Journal of Neuroendocrinology最新文献

{"title":"Anatomic distribution of kisspeptin neurons in the adult sheep amygdala: Associations with sex, estrogen receptor alpha, androgen receptor, and sexual partner preference","authors":"Anna Igler,&nbsp;Rebecka Amodei,&nbsp;Charles E. Roselli","doi":"10.1111/jne.70011","DOIUrl":"10.1111/jne.70011","url":null,"abstract":"<p>Kisspeptin neurons are primarily known for regulating reproductive function by stimulating hormone release that controls puberty and fertility. While typically associated with the hypothalamus, recent research suggests their presence in other brain regions, including the amygdala. The amygdala, crucial for emotional processing and social behaviors, consists of various nuclei. However, the specific distribution and potential functional implications of kisspeptin neurons within this region remain unclear. Understanding kisspeptin neuron distribution in the sheep amygdala could provide insights into their roles in modulating reproductive functions, emotional, and social behaviors in a species closely related to humans. This study employed immunohistochemistry and RNAscope™ fluorescent in situ hybridization to map the distribution of kisspeptin fibers and cells in the amygdala of intact adult male and luteal-phase female sheep. The research also investigated the co-expression of <i>Kiss1</i> with estrogen receptor-α (<i>ESR1</i>) and androgen receptor (<i>AR</i>) mRNA, as well as the presence of kisspeptin receptor (<i>Kiss1r</i>) mRNA-containing cells. Kisspeptin immunoreactive fibers were most dense in the medial amygdala, while <i>Kiss1</i> mRNA-containing cells were abundant in the medial, cortical, and basal nuclei. Extensive co-expression of <i>Kiss1</i> with <i>ESR1</i> and <i>AR</i> mRNA was observed. In the posterior medial nucleus, 80% of kisspeptin neurons co-expressed <i>ESR1</i>, and 40% co-expressed AR. <i>Kiss1r</i> mRNA-containing cells were found in the medial, cortical, and basal nuclei and co-localized within cells expressing <i>Kiss1</i> mRNA. No differences in kisspeptin cell numbers were found between rams and ewes or between rams with different sexual partner preferences. This study provides a foundational map of the kisspeptin system in the sheep amygdala, offering insights into its potential roles in reproductive, emotional, and social behaviors. The extensive co-expression of <i>Kiss1</i> mRNA with <i>ESR1</i> and <i>AR</i> mRNA suggests possible regulation by sex steroids, while the presence of <i>Kiss1r</i> mRNA-containing cells indicates potential autocrine or paracrine signaling. These findings contribute to our understanding of kisspeptin neurons' distribution and potential functions beyond the hypothalamus, particularly in the amygdala.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical role of arcuate nucleus kisspeptin and Kiss1R in regulation of the ovine luteinizing hormone surge","authors":"Max J. Griesgraber,&nbsp;Lique M. Coolen,&nbsp;Kayla M. Onslow,&nbsp;Jacob R. Corey,&nbsp;Rachel E. Rice,&nbsp;Eliana G. Aerts,&nbsp;Elizabeth C. Bowdridge,&nbsp;Steven L. Hardy,&nbsp;Michael N. Lehman,&nbsp;Robert L. Goodman,&nbsp;Stanley M. Hileman","doi":"10.1111/jne.70010","DOIUrl":"10.1111/jne.70010","url":null,"abstract":"<p>Hypothalamic kisspeptin (Kiss), neurokinin B (NKB), and dynorphin-containing (KNDy) neurons in the arcuate nucleus (ARC) have consistently been shown to be the central generator of gonadotropin-releasing hormone (GnRH) and corresponding luteinizing hormone (LH) pulses in mammals and possibly contribute to surge secretion as well. Additionally, recent evidence from experiments in sheep suggests that ARC Kiss1R-containing neurons play an important role in regulating the timing and amplitude of LH pulses. In this study, we examined the functional role of ARC KNDy and Kiss1R-containing neurons in ovine LH surge secretion via injection of saporin–ligand conjugates (SAP) to ablate these neural populations. NKB-SAP injections significantly reduced the percentage of ARC <i>Kiss1</i> (~65% decrease) cells compared to control animals, and a surge-like increase of LH was prevented in ewes with the greatest degree of <i>Kiss1</i> cell ablation. Kiss-SAP injections had no effect on <i>Kiss1</i> cell percentage or ARC <i>Kiss1R</i> cell number compared to controls, the latter perhaps due to Kiss1R suppression in control animals from elevated estradiol concentrations during the LH surge. However, Kiss-SAP injections consistently and robustly decreased LH surge amplitude, with 80% of Kiss-SAP-treated ewes failing to generate a surge. While the exact identity of these ARC Kiss1R neurons has yet to be fully elucidated, they likely act downstream or in concert with KNDy neurons and possibly integrate other surge-centric signaling pathways to generate the ovine LH surge. These results support the conclusion that KNDy neurons contribute significantly to the ovine LH surge, while ARC Kiss1R neurons appear to be necessary for a functional surge to occur in sheep.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide receptor radionuclide therapy (PRRT) special issue","authors":"Shaunak Navalkissoor,&nbsp;Robert P. Millar","doi":"10.1111/jne.70014","DOIUrl":"10.1111/jne.70014","url":null,"abstract":"","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogens produced within the central amygdala inhibit varicella zoster-induced orofacial pain","authors":"Phillip Kramer,&nbsp;Lauren Nguyen,&nbsp;Paul R. Kinchington","doi":"10.1111/jne.70012","DOIUrl":"10.1111/jne.70012","url":null,"abstract":"<p>Varicella zoster virus (VZV) causes chicken pox, and reactivation of this virus later in life causes shingles. Previous work demonstrated that estrogens could reduce VZV-induced orofacial pain and affect gene expression in the central amygdala. It is known that the central amygdala processes pain signals from the orofacial region and that estrogens produced by the enzyme aromatase within the central amygdala regulate neuronal function. Based on the previous studies, it was hypothesized estrogens produced within the central amygdala attenuate VZV-induced orofacial pain. To address this hypothesis, male Long–Evans rats were implanted with cannulas terminating in the central amygdala. Through these cannulas, the aromatase inhibitor letrozole or estrogen receptor alpha (ERα) agonist, 4,4′,4″-(4-propyl-[1<i>H</i>]-pyrazole-1,3,5-triyl)<i>tris</i>phenol (PPT), was infused in the central amygdala. The whisker pad of each rat was injected with either MeWo cells or MeWo cells containing VZV. One week after VZV injection, letrozole or PPT was infused into the central amygdala, followed by measuring pain behavior, GABA release, and estradiol concentrations. Tissues in the orofacial pain pathway were isolated, and neuronal activity was quantitated by counting c-Fos-positive neurons. Letrozole significantly increased the pain response and decreased GABA release. Letrozole also decreased estradiol within the central amygdala. Infusion of PPT reduced pain and increased GABA release. Moreover, letrozole increased the number of active neurons in the lateral parabrachial nucleus and spinal trigeminal nucleus, while PPT reduced the number of active neurons in the trigeminal ganglia, lateral parabrachial nucleus, and spinal trigeminal nucleus. The results suggest aromatase-derived estradiol interacts with ERα within the central amygdala to attenuate VZV-induced pain by increasing GABA release and reducing neuronal activity in the pain pathway.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frontiers in radiopharmaceuticals for neuroendocrine tumors","authors":"Ameya D. Puranik,&nbsp;Indraja D. Dev,&nbsp;Vikas Prasad","doi":"10.1111/jne.70006","DOIUrl":"10.1111/jne.70006","url":null,"abstract":"<p>Neuroendocrine tumors encompass a wide range of tumors which originate from neural crest cells. These tumors were thought to be rare tumors, however, with the advent of advanced diagnostic techniques along with better understanding of the clinical presentation and histology of these tumors, the incidence of these tumors is exponentially rising. As the incidence and detection rate of NENs increased, the concept of ‘heterogeneity’ came into picture, which in turn led to dual-tracer imaging with addition of FDG PET/CT. Despite an imaging-based decision-making approach for NENs, there is still a significant subset of patients where the imaging-based biomarkers fall short in disease assessment, prognostication and improving outcomes. Alternate pathways as well as better peptide vectors for targeting the somatostatin receptor need to be studied. In this article, we address the existing as well as emerging trends in radiopharmaceuticals used for NENs, which are likely to impact not just the diagnostic algorithms in future, but also management strategies.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell genomics meets systems neuroscience: Insights from mapping the brain circuitry of stress","authors":"Naresh K. Hanchate","doi":"10.1111/jne.70005","DOIUrl":"10.1111/jne.70005","url":null,"abstract":"<p>Responses to external and internal dangers is essential for survival and homeostatic regulation. Hypothalamic corticotropin-releasing hormone neurons (CRHNs) play a pivotal role in regulating neuroendocrine responses to fear and stress. In recent years, the application of neurogenetic tools, such as fiber photometry, chemogenetics and optogenetics, have provided new insights into the dynamic neuronal responses of CRHNs during stressful events, offering new perspectives into their functional significance in mediating neurobehavioural responses to stress. Transsynaptic viral tracers have facilitated the comprehensive mapping of neuronal inputs to CRHNs. Furthermore, the development and application of innovative single-cell genomic tools combined with viral tracing have begun to pave the way for a deeper understanding of the transcriptional profiles of neural circuit components, enabling molecular-anatomical circuit mapping. Here, I will discuss how these systems neuroscience approaches and novel single-cell genomic methods are advancing the molecular and functional mapping of stress neurocircuits, their associated challenges and future directions.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative lengthening of telomeres and Ki-67 proliferation index provide complementary information on recurrence risk after resection of pancreatic neuroendocrine tumors","authors":"Hallbera Gudmundsdottir,&nbsp;Rondell P. Graham,&nbsp;Patricia T. Greipp,&nbsp;Elizabeth B. Habermann,&nbsp;Ryan A. Knudson,&nbsp;Carrie A. Brandt,&nbsp;Patrick Starlinger,&nbsp;Cornelius A. Thiels,&nbsp;Susanne G. Warner,&nbsp;Rory L. Smoot,&nbsp;Mark J. Truty,&nbsp;Michael L. Kendrick,&nbsp;David M. Nagorney,&nbsp;Sean P. Cleary,&nbsp;Thorvardur R. Halfdanarson","doi":"10.1111/jne.70003","DOIUrl":"10.1111/jne.70003","url":null,"abstract":"<p>Given the heterogeneous clinical behavior of pancreatic neuroendocrine tumors (pNETs), improved prognostic markers are needed to guide management and post-resection surveillance. Patients who underwent resection of large (≥3 cm) sporadic well-differentiated pNETs from 2000 to 2019 were identified. The Ki-67 proliferation index was determined using immunohistochemistry, and alternative lengthening of telomeres (ALT) status was assessed using fluorescence in situ hybridization. Recurrence-free and overall survival were estimated using Kaplan–Meier analysis. Multivariable Cox regression analysis evaluated factors associated with recurrence-free survival. A total of 106 patients were identified. ALT was positive in 57 (54%) and negative in 49 (46%). Ki-67 was ≥3% in 74 (70%) and &lt;3% in 32 (30%). Tumors with Ki-67 ≥3% were more likely to be ALT positive (61% vs. 38%, <i>p</i> = .046). Stratifying by ALT status and Ki-67 proliferation index, median recurrence-free survival was 4.6 years for patients with ALT-positive/Ki-67 ≥3% tumors, 3.1 years for patients with ALT-positive/Ki-67 &lt;3% tumors, 12.4 years for patients with ALT-negative/Ki-67 ≥3% tumors, and 20.2 years for patients with ALT-negative/Ki-67 &lt;3% tumors (<i>p</i> &lt; .001). Initial recurrence was distant in 82% and locoregional in 18%. Across all groups, overall survival was similar (<i>p</i> = .19). In multivariable analysis, advanced age, ALT positivity, perineural invasion, and lymph node metastases were associated with increased recurrence risk (all <i>p</i> &lt; .05). ALT and Ki-67 provide complementary information on post-resection recurrence risk, which can guide subsequent surveillance and management strategies. These data support the incorporation of ALT testing into routine clinical practice.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NETest® 2.0—A decade of innovation in neuroendocrine tumor diagnostics","authors":"M. Kidd,&nbsp;I. A. Drozdov,&nbsp;A. Chirindel,&nbsp;G. Nicolas,&nbsp;D. Imagawa,&nbsp;A. Gulati,&nbsp;T. Tsuchikawa,&nbsp;V. Prasad,&nbsp;A. B. Halim,&nbsp;J. Strosberg","doi":"10.1111/jne.70002","DOIUrl":"10.1111/jne.70002","url":null,"abstract":"&lt;p&gt;Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are challenging to diagnose and manage. Because there is a critical need for a reliable biomarker, we previously developed the NETest, a liquid biopsy test that quantifies the expression of 51 neuroendocrine tumor (NET)-specific genes in blood using real-time PCR (NETest 1.0). In this study, we have leveraged our well-established laboratory approach (blood collection, RNA isolation, qPCR) with contemporary supervised machine learning methods and expanded training and testing sets to improve the discrimination and calibration of the NETest algorithm (NETest 2.0). qPCR measurements of RNA-stabilized blood-derived gene expression of 51 NET markers were used to train two supervised classifiers. The first classifier trained on 78 Controls and 162 NETs, distinguishing NETs from controls; the second, trained on 134 stable disease samples, 61 progressive disease samples, differentiated stable from progressive NET disease. In all cases, 80% of data was retained for model training, while remaining 20% were used for performance evaluation. The predictive performance of the AI system was assessed using sensitivity, specificity, and Area under Received Operating Characteristic curves (AUROC). The algorithm with the highest performance was retained for validation in two independent validation sets. Validation Cohort #I consisted of 277 patients and 186 healthy controls from the United States, Latin America, Europe, Africa and Asia, while Validation Cohort #II comprised 291 European patients from the Swiss NET Registry. A specificity cohort of 147 gastrointestinal, pancreatic and lung malignancies (non-NETs) was also evaluated. NETest 2.0 Algorithm #1 (Random Forest/gene expression normalized to &lt;i&gt;ATG4B&lt;/i&gt;) achieved an AUROC of 0.91 for distinguishing NETs from controls (Validation Cohort #I), with a sensitivity of 95% and specificity of 81%. In Validation Cohort #II, 92% of NETs with image-positive disease were detected. The AUROC for differentiating NETs from other malignancies was 0.95; the sensitivity was 92% and specificity 90%. NETest 2.0 Algorithm #2 (Random Forest/gene expression normalized to &lt;i&gt;ALG9&lt;/i&gt;) demonstrated an AUROC of 0.81 in Validation Cohort #I and 0.82 in Validation Cohort #II for differentiating stable from progressive disease, with specificities of 81% and 82%, respectively. Model performance was not affected by gender, ethnicity or age. Substantial improvements in performance for both algorithms were identified in head-to-head comparisons with NETest 1.0 (diagnostic: &lt;i&gt;p&lt;/i&gt; = 1.73 × 10&lt;sup&gt;−9&lt;/sup&gt;; prognostic: &lt;i&gt;p&lt;/i&gt; = 1.02 × 10&lt;sup&gt;−10&lt;/sup&gt;). NETest 2.0 exhibited improved diagnostic and prognostic capabilities over NETest 1.0. The assay also demonstrated improved sensitivity for differentiating NETs from other gastrointestinal, pancreatic and lung malignancies. The validation of this tool in geographically diverse cohorts highlights their potential for widespread c","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): An updated systematic review of population-based reports from 2010 to 2023","authors":"Magnus Andreas Nordstrand,&nbsp;Dordi Lea,&nbsp;Jon Arne Søreide","doi":"10.1111/jne.70001","DOIUrl":"10.1111/jne.70001","url":null,"abstract":"<p>There is a general perception that the incidence of neuroendocrine neoplasms (NENs) has been increasing. Nevertheless, reports of actual population-based studies are scarce, and pertinent data from some geographical regions still need to be available. In this systematic literature review of population-based studies, we aimed to evaluate the available data to provide updated figures on the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Guided by the PRISMA 2020 statement reporting items for systematic reviews, this study conducted a systematic search using Ovid in the bibliographic databases Embase, Medline, and Web of Science Core Collection. Only incidence-reporting studies were included. In total, 847 articles were identified, and through a strict evaluation process using predefined inclusion and exclusion criteria, we found 19 papers that reported the general incidence of GEP-NENs from all sites. In addition, we considered another 15 papers that focused on the epidemiologic aspects of single-organ studies. While the incidence rates of GEP-NEN vary across similar countries, the general incidence of GEP-NEN has been increasing worldwide in recent decades. The incidence of GEP-NENs has increased worldwide over the last two decades, and reliable figures from new regions add to this pattern. Nevertheless, variations in the classification, grading, and reporting of GEP-NENs in various studies make direct comparisons difficult.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase Ib/II study of Pembrolizumab with Lanreotide depot for advanced, progressive Gastroenteropancreatic neuroendocrine tumors (PLANET)","authors":"Michael A. Morse,&nbsp;Erika J. Crosby,&nbsp;Daniel M. Halperin,&nbsp;Hope E. Uronis,&nbsp;S. David Hsu,&nbsp;Herbert I. Hurwitz,&nbsp;Christel Rushing,&nbsp;Emily K. Bolch,&nbsp;Dana A. Warren,&nbsp;Ashley N. Moyer,&nbsp;Melissa E. Lowe,&nbsp;Donna Niedzwiecki","doi":"10.1111/jne.13496","DOIUrl":"10.1111/jne.13496","url":null,"abstract":"<p>While performing a study of immune checkpoint blockade with the anti-PD-1 antibody pembrolizumab combined with the somatostatin analogue (SSA) lanreotide in patients with low- and intermediate-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we studied whether there were any immune correlates of response to the anti-PD-1 therapy that could guide future attempts to integrate immunotherapy into the treatment of NETs. Patients with grade 1 and 2 GEP-NETs who had progressed on a prior SSA received lanreotide 90 mg subcutaneously and pembrolizumab 200 mg intravenously every 3 weeks until progression or intolerable toxicity. Objective response rate (ORR) at any time in the study, clinical benefit rate (CBR, defined as stable disease or better), progression-free survival (PFS), and overall survival (OS) were measured. Changes in T cell subsets in peripheral blood before and during therapy were analyzed by multiparameter mass cytometry (CyTOF). Archived tissue samples were analyzed for PD-L1 expression and TIL infiltration. Twenty-two (22) patients (GI/pancreatic 14/8, median Ki67 7% [IQR 4, 10%], median 1.5 prior systemic therapies [range 1–4]) were enrolled. Among the GI-NETs, there was one partial response, the CBR was 50%, the median PFS was 8.5 months, and the median OS was 32.7 months. No responses were seen in pancreatic NETs, which had 0% CBR, a PFS of 2.7 months, and an OS of 23.9 months. Of the 16 analyzable tumors, 6 had detectable PD-L1 expression and 15 had detectable TILs. Neither TILs nor PD-L1 expression correlated with ORR or CBR. However, clinical benefit (SD or better) was associated with peripheral blood on-treatment effector memory T cell activation and progressive disease was associated with baseline peripheral blood regulatory T cell (Treg) activation. We conclude that immune checkpoint blockade had low activity in unselected patients with grade 1 and 2 GEP-NETs. Further study of strategies to reduce Treg activation or enhance effector memory activation during immunotherapy is warranted.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}