Pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous tumors arising from neuroendocrine cells, representing approximately 10 % of all Gastro-Entero-Pancreatic neuroendocrine neoplasms. While most pNENs are sporadic, a subset is associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel-Lindau disease (VHL). pNENs are further classified into functioning and non-functioning tumors, with distinct clinical behaviors, prognoses, and treatment approaches. This review explores genetic and environmental biomarkers that influence the risk, prognosis, and therapeutic responses in pNENs. The epidemiology of pNENs reveals an increasing incidence, primarily due to advancements in imaging techniques. Genetic factors play a pivotal role, with germline mutations in MEN1, VHL, and other genes contributing to familial pNENs. Somatic mutations, including alterations in the mTOR pathway and DNA maintenance genes such as DAXX and ATRX, are critical in sporadic pNENs. These mutations, along with epigenetic dysregulation and transcriptomic alterations, underpin the diverse clinical and molecular phenotypes of pNENs. Emerging evidence suggests that epigenetic changes, including DNA methylation profiles, can stratify pNEN subtypes and predict disease progression. Environmental and lifestyle factors, such as diabetes, smoking, and chronic pancreatitis, have been linked to an increased risk of sporadic pNENs. While the association between these factors and tumor progression is still under investigation, their potential role in influencing therapeutic outcomes warrants further study. Advances in systemic therapies, including somatostatin analogs, mTOR inhibitors, and tyrosine kinase inhibitors, have improved disease management. Biomarkers such as Ki-67, somatostatin receptor expression, and O6-methylguanine-DNA methyltransferase (MGMT) status are being evaluated for their predictive value. Novel approaches, including the use of circulating biomarkers (NETest, circulating tumor cells, and ctDNA) and polygenic risk scores, offer promising avenues for non-invasive diagnosis and monitoring. Despite these advancements, challenges remain, including the need for large, well-annotated datasets and validated biomarkers. Future research should integrate multi-omics approaches and leverage liquid biopsy technologies to refine diagnostic, prognostic, and therapeutic strategies. Interdisciplinary collaborations and global consortia are crucial for overcoming current limitations and translating research findings into clinical practice. These insights hold promise for improving prevention, early detection, and tailored treatments, ultimately enhancing patient outcomes.

SANET-ep (NCT02588170) and SANET-p (NCT02589821) demonstrated the efficacy and safety of surufatinib versus placebo in patients with advanced extra-pancreatic and pancreatic neuroendocrine tumours (NETs). Here, we present a pooled analysis of final overall survival (OS) from two randomised phase 3 studies.

The SANET studies were randomised, placebo-controlled, double-blind, phase 3 studies in China, comparing the efficacy and safety of oral 300-mg surufatinib (n = 265) versus placebo (n = 133) in patients with unresectable/metastatic, well-differentiated NETs (grade 1/2). After progression of disease or study unblinding, patients receiving placebo crossed over/switched to open-label surufatinib. By pooling the data from the two studies, OS analysis was completed using Kaplan-Meier methodology and a Cox proportional hazards model in the intention-to-treat population. Exploratory analyses were performed using different models to correct the confounding effect introduced by crossover. Long-term safety was assessed.

At study termination, 69 % of the placebo group had crossed over/switched to surufatinib. Median OS was 50.1 versus 46.8 months for patients initially on surufatinib versus those initially on placebo (stratified hazard ratio [HR] 0.935, 95 % confidence interval [CI] 0.684-1.278; p = 0.6727). After correcting the confounding effect introduced by crossover/switching, the HR ranged from 0.558 to 0.825. Commonly (≥10 %) reported treatment-related adverse events (grade 3/4) included hypertension and proteinuria.

OS of patients initially on surufatinib was not significantly longer versus patients initially on placebo, likely due to the high amount of crossover from placebo to surufatinib. No new safety signals were observed.

SANET-ep (NCT02588170) and SANET-p (NCT02589821).

Metastatic neuroendocrine neoplasms (mNEN) require new treatment options. Intralesional (IL) PV-10 is an autolytic chemotherapy that may elicit an adaptive immune response.

This phase 1 study evaluated IL PV-10 administered percutaneously to hepatic lesions in patients with progressive mNEN. IL PV-10 was injected in a single lesion per treatment cycle. A treatment cycle could be repeated after ≥ 6 weeks if multiple targetable lesions were present. The primary endpoint was safety.

Twelve patients were enrolled with a median age of 66 years (range 47-79). All patients had progressive disease at enrolment and received prior somatostatin analogues; 10 patients had peptide receptor radionuclide therapy (PRRT) treatment. One lesion was injected per cycle for all 12 patients. Reported grade 3 side effects were photosensitivity (1 patient), face oedema (1 patient), elevated transaminases (1 patient), hypertension (2 patients). Response rate was 42% of injected lesions with patient-level disease control of 84%, PFS 9.4 months and median OS 24.0 months.

IL PV-10 elicited no safety concerns. Encouraging evidence of local and systemic disease control was seen in a heavily pre-treated, progressing mNEN population.

NCT02693067.

P-glycoprotein (P-gp) transporter is included in the failure of various carcinoma chemotherapeutics because of the multidrug resistance (MDR) phenomenon, in which the chemotherapeutic drugs are eliminated from target cells. Consequently, inhibiting P-gp transporter function is a prospective strategy for cancer treatment. In the current study, the SuperDRUG2 database containing >4600 pharmaceutical compounds was virtually screened toward the P-gp transporter utilizing the docking predictions. For inhibitors with a docking score lower than -10.5 kcal/mol, molecular dynamics (MD) simulations were performed, accompanied by binding energy evaluations using the MM-GBSA approach. In accordance with the MM-GBSA//100 ns MD, angiotensin amide (SD003508), terlipressin (SD002603), argipressin (SD002535), and lanreotide (SD001365) exhibited potential binding affinities against the P-gp transporter with ΔGbinding < -120.0 kcal/mol. The outstanding consistency of the investigated inhibitors inside the P-gp binding pocket was shown by the post-dynamics analyses. Additionally, MD simulations of the inhibitor-P-gp complexes in a POPC membrane environment were conducted to mimic the physiological conditions. These results demonstrated that angiotensin amide, terlipressin, argipressin, and lanreotide are promising P-gp inhibitors and deserve additional in-vitro/in-vivo studies.

Radiolabeled somatostatin analogs (SSAs), such as [68Ga]Ga-DOTA SSAs, have transformed imaging and therapeutic strategies. However, their use is constrained by the high cost of generators and their short half-life. In contrast, [18F]SITATE presents a promising alternative, offering the advantage of a longer half-life than 68Ga, along with the cost-effectiveness of cyclotron-based production. This study evaluated the first histologic ex vivo validation of [18F]SITATE. Methods: This study retrospectively included 47 patients (57% male; mean age, 66.9 ± 14.9 y) with histologically confirmed well-differentiated neuroendocrine neoplasms who underwent [18F]SITATE PET followed by surgery within 4 mo. Lesion uptake was quantified using SUVmean, SUVpeak, SUVmax, and tumor-to-liver ratio (TLR). Histologic somatostatin receptor (SSTR) type 2 expression was determined using histological scores (H-scores), with thresholds defining SSTR scores 1-3. The accuracy of PET imaging for preoperative metastatic detection was evaluated against surgical histology. Results: PET imaging demonstrated a significant correlation between [18F]SITATE uptake (SUVmean and TLR) and SSTR type 2 H-scores (r = 0.618 and 0.622, respectively; P < 0.0001). SSTR score 3 correlated with increased SUVmean and TLR (P < 0.0001). Among 35 patients with primary resection and lymphadenectomy, PET achieved a sensitivity of 73.9% and specificity of 100%. Conclusion: [18F]SITATE PET imaging strongly correlates with histologic SSTR expression, demonstrating utility in staging and guiding therapeutic decisions in neuroendocrine neoplasms. This 18F-labeled tracer shows specificity comparable to historical [68Ga]Ga-DOTA SSA data, whereas an increase in sensitivity for the detection of locoregional metastases appears possible. Further head-to-head comparisons of [18F]SITATE with traditional [68Ga]Ga-DOTA SSA and histologic validation are warranted to optimize its diagnostic accuracy and clinical impact.

Pancreatic neuroendocrine tumors (pNETs) often overexpress somatostatin receptor type 2 (SSTR2), making them ideal targets for theranostics, which integrates molecular imaging with targeted radionuclide therapy. 177Lu-DOTATATE significantly extends progression-free survival (22.8 vs. 8.5 months) compared to octreotide LAR. Despite these advances, challenges remain, including treatment resistance and long-term toxicities. In this review, we explore advancements in specialized imaging techniques, rationale combination strategies, and exploring next-generation radiopharmaceuticals.

Peptide receptor radionuclide therapy (PRRT) is recommended and approved in advanced neuroendocrine tumors (NETs). There is a lack of data on the utility of PRRT in multiple endocrine neoplasia (MEN) syndrome. This study explores the utility of PRRT in MEN syndrome patients with inoperable/metastatic NETs.

A single-center retrospective analysis of MEN syndrome patients with advanced NETs referred for PRRT was done. Upto 4 cycles of 177Lu-DOTATATE (5.5-7.4 GBq/cycle) were administered every 8-12 weeks. Treatment-related adverse events were assessed using CTCAE v5. The best response to PRRT was evaluated using RECIST 1.1. Follow-up was done to calculate the progression-free survival (PFS) and overall survival (OS).

The data of 15 patients with a median age of 36 years (IQR: 32-49) was analyzed. Fourteen patients had MEN-1 syndrome, and 1 had MEN-2 syndrome. Thirteen patients with MEN-1 syndrome had gastroenteropancreatic (GEP) NET, with the multifocal primary as the most common finding (n=7). One patient had thymic carcinoid. All patients had hyperparathyroidism, while 6 had pituitary adenoma. Fifty-three cycles of 177Lu-DOTATATE (range: 1-4) were administered with a median cumulative activity of 27.8 GBq. Twelve patients (80%) showed grade 1/2 adverse events, with leukopenia being the most common. Six patients achieved partial response (43% ORR), 6 showed stable disease (86% DCR), 2 (14%) showed disease progression during PRRT, while 1 patient was lost to follow-up. The median PFS was 32.6 months (95% CI: 14.7-not reached) with an estimated 1- and 5-year PFS rate of 86.2% (95% CI: 68-100) and 46.3% (95% CI: 13-80), and estimated 5-year OS rate of 76.2% (95% CI: 52.1-100).

177Lu-DOTATATE is a safe and effective treatment option for advanced NETs in MEN syndrome. However, large-sized multicentric prospective studies are required.

Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.

Orbitides, also known as Caryophyllaceae-type cyclic peptides, from the Traditional Chinese Medicine plant Pseudostellaria heterophylla (Miq.) Pax, exhibit great potential for improving memory and treating diabetes. Orbitides are ribosomally encoded and post-translationally modified peptides; however, the key biosynthetic enzyme mediating this process remains unknown in P. heterophylla. In this study, we investigated the distribution of orbitides in P. heterophylla and mined novel precursor peptide genes and peptide cyclases from multiple omics datasets. The function of PhPCY3, a gene encoding a key tailoring enzyme, was elucidated using transient heterologous expression and virus-induced gene silencing systems. Our findings suggest that PhPCY3 specifically cyclizes linear precursor peptides in planta. Molecular docking and multiple sequence alignment, followed by site-directed mutagenesis, identified N500 and S502 as critical amino acid residues for PhPCY3 function. We identified gene sequences for over 100 precursor peptides and successfully biosynthesized known active orbitides, such as heterophyllin B and pseudostellarin E/F/G. Additionally, four novel orbitides, cyclo-[LDGPPPYF], cyclo-[WGSSTPHT], cyclo-[GLPIGAPWG], and cyclo-[FGDVGPVI], were synthesized using a heterologous expression platform. This study introduces a gene-guided approach for elucidating the biosynthesis pathway and discovering novel orbitides, providing a strategy for mining and biosynthesizing novel orbitides in P. heterophylla and other plants to further investigate their activities.

Assessing treatment response in neuroendocrine tumors (NET) remains a significant challenge due to their typically indolent growth and heterogenity, the frequent occurrence of disease stabilization rather than tumor shrinkage after therapy, and the inherent limitations of conventional imaging criteria. While molecular imaging-primarily somatostatin receptor (SST) PET/CT-has improved lesion detection, the absence of standardized response criteria limits its clinical utility and prevents its use as full replacement of conventional imaging. Emerging strategies, including revised thresholds for dimensional changes, criteria evaluating different features, such as lesions' density and functional tumor volumes, offer potential improvements in response evaluation but require further validation for routine clinical implementation. This review examines the current challenges in assessing NET treatment response, evaluates the strengths and limitations of available imaging modalities, and discusses emerging approaches and future directions for optimizing therapeutic monitoring in the heterogeneous panorama of NET.

Relative to other lung tumors, pulmonary carcinoid tumors are rare and have unique histopathological and clinical features. The purpose of this review is to summarize the presentation and management of pulmonary carcinoid tumors, with a particular focus on recent clinical trials in the management of advanced and metastatic disease.

Surgical resection remains a central tenet in the management of pulmonary carcinoid tumors that are localized and even those that have locoregional spread. However, in recent years, the treatment of pulmonary carcinoid has expanded to include several systemic hormonal and cytotoxic therapies as well as radiation and endobronchial strategies. The decision to initiate any of these therapies as either primary or adjuvant treatment after resection depends upon several factors including tumor stage, disease burden, patient's functional status, and whether they will tolerate surgery.

The treatment of pulmonary carcinoid tumors has expanded beyond just surgical resection. Novel regimens of systemic hormonal and cytotoxic therapies as well as radiation and endobronchial intervention should be customized for each patient by a multidisciplinary team of surgeons, medical and radiation oncologists, pulmonologists, and pathologists.

Somatostatin is expressed in various tissues - including the hypothalamus - and strongly suppresses Growth Hormone levels to maintain homeostasis. Synthetic somatostatin analogs are currently used in clinics to treat neuroendocrine tumors and acromegaly. An emerging body of evidence suggests that those synthetic peptides exert anti-inflammatory activities. The present study examines the effect of Lanreotide (LAN) on Lipopolysaccharide (LPS)-triggered injury in endothelial cells and mice. Our findings indicate that LAN effectively mitigates LPS-induced endothelial hyperpermeability, inflammation, and reactive oxygen species (ROS) generation in bovine pulmonary artery endothelial cells (BPAEC) and human lung microvascular endothelial cells (HULEC-5a). A murine model of LPS-induced acute lung injury was also utilized, to examine the effects of LAN in lung edema and inflammation. Our observations suggest that LAN suppresses LPS-induced myosin light chain 2 (MLC2), Cofilin, extracellular signal-regulated kinase 1/2 (ERK1/2), STAT1, STAT3, P38 activation; and lung edema. In conclusion, and based on the aforementioned observations, it is suggested that LAN counteracts experimental LPS-induced injury in endothelial cells and mice.

The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of MEN1 alterations using Men1-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, and clinicopathological features. Drug screening using patient-derived tumor organoids identifies cyclin-dependent kinase (CDK) 5 and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D) as ubiquitous and subtype-specific targets, respectively, with in vivo validation using xenograft models. Together, our proteogenomic analyses illustrate a comprehensive molecular landscape of NF-PanNETs, revealing biological insights and therapeutic vulnerabilities.

To evaluate the use of long-acting somatostatin-analogs (SSA) for treating non-advanced, resectable pancreatic neuroendocrine tumors (PNETs) with indications to surgery, in high-risk patients who were not candidates for surgery.

Patients diagnosed with histology-proven, non-advanced G1/low-G2 68Ga-TC/PET-positive PNETs >20 mm who did not undergo surgery due to comorbidities/old age/high-risk surgical profile, which were treated with SSA at a single, high-volume institution were included. The efficacy of SSA was evaluated using the analysis of tumor growth rate (TGR). "Negative TGRTx-TpreSSA" was defined as the first time point after the initiation of SSA when a negative TGRTx-TpreSSA was observed.

Between 2014 and 2024, 20 patients were treated with long-acting SSA. The median age was 76 (IQR 72-80), and the median ASA score was 3 (IQR 3-3). Fifteen patients (75 %) received Lanreotide, and five (25 %) octreotide acetate (Sandostatin® LAR). The median overall survival was 68.5 months (IQR 60-99). In four patients (20 %), SSA were interrupted when the tumor had shrunk below 2 cm. In one of them, SSA reintroduction was necessary due to disease progression (after 14 months). In two patients (10 %), the treatment was interrupted due to side effects. In one of these, the disease progressed until death at 87 years old. At the last follow-up, sixteen patients were alive, 3 had died (1 death of disease), and 13 were receiving SSA. T2 PNETs presented a significantly faster response to SSA therapy compared to T3 (Median time to "Negative TGRTx-TpreSSA": 6 [95 % CI 5, na] vs 52 [95 % CI 19, na] months, respectively; p = 0.0092) CONCLUSION: In patients at high surgical risk, with localized, resectable, G1 or low-G2, 68Ga-TC/PET-positive PNETs >20 mm, SSA can obtain disease control with a manageable safety profile.

Molecular modelling is a vital tool in the discovery and characterisation of bioactive peptides, providing insights into their structural properties and interactions with biological targets. Many models predicting bioactive peptide function or structure rely on their intrinsic properties, including the influence of amino acid composition, sequence, and chain length, which impact stability, folding, aggregation, and target interaction. Homology modelling predicts peptide structures based on known templates. Peptide-protein interactions can be explored using molecular docking techniques, but there are challenges related to the inherent flexibility of peptides, which can be addressed by more computationally intensive approaches that consider their movement over time, called molecular dynamics (MD). Virtual screening of many peptides, usually against a single target, enables rapid identification of potential bioactive peptides from large libraries, typically using docking approaches. The integration of artificial intelligence (AI) has transformed peptide discovery by leveraging large amounts of data. AlphaFold is a general protein structure prediction tool based on deep learning that has greatly improved the predictions of peptide conformations and interactions, in addition to providing estimates of model accuracy at each residue which greatly guide interpretation. Peptide function and structure prediction are being further enhanced using Protein Language Models (PLMs), which are large deep-learning-derived statistical models that learn computer representations useful to identify fundamental patterns of proteins. Recent methodological developments are discussed in the context of canonical peptides, as well as those with modifications and cyclisations. In designing potential peptide therapeutics, the main outstanding challenge for these methods is the incorporation of diverse non-canonical amino acids and cyclisations.

The somatostatin analogs (SSA) octreotide and lanreotide are a mainstay in the treatment of neuroendocrine tumors (NET). The two pivotal trials differed considerably in terms of patient characteristics and are not directly comparable. Further comparative data are lacking.

This retrospective chart review study included patients with gastroenteropancreatic NET grade 1 or 2 who were treated with octreotide LAR or lanreotide autogel. The main aim was to compare the two SSA based on progression-free survival (PFS) and overall survival (OS) from treatment start.

In total, 129 patients were analyzed, 60% (n = 77) had a small intestinal NET and 31% (n = 40) a pancreatic NET. Histologically, 34% (n = 44) had NET G1, 55% (n = 71) a NET G2, and 11% (n = 14) a NET G1/G2 unclassified. Lanreotide was used in 90 patients (70%) and octreotide in 39 patients (30%). Overall, the median PFS was 32.2 months (95% CI 23.0-42.9 months). No PFS difference (p = 0.8) was observed between lanreotide (29.8 months, 95% CI 18.7-48.5 months) and octreotide (36.0 months, 95% CI 23.2-68.2 months). Median OS from treatment start was calculated at 93.5 months (95% CI 71.1-132.9 months). Again, the median OS following lanreotide (113.4 months, 95% CI 62.3-NA months) or after octreotide (90.3 months, 95% CI 71.1-NA months) did not differ significantly (p > 0.9).

Our long-term experience with octreotide and lanreotide in NET did not reveal differences in antitumor effectiveness. This is consistent with previous reports and might suggest that both SSA can be used interchangeably if needed.

Lymph node dissection is required for many pancreatic neuroendocrine neoplasms. However, the need for such dissection has rarely been examined in detail by the tumor size, tumor location, or World Health Organization grading. The objective is to determine which characteristics of pancreatic neuroendocrine neoplasms require lymph node dissection, and to what extent lymph node dissection should be performed.

A retrospective review was performed of patients who had undergone pancreatectomy with lymph node dissection between 2000 and 2022. Frequency of lymph node metastases stratified by tumor size and grade, and efficacy index (calculated by multiplying the frequency of metastasis to the lymph node station by the 5-year overall survival rate of patients with metastasis to that station) for each lymph node station were evaluated.

Among 130 patients, 29 (22.3%) had lymph node metastases. Tumors larger than 2 cm had a 33.3% lymph node metastasis rate, whereas grade 1 and grade 2 neuroendocrine tumors had rates of 2.4% and 31.8%, respectively. In grade 1 neuroendocrine tumor, for pancreatic head tumor, only peripancreatic head lymph node had an efficacy index of 5.0. Pancreatic body and tail tumor had no lymph node metastases. In grade 2 neuroendocrine tumor, for pancreatic head tumor, peripancreatic and superior mesenteric artery lymph nodes had efficacy indexes of 29.2 and 14.3, respectively. For pancreatic body tumor, peridistal pancreatic lymph node had an efficacy index of 27.3, whereas for pancreatic tail tumor, peridistal pancreatic lymph node and splenic hilum lymph node had an efficacy index of 27.8 and 7.1, respectively.

The optimal extent of lymph node dissection for pancreatic neuroendocrine neoplasms should be determined by considering both the tumor size and grade for each tumor location.

Neuroendocrine tumors (NETs) are a diverse group of neoplasms whose prevalence is increasing globally, primarily due to advancements in diagnostic techniques. NETs arise from cells of the diffuse endocrine system and can occur in various locations, with the gastrointestinal tract being the most common. Their diverse clinical presentations, which range from asymptomatic to severe hormone-induced syndromes, pose significant diagnostic challenges. In emergency care, prompt recognition and management of complications such as bowel obstruction, ischemic events, hormonal crises, and metastases are critical. This review discusses the radiologic spectrum of NETs in emergent care, emphasizing the role of imaging in timely diagnosis and intervention.

Background: Therapy using lutetium-177 dotatate (177LU) was approved in Europe for the treatment of advanced neuroendocrine tumors (NETs) in 2017. Since then, it has become part of the strategies in the treatment of NETs, making it now possible to evaluate real-life results. Research Design and Methods: Single-arm, retrospective, multicenter, cohort study of all the patients with metastatic NETs treated with 177LU (four cycles of 200 mCi every 8 weeks) in the two medical centers dedicated to the treatment of NETs from the region of Aragón, Spain, from 2017 to 2024. Descriptive analysis of demographic characteristics, efficacy, and survival analysis were performed using the statistics software Jamovi 2.6.14. Results: Sixty-eight patients were included. The majority were male, and the most frequent primary location was the pancreas. The ORR was 30.9%. The DCR was 88%. The median OS was 47.4 months [95% CI, 25.6-NE]. The median PFS was 26.1 months [95% CI, 18.5-68.3]. High-grade tumors, multiple previous treatments, and pancreatic location presented worse OS. In total, 42.6% presented any grade adverse event (17.2% hematologic, 30.9% GI symptoms). Conclusions: The efficacy of 177LU in our study is like that observed in similar studies. Acceptable tolerance has been shown. Pancreatic tumors, previous treatments, and higher grades demonstrated worse outcomes. The new research line must consider the use of treatment with 177LU in earlier lines for metastatic disease as well as its possible use in local or locally advanced disease.

Skin paraneoplastic syndromes (SPNSs) are a group of disorders that arise as a consequence of cancer but are not directly related to the tumor mass itself. This review aims to provide a comprehensive overview of these syndromes, encompassing their pathophysiology, clinical features, diagnostic approaches, differential diagnosis, and management strategies. These syndromes, which include conditions such as Bazex syndrome, acanthosis nigricans, dermatomyositis, and necrolytic migratory erythema often manifest prior to or concurrently with a cancer diagnosis, serving as potential early warning signs of underlying malignancies. This review delves into the spectrum of SPNSs and their associations with specific cancer types. Special emphasis is placed on the critical role of dermatologists and oncologists in identifying these skin manifestations as potential markers of malignancy. By raising awareness of SPNSs, this paper highlights the pivotal importance of prompt recognition and intervention in reducing cancer-related mortality.

The Eastern Canadian Gastrointestinal Cancer Consensus Conference was an annual meeting that was held in St. John's, Newfoundland and Labrador, from 26 to 28 September 2024. This included experts in medical oncology, radiation oncology, surgical oncology, nuclear medicine, and general practitioners in oncology (GPO) from across the eastern Canadian provinces who are involved in the management of patients with gastrointestinal malignancies. This consensus statement generated by the conference addresses multiple topics, including the management of localized rectal cancer, liver-limited colorectal cancer, systemic therapy for advanced biliary tract cancers, radioligand therapy for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), systemic therapy for pancreatic and midgut well-differentiated NETs, and systemic therapy for HER2-positive gastroesophageal cancers.

Neuroendocrine tumors (NETs) are a diverse group of malignancies that can occur in various organs, with a notable prevalence in the lungs and gastrointestinal tract, which are the focus of this Review. Although NETs are rare in individual organs, their incidence has increased over recent decades, highlighting the urgent need for current classification systems to evolve by incorporating recent advances in the understanding of NET biology. Several omics studies have revealed molecular subtypes, which, when integrated into existing classification frameworks, may provide more clinically relevant insights for patients with NETs. This Review examines recent progress in elucidating the biology of NETs, with a particular emphasis on the tumor microenvironment and cells of origin. The existence of different cells of origin, which may contribute to distinct molecular groups, along with profiles of immune infiltration - despite being generally low - could explain the emergence of more aggressive cases and the potential for metastatic progression. Given the molecular heterogeneity of NETs and the diversity of their microenvironments and different cells of origin, there is an urgent need to develop morphomolecular classification systems. Such systems would make it possible to better characterize tumor progression, identify new therapeutic targets, and, ultimately, guide the development of personalized therapies.

Lung carcinoids are rare tumors representing 1-2% of all invasive lung malignancies. They include typical and atypical carcinoids, whose distinction is made based on the mitotic index and presence or absence of necrosis. The 10-year overall survival for stage IV typical carcinoid is 47% and 18% for atypical carcinoid, reflecting the indolent growth of these tumors. There are limited approved treatment options for them and most of the evidence comes from retrospective analyses, single-arm trials, subgroup analysis of phase II/III trials for metastatic neuroendocrine tumors and extrapolation of data from phase III trials for gastroenteropancreatic neuroendocrine tumors. Management of metastatic lung carcinoids requires a multidisciplinary standardized approach in specialized centers. Treatment should have a dual objective, control of tumor growth and control of symptoms related to hypersecretion syndromes, aiming to improve quality of life and survival. In the continuum of treatment disease, locoregional treatment options need to be considered in parallel with systemic treatments. In this paper, we review the present treatment options and their rational and we give an insight into future alternatives.

There is a lack of data on the efficacy, effectiveness, and safety of lanreotide autogel in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of Chinese ethnicity. This noninterventional, retrospective study evaluated the effectiveness and safety of lanreotide autogel in patients of Chinese ethnicity with GEP-NETs in clinical practice.

Patients' charts were abstracted from five hospitals in Hong Kong and Taiwan (July-September 2021), where lanreotide autogel is approved for treating GEP-NETs. Included patients were adults with unresectable, metastatic, or locally advanced GEP-NETs who received a first injection (index) of lanreotide autogel 120 mg between 01 January 2017 and 30 June 2020 (planned sample size: N = 30). Follow-up ran from index to a maximum of 48 (± 4) weeks or until disease progression, start of new antitumor treatment, or death. The primary endpoint was progression-free survival (PFS) rate at week 48 (±4), and secondary endpoints included PFS rate at week 24 (±4), estimated using Kaplan-Meier analyses. All analyses were descriptive.

Of 27 patients enrolled, 22 (81.5%) had 48 weeks of follow-up. Tumors of pancreatic origin were the most common (73.9%). PFS rate was 0.96 (95% confidence interval: 0.72 - 0.99) at 24 weeks and 0.82 (0.53-0.94) at 48 weeks. Overall, 74.1% patients experienced ≥ 1 treatment-emergent adverse event; none were serious. No deaths were reported.

Lanreotide autogel was well tolerated and showed good tumor control rate in a real-world setting. These findings align with results from previous studies in Caucasian, Japanese, and Korean patients, thus supporting lanreotide autogel for treating patients with GEP-NETs of Chinese ethnicity.

Gastrinoma is a rare neuroendocrine tumor characterized by the hypersecretion of gastrin. Early diagnosis is challenging due to its rarity, and patients present to the outpatient department with nonspecific complaints such as diarrhea, weight loss, and fatigue, which often lead to a broad differential diagnosis. This report presents the case of a 59-year-old female who has come to the internal medicine department for a workup of chronic diarrhea, low-grade fever, 8kg weight loss, and severe reflux of eight months duration, not responding to empiric therapy. After multiple hospital visits and evaluations, she was found to have duodenal gastrinoma. This case report aims to create awareness and underscores the importance of considering neuroendocrine tumors as an initial differential diagnosis for patients with nonspecific or unexplained gastrointestinal symptoms to facilitate early diagnosis.

Objectives: The aim of this study was to investigate the treatment patterns and outcomes in two propensity score-matched cohorts of patients with neuroendocrine tumours (NETs) treated with first-line somatostatin analogue (SSA). Methods: Metastatic NET patients treated with first-line SSA (2009-2022) were retrospectively examined. First-line lanreotide vs. octreotide cohorts were matched 1:1 by propensity scores for demographics, tumour characteristics, and diagnosis year. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier analysis and the Cox proportional hazards model. Results: Among 441 patients, 310 were matched (155 in both the octreotide and lanreotide groups). First-line SSA was monotherapy (63.5%) or combination with other medications (36.5%). A total of 77% of second-line patients (188/244) maintained their initial SSA medication in combination with other therapies. Radioligand therapy with lanreotide (N = 72; 29.5%) or octreotide (N = 70; 28.7%) was the most common second-line treatment. First-line lanreotide and octreotide cohorts had similar median PFS (15.5; 95% CI: 13.6-19.1 vs. 14.0; 95% CI: 12.0-15.8 months), despite octreotide having a 36% higher likelihood of moving to the second line than lanreotide (95% CI: 1.05-1.76, p = 0.018). Multiple metastases (HR = 1.45; p = 0.004, 95% CI: 1.13-1.87) and Ki-67 > 20% (HR = 2.34; p < 0.001, 95% CI: 1.43-3.83) were significantly associated with the worst PFS. First-line lanreotide patients had a median OS of 10.4 years (95% CI: 7.5-NA) and octreotide 9.2 years (95% CI: 7.3-NA) (p = 0.537). Bone metastases increased death risk by 91% (p = 0.014; 95% CI: 1.14-3.20). Conclusions: SSA monotherapy is the main first-line treatment and most subsequent treatments include SSA with additional medications. Cohorts had similar PFS/OS, but octreotide demonstrated a 36% significantly higher likelihood of moving to the second-line treatment.

Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear.

We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety.

In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events.

Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).

The parathyroid-hormone-related peptide has been shown in earlier studies to be secreted by pancreatic neuroendocrine tumors, although its secretion by gastroenteropancreatic neuroendocrine tumors is very rare. In contrast, a number of solid tumors, such as lung cancer and renal cell carcinoma, have frequently been shown to secrete parathyroid-hormone-related peptide.

We describe a case report of a 53-year-old Canadian white patient with refractory parathyroid-hormone-related-peptide-mediated hypercalcemia associated with metastatic pancreatic neuroendocrine tumors and review the available research. Our patient had severe hypercalcemia initially refractory to treatment. Computed tomography scan of the abdomen revealed a pancreatic lesion and multiple hepatic metastases. A liver biopsy confirmed metastatic pancreatic neuroendocrine tumor expressing parathyroid-hormone-related peptide. Circulating parathyroid-hormone-related peptide levels were at the upper limit of normal preoperatively and decreased sharply postoperatively following debulking of the tumor. Blood calcium levels eventually normalized on long-term administration of the somatostatin analog lanreotide in combination with denosumab.

We describe a case with parathyroid-hormone-related-peptide-mediated hypercalcemia in a pancreatic neuroendocrine tumor (parathyroid-hormone-related peptide tumor). Refractory hypercalcemia was likely the result of parathyroid-hormone-related peptide overproduction by the tumor and resolved following normalization of parathyroid-hormone-related peptide levels.

Neuroendocrine neoplasms (NENs) represent a heterogeneous group of tumors that pose significant therapeutic challenges due to their potential for progression, metastasis, and hormonal syndromes. Somatostatin analogs (SSAs) have emerged as a cornerstone in NEN treatment, offering both antisecretory and antiproliferative effects by targeting somatostatin receptors (SSTRs). Despite their proven efficacy, intrinsic and acquired resistance mechanisms, including receptor downregulation, tumor heterogeneity, and microenvironmental influences, limit their long-term effectiveness. Recent advances, including high-dose SSA regimens and novel formulations, have aimed to optimize their therapeutic utility and address these limitations. Body of the review. This review explores the cellular and molecular mechanisms underlying the antitumor effects of SSAs, including receptor-mediated signaling pathways, cell cycle arrest, apoptosis induction, and antiangiogenesis. The role of SSAs in combination therapies with mTOR inhibitors and peptide receptor radionuclide therapy (PRRT) is analyzed, emphasizing their synergistic potential. Key clinical trials, such as RADIANT-2, EVERLAR, and NETTER-1, support the efficacy of these approaches, demonstrating improved outcomes when SSAs are combined with targeted agents or radiolabeled therapies. Emerging strategies include high-dose SSA regimens, particularly in progressive cases with low Ki67 indices. Finally, novel formulations, including oral octreotide, paltusotine, and subcutaneous depot formulations like CAM2029, offer improved pharmacokinetics, bioavailability, and patient adherence. Ongoing clinical trials, including SORENTO, further evaluate their efficacy and safety profiles.

This paper provides a comprehensive analysis of the cellular and molecular mechanisms of SSAs. SSAs remain integral to the management of NENs, providing effective tumor stabilization and symptom control. However, resistance mechanisms and tumor heterogeneity necessitate innovative approaches, including high-dose regimens, combination strategies, and next-generation formulations. Future research should focus on refining these strategies to optimize patient outcomes, enhance long-term efficacy, and expand the therapeutic landscape for NENs.

Patients with advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have impaired nutritional and physical performance due to the cancer pathophysiology and its treatment. The NUTRIGETNE study sought to characterize the nutritional status of patients with advanced GEP-NENs in Spain. This is a cross-sectional study that included patients with advanced GEP-NENs receiving active oncological treatment. Patients had a complete physical examination, anthropometry, bioelectrical impedance, dynamometry, laboratory analysis, and a comprehensive nutritional risk assessment. Malnutrition was defined according to Global Leadership Initiative on Malnutrition (GLIM) criteria. The study included 399 patients out of the 400 planned (Pearson's χ2; α 0.05). Median age was 62 years (22-83). Tumors most commonly originated in the small intestine (43.9%) and the pancreas (41.6%), 94.7% were metastatic, and 36.7%, 49.4%, and 12.5% were G1, G2, and G3, respectively. Malnutrition prevalence was 61.9% (25.8% moderate; 36.1% severe), mainly due to low muscle mass (50.9%), which was the most prevalent GLIM phenotypic criteria. Moreover, malnutrition showed a correlation with decreased hand grip strength (mean 23 vs 31.9 kg; P <.001) and phase angle (median 5o vs 5.6o; P <.001). The prevalence of sarcopenia was 15%. Malnutrition was more frequent in patients with diabetes (74.4% vs 56.7%; P <.001), NECs (82.1% vs 60.3%; P =.062), and in those treated with chemotherapy (71.2% vs 59.7%; P =.058), whereas it did not correlate with tumor origin (P =.507), histological grade (P =.781), or functionality (P =.465). Malnutrition was correlated to body mass index (BMI) (P =.015), although it was also diagnosed in a high proportion of patients with no weight loss (63%, 54.1%, and 65.1% of patients with normal BMI, overweight, and obesity, respectively). Cachexia was present in 109 (27.3%) patients. Malnutrition is very prevalent and commonly underdiagnosed in patients with GEP-NENs. It is associated with sarcopenia and a worse QoL, requiring a multifactorial nutritional assessment. Certain factors such as the presence of diabetes may require closer monitoring due to a higher risk of malnutrition.

Pancreatic neuroendocrine neoplasms (pNENs) diagnosed in childhood are very rare, with few data available. The aim was to describe the clinical presentation and behavior of children with pNENs at a national level.

National multicenter retrospective study of all patients, aged from 0 to 17 years at diagnosis, treated from 2011 to 2020 for a pNEN and registered in the French National Registry of Childhood Cancers or FRACTURE database.

Fifteen patients, 13 well-differentiated pancreatic neuroendocrine tumors (pNETs) and two neuroendocrine carcinomas (pNECs), were selected. Median age at diagnosis was 14 years (range, 7-17). Eight patients, all with localized disease, had a cancer predisposition syndrome (CPS), including five cases diagnosed during systematic screening. Five (31%) had metastatic disease at diagnosis: three grade 2 pNETs and two pNECs. First line therapy included exclusive pancreatectomy (seven cases, all M0), active surveillance (three cases, all M0), medical therapies (somatostatin analogues, chemotherapy; four cases, all M1), and surgery with medical therapy (one M1 case). Three-year progression-free survival was 57% (confidence interval [CI] 95%: 27-78) and was significantly better for patients with low-grade well differentiated (73 vs. 0%; p < 10-4) and localized (76 vs. 20%; p = .02) tumors. The two patients with pNECs died. Three-year overall survival was 92% (CI95%: 59-99) and was significantly better in patients with low-grade tumor (100 vs. 50%; p = 10-4).

Childhood pNENs occur more frequently in adolescents with CPS. Localized low-grade pNETs in children have a very good prognosis, whereas the treatment of high-grade and metastatic pNETs/pNECs should be better defined.