Search Results (101)

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors that have traditionally been regarded as “immune cold” and largely refractory to PD-1/PD-L1 checkpoint blockade, with notable exceptions such as Merkel cell carcinoma (MCC). The advent of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled unprecedented dissection of the NEN tumor microenvironment (TME), but a cross-subtype synthesis is lacking. This review aims to integrate single-cell and spatial transcriptomic findings across major NEN subtypes to reframe NEN immunosuppression and delineate translational implications. To this end, we performed a structured narrative review of PubMed-indexed studies up to 30 April 2026, prioritizing original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies of NENs, supplemented by mechanistic, clinical, and biomarker-focused reports providing essential context. Across these studies, synthesis spanning pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, adrenal, and other NEN subtypes highlights conserved features beyond the PD-1/PD-L1 axis, including myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9), cancer-associated fibroblast-mediated immune exclusion, lineage-state-dependent immune visibility, and direct immunomodulation by neuroendocrine secretory products such as calcitonin gene-related peptide. We propose a four-layer framework integrating these mechanisms and linking them to emerging biomarkers and therapies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and peptide receptor radionuclide therapy combinations. Together, these findings indicate that single-cell and spatial transcriptomic studies reframe NEN immunosuppression as a multilayered, subtype-dependent process, providing a conceptual scaffold for biomarker-guided, subtype-adapted therapeutic strategies and prospective clinical trial design in neuroendocrine oncology. Full article

Background: Spleen-preserving (SP) distal pancreatectomy (DP) with splenic vessels resection (SVR) (Warsaw procedure, WP) is an option for the treatment of tumors with low malignant potential. The reverse blood flow through the short gastric arteries (SGA) explains the preservation of the spleen after SVR, but leaves the source of the blood supply to the SGAs hidden. The types of blood supply to the spleen after WP and their incidence have not been previously described, nor has the significance of these types for locally advanced pancreatic head cancer (LAPHC) surgery been determined. Aim: To determine the main types of spleen blood supply after WP, and to assess the feasibility and safety of splenic artery (SA) rotation for the organ-preserving surgery of LAPHC. Methods: Retrospective analyses of demographic and perioperative data, including CT scans, overall (OS) and progression-free (PFS) survival after 71 SP DP SVR and 41 SP SVR pancreaticoduodenectomies (PD) and total pancreatectomies (TP) for LAPHC (2007–2025). Results: In 134 SP procedures, SA was resected in 115 cases (71DP, 9 TP, 3 central, and 32 PD). Indications for surgery were MCN (41), IPMN (14), CSA (3), NEN (25), SPPN (8), PHDAC (40), sarcoma (1), autoimmune (1), and calculous chronic pancreatitis (1). There were no deaths or ischemia-related splenectomies. Morbidity—31% (n23); Dindo–Clavien (D-C) > 3b-2.8%; POPF-grade B-n7 (10.6%); splenic infarctions on CT after SVR-n18 (23%), one symptomatic. CT revealed three types of arterial blood supply to the spleen after SPDP SVR: left gastric artery (LGA) type (n50, 70, 5%), gastro-epyploic arcade (GEA) type (n9, 12, 5%), and an intermediate type (n12, 17%). Spleen- and pancreas tail-preserving SVR pancreatectomies for LAPHC (n41) were accompanied by rotation of the SA to substitute resected SMA (n19) and CHA (n15) for 26 Whipples and 8TPs. There were no ischemic complications. D-C > 3–19.5%. Median OS and PFS for PDAC were 35 and 21 months for 29.5 months median follow-up. Conclusions: Despite the preservation of blood flow through all potential sources of splenic blood supply following resection of the splenic artery, the main collaterals supplying the spleen after WP are LGA branches (~90%). This knowledge, with strict adherence to the developed criteria, allows for the safe preservation of the spleen, pancreatic tail, and stomach during pancreatectomies with SA resection, including its rotation for the substitution of the SMA and CHA in LAPHC. Full article

Capecitabine plus temozolomide (CAPTEM) improves progression-free survival (PFS) in pancreatic endocrine and neuroendocrine neoplasms (PNENs), yet its real-world effectiveness across other endocrine and neuroendocrine neoplasm (ENEN) subtypes remains uncertain. We conducted a retrospective population-based cohort study including 159 adults with ENENs treated with CAPTEM in Alberta, Canada (2011–2021). Patients were stratified by primary tumor site, treatment line, and number of CAPTEM cycles received. Kaplan–Meier methods and Cox proportional hazards models adjusted for age and sex were used to evaluate PFS and overall survival (OS). Compared with pancreatic neuroendocrine neoplasms PNENs, gastrointestinal neuroendocrine neoplasms (GINENs) demonstrated similar PFS and OS. In contrast, pulmonary neuroendocrine neoplasms (PuNENs) and other ENENs (OENENs) were associated with significantly shorter PFS and OS. Use of CAPTEM in the first-line setting was associated with improved PFS (HR 0.56, 95% CI 0.40–0.78, p < 0.001) and OS (HR 0.42, 95% CI 0.29–0.62, p < 0.001). Receipt of ≥6 treatment cycles was also strongly associated with superior PFS (HR 0.22, 95% CI 0.16–0.32, p < 0.001) and OS (HR 0.22, 95% CI 0.14–0.34, p < 0.001). CAPTEM shows comparable real-world effectiveness in GINENs and PNENs but appears less effective in PuNENs and other OENEN subtypes. Early initiation and adequate treatment duration are key factors associated with improved survival outcomes. Full article

Background: Pancreatic neuroendocrine neoplasms (PanNENs) represent a heterogeneous tumor entity with a steadily rising incidence, mainly due to advances in imaging and growing diagnostic awareness. In pancreatic ductal adenocarcinoma (PDAC), the mesopancreas (MP) has been identified as a frequent site of microscopic tumor spread and a key determinant of circumferential resection margin (CRM) status, leading to the concept of standardized mesopancreatic excision (MPE). While its oncological relevance in PDAC is increasingly recognized, the role of the mesopancreas in PanNENs remains unclear. This study aimed to systematically evaluate mesopancreatic infiltration in PanNENs and to identify associated clinicopathological predictors. Methods: Consecutive patients undergoing oncological pancreatoduodenectomy, spleen-preserving distal pancreatectomy, or distal splenopancreatectomy for PanNENs and PanNECs were included. The mesopancreas was histopathologically examined for tumor infiltration within CRM assessment. Results: MP infiltration was detected in 60% of patients. It was associated with higher Ki-67 index, larger tumor size, lymph node involvement, venous invasion, and positive CRM status. A Ki-67 index ≥ 5% and tumor size ≥ 21.5 mm were identified as predictors of MP infiltration. Higher T stage predicted reduced overall survival (OS), whereas MP infiltration, lymphatic (L1) and venous (V1) invasion, and Ki-67 ≥ 5% were associated with impaired disease-free survival (DFS). Conclusions: Mesopancreatic infiltration is frequently present in PanNENs and correlates with aggressive tumor characteristics. Given its association with CRM positivity and reduced DFS, consideration of the mesopancreas in staging and surgical strategies appears oncologically justified. Larger studies are required to validate these findings. Full article

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors with significant biological diversity. Despite significant improvements in diagnostics and a growing range of available therapies, long-term disease control remains difficult in advanced cases. The tumor microenvironment, which in pNENs adopts a predominantly immunosuppressive profile and promotes tumor development, is attracting increasing attention. A complex network of interactions dominates the tumor tissue, including M2 macrophages, regulatory T cells, and numerous pathways that inhibit effector lymphocyte activity. M2 macrophages, through the secretion of anti-inflammatory cytokines and exosome-mediated signaling, support angiogenesis while simultaneously attenuating the cytotoxic response. Simultaneously, receptors and ligands associated with immune checkpoints are overexpressed. In addition to classic molecules such as PD-1/PD-L1 and CTLA-4, the role of B7x and CD276 is increasingly being emphasized, as their presence correlates with rapid disease progression and poor prognosis. To date, attempts to use checkpoint inhibitors as monotherapy have yielded modest clinical benefits. However, approaches based on combination strategies—both in the form of dual immune blockade and in combination with chemotherapy or angiogenesis-targeted therapy—have shown significantly greater activity. Therapies using tyrosine kinase inhibitors, such as sunitinib and newer drugs (lenvatinib, surufatinib, cabozantinib), may partially normalize the tumor’s disrupted vascular architecture and thus increase its susceptibility to immunological interventions. In the coming years, it will be crucial not only to overcome the immunosuppressive nature of the TME but also to identify predictive biomarkers that will allow for more precise patient selection. This approach may open the way to more effective, personalized therapies for pNENs. Full article

The clinical management of Pancreatic Neuroendocrine Neoplasms (Pan-NENs) is complicated by the disease’s intrinsic variability, which creates significant hurdles for accurate risk profiling and the standardization of treatment protocols. Recently, Artificial Intelligence (AI) has offered a promising avenue to address these challenges. By integrating and processing high-dimensional multimodal datasets (encompassing clinical history, radiomics, and pathology), these computational tools can refine survival forecasts and support the development of personalized medicine. However, the transition from experimental success to routine clinical use is currently obstructed by reliance on limited, retrospective cohorts that lack external validation, alongside unresolved concerns regarding algorithmic transparency and ethical governance. This review evaluates the current landscape of AI-driven prognostic modeling for Pan-NENs and critically examines the pathway towards their reliable integration into clinical practice. Full article

Pancreatic neuroendocrine neoplasms (PanNENs) are a diverse group of cancers with varying clinical presentations and prognoses due to differences in morphology and clinical stage. Most are non-functional tumors that express somatostatin receptors (SSTRs). Several treatment options have been established for patients with locally advanced or metastatic PanNETs, but the optimal choice of treatment approach and the sequence of available therapies are not yet clearly defined and are currently being studied in multiple ongoing clinical trials. Additionally, new drugs are being researched for PanNET treatment, including immune checkpoint inhibitors, next-generation peptide receptor radionuclide therapy, and other targeted biological therapies. To improve treatment outcomes for patients with PanNETs, a multidisciplinary team should evaluate systemic treatment options. The aim of this article is to review currently available therapies and discuss new and emerging systemic treatment strategies for patients with advanced PanNETs. Full article

Pancreatic neuroendocrine neoplasms (pNENs) are the second most common type of pancreatic cancer after pancreatic ductal adenocarcinoma. Germline mutations in DNA repair genes drive several hereditary and sporadic cancers; however, their role in pNENs remains poorly defined. This pilot study aimed to assess the frequency and clinical relevance of germline DNA repair gene mutations in patients with pNENs, both with and without a family history of cancer. Germline DNA from 57 Polish patients with pNENs was analyzed using targeted next-generation sequencing to identify variants in a panel of DNA repair genes. Variant classification followed the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Germline mutations were identified in 14 patients (24.6%), both with and without a family history of malignancy. Two patients carried pathogenic variants in BRCA2 and CHEK2, while seven carried variants of uncertain significance (VUS). The identified variants have been implicated in various cancer types, including breast, ovarian, prostate, gastric, colorectal, and pancreatic cancers. These findings indicate that germline mutations in DNA repair genes may contribute to the pathogenesis of pNENs, even in patients without a family history. Broader germline testing and population-specific studies are needed to clarify the genetic landscape and clinical implications of these alterations. Full article

Background: Pancreatic neuroendocrine neoplasia (PanNEN) comprises a spectrum, from well-differentiated (i.e., G1, G2) pancreatic neuroendocrine tumors (PanNETs) to poorly differentiated carcinomas (PanNECs). Therapeutic progress is limited by the lack of representative preclinical models. Patient-derived organoids (PDOs) offer potential as translational models, but evidence remains scattered. Methods: We conducted a systematic review of PubMed (Jan 2009–Aug 2025) for original studies reporting on PDOs from PanNEN patients. Eligible studies were screened using the Rayyan software and data extracted from PDO take rates, validation methods, and clinical applications. Results: Twelve studies were included for qualitative and quantitative analyses. PDOs were successfully generated from both PanNETs (G1–G3; n = 26) and PanNECs (n = 6), primarily derived from primary tumors, but several studies also included metastatic sites. Take rates ranged from 33% to 100%, for a cumulative 33 PDOs from 44 attempts (overall take rate: 75%). Validation consistently employed histology, immunohistochemistry, and molecular profiling, with several studies incorporating xenotransplantation or omics approaches. PDOs demonstrated variable culture durations, from short-term (<3 weeks) to long-term (>20 passages). Drug screening studies (n = 7) revealed heterogenous responses to standard agents and pathways (everolimus, sunitinib, and temozolomide) and identified novel vulnerabilities, including EZH2 dependency, PI3K/CDK4/6 synergy, and Bcl-2-linked sensitivities in PanNECs. One study provided evidence of concordance between PDO drug sensitivity and patient responses. Conclusions: Research into PanNEN organoids remains limited. However, PDOs can preserve key histological and molecular features, enable pharmacotyping, and uncover candidate biomarkers for therapy. Despite feasibility across subtypes, progress is constrained by variability in culture success. Standardization and prospective validation are essential to advance PDOs as tools for personalized medicine in PanNENs. Full article

Background and Objectives: Neuroendocrine neoplasms (NENs) are rare, mainly gastro-entero-pancreatic tumors with heterogeneous biology and multiple therapeutic options. Assessing treatment response remains challenging. Standard evaluation relies on RECIST 1.1, although its limitations are well recognized. Tumor growth rate (TGR), defined as the monthly percentage change in tumor size between two imaging assessments, has been proposed as a dynamic parameter to complement conventional criteria. This review explores the role of TGR in NEN. Results: Two different evaluations of TGR, once conducted between baseline diagnostic scan and a radiological assessment 12–24 weeks after (TGR0), and another conducted between baseline scan and a diagnostic evaluation three months after (TGR3m), proved to be well correlated to progression free survival (PFS) in G1 and low-G2 NEN, with cut off of 4%/month and 0.8%/month, respectively. Conclusions: TGR offers additional insights into tumor kinetics and may help refine treatment monitoring in NEN. While retrospective evidence supports its prognostic utility, prospective studies are required to validate TGR as a standard clinical tool. Full article

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) represent a challenging disease. Their large heterogeneity limits the possibility of providing accurate risk assessments or standardizing the most effective therapies for these patients. In recent years, artificial intelligence (AI), and in particular machine learning approaches, have shown real promise in addressing these complexities. By analyzing large volumes of clinical, imaging, and pathological data, AI-based tools can significantly improve the accuracy of survival predictions and guide more tailored treatment strategies. In this narrative review, we examine the potential applications of AI to develop effective prognostic models in GEP-NENs, and how these models may help clinicians in predicting survival and optimizing patient management. While early results are encouraging, important limitations remain, since available data stem from small, retrospective datasets, sometimes lacking external validation, and concerns around transparency and ethics still represent an open issue. Addressing these gaps will be key to moving from research applications to practical tools that can support everyday clinical decision-making. Full article

Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies that consist of two major subtypes: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Glucagon-like peptide-1 receptor agonists (GLP-1Ra) have demonstrated favorable results in preclinical studies, but their impact on NEN outcomes remains unexplored. Methods: Using the TriNetX US Research Network, we identified adult patients with NEN and either diabetes or obesity. After 1:1 propensity score matching based on demographics, comorbidities, procedures, and medication use, we compared survival outcomes between patients who received GLP-1Ra after NEN diagnosis and those who did not. Results: Among 32,464 eligible patients, 3139 received GLP-1Ra and 29,325 did not. After propensity matching, each cohort included 3043 patients with well-balanced baseline characteristics. During follow-up periods extending up to 15 years, all-cause mortality occurred in 356 (11.7%) GLP-1Ra users versus 753 (24.7%) non-users, representing a 13.0% absolute risk reduction (p < 0.001). GLP-1Ra use was associated with significantly improved survival (HR = 0.56, 95%CI = 0.49–0.63, p < 0.001). Both well-differentiated (HR = 0.52) and poorly differentiated tumors (HR = 0.56) showed significant improvement. Among primary sites, lung NENs demonstrated the most pronounced benefit (HR = 0.42). Tirzepatide showed the strongest association with reduced mortality (HR = 0.16), followed by semaglutide (HR = 0.27) and dulaglutide (HR = 0.52). Results: In this large propensity-matched study, GLP-1Ra use was associated with a 44.3% reduction in mortality risk among NEN patients with diabetes or obesity. The magnitude of the observed benefit suggests a potential role for GLP-1Ra as adjunctive therapy in this patient population. Prospective clinical trials are warranted to confirm these findings and explore underlying mechanisms. Full article

Background/Objective: Identifying patterns of diagnostic imaging workflow parallel to the influence of certain variables, such as pathology guidelines over time, provides valuable insight for clinical decision making. This study presents a recurring trend of initial imaging orders and follow-ups, up to the diagnosis of pancreatic neuroendocrine tumors (pNETs), across two decades, with scans which led to pathological investigation. Methods: Three readers evaluated common conventional imaging among initial and follow-up studies for lesion detection and localization. Inter-reader and intra-reader analyses were controlled as contributing factors to the imaging diagnostic trend. Results: Our results show that CT was the prominent initial scan in pNET workup, likely due to their wide availability, high spatial resolution, and rapid acquisition, with a sufficient detection rate throughout both decades, regardless of technical advances. However, MRI scans also gained soaring popularity, especially among syndromic patients, likely due to follow-up and anatomical surgery precision. Conclusions: Newer modalities may be eventually useful and only requested for pNETs staging and further treatment. Full article

Introduction: Bronchopulmonary Neuroendocrine Neoplasms (NEN) occur in 2–7% of patients with multiple endocrine neoplasia type 1 (MEN1). Precursor lesions have been identified for MEN1-related pancreatic, duodenal, and gastric NEN. The aim of the current study using a MEN1 mouse model was to define the precursor lesions of bronchopulmonary NEN and evaluate the potential prophylactic antitumor effects of somatostatin analogues in a transgenic MEN1 mouse model. Methods: Fifteen mice, germline heterozygous for Men1(+/T), were treated with subcutaneous injections of lanreotide autogel (Somatuline Autogel^®, IPSEN Pharma), while 15 mice were treated with subcutaneous injections of physiologic sodium chloride as the control group. Five mice from each group were euthanized after 12, 15, and 18 months, respectively. The complete lungs were resected and evaluated after hematoxylin and eosin staining and immunohistochemistry for synaptophysin and chromogranin A. Results: In the lungs of the 30 evaluated mice, whether treated or placebo treated, no bronchopulmonary neuroendocrine cell hyperplasia nor neuroendocrine neoplasia was detected through histopathology. However, pulmonary adenocarcinoma developed in 2 (13%) of the 15 untreated mice and in 1 (7%) of the 15 lanreotide-treated mice. Conclusions: Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary NEN or precursor lesions, but pulmonary adenocarcinoma. This surprising result needs to be investigated in more detail. Full article

Pancreatic neuroendocrine neoplasms (pNENs) represent approximately 2% of all solid pancreatic tumors. The incidence of pNENs has been increasing in the last decade. The clinical manifestations of pNENs range from hormone secretion syndromes in functioning neoplasms (F-pNENs) to local infiltration or distant metastases in late-stage diagnoses or incidental findings in small non-functioning neoplasms (NF-pNENs). While surgery is the gold-standard treatment for larger and more aggressive tumors, small and low-grade tumors (G1) may be followed-up due to the indolent course of disease. Recently, endoscopic ultrasound (EUS)-guided ablative techniques, such as ethanol injection (EUS-EI) and radiofrequency ablation (EUS-RFA), have emerged as promising options for loco-regional ablations in selected cases. Despite promising safety profile and efficacy, high-quality evidence is needed to support their widespread adoption. This article reviews the current state of EUS-guided locoregional therapies, patient selection criteria, procedural details, and associated risks. Full article