK33) has been reported to play an important role in cancer cell proliferation. We investigated the role of STK33 in pancreatic neuroendocrine tumour (PNET) and the underlying mechanisms. Methods: PNET specimens and adjacent non-tumorous pancreatic tissues from 84 patients who underwent curative surgery for PNET were stained by immunochemistry for STK33. The relationships among STK33 expression, clinicopathological parameters and clinical prognosis were statistically analysed. MTT, scratching, Transwell and apoptosis assays were employed to detect the effects of STK33 knockdown (siSTK33) or STK33 overexpression (pSTK33) on major oncogenic properties of cells of 2 PNET cell lines (BON and QGP-1), and real-time PCR and western blot were used to examine the expression of relevant genes. Results: Relative to its expression in normal pancreatic tissue, STK33 was overexpressed in PNET specimens. Furthermore, STK33 expression was significantly associated with World Health Organization classification (p < 0.001), American Joint Committee on Cancer stage (p < 0.001), lymph node metastasis (p < 0.001), tumour size (p = 0.022), sex (p = 0.003), perineural invasion (p < 0.001) and shorter disease-free survival of patients with PNET (p < 0.001). Enforced STK33 expression promoted PNET cell proliferation, migration and invasion and tumour growth and inhibited cell apoptosis, whereas STK33 depletion exerted the opposite effects. Mechanistic studies revealed that STK33 promoted growth and progression of PNET via activation of the phosphotidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Conclusions: STK33 plays important roles in the tumour growth and progression of PNET via activation of the PI3K/AKT/mTOR pathway and has potential as a therapeutic target to improve PNET treatment. [ABSTRACT FROM AUTHOR]

Predicting grade 1 (G1) and 2 (G2) primary pancreatic neuroendocrine tumour (panNET) is crucial to foresee panNET clinical behaviour. Fifty-one patients with G1-G2 primary panNET demonstrated by pre-surgical [68Ga]Ga-DOTANOC PET/CT and diagnostic conventional imaging were grouped according to the tumour grade assessment method: histology on the whole excised primary lesion (HS) or biopsy (BS). First-order and second-order radiomic features (RFs) were computed from SUV maps for the whole tumour volume on HS. The RFs showing the lowest p-values and the highest area under the curve (AUC) were selected. Three radiomic models were assessed: A (trained on HS, validated on BS), B (trained on BS, validated on HS), and C (using the cross-validation on the whole dataset). The second-order normalized homogeneity and entropy was the most effective RFs couple predicting G2 and G1. The best performance was achieved by model A (test AUC = 0.90, sensitivity = 0.88, specificity = 0.89), followed by model C (median test AUC = 0.87, sensitivity = 0.83, specificity = 0.82). Model B performed worse. Using HS to train a radiomic model leads to the best prediction, although a “hybrid” (HS+BS) population performs better than biopsy-only. The non-invasive prediction of panNET grading may be especially useful in lesions not amenable to biopsy while [68Ga]Ga-DOTANOC heterogeneity might recommend FDG PET/CT.

Purpose: Pancreatic adenocarcinoma (PAC) represents one of the most fatal types of cancer with an exceptionally poor prognosis, underscoring the need for improved diagnostic and treatment approaches. An over-expression of somatostatin receptors (SST) as well as of the chemokine receptor CXCR4 has been shown for many tumour entities. Respective expression data for PAC, however, are scarce and contradictory. Methods: Overall, 137 tumour samples from 70 patients, 26 of whom were diagnosed with PAC and 44 with pancreatic neuroendocrine tumour (PanNET), were compared in terms of SST and CXCR4 expression by immunohistochemical analysis using well-characterized rabbit monoclonal antibodies. Results: Only SST1 and CXCR4 expression was detected in PAC tumours, with SST1 present in 42.3% and CXCR4 in 7.7% of cases. However, the overall staining intensity was very weak. In contrast to the tumour cells, in many PAC cases, tumour capillaries exhibited strong SST3, SST5, or CXCR4 expression. In PanNETs, SST2 was the most-prominently expressed receptor, observed in 75.0% of the tumours at medium–strong intensity. SST5, SST1, and CXCR4 expression was detected in 20.5%, 15.9%, and 11.4% of PanNET cases, respectively, but the staining intensity was only weak. SST2 positivity in PanNET, but not in PAC, was associated with favourable patient outcomes. Conclusions: SST or CXCR4 expression in PAC is clearly of no therapeutic relevance. However, indirect targeting of these tumours via SST3, SST5, or CXCR4 on tumour microvessels may represent a promising additional therapeutic strategy. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a relatively rare group of heterogeneous tumours originating from neuroendocrine cells found throughout the body. Pancreatic NENs (PanNENs) are the second most common pancreatic malignancy accounting for 1-3% of all neoplasms developing in the pancreas. Despite having a low background mutation rate, driver mutations in MEN1, DAXX/ATRX and mTOR pathway genes (PTEN, TSC1/2) are implicated in disease development and progression. Their increased incidence coupled with advances in sequencing technologies has reignited the interest in PanNEN research and has accelerated the acquisition of molecular data. Studies utilising such technological advances have further enriched our knowledge of PanNENs' biology through novel findings, including higher-than-expected presence of germline mutations in 17% of sporadic tumours of no familial background, identification of novel mutational signatures and complex chromosomal rearrangements and a dysregulated epigenetic machinery. Integrated genomic studies have progressed the field by identifying the synergistic action between different molecular mechanisms, while holding the promise for deciphering disease heterogeneity. Although our understanding is far from being complete, these novel findings have provided the optimism of shaping the future of PanNEN research, ultimately leading to an era of precision medicine for NETs. He re, we recapitulate the existing knowledge on pancreatic neuroendocrine tumours (PanNETs) and discuss how recent, novel findings have furthered our understanding of these complex tumours. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumours (PNETs) are relatively uncommon, accounting for 1–2% of all pancreatic neoplasms. Tumour grade (based on the Ki67 proliferative index and mitotic rate) is associated with metastatic risk across large cohorts; however, predicting the behaviour of individual tumours can be difficult. Therefore, any tool which could further stratify metastatic risk may be clinically beneficial. We sought to investigate microRNA (miRNA) expression as a marker of metastatic disease in PNETs. Tumours from 37 patients, comprising 23 with locoregional disease (L) and 14 with distant metastases (DM), underwent miRNA profiling. In total 506 miRNAs were differentially expressed between the L and DM groups, with four miRNAs (miR-3653 upregulated, and miR-4417, miR-574-3p and miR-664b-3p downregulated) showing statistical significance. A database search demonstrated that miRNA-3653 was associated with ATRX abnormalities. Mean survival between the two groups was correlated with mean expression of miRNA-3653; however, this did not reach statistical significance (p = 0.204). Although this is a small study, we conclude that miRNA-3653 upregulation may be associated with an increased risk of metastatic disease in PNETS, perhaps through interaction with ATRX and the alternate lengthening of telomeres pathway. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumours (pNET) are a group of heterogeneous tumours. Despite being rare, their incidence is rising. While localized lesions can be cured with surgical resection, most patients present with metastatic disease. Systemic therapy is thus integral for the management of this rare entity. Numerous advancements have been made in the past decade in the systemic treatment of unresectable, metastatic pNET. Treatment options for pNET include somatostatin analogues, cytotoxic chemotherapy, targeted agents and peptide receptor radionuclide therapy. In this Review, we present the latest evidence for these treatment options. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the preoperative tumour grade of pancreatic neuroendocrine neoplasms (panNENs) by determining the Ki‐67 index in endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) material and to correlate the preoperative tumour grade with the postoperative tumour grade in surgical specimens. Methods: We performed a retrospective review of the institutional pathology database over a 10‐year period (2007‐2017) to identify all cases of panNENs with corresponding preoperative EUS‐FNA cytological material and surgical specimens. Fifteen cases with adequate EUS‐FNA material (more than 400 tumour cells on cellblock) were identified. The cytological and histological samples were graded based on the mitotic rate and the Ki‐67 index in accordance with the 2017 World Health Organisation grading system for panNENs. The tumour grades determined on EUS‐FNA cellblock material were compared with the histological tumour grades. Results: Mean age at diagnosis was 64.8 ± 12.7 years (range, 38‐85 years). The grading scores assigned to the cytological and histological samples were concordant in all 15 (100%) cases. Of those, two (13%) cases were scored as grade 1, nine (60%) cases as grade 2 and four (27%) cases as grade 3 tumours. Conclusion: Our study shows that tumour grade in patients with PanNENs can be reliably determined by assessing the Ki‐67 index in EUS‐FNA specimens based on the 2017 World Health Organisation classification and grading system. In this article we assessed the preoperative tumor grade of pancreatic neuroendocrine neoplasms (panNENs) by determining the Ki‐67 index in endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) material using the 2017 WHO grading guidelines. We correlated the preoperative tumor grade with the postoperative tumor grade in surgical specimens and found that tumor grade in patients with PanNENs can be reliably determined by assessing the Ki‐67 index in EUS‐FNA specimens based on the 2017 WHO classification and grading system. [ABSTRACT FROM AUTHOR]

Background: Insulinoma‐associated protein 1 (INSM1) has been reported to be a useful marker for diagnosing pancreatic neuroendocrine tumours (PNETs). However, INSM1 expression in endoscopic ultrasound‐guided fine needle aspiration cytology has not been examined. We evaluated INSM1 expression in the cytology of cases diagnosed with PNETs. Methods: We immunocytochemically stained INSM1 and Ki‐67 in 14 PNET cases, and according to the 2017 World Health Organisation criteria, seven PNET Grade 1 cases, four Grade 2 cases and three Grade 3/neuroendocrine carcinoma cases were identified. As a control for INSM1 and Ki‐67 expression, we used cytological specimens from 15 cases of pancreatic ductal adenocarcinoma. Results: In PNET cases, INSM1‐expressing tumour cells were identified in all cytological specimens of PNET. The median INSM1 expression rate in Grade 1 cases was 49.8% (mean ± standard deviation: 55.1 ± 12.5%, min: 39.3%, max: 74.1%), and in Grade 2 and Grade 3/neuroendocrine carcinoma cases was 81.1% (mean ± standard deviation: 77.6 ± 18.6%, min: 50.3%, max: 100%). However, there was no correlation between INSM1 and Ki‐67 expression (r = −0.15). The median expression rate in PNET cases was 64.3%, which was significantly higher than that in pancreatic ductal adenocarcinoma cases (P < 0.0001). Conclusion: INSM1 immunocytochemistry of cytological specimens obtained from endoscopic ultrasound‐guided fine needle aspiration cytology can accurately diagnose PNETs; therefore, INSM1 could be an important diagnostic tool in assessing therapeutic strategies, including molecular‐targeted therapy. Recently, neuroendocrine markers such as SYP, CGA, and NCAM have been used with high specificity and sensitivity for PNETs. However, there are similarities in cell structure and immunocytochemistry between pancreatic solid tumors. We reported INSM1 positivity in all histological specimens of PNETs examined including high grade PNETs. This can be considered a useful biomarker. [ABSTRACT FROM AUTHOR]

Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9–16.7): 13.2 (7.4–16.8) and 13.0 (9.2–20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7–33.8) in the total population: 21.3% (11.9–33.7) in treatment-naive and 28.9% (16.4–44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0–not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib. [ABSTRACT FROM AUTHOR]

Background/objectives Primary and metastatic pancreatic neuroendocrine tumours (PNET) can be treated with combination of surgery, locoregional and systemic therapy. Survival benefits from individual treatments have been well reported, however, the combined outcome from multimodal treatments are not well described in the literature. We report outcomes in a cohort of PNET patients treated with proactive, multimodality therapy. Methods 106 patients were identified from a single tertiary referral centre prospective database. Outcomes of treatment were studied, with the primary end point being death from any cause. Results Median follow-up was 71 months and overall 5-year survival of 62%. In patients with stage I-III disease (51 patients) estimated 5-year survival was 90%. Median survival in patients with stage IV disease was 51 months with an estimated 5-year survival of 40% in this group. A total of 80 patients (75%) had surgery of which 16% suffered complications requiring intervention. There was no perioperative mortality. Conclusions This study demonstrates that proactive multimodal treatment is safe and may confer a survival benefit to patients in this cohort compared to historical data. [ABSTRACT FROM AUTHOR]

Background Serotonin secretion occurs in approximately 1%-4% of patients with a pancreatic neuroendocrine tumour ( PNET), but the incidence is not well defined. The aim of this study was to determine the incidence of serotonin secretion with and without carcinoid syndrome and the prognostic value for overall survival ( OS). Methods Data were collected from 255 patients with a PNET if 24-hours urinary 5-hydroxyindoleacetic acid excretion (5- HIAA) was assessed. Patients were diagnosed with serotonin secretion if 24-hours urinary 5- HIAA excretion was more than 3× the upper limit of normal ( ULN) of 50 μmol/24 hours during follow-up. The effect of serotonin secretion on OS was estimated with uni- and multivariate analyses using a Cox regression. Results Two (0.8%) patients were diagnosed with carcinoid syndrome, and another 20 (7.8%) had a serotonin-secreting PNET without symptoms. These patients mostly had ENETS stage IV disease with high chromogranin A (CgA). Serotonin secretion was a negative prognostic factor in univariate analysis ( HR 2.2, 95% CI: 1.27-3.81), but in multivariate analysis, only CgA>10× ULN ( HR: 1.81, 95% CI: 1.10-2.98) and neuron-specific enolase ( NSE) > ULN ( HR: 3.51, 95% CI: 2.26-5.46) were predictors for OS. Immunohistochemical staining for serotonin was positive in 28.6% of serotonin-secreting PNETs (one with carcinoid syndrome) and negative in all controls. Conclusion Carcinoid syndrome is rare in patients with a PNET, but serotonin secretion occurs often. This is a negative prognostic factor for OS, but after correction for CgA and NSE, it is no longer a predictor and probably only a 'not-so innocent bystander' in patients with high tumour burden. [ABSTRACT FROM AUTHOR]

Background: Insulinoma is a rare type of pancreatic neuroendocrine tumor with low incidence and low-malignant features. While very few insulinomas present with malignant behaviours, such as lymph node and liver metastasis, only a few studies have focused on this field owing to the limitation of samples. Existing evidence suggests that metastatic insulinoma largely derive from non-functional pancreatic neuroendocrine tumor. However, we found a portion of metastatic insulinomas may derive from non-metastatic insulinomas and explored their clinicopathological signatures and genetic characteristics., Methods: Four metastatic insulinoma patients with synchronous liver metastasis or lymph node metastasis at the Peking Union Medical College Hospital between October 2016 and December 2018 were enrolled, and whole exon and genome sequencing were performed on fresh frozen tissues and peripheral blood samples. Clinicopathological information and genomic sequencing results were collected and matched to explore the characteristics of the metastatic insulinomas., Results: These four metastatic insulinoma patients underwent surgery or interventional therapy, and their blood glucose levels immediately increased and maintained within standard range after treatment. For these four patients, the proinsulin/insulin molar ratio <1 and primary tumors were all present as PDX1+, ARX-, and insulin+, which were similar to non-metastatic insulinomas. However, the liver metastasis showed PDX1+ and ARX+, insulin+. Meanwhile, genomic sequencing data showed no recurrently mutations and typical CNV patterns. However, one patient harboured the YY1 T372R mutation, a recurrently mutated gene in non-metastatic insulinomas., Conclusions: A portion of metastatic insulinomas were largely derived from non-metastatic insulinomas in hormone secretion and ARX/PDX1 expression patterns. Meanwhile, the accumulation of ARX expression may be involved in the progression of metastatic insulinomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Jiang, Hong, Wu, Han and Wu.)

Purpose: To evaluate the correlation between grade of pancreatic neuroendocrine tumours (pNETs) based on the 2010 World Health Organization (WHO) classification and the apparent diffusion coefficient (ADC), and to assess whether the ADC value and WHO classification can predict recurrence-free survival (RFS) after surgery for pNETs.Methods: This retrospective study was approved by the Institutional Review Board. The requirement for informed consent was waived. Between March 2009 and November 2014, forty-nine patients who underwent magnetic resonance (MR) imaging with diffusion-weighted image and subsequent surgery for single pNETs were included. Correlations among qualitative MR imaging findings, quantitative ADC values, and WHO classifications were assessed. An ordered logistic regression test was used to control for tumour size as a confounding factor. The association between ADC value (or WHO classification) and RFS was analysed.Results: All tumors (n=49) were classified as low- (n=29, grade 1), intermediate- (n=17, grade 2), and high-grade (n=3, grade 3), respectively. The mean ADC of pNETs was moderately negatively correlated with WHO classification before and after adjustment for tumour size (ρ=-0.64, p<0.001 and ρ=-0.55, p=0.001 respectively). RFS was significantly associated with WHO classification (p=0.007), but not with the ADC value (p=0.569).Conclusion: The ADC value of pNETs is moderately correlated with WHO tumour grade, regardless of tumour size. However, the WHO tumour classification of pNET may be more suitable for predicting RFS than the ADC value. [ABSTRACT FROM AUTHOR]

Non-functioning pancreatic neuroendocrine tumours (NF-pNETs) are potentially malignant neoplasms that are detected with increasing frequency. The management of small (≤ 2 cm) asymptomatic NF-pNETs remains an area of controversy and clinical dilemma. Follow-up seems to be a reasonable strategy because of the relatively limited metastatic potential of these tumours, the good clinical prognosis, and considering the high complication rate associated with surgery. However, some studies show metastatic potential of these tumours, fuelling an ongoing debate in the literature regarding their management. Making the decision to observe or perform surgery is thus not an easy task. New, promising therapeutic methods involving ablation under endoscopic ultrasound (EUS) guidance with ethanol or radiofrequency ablation have been applied for these lesions with good clinical outcomes but only with short-term follow-up data. In this review, we address the emerging question of when to follow-up and when to perform surgery for small asymptomatic pancreatic tumours, with consideration of the potential of ablative therapies.

Background Assessment of the pathological characteristics of pancreatic neuroendocrine tumours is crucial for appropriate management. We compared preoperative pathological data with surgical specimens for accuracy. Methods Surgical patients with pancreatic neuroendocrine tumours who underwent preoperative endoscopic ultrasound-guided fine needle aspiration of the primary tumour or biopsy of liver metastasis were retrospectively included. Tumour differentiation and the Ki67 proliferation index on biopsies were compared with pancreatic specimens. Results Fifty-seven patients were included. A preoperative biopsy of the primary tumour or of a liver metastasis was obtained in 48 and 9 patients respectively. Tumour differentiation was high in 98%, and poor in 2% on biopsy and high in 100% of surgical specimens. Ki67 index values were 0 (0–19) and 2 (0–15) on biopsy and surgical specimens ( p = 0.01). Correlation between preoperative and surgical findings was stronger for liver ( r = 0.62, p = 0.001) than for pancreas ( r = 0.23, p = 0.11). Correlation for pancreas varied according to the tumour pattern: solid ( r = 0.24, p = 0.16), mixed ( r = 0.91, p = 0.0036) or cystic ( r = 0.04, p = 0.89). Tumour grade was different between pancreatic biopsies and surgical specimens, for grade 1 (63% vs 37%) and grade 2 (28% vs 72%), p = 0.0007. Conclusions Tumour grade assessment is accurate in biopsies of liver metastases of pancreatic neuroendocrine tumours, while pancreatic fine-needle aspiration biopsies are less accurate. [ABSTRACT FROM AUTHOR]

Background The role of systemic chemotherapy for pancreatic neuroendocrine tumours (pNET) is controversially discussed. Objective response rates (RR) reported for streptozocin (STZ)-based chemotherapy are variable and novel targeted drugs have recently been approved. However, the sequence of treatment remains unclear. We aimed to evaluate the efficacy of STZ plus 5-fluorouracil (STZ/5-FU) in a large pNET cohort. Methods Data from 96 pNET patients treated with STZ/5-FU were analysed retrospectively. Endpoints of the study were RR, time to tumour progression (TTP) and overall survival (OS). Results Mean age of patients at the start of chemotherapy was 57.6 years (range, 32.1–80.4). STZ/5-FU was the 1st line treatment in 56.3%. 11.5% had G1, 79.2% G2 and 6.3% G3 neoplasms. Baseline progression was evident in 74%. Objective response rate was 42.7%. 40.6% of patients showed stable disease as best response while 16.7% showed progressive disease. Treatment was discontinued due to toxicity in 16 patients. Median TTP and OS were 19.4 (95% confidence interval (CI), 13.6–25.2) and 54.8 months (95% CI, 34.7–74.9), respectively. In Cox regression analysis, Ki67 > 15% was the only negative prognostic factor for TTP (hazard ratio (HR), 3.3; P < 0.001), confirmed by multivariate analysis (HR, 6.7; P = 0.001). Conclusions STZ/5-FU was associated with considerable RR. Treatment was associated with durable TTP especially in patients with Ki67-index of ⩽15%. These findings along with good tolerability strengthen the value of this two-drug chemotherapy for the management of unresectable pNET. [ABSTRACT FROM AUTHOR]

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Aims Recently, we described a series of pancreatic neuroendocrine tumours (Pan NETs) featuring prominent stromal fibrosis, which we called sclerosing Pan NETs. The aim of this study was to examine the pathological, immunophenotypic and clinical differences between sclerosing and non-sclerosing Pan NETs. Methods and results One hundred and six Pan NETs were identified, of which 15 (14%) were sclerosing NETs. Tissue microarrays containing 44 non-sclerosing and five sclerosing Pan NETs, as well as sections from 10 additional sclerosing tumours, were immunohistochemically labelled for serotonin, CDX2, CDH17, and islet 1. Sclerosing Pan NETs were smaller ( P = 0.045) and more likely to show an infiltrative growth pattern ( P < 0.001) than non-sclerosing Pan NETs. They were frequently associated with a large pancreatic duct, causing duct stenosis. Additionally, we found significantly increased expression of the small intestinal NET markers serotonin, CDX2 and CDH17 in sclerosing Pan NETs ( P < 0.001) as compared with non-sclerosing Pan NETs. No difference in clinical outcome was found; however, more sclerosing Pan NETs were stage IIB or above ( P = 0.035), with lymph node metastasis being seen in three of nine sclerosing Pan NETs with a tumour size of <20 mm. Conclusions Sclerosing Pan NETs have distinct pathological features and biomarker expression profiles. In addition, lymph node metastasis can be present even with small sclerosing Pan NETs. [ABSTRACT FROM AUTHOR]

Background: Necrolytic migratory erythema (NME) is most commonly a paraneoplastic condition. It is the dermatologic manifestation classically associated with glucagonoma pancreatic neuroendocrine tumour. Glucagonoma syndrome has been defined by the constellation of secreting tumour associated with overproduction by the α-cells in the pancreatic islets of Langerhans, abnormally elevated blood level of glucagon, and skin findings of NME. Objective: Although rare, all dermatologists must know and recognise NME promptly to request useful investigations for the diagnosis of this characteristic neuroendocrine tumour. Methods and Results: We report a case of a middle-aged woman seen in our dermatology clinic with longstanding skin findings suggestive of NME revealing a glucagonoma. Surgical removal was associated with complete resolution of the cutaneous and systemic features. Conclusion: NME is often the first clinical finding of an occult neuroendocrine pancreatic neoplasia. Dermatologists must be aware of this condition since they can be the first physician to suspect it and allow multidisciplinary management, which influences the prognostic value. Surgical removal is the first-line therapy if early diagnosis is done before liver metastases occur. [ABSTRACT FROM AUTHOR]

Objective To determine the diagnostic accuracy and pitfalls of endoscopic ultrasound ( EUS)-guided fine needle aspiration ( FNA) cytology of pancreatic neuroendocrine tumour (Pan NET). Methods A search of our laboratory information system was performed from July 1992 to June 2010 to identify all FNA cytology and corresponding surgical specimens in which the diagnosis of Pan NET was rendered or considered. Results One hundred and thirty-two cases diagnosed by EUS-guided FNA were collected. Histological correlation was available for 77 (58%) of FNAs; 55 patients may have been treated elsewhere or had no surgery because of advanced disease or co-morbidity. Among 56 cases diagnosed as Pan NET on FNA, 54 (96%) were confirmed histologically; the remaining two were poorly differentiated adenocarcinoma with focal neuroendocrine features in one case and no tumour was found in the other. Follow-up histology of nine patients diagnosed as suspicious for Pan NET on FNA showed four Pan NETs, two pancreatic ductal adenocarcinomas ( PDA), one solid pseudopapillary tumour ( SPT) and two cases of chronic pancreatitis. Nine cases rendered by FNA as atypical ( n = 3), no atypical cells identified ( n = 4) or unsatisfactory ( n = 2) were Pan NETs on histology. Lastly, three cases of oncocytic variant of Pan NET were misdiagnosed on FNA as either adenocarcinoma ( n = 2) or as suspicious for carcinoma ( n = 1). Conclusions Overall, 54 of the 70 histologically confirmed Pan NET cases (77%) were correctly diagnosed by preoperative FNA as Pan NET. FNA cases designated as no atypical cells identified and unsatisfactory (7/132, 5%) were attributable to sampling error. Diagnostic pitfalls in our study mainly included PDA, SPT and chronic pancreatitis. [ABSTRACT FROM AUTHOR]

Background/Aims: O6-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. Methods: We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. Results: In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. Conclusion: Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Pancreatic neuroendocrine tumours (pNETs) are rare and the majority of patients present with advanced disease. Such patients have limited treatment options. We conducted a systematic review of published clinical trials of non-surgical interventions in pNET, to understand the efficacy, safety and health related quality of life (HRQoL) outcomes from the current evidence base. Methods: Electronic databases and manual bibliographic searches were conducted to identify relevant studies. Data were extracted by two independent reviewers. Results: Forty seven clinical studies met the predefined inclusion criteria. The following interventions were included: targeted therapies (two RCTs and six single-arm studies), chemotherapy (two RCTs, one prospective nonrandomised, comparative study and 14 single-arm studies);somatostatin analogues (SSA) and radiolabeled SSA therapies (nine single-arm studies), liver-directed therapies (six single-arm studies), mixed treatment regimens (one RCT, four single-arm studies) and other interventions such as interferon and recombinant human endostatin (one single-arm study for each). The paucity of RCT data and lack of consistency in reporting validated study outcomes and differing patient inclusion criteria between studies made it difficult to compare the relative efficacy of therapies. Discussion: The majority of published studies assessing treatment regimens for the management of pNET are single arm, non-randomised studies, often enrolling a small number of patients and not reporting clinically meaningful outcomes. However data from recently conducted studies assessing targeted therapies indicate that it is possible to conduct adequately powered RCTs reporting standardised oncological endpoints in this rare cancer. Further, similarly robust studies should be conducted to define the optimal treatment algorithm. [Copyright &y& Elsevier]