bims-necame 2025-11-30 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–11–30
37 papers selected by
Grigor Varuzhanyan, UCLA

Multiprobe PET Imaging: Insignia of Tumor Heterogeneity in a Case of Neuroendocrine Prostate Cancer.
NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer.
Dietary Glycemic Index, Glycemic Load, and Risk of Lung Cancer: A Population-Based Cohort Study.
NEUROG3 Is Sufficient to Drive Neuroendocrine Differentiation in Prostate Cancer Cells.
Targeting FOXM1 reshapes antitumor immunity to attenuate small cell lung cancer progression.
YAP1 defines an emergent, plastic population of relapsed small cell lung cancer.
[A Case of Combined Small Cell Lung Cancer and Literature Review].
Primary Intracranial Neuroendocrine Carcinoma Revealed by 18F-FDG PET/CT.
Natural compound triptolide induces caspase-3/GSDME-mediated pyroptosis by promoting ROS accumulation in small cell lung cancer.
Peroxisome proliferator-activated receptors as novel targets of small cell lung cancer circulating tumor cells.
KDM6B inhibition enhances chemotherapeutic response in small cell lung cancer via epigenetic regulation of apoptosis and ferroptosis.
Epidemiology and treatments of neuroendocrine prostate cancer in a large commercially insured population in the US.
Spatial proteomic profiling reveals conserved prognostic immune microenvironment features across molecular subtypes in small cell lung cancer.
Prognostic role of pretreatment serum α-hydroxybutyrate dehydrogenase in patients with small cell lung cancer.
Development of small cell lung cancer following gunshot wound to the chest.
FGF12 Enhances Prostate Cancer Cell Survival via the YB1-lncRNA Axis.
NSD2 targeting reverses plasticity and drug resistance in prostate cancer.
Transcription factor-based subtype assignment in pulmonary large cell neuroendocrine carcinoma.
Divergent roles of DNA methylation, TRIM28, and p53 surveillance in human embryonic and trophoblast stem cells.
Metabolomics-Based Diagnosis of Medullary Thyroid Cancer: A Plasma 1H NMR Approach.
The Utility of Cabozantinib in the Therapy of Endocrine Tumours.
DLL3-targeted immunoPET and radioimmunotherapy ligands.
Few-shot learning for the classification of colorectal neuroendocrine tumors and polyps on endoscopic images.
A Young Woman with Paraneoplastic Cushing's Syndrome Due to a Pulmonary Carcinoid.
YM155 Inhibition of Survivin Enhances Carboplatin Efficacy in Metastatic Castration-Resistant Prostate Cancer.
Corrigendum to "A novel mechanism of SRRM4 in promoting neuroendocrine prostate cancer development via a pluripotency gene network" EBioMedicine 2018 Sep: 35: 167-177.
Neuroendocrine neoplasms of the stomach. Update on diagnostic criteria, classification, and prognostic markers.
Clinical pathological analysis of primary small cell neuroendocrine carcinoma of the cervix: A retrospective study.
Neuroendocrine carcinoma of the cervix (NECC): A retrospective study of 175 Chinese patients.
Surgery versus definitive radiotherapy in the management of stage I-II small cell neuroendocrine carcinoma of the cervix: A systematic review and meta-analysis.
Gastric Glomus Tumor with Neuroendocrine Features: A Diagnostic Pitfall for Neuroendocrine Tumors.
Efficacy and Safety of Non-Surgical Treatments for Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis.
Experimental approach for optimizing dose regimen of 68Ga-DOTATATE PET/CT for neuroendocrine tumor (NET) imaging in current high sensitivity scanners: Phantom and Patient Study.
RBM39 Contributes to MGMT Maintenance in Response to Temozolomide-Induced DNA Damage.
Case Report: Diagnostic challenges in cervical small cell neuroendocrine carcinoma of a reproductive-age woman.
Tissue and Organ-specific Tumor Heterogeneity on dual tracer PET-CT ([68Ga] Ga-PSMA-11 and [18F] FDG) and Dural-based Brain metastasis in Metastatic Prostate Cancer.
First Autopsy-confirmed Complete Remission of Metastatic Neuroendocrine Neoplasm of Tailgut Cyst After a Single Cycle of Alpha-Peptide Receptor Radionuclide Therapy With [225Ac]Ac-DOTA-LM3.

Clin Nucl Med. 2025 Oct 15.

Multiprobe PET Imaging: Insignia of Tumor Heterogeneity in a Case of Neuroendocrine Prostate Cancer.

Akshay Bedmutha, Bruce Barron, Stephen Lau, Kyle Oi, David Brandon.

  Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, often developing from androgen receptor (AR) independence, characterized by neuroendocrine molecular markers and nonresponsiveness to standard treatments of prostate adenocarcinoma. The evolution of adenocarcinoma to NEPC is characterized by epigenetic changes, leading to the downregulation of the PSMA transmembrane protein, as well as the upregulation of FDG-uptake pathways and somatostatin receptor expression. We present a case of NEPC that depicts a significant metastatic intertumoral heterogeneity as depicted on PSMA, FDG, and DOTATATE PET/CT scans. Such multiprobe PET evaluation of NEPC may assist in sampling the most aggressive disease and guide an appropriate management strategy. It also provides a cellular-level insight into this dreadful disease with very limited treatment options.

Keywords:  DOTATATE; FDG; PET/CT; PSMA; neuroendocrine; prostate cancer; tumor heterogeneity

DOI:  https://doi.org/10.1097/RLU.0000000000006182
bioRxiv. 2025 Nov 13. pii: 2025.11.12.687734. [Epub ahead of print]

NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer.

Umar Mehraj, Uran Maimekov, Shaista Manzoor, Emily Cordova, Manasiben Patel, Ikeer Y Mancera-Ortiz, Stefanie Howell, Zachary W Davis-Gilbert, Mu-En Wang, Ming Chen, Jung Wook Park, Yuzhuo Wang, Andrew J Armstrong, Jiaoti Huang, David H Drewry, Antonina Mitrofanova, Everardo Macias.

Prostate cancer (PC) remains the second leading cause of cancer-related mortality in men. The emergence of treatment-emergent neuroendocrine prostate cancer (NEPC) arising from androgen receptor (AR) pathway inhibition poses a significant clinical challenge. Here, we report that NUAK family kinase 2 (NUAK2) is an actionable therapeutic target in NEPC. NUAK2 expression is markedly elevated in NEPC patient specimens and preclinical models, and its genetic or pharmacologic inhibition suppresses NEPC tumor growth. The FDA-approved CDK4/6 inhibitor trilaciclib exerts potent inhibition of NUAK2, leading to marked tumor suppression alone and enhanced efficacy in combination with carboplatin. Integrated phospho-target and interactome analyses demonstrate that NUAK2 engages core spliceosome components to regulate pre-mRNA splicing. As proof of principle, we validated that NUAK2 inhibition perturbs pre-mRNA splicing of EZH2 and TTK leading to reduced translation. Collectively, these findings establish NUAK2 as a clinically actionable regulator of RNA splicing and tumor progression in NEPC, revealing a novel mechanism by which trilaciclib exerts antitumor activity in NEPC.

DOI: https://doi.org/10.1101/2025.11.12.687734
Ann Fam Med. 2025 Nov 24. 23(6): 524-534

Dietary Glycemic Index, Glycemic Load, and Risk of Lung Cancer: A Population-Based Cohort Study.

Jinping Wang, Li Li, Kanran Wang.

   BACKGROUND: There is considerable inconsistency regarding study results on the association of dietary glycemic index (GI) and glycemic load (GL) with lung cancer risk. We aimed to investigate this relation in the US National Cancer Institute's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial cohort.
METHODS: Baseline characteristics were collected with the baseline questionnaire, and diet was assessed with the diet history questionnaire. All incident lung cancer cases were verified via pathology. We estimated hazard ratios (HRs) and 95% CIs for lung cancer risk associated with GI and GL by Cox regression modeling.
RESULTS: During a median follow-up of 12.2 years (1,213,533 person-years), a total of 1,706 incident lung cancer events occurred including 1,473 (86.3%) cases of non-small cell lung cancer (NSCLC) and 233 (13.7%) of small cell lung cancer (SCLC). After multivariate adjustment, GI was positively associated with lung cancer (4th quartile [Q4] vs 1st quartile [Q1]; HR 1.13; 95% CI, 1.05-1.31), NSCLC (Q4 vs Q1; HR 1.11; 95% CI, 1.05-1.29), and SCLC (Q4 vs Q1; HR 1.34; 95% CI, 1.02-2.27). Conversely, we found an association between dietary GL and a decreased risk of lung cancer (Q4 vs Q1; HR 0.72; 95% CI, 0.57-0.90) and NSCLC (Q4 vs Q1; HR 0.68; 95% CI, 0.53-0.87) but not SCLC (Q4 vs Q1; HR 0.90; 95% CI, 0.51-1.58). These results were consistently observed across subgroup analyses.
CONCLUSIONS: These findings show that high dietary GI is associated with an increased risk of lung cancer, NSCLC, and SCLC, whereas GL is inversely associated with the risk of lung cancer and NSCLC.

Keywords:  glycemic index; glycemic load; lung cancer; non–small cell lung cancer; small cell lung cancer

DOI:  https://doi.org/10.1370/afm.250132
bioRxiv. 2025 Nov 12. pii: 2025.11.10.687642. [Epub ahead of print]

NEUROG3 Is Sufficient to Drive Neuroendocrine Differentiation in Prostate Cancer Cells.

Abdelkader Daoud, Lu Han, Rachael K Christensen, Jorge O Múnera.

Treatment-emergent neuroendocrine prostate cancer (t-NEPC) arises following androgen deprivation therapy, leading to androgen-independent growth. Although multiple factors have been shown to be necessary for neuroendocrine differentiation (NED), their sufficiency has not been demonstrated. The prostate and colorectum share a common hindgut origin, and prostate neuroendocrine cell markers overlap with colorectal enteroendocrine cell (EEC) markers. Analysis of patient datasets revealed NEUROG3 amplification in both castration-resistant and neuroendocrine prostate cancers, correlating with poor survival. Because Neurogenin-3 (NEUROG3) is necessary and sufficient for EEC differentiation in the colorectum, we hypothesized that it could similarly drive NED in prostate cancer cells. A transient pulse of NEUROG3 repressed luminal identity and activated neuroendocrine programs, producing neuroendocrine cells within seven days. In summary, our findings identify NEUROG3 as a potential mediator of prostate cancer progression and establish a rapid in vitro model in which its transient activation is sufficient to initiate neuroendocrine differentiation.

DOI: https://doi.org/10.1101/2025.11.10.687642
Cancer Lett. 2025 Nov 21. pii: S0304-3835(25)00732-3. [Epub ahead of print]638 218160

Targeting FOXM1 reshapes antitumor immunity to attenuate small cell lung cancer progression.

Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Laiba Anwar, Zahraa Wajih Alsafwani, Aatiya Ahmad, Mohammad Ali Abbas Zaidi, Jesse L Cox, Areem Zahid, Sameer Mohiuddin, Sung Hoon Kim, Juan A Santamaria-Barria, Imayavaramban Lakshmanan, Benita S Katzenellenbogen, John A Katzenellenbogen, Apar K Ganti, Surinder K Batra, Mohd Wasim Nasser.

  Small cell lung cancer (SCLC) is a lethal lung malignancy, which is associated with distant metastasis and chemoresistance. Due to the limited availability of targeted therapies, identifying a potential therapeutic target is a pressing unmet need in SCLC. Single-cell and bulk-transcriptomic datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression was observed in human and murine SCLC tissues and cell lines. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1fl/fl; TP53 fl/fl; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8+ T cells, and T cell-mediated killing of SCLC cells. Additionally, FOXM1 inhibition enhanced CD8+ T cell and macrophage recruitment in the tumor microenvironment (TME) of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.

Keywords:  Chemotherapeutic resistance; FOXM1 inhibitors; Metastasis; Small cell lung cancer; T cell activation

DOI:  https://doi.org/10.1016/j.canlet.2025.218160
bioRxiv. 2025 Oct 22. pii: 2025.10.21.683746. [Epub ahead of print]

YAP1 defines an emergent, plastic population of relapsed small cell lung cancer.

C Allison Stewart, Kavya Ramkumar, Runsheng Wang, Yuanxin Xi, Alexa Halliday, Lixia Diao, Qi Wang, Alejandra Serrano, Sarah Groves, Simon Heeke, Azusa Tanimoto, Laura Kaiser, Whitney Lewis, Mukulika Bose, Pedro Da Rocha, Loukia Karacosta, Vito Quaranta, Jing Wang, Julie George, Luisa Maren Solis Soto, Bingnan Zhang, John V Heymach, Lauren A Byers, Carl M Gay.

  Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid onset of chemoresistance and poor clinical outcomes. Transcriptional heterogeneity among treatment-naïve SCLC tumors underlies four transcriptional subtypes, each with distinct clinical vulnerabilities. Though previously hypothesized to delineate a distinct subtype, expression of YAP1 is largely absent from treatment-naïve, pure SCLC. To characterize relapsed SCLC, circulating tumor DNA, circulating tumor cells, and core needle biopsies from SCLC patients and preclinical models following resistance to standard-of-care therapies were analyzed. In contrast to treatment-naïve SCLC, these analyses reveal an emergent YAP1-positive cell population that coincides with treatment resistance. These YAP1-positive cells exhibit characteristics of drug tolerant persister cells, including senescence, stemness, and plasticity, as YAP1 positive cells largely abandon features characteristic of SCLC to adopt those of large-cell neuroendocrine carcinoma (LCNEC). As a result of this SCLC-like to LCNEC-like evolution, YAP1-positive cells lack several clinically relevant SCLC surface targets (i.e., DLL3, SEZ6), but are enriched for others (i.e., B7-H3, TROP2). We propose a model where YAP1 expressing cells emerge with SCLC treatment resistance and characterize a tenacious subpopulation capable of diverging from the treatment naïve lineage and adopting features to evade therapeutic response.

Keywords:  SCLC; YAP1; intratumoral heterogeneity; plasticity

DOI:  https://doi.org/10.1101/2025.10.21.683746
Zhongguo Fei Ai Za Zhi. 2025 Sep 20. 28(9): 721-726

[A Case of Combined Small Cell Lung Cancer and Literature Review].

Minglang Gao, Xiao Lu, Bo Hao, Ning Li, Songping Xie.

  Combined small cell lung cancer (CSCLC) is a cancer that mixes small cell lung cancer (SCLC) with non-small cell lung cancer (NSCLC) components according to the World Health Organization's 2015 New Pathologic Classification of Lung Cancer. Composed of a mixture of SCLC and NSCLC components, CSCLC is classified as a subtype of SCLC in neuroendocrine tumors. Currently, research on SCLC mainly focuses on single-component pure SCLC, with relatively few studies on CSCLC, which is clinically rare and has no standardized treatment protocols and lacks a unified perception of the clinicopathological features and prognostic predictive indexes of CSCLC. Further observation of efficacy and prognosis is needed. We report the treatment course of a case of CSCLC and provide a literature review of the current status of research on CSCLC. .

Keywords:  Case report; Combined small cell lung cancer; Literature review; Lung neoplasms; Squamous cell carcinoma

DOI:  https://doi.org/10.3779/j.issn.1009-3419.2025.101.15
Clin Nucl Med. 2025 Oct 29.

Primary Intracranial Neuroendocrine Carcinoma Revealed by 18F-FDG PET/CT.

Hangyu Xie, Shuhui Huang, Lin Li.

  Neuroendocrine carcinoma (NEC) is a rare and aggressive malignancy that most commonly arises from neuroendocrine cells in the gastrointestinal tract and lungs. Primary intracranial NEC is exceedingly rare, with limited cases reported in the literature. We present the FDG PET/CT imaging finding of a rare case of a large primary intracranial NEC involving the cerebral parenchyma, which appeared as a cystic-solid mass with intense FDG uptake in the irregular rim and solid component.

Keywords:  ; PET/CT; cerebral parenchyma; intracranial; primary neuroendocrine carcinoma

DOI:  https://doi.org/10.1097/RLU.0000000000006198
Cancer Cell Int. 2025 Nov 28. 25(1): 426

Natural compound triptolide induces caspase-3/GSDME-mediated pyroptosis by promoting ROS accumulation in small cell lung cancer.

Yuheng Yan, Zhaolin Xu, Chengyan Wang, Ying Liu, Yaling Long, Xun Yuan, Qian Chu.

   BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. Triptolide (TPL), a natural compound derived from the traditional Chinese herbal medicine Tripterygium wilfordii Hook F., exhibits broad antitumor effects. However, its role in SCLC remains unexplored.
METHODS: We evaluated the effects of TPL on SCLC cell proliferation, migration, and invasion through in vitro assays, including Cell Counting Kit-8, clonogenic, 5-ethynyl-2'-deoxyuridine, cell cycle, and Transwell assays. To predict the potential antitumor targets of TPL against SCLC, we performed a network pharmacology analysis. Pyroptosis was examined by morphological observation, lactate dehydrogenase release assay, and Western blot analysis. The in vivo role of TPL was confirmed using a mouse xenograft model and immunohistochemical assays.
RESULTS: TPL inhibited proliferation, triggered cell cycle arrest at the S-phase, and concomitantly produced a dose-dependent inhibition of SCLC cell invasion and migration. Network pharmacology analysis revealed that the antitumor effect of TPL in SCLC was associated with its potential to regulate inflammatory and apoptotic pathways, indicating the specific mode of cell death induced by TPL in SCLC cells. We confirmed that TPL induces caspase-3/GSDME-mediated pyroptosis in NCI-H1688 and NCI-H1339 cells. Furthermore, TPL induced pyroptosis by promoting reactive oxygen species (ROS) accumulation, whereas ROS inhibition significantly abolished these pyroptotic effects. Additionally, TPL suppressed tumor growth in mice with SCLC xenografts and induced pyroptosis in vivo.
CONCLUSIONS: This study demonstrated the antitumor role of TPL in SCLC and its ability to trigger caspase-3/GSDME-mediated pyroptosis through ROS accumulation, providing new insights into SCLC treatment.

Keywords:  Caspase-3/GSDME signaling; Pyroptosis; Small cell lung cancer; Traditional chinese herbal medicine; Triptolide

DOI:  https://doi.org/10.1186/s12935-025-04071-8
Neoplasma. 2025 Nov 25. pii: 250917N396. [Epub ahead of print]

Peroxisome proliferator-activated receptors as novel targets of small cell lung cancer circulating tumor cells.

Gerhard Hamilton, Marie-Therese Eggerstorfer, Lukas Weigl, Maximilian Johannes Hochmair, Sandra Stickler.

Small cell lung cancer (SCLC) has a dismal prognosis with a low 2-year survival rate. Chemotherapy for recurrent SCLC fails invariably, and novel tumor targets are needed. Here, the effects of agents targeting the peroxisome proliferator-activated receptors (PPARs) in SCLC are investigated. Initial screening of 96 PPAR-directed agents was performed in two SCLC CTC-derived lines (BHGc10, BHGc16). Compounds showing high cytotoxicity were subsequently tested in two pleural effusion-derived lines (S457, S1392) and the SCLC line NCI-H69. Several PPARs emerged as actionable targets: eight PPARγ ligands and nine ligands for PPARα, PPARα/δ, or PPARβ/δ. For the six most effective compounds, treatment-induced protein changes were further profiled in BHGc16 using protein arrays. Cytotoxicity varied by compound, while the PPARγ agonist pioglitazone and the PPARα agonist fenofibrate were preferentially active in CTC lines, DG172 hydrochloride was selective for pleural effusion-derived lines, while rosiglitazone maleate, cloxiquine, and agrimol B showed no selectivity. Mechanistically, in the CTC-derived cell line BHGc16, these six PPAR-directed agents increased pro-apoptotic proteins (Bax, Bad, caspase-3/9), decreased anti-apoptotic and invasion proteins (Bcl-2, Bcl-XL, c-FLIP-L, ICAM-1, CXCR4), and suppressed Akt/mTOR, MEK/ERK, p38 MAPK, and JAK2/STAT3 signaling. These findings support PPARs as clinically relevant targets in SCLC, with PPAR-directed agents showing cytotoxic effects comparable to those reported in other malignancies. Such agents may aid SCLC treatment and help delineate biological differences between CTCs and resident tumor cells.

DOI: https://doi.org/10.4149/neo_2025_250917N396
Cell Biosci. 2025 Nov 26. 15(1): 162

KDM6B inhibition enhances chemotherapeutic response in small cell lung cancer via epigenetic regulation of apoptosis and ferroptosis.

Zhongliang Wang, Ziyuan Liu, Yufan Yang, Wenyang Wang, Qian Chen, Shumei Liang, Linlang Guo, Man Li.

   BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression and the frequent emergence of resistance to standard chemotherapeutic agents such as cisplatin (DDP) and etoposide (VP16), resulting in poor clinical outcomes.
METHODS AND RESULTS: To elucidate mechanisms underlying chemoresistance, we conducted a genome-wide CRISPR/Cas9 knockout screen, which identified the histone demethylase KDM6B as a critical mediator of drug resistance in SCLC. Genetic silencing of KDM6B significantly reduced IC₅₀ values of DDP and VP16, particularly in H69-AR cells, and enhanced chemotherapy-induced apoptosis. Consistently, pharmacological inhibition of KDM6B using the dual KDM6A/B inhibitor Gskj1 markedly potentiated the effects of DDP and VP16, while exhibiting minimal cytotoxicity as monotherapy. Overexpression of KDM6B rescued the chemosensitizing effect of Gskj1, thereby excluding confounding contributions from KDM6A. In vivo, the combination of Gskj1 with chemotherapy synergistically suppressed tumor growth without detectable systemic toxicity. To explore the downstream regulatory pathways, we performed transcriptome analysis via RNA-seq followed by KEGG pathway enrichment analysis, which revealed that Gskj1 treatment modulates key oncogenic signaling pathways. Integration of RNA-seq with H3K27me3 ChIP-seq data identified EGR3 as a direct epigenetic target of KDM6B inhibition. STRING analysis further suggested that EGR3 is co-expressed with c-FOS. Functional assays, including qRT-PCR, Western blotting, Co-immunoprecipitation (Co-IP), and dual-luciferase reporter assays, confirmed that EGR3 transcriptionally activates c-FOS, establishing an EGR3/c-FOS regulatory axis downstream of KDM6B. Mechanistically, inhibition of this axis enhanced chemosensitivity by promoting apoptosis, as evidenced by activation of caspase signaling, and by inducing ferroptosis through downregulation of GPX4, upregulation of ACSL4, lipid peroxidation, and modulation of HO-1. Rescue experiments with Z-VAD and ferrostatin-1 further validated that both apoptosis and ferroptosis contribute to the chemosensitizing effects of KDM6B inhibition.
CONCLUSION: Finally, in vivo experiments using patient-derived xenograft (PDX) models demonstrated that Gskj1 effectively enhances the antitumor efficacy of chemotherapy in SCLC, providing compelling evidence for the clinical potential of targeting KDM6B to overcome chemoresistance.

Keywords:  Chemotherapy resistance; Drug combination; KDM6B; KDM6B/ERG3/c-FOS axis; Small cell lung cancer

DOI:  https://doi.org/10.1186/s13578-025-01496-6
Cancer Treat Res Commun. 2025 Nov 17. pii: S2468-2942(25)00174-1. [Epub ahead of print]45 101038

Epidemiology and treatments of neuroendocrine prostate cancer in a large commercially insured population in the US.

Zdravko Vassilev, Qayyim Said, Jihong Zong, Nasreen Khan, Christine Rentzsch, Gal Barel, Lorelei Mucci, Orsolya Lunacsek.

   BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a highly aggressive prostate cancer (PCa) subtype diagnosed de novo or arising from neuroendocrine differentiation of adenocarcinoma following androgen deprivation therapy (ADT) or antiandrogen-based therapy. The objective of the study was to describe socio-demographic and clinical characteristics at the time of NEPC diagnosis and treatment patterns prior to and after NEPC diagnosis.
PATIENTS AND METHODS: A real-world cohort of men diagnosed with NEPC was identified using the US Optum Clinformatics® administrative claims database between 2007 and 2023. The study was descriptive in nature, without comparative analyses.
RESULTS: Of the 607,280 patients diagnosed with PCa, 2267 (0.4%) had a diagnosis of NEPC. Median age at NEPC diagnosis was 76 years; 72% of patients were White, and half of patients had a Charlson Comorbidity Index score of 0-2 (57%). Median time from first PCa diagnosis to NEPC diagnosis was 21 months; 44% of patients with NEPC had metastases prior to NEPC diagnosis. In a subpopulation of 1767 patients with NEPC diagnosed between 2014 and 2023-representing a more recent time period with contemporary treatments-the most frequently received treatments both before and after NEPC diagnosis were radiation (39% and 31%) and ADT (34% and 25%).
CONCLUSION: The findings of this study align with NEPC having a low real-world diagnostic prevalence among patients with PCa, especially in comparison to histology-based analyses, suggesting that treatment-induced NEPC may be underdiagnosed. This study underscores the need for further research in the NEPC population to advance diagnosis and treatment.

Keywords:  Epidemiology; Neuroendocrine prostate cancer; Prostate cancer; Real-world data; Treatment patterns

DOI:  https://doi.org/10.1016/j.ctarc.2025.101038
Pharmacol Res. 2025 Nov 23. pii: S1043-6618(25)00473-6. [Epub ahead of print] 108048

Spatial proteomic profiling reveals conserved prognostic immune microenvironment features across molecular subtypes in small cell lung cancer.

Modi Zhai, Zicheng Zhang, Jiyan Dong, Zhuo Li, Yuqing Cao, Ruanqi Chen, Meng Zhou, Lin Yang.

  Small cell lung cancer (SCLC) molecular subtypes, defined by neuroendocrine (NE) status and transcription factor (TF) expression, provide insight into tumor biology but fails to fully capture the spatial complexity of the immune microenvironment (IME) and possess limited prognostic power. In this study, we performed an integrative analysis of targeted bulk transcriptomics, digital spatial proteomics (DSP) and multiplex immunohistochemistry (IHC) with extensive multiregional sampling across tumor core (CT), invasive margin (IM), and peri-tumoral (PT) compartments in treatment-naïve formalin-fixed, paraffin-embedded SCLC samples to investigate the IME heterogeneity and its clinical significance across molecular subtypes. Targeted bulk transcriptomics of immune gene panel identified two major immune subgroups, immune-hot (IHG) and immune-cold (ICG), which are associated with NE status but independent of TF subtypes and showed limited prognostic value. In contrast, DSP profiling revealed profound spatial immune heterogeneity within individual tumors, and identified immune activation specifically within the tumor core as a dominant and independent prognostic biomarker that transcends traditional NE and TF subtypes. IHG-CT tumors, characterized by enriched cytotoxic T cells, activated antigen presentation, and myeloid engagement, were significantly associated with improved survival outcomes, whereas immune heterogeneity in the IM and PT regions did not correlate with survival outcomes, as validated by multiplex IHC. Additionally, the IHG status was associated with clinical benefit from immune checkpoint blockade. Collectively, our study highlights the importance of spatial context for understanding clinically relevant IME features, and provides a transformative spatially informed framework for SCLC patient stratification and therapeutic development.

Keywords:  Digital Spatial Profiler; Molecular subtypes; Small cell lung cancer; Spatial proteomics; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2025.108048
BMC Pulm Med. 2025 Nov 25. 25(1): 545

Prognostic role of pretreatment serum α-hydroxybutyrate dehydrogenase in patients with small cell lung cancer.

Qizhong Xu, Maoquan Liang, Fan Zhang, Xuewen Hou.

   BACKGROUND AND OBJECTIVES: The role of pretreatment serum α-hydroxybutyrate dehydrogenase (α-HBDH) in small cell lung cancer (SCLC) prognosis prediction remains unknown. We sought to investigate the influence of pretreatment α-HBDH level on the survival of patients with SCLC.
METHODS: The serum concentration of α-HBDH was measured in 400 SCLC patients. The correlations between pretreatment serum α-HBDH concentration and clinicopathological characteristics were analysed. Univariate and multivariate Cox regression analyses were used to evaluate the relationships between α-HBDH levels and the progression-free survival (PFS) and overall survival (OS) of SCLC patients.
RESULTS: Pretreatment α-HBDH levels were closely associated with tumour stage, NSE levels, LDH levels, and surgical treatment. Patients with high α-HBDH were more likely to have extensive disease, high NSE levels, and high LDH levels (< 250 vs. ≥ 250 U/L, 13.0% vs. 94.8%) and were less likely to have surgery (p < 0.005 for all). Multivariate analysis revealed that tumour stage, tumour size, chemotherapy plus surgery, pretreatment α-HBDH, NSE, and LDH were associated with OS in SCLC patients. Patients in the high α-HBDH group had a 33.9% greater risk of death than patients in the normal α-HBDH group did [HR 1.339; 95% CI: 1.070-1.674]. Patients with high α-HBDH had worse OS than patients with normal α-HBDH did (median OS, 10.0 vs. 15.0 months).
CONCLUSIONS: Elevated pretreatment serum α-HBDH is independently associated with poor OS in SCLC patients. The potential of HBDH as a complementary marker for the prediction of SCLC survival warrants further investigation in conjunction with other indicators.

Keywords:  Overall survival; Prognostic factor; Small cell lung cancer; Α-hydroxybutyrate dehydrogenase

DOI:  https://doi.org/10.1186/s12890-025-03996-0
BMJ Case Rep. 2025 Nov 26. pii: e268162. [Epub ahead of print]18(11):

Development of small cell lung cancer following gunshot wound to the chest.

Alexandra Bartholomew, Isabella Bartholomew, Ashley Cao, Jonathan Kiev.

  Small cell lung cancer (SCLC) is an aggressive malignancy that often presents with advanced disease and is highly associated with tobacco use. While some studies demonstrate a potential relationship between sites of trauma and cancer development, the development of SCLC in relation to traumatic injury has not been well studied. The authors report the case of a man in his 70s who presented with biopsy-proven limited stage SCLC in the left upper lobe of the lung 45 years following a gunshot wound to the chest. The patient underwent surgical resection and postoperative adjuvant chemoradiation therapy. Three years after biopsy, surveillance imaging demonstrated no sign of recurrence. He remains clinically well. This case suggests a possible relationship between small cell carcinoma and trauma associated with foreign bodies, such as metallic bullets.

Keywords:  Cancer intervention; Cardiothoracic surgery; Lung cancer (oncology); Surgery

DOI:  https://doi.org/10.1136/bcr-2025-268162
Cells. 2025 Nov 20. pii: 1828. [Epub ahead of print]14(22):

FGF12 Enhances Prostate Cancer Cell Survival via the YB1-lncRNA Axis.

Zechao Huang, Sonia H Y Kung, Hans Adomat, Htoo Zarni Oo, Connor Forbes, Faraz Hach, Xuesen Dong.

  Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer characterized by lineage plasticity and poor response to standard chemotherapy and androgen deprivation therapy. Although transcriptional mechanisms driving t-NEPC have been extensively studied, the contribution of post-transcriptional regulation remains less defined. Here, we report fibroblast growth factor 12 (FGF12) as a critical post-transcriptional regulator of t-NEPC progression. Transcriptomic analyses of patient biopsies, patient-derived xenografts, and prostate cancer cell models consistently demonstrated elevated FGF12 expression in t-NEPC, which was further validated by immunohistochemistry in archival specimens. Functional assays revealed that FGF12 expression conferred survival of cancer cells to chemotherapeutic agents, including etoposide and camptothecin. Integrative RNA sequencing and affinity purification-mass spectrometry showed that FGF12 mediates these functions mainly through interaction with the RNA-binding protein YB1, leading to stabilization of oncogenic long noncoding RNAs, including NEAT1 and MALAT1, whereas RNA silencing of YB1 abrogated the ability of FGF12 to upregulate these transcripts. Collectively, these findings uncover a previously unrecognized FGF12-YB1-lncRNA signaling axis that drives t-NEPC progression. Targeting this pathway may provide new therapeutic opportunities for patients with this aggressive disease.

Keywords:  Y-box binding protein 1 (YB1); fibroblast growth factor 12 (FGF12); long noncoding RNAs (lncRNAs); post-transcriptional regulation; treatment-induced neuroendocrine prostate cancer (t-NEPC)

DOI:  https://doi.org/10.3390/cells14221828
Nature. 2025 Nov 26.

NSD2 targeting reverses plasticity and drug resistance in prostate cancer.

Jia J Li, Alessandro Vasciaveo, Dimitris Karagiannis, Zhen Sun, Kristjan H Gretarsson, Xiao Chen, Ouathek Ouerfelli, Fabio Socciarelli, Ziv Frankenstein, Hanyang Dong, Min Zou, Wei Yuan, Guangli Yang, Gabriel M Aizenman, Tania Pannellini, Xinjing Xu, Himisha Beltran, Yu Chen, Kevin Gardner, Brian D Robinson, Johann de Bono, Or Gozani, Cory Abate-Shen, Mark A Rubin, Massimo Loda, Charles L Sawyers, Andrea Califano, Chao Lu, Michael M Shen.

Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance1,2. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)3-5. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase6. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice7 that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment.

DOI: https://doi.org/10.1038/s41586-025-09727-z
Histopathology. 2025 Nov 26.

Transcription factor-based subtype assignment in pulmonary large cell neuroendocrine carcinoma.

Yin P Hung, Komson Wannasai, Catherine B Meador, Maria L Ganci, Anna B Rider, Charlotte I Wang, Mari Mino-Kenudson.

   AIMS: Pulmonary large cell neuroendocrine carcinoma (LCNEC) can be difficult to diagnose due to histological overlap with small cell lung carcinoma (SCLC). SCLC comprises multiple transcription factor-based subtypes. We aimed to evaluate the clinicopathological significance of transcription factor-based subtyping in pulmonary LCNEC.
METHODS AND RESULTS: We identified a consecutive series of 117 patients in 2010-2024 with samples diagnosed as pulmonary LCNEC (n = 70) or high-grade neuroendocrine carcinoma with combined or intermediate morphology (n = 47). Cytomorphological score was assessed as a weighted average from two areas. Immunohistochemistry (IHC) for ASCL1, NeuroD1, POU2F3, YAP1, and HNF4A was evaluated using H-scores, with subtype assignment based on the highest H-score. Next-generation sequencing (NGS) was performed in selected cases. IHC subtyping identified 73 (62%) ASCL1-dominant, 20 (17%) YAP1-dominant, 9 (8%) NeuroD1-dominant, 7 (6%) POU2F3-dominant, 2 (2%) HNF4A-dominant, and 6 (5%) quintuple-negative samples. While YAP1 was often co-expressed with other subtypes and HNF4A was frequently co-expressed with ASCL1, POU2F3 was mutually exclusive from ASCL1/NeuroD1/HNF4A. Unlike ASCL1/NeuroD1/POU2F3, YAP1 and HNF4A H-scores each correlated with large-cell morphology-both across the entire cohort and in the lung resection subgroup. NeuroD1 dominance was more common in tumours with combined/intermediate morphology than LCNEC. Some of the tumours with intermediate morphology straddling between prototypical LCNEC and SCLC harboured POU2F3 dominance, or EGFR or other non-KRAS driver mutations. In 19 patients with multiple samples (including nine with paired pre- and post-treatment samples), all showed concordant subtypes after accounting for codominance.
CONCLUSION: YAP1 and HNF4A expression correlated significantly with large-cell morphology.

Keywords:  ASCL1; HNF4A; NeuroD1; POU2F3; YAP1; large cell neuroendocrine carcinoma

DOI:  https://doi.org/10.1111/his.70055
bioRxiv. 2025 Oct 20. pii: 2025.10.19.683051. [Epub ahead of print]

Divergent roles of DNA methylation, TRIM28, and p53 surveillance in human embryonic and trophoblast stem cells.

Deepak Saini, Megan S Katz, Skye G A Beck, Taylor E Ireland, Soma Ray, Asef Jawad Niloy, Radman Mazloomnejad, Anna Fleming, Sophia C Vetrici, Jessica K Cinkornpumin, Tanja Sack, Stephanie Duhamel, Rima Slim, Morag Park, Jennifer M Frost, Soumen Paul, Raquel Cuella Martin, William A Pastor.

Transcriptional regulation of transposons and genes by TRIM28 and 5mC is critical for proper mammalian embryonic development, but the specific roles for these mediators in human embryonic and placental lineage remain unclear. We find that loss of TRIM28 has a limited effect on global transposon expression and instead results in upregulation of genes proximal to TRIM28-bound Long Terminal Repeats (LTRs) in both human trophoblast stem cells (hTSCs) and human embryonic stem cells (hESCs). MER11A elements show especially strong regulatory importance in hTSCs: these elements are bound by both TRIM28 and placental transcription factors and show both heterochromatic and euchromatic features. Some genes are positively regulated by MER11A elements in hTSC basal state, while other MER11A-proximal genes show upregulation only upon TRIM28 deletion. By contrast, loss of DNA methylation in hESCs or hTSCs leads to a global increase in transposon expression. While many genic 5mC targets are shared in hESCs and hTSCs, we also observe evidence that a handful of genes important for somatic development are repressed by 5mC in trophoblast, while a small parallel set of placental genes are repressed by methylation in embryonic tissue. Interestingly, loss of DNMT1 causes hESCs to be rapidly lost from culture in a TP53 and mitotic surveillance checkpoint-dependent manner, while hTSCs show little p53 response to DNMT1 loss or DNA damage generally, instead showing gradual mitotic defects and aneuploidy and slow loss from culture. This discrepancy may explain the higher frequency of karyotypic abnormality found in human placental cells. Together, this study charts the role of TRIM28 and DNA methylation in regulating embryonic and placental transcription and demonstrates divergent p53-dependent responses to genomic instability.

DOI: https://doi.org/10.1101/2025.10.19.683051
Iran J Public Health. 2025 Sep;54(9): 2005-2014

Metabolomics-Based Diagnosis of Medullary Thyroid Cancer: A Plasma 1H NMR Approach.

Khadijeh Saeidi, Mehdi Hedayati, Monireh Movahedi, Maryam Sadat Daneshpour.

   Background: Medullary thyroid cancer (MTC) is a rare neuroendocrine malignancy, accounting for 5-10% of all thyroid cancer cases. The precise molecular processes driving MTC remain largely elusive. We aimed to conduct a pilot study analyzing plasma metabolic profiles of MTC patients to uncover disruptions in metabolic pathways that may contribute to MTC tumorigenesis.
Methods: Proton nuclear magnetic resonance (1H-NMR) spectroscopy was performed to screen metabolic changes in plasma samples from MTC patients (n=16) and healthy subjects (n=12). Multivariate and univariate analyses were applied using MetaboAnalyst and SIMCA software.
Results: A total of 30 compounds were identified, of which three metabolites-glycerol, isobutyric acid, and valine-showed significant differences between MTC patients and the control group (P<0.05).
Conclusion: The findings from this study contribute to the current understanding of MTC metabolism and suggest that the NMR-based metabolomics approach can provide a metabolic pattern of MTC, potentially improving diagnostic procedures.

Keywords:  Diagnosis; Medullary thyroid cancer; Metabolic perturbation; Metabolomics

DOI:  https://doi.org/10.18502/ijph.v54i9.19867
Endocr Pathol. 2025 Nov 26. 36(1): 48

The Utility of Cabozantinib in the Therapy of Endocrine Tumours.

Eleni Armeni, Tu-Vinh Luong, Ashley Grossman.

  Endocrine and neuroendocrine malignancies, including epithelial neuroendocrine neoplasms (NENs), phaeochromocytoma/paraganglioma (PPGL), adrenocortical carcinoma (ACC) and thyroid cancers, represent a heterogeneous group of tumours often characterised by dysregulated receptor tyrosine kinase signalling and with limited systemic treatment options. Cabozantinib is a multikinase inhibitor implicated in tumour angiogenesis, growth, and therapeutic resistance, and its use has been reported in many of these tumours. We performed a narrative review assessing cabozantinib monotherapy or combination regimens in patients with progressive neuroendocrine neoplasms. In NENs, monotherapy achieved a disease control rate (DCR) of up to 83% and a progression-free survival (PFS) of 8.4 months in extra-pancreatic subtypes, and 13.8 months in pancreatic subtypes. Combination therapies yielded modest efficacy with a PFS up to 13.0 months. In metastatic PPGLs, monotherapy achieved an objective response rate (ORR) of 25%, a median PFS of 16.6 months and overall survival (OS) of 24.9 months; combination with atezolizumab showed an ORR of 15.4% and a PFS of 8.4 months. In adrenocortical cancer, the DCR reached 78%, PFS up to 7.2 months, and OS up to 23.9 months. In differentiated thyroid cancer, PFS 11.4 months and OS 26.3 months; in RET M918T-mutant medullary thyroid cancer, OS improved to 44.3 months. Cabozantinib represents a promising therapeutic option across endocrine and neuroendocrine malignancies, particularly in settings with limited treatment alternatives, although the reported rates of control have not been dramatic and adverse effects not insignificant. However, it offers the possibility of exploring more effective molecular approaches, especially with biomarker-based stratification and combinatorial approaches.

Keywords:  Adrenocortical carcinoma; Cabozantinib; Endocrine malignancies; Neuroendocrine neoplasms; Paraganglioma; Phaeochromocytoma; Thyroid cancer

DOI:  https://doi.org/10.1007/s12022-025-09890-z
Am J Nucl Med Mol Imaging. 2025 ;15(5): 215-218

DLL3-targeted immunoPET and radioimmunotherapy ligands.

Steven H Liang.

  DLL3 is overexpressed on the cell surface of NENs, such as SCLC and NEPC, but notably restricted to cytoplasm with low expression levels in normal adult human tissues. Several radioligands have been developed by targeting DLL3 for immunoPET or radioimmunotherapy use. These ligands hold great promise for mapping the heterogeneous DLL3 expression in neuroendocrine tumors and guiding the DLL3-directed therapeutic strategies.

Keywords:  DLL3; SCLC; immunopet; in vivo imaging; notch signaling

DOI:  https://doi.org/10.62347/MRZS8767
J Int Med Res. 2025 Nov;53(11): 3000605251395564

Few-shot learning for the classification of colorectal neuroendocrine tumors and polyps on endoscopic images.

Shiqi Zhu, Hailong Ge, Yu Wang, Jiaxi Lin, Rufa Zhang, Minyue Yin, Jinzhou Zhu, Chen Chao.

  ObjectiveColorectal neuroendocrine tumors and polyps share similar endoscopic features, often resulting in misdiagnosis. As neuroendocrine tumors are rare, obtaining a sufficient number of images for deep learning models is challenging.MethodsThis study introduces a few-shot learning model for ternary classification of neuroendocrine tumors, serrated lesions and polyps, and traditional adenomas using endoscopic images. Three groups of images (56 serrated lesions and polyps, 86 adenomas, and 53 neuroendocrine tumors) were collected retrospectively and divided into Support Sets and Query Sets. The proposed few-shot learning model involved transfer learning using ResNet50 V2 pretrained on ImageNet and esophageal endoscopic images, followed by metric learning based on Euclidean distances and K-nearest neighbor classification.ResultsEvaluated across three rounds, the few-shot learning model outperformed conventional deep learning models and both junior and senior endoscopists in several metrics, achieving an average macro-area under the curve of 0.731, macro-F1-score of 0.674, Matthews correlation coefficient of 0.526, and Cohen's kappa of 0.523. When identifying neuroendocrine tumors specifically, the model achieved the highest accuracy (0.823), sensitivity (0.653), precision (0.673), and F1-score (0.659).ConclusionsThe few-shot learning approach effectively addresses data scarcity issues and improves diagnostic accuracy, offering a promising tool for computer-aided diagnosis of rare gastrointestinal diseases.

Keywords:  Neuroendocrine tumors; adenoma; artificial intelligence; colonoscopy; few-shot learning; serrated lesions and polyps

DOI:  https://doi.org/10.1177/03000605251395564
Reports (MDPI). 2025 Nov 03. pii: 226. [Epub ahead of print]8(4):

A Young Woman with Paraneoplastic Cushing's Syndrome Due to a Pulmonary Carcinoid.

Marine Sluys, Pauline Delannoy, Laurence Lousberg, Marie Strivay, Adrian F Daly, Patrick Pétrossians.

  Background and Clinical Significance: Ectopic ACTH secretion is a rare, potentially life-threatening cause of Cushing's syndrome that can be overlooked when small neuroendocrine tumors evade standard imaging. Case Presentation: A 34-year-old woman presented with rapidly progressing clinical signs/symptoms of Cushing's syndrome and demonstrated marked hypercortisolism (cortisol 2428 nmol/L; ACTH 163 ng/mL; urinary free cortisol 815 μg/24 h; K+ 2.4 mmol/L). Small hypermetabolic nodules were noted in her right lung on 18F-FDG PET/CT but were initially deemed to be infectious; DOTANOC PET-CT and inferior petrosal sinus sampling were non-diagnostic. After medically induced inhibition of cortisol, repeat PET/CT showed a persistent 13 mm lung nodule. Biopsy confirmed a well-differentiated pulmonary carcinoid (Ki-67 3%), and lobectomy achieved biochemical remission. Conclusions: Diagnostic delay stemmed from human factors despite early suggestive imaging. Ectopic ACTH secretion should remain high on the differential diagnosis in rapidly evolving, severe ACTH-dependent Cushing's disease; early, decisive diagnosis and coordinated care overseen by endocrinologists-preferably in expert centers-can shorten exposure to deleteriously high cortisol levels and improve outcomes.

Keywords:  Cushing’s syndrome; ectopic ACTH; neuroendocrine tumor; pulmonary carcinoid

DOI:  https://doi.org/10.3390/reports8040226
Pharmaceuticals (Basel). 2025 Nov 18. pii: 1752. [Epub ahead of print]18(11):

YM155 Inhibition of Survivin Enhances Carboplatin Efficacy in Metastatic Castration-Resistant Prostate Cancer.

Vicenç Ruiz de Porras, Martin K Bakht, Maria Fernandez-Saorín, Clara Alcon, Luis Palomero, Júlia Francisco-Rodon, Mariona Figols, Joan Montero, Vincenza Conteduca, Himisha Beltran, Albert Font.

  Background/Objectives: Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge due to its aggressive behavior and resistance to therapy. Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in various cancers and associated with poor prognosis. YM155 (Sepantronium bromide) suppresses survivin expression and has demonstrated antitumor activity in preclinical models. We investigated the association between survivin expression and clinical outcomes in mCRPC patients and evaluated the antitumor activity of YM155, alone and in combination with carboplatin, in mCRPC cell lines. Methods: Analysis of publicly available RNA-seq datasets from mCRPC patients was performed to assess correlations between survivin expression and clinical outcomes. Radiographic progression-free survival (rPFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared via log-rank or Fisher's exact tests. In vitro assays were conducted on mCRPC cell lines treated with YM155, carboplatin, or both, to evaluate cell viability, clonogenicity, and apoptosis. Results: Survivin was significantly overexpressed in mCRPC compared with localized prostate cancer and was even higher in castration-resistant neuroendocrine disease. High survivin levels were associated with shorter OS (p = 0.006). In patients treated with platinum-based therapies, high survivin was also linked to shorter rPFS (p = 0.01), reduced OS (p = 0.006), and a smaller PSA decline (p = 0.006). In vitro, YM155 reduced survivin expression, impaired cell viability and colony formation, induced apoptosis, and synergistically enhanced the cytotoxicity of carboplatin. Conclusions: Our findings suggest that survivin may serve as a prognostic biomarker and potential therapeutic target in platinum-treated, AR-independent mCRPC. The integration of clinical and functional data provides translational support for combining the survivin inhibitor YM155 with platinum-based therapy. These results warrant further validation in larger patient cohorts and in vivo models.

Keywords:  YM155; carboplatin; metastatic castration-resistant prostate cancer; survivin

DOI:  https://doi.org/10.3390/ph18111752
EBioMedicine. 2025 Nov 22. pii: S2352-3964(25)00427-X. [Epub ahead of print]122 105983

Corrigendum to "A novel mechanism of SRRM4 in promoting neuroendocrine prostate cancer development via a pluripotency gene network" EBioMedicine 2018 Sep: 35: 167-177.

Ahn R Lee, Yu Gan, Yuxin Tang, Xuesen Dong.

DOI: https://doi.org/10.1016/j.ebiom.2025.105983
Virchows Arch. 2025 Nov 22.

Neuroendocrine neoplasms of the stomach. Update on diagnostic criteria, classification, and prognostic markers.

Silvia Uccella, Stefano La Rosa.

  Gastric neuroendocrine neoplasms (gNENs) encompass all the spectrum of NENs including neuroendocrine carcinomas (gNECs), mixed neuroendocrine/non-neuroendocrine neoplasms (gMiNENs) and neuroendocrine tumors (gNETs). Differently from other digestive sites, gNETs are subclassified according to the clinicopathologic setting in which they arise, with important prognostic implications. Since gastric endoscopic biopsies represent a high-volume daily activity in both referral and community hospitals, pathologists should be increasingly aware of this disease. This will allow to correctly identify the different entities and, when present, their precursor lesions, giving useful information to clinicians for the best patient management. This review paper aims to provide morphologic, immunophenotypic, and, when necessary, molecular criteria for the correct diagnosis and subtyping of gNENs. In addition, a simplified prognostic classification schema of enterochromaffin-like (ECL)-cell NETs is proposed, based on gastrin serum levels and the status of gastric acid secretion.

Keywords:  Classification; MiNEN; Neuroendocrine carcinoma; Neuroendocrine tumor; Prognosis; Stomach

DOI:  https://doi.org/10.1007/s00428-025-04340-x
Medicine (Baltimore). 2025 Nov 21. 104(47): e46168

Clinical pathological analysis of primary small cell neuroendocrine carcinoma of the cervix: A retrospective study.

Pu Jin, Congyang Gu, Shiyue Huang, Xiaohua Liu.

  To explore the clinical and pathological features of primary small cell neuroendocrine carcinoma of the cervix. Clinical data of 4 patients with primary small cell neuroendocrine carcinoma of the cervix were collected, and the clinical features, histopathological characteristics, immunohistochemical staining results, treatment, and prognosis were summarized and analyzed. The relevant literature was reviewed and summarized. The age of the 4 patients ranged from 48 to 62 years, with an average age of 54.3 years. Patients 1, 2, and 3 sought medical attention because of irregular vaginal bleeding, whereas patient 4 presented with lower abdominal pain and discomfort. Histologically, all 4 cases were small-cell neuroendocrine carcinomas. Immunophenotyping: tumor cells were diffusely strongly positive for P16, and expressed 2 or more neuroendocrine markers, with positive rates of CD56 100% (4/4), synaptophysin (SYN) 100% (4/4), and chromogranin (CgA) 50% (2/4). The first and second cases were positive for TTF-1, epithelial marker panCK was positive, and Ki-67 proliferation index was >70% in all cases. This is a relatively rare and highly malignant cervical tumor with strong invasiveness and a poor prognosis. This may be related to human papillomavirus infection. A definitive diagnosis can be made based on the histopathological morphology and immunophenotype.

Keywords:  HPV; cervix; differential diagnosis; immunohistochemistry; missed diagnosis; neuroendocrine carcinoma; small cell carcinoma

DOI:  https://doi.org/10.1097/MD.0000000000046168
Eur J Obstet Gynecol Reprod Biol X. 2025 Dec;28 100434

Neuroendocrine carcinoma of the cervix (NECC): A retrospective study of 175 Chinese patients.

Ning Su, Xiao Li, Dian Wang, Min Wang, Shuping Yan, Haifeng Qiu.

   Purpose: Neuroendocrine carcinoma of the cervix (NECC) is rare and aggressive. We analyzed a dual-center Chinese cohort to describe clinicopathologic features, outcomes, and treatment patterns, and to identify prognostic factors.
Methods: We retrospectively included patients with pathologically confirmed NECC treated from June 2012 to June 2021. Variables included age at diagnosis, symptoms, high-risk human papillomavirus (hrHPV), FIGO 2009/2018 stage, tumor histology, tumor diameter, depth of stromal invasion (DOI), lymphovascular space invasion (LVSI), lymph-node metastasis (LNM), and treatments. Follow-up followed NCCN guidance. Survival was assessed using Kaplan-Meier and Cox regression.
Results: We analyzed 175 patients. hrHPV was positive in 54.3 % (95/175); 84.0 % (147/175) presented with abnormal vaginal bleeding. By FIGO 2018, 39.4 % (69/175) had stage IIB-IVB disease. On univariable Cox regression analysis, younger age, higher FIGO stage (2009 and 2018), pure NECC histology, deeper DOI, larger tumor diameter, and positive LNM were associated with worse survival. In contrast, multivariable Cox regression analysis revealed that FIGO 2009 stage and DOI were independent predictors of both progression-free survival (PFS) and overall survival (OS); tumor histology was independently associated with OS. Survival did not differ between abdominal and laparoscopic radical hysterectomy. Among surgically treated patients, adjuvant radiotherapy did not improve PFS or OS across early-stage, locally advanced, or late-stage subgroups.
Conclusions: In this cohort, primary-tumor factors-especially DOI-and FIGO 2009 stage were independent prognostic factors, whereas surgical route and postoperative radiotherapy showed no survival benefit; these findings can inform staging considerations and treatment decisions for NECC.

Keywords:  Neuroendocrine carcinoma of the cervix; Overall survival; Progression-free survival; Radiotherapy; Retrospective cohort

DOI:  https://doi.org/10.1016/j.eurox.2025.100434
Gynecol Oncol. 2025 Nov 26. pii: S0090-8258(25)01099-6. [Epub ahead of print]204 118-123

Surgery versus definitive radiotherapy in the management of stage I-II small cell neuroendocrine carcinoma of the cervix: A systematic review and meta-analysis.

Kevin Yijun Fan, Rania Chehade, Andrew Yuanbo Wang, Anjali Sachdeva, Farideh Tavangar, Helen J MacKay, Amandeep S Taggar.

   BACKGROUND: Small cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare malignancy with poor prognosis. Optimal management of stage I-II disease remains uncertain, with guidelines variably recommending primary surgery or definitive radiotherapy. This study aimed to compare overall survival (OS) in patients with stage I-II SCNECC treated with primary surgery versus definitive radiotherapy through a systematic review and meta-analysis of the current literature.
METHODS: Medline and Embase were searched for English-language studies reporting OS for stage I-II SCNECC treated with either primary surgery or definitive radiotherapy. Studies with ≥5 patients per treatment group were included. Hazard ratios (HR) for OS were pooled using a random-effects meta-analysis. Heterogeneity was assessed with I2. The impact of including stage IIB patients was evaluated using a Likelihood Ratio Test comparing Cox proportional hazards models.
RESULTS: Of 621 unique records, five studies met the inclusion criteria, encompassing 650 patients treated for stage I-II SCNECC between 1987 and 2012 in 38 hospitals across three countries. Among these patients, 474 underwent primary surgery and 176 received definitive radiotherapy. Of all patients, 84 % received chemotherapy. Median follow-up ranged from 31 to 83 months, and median OS ranged from 21 to 111 months. The pooled HR for OS favoured primary surgery compared to definitive radiotherapy (HR 0.53; 95 % CI 0.31-0.91; p = 0.021). Inter-study heterogeneity was substantial (I2 = 64 %, p = 0.024). Inclusion of stage IIB patients did not significantly affect the overall HR (p = 0.914).
CONCLUSIONS: In stage I-II SCNECC, primary surgery is associated with longer OS compared to definitive radiotherapy. While findings are limited by the retrospective nature of included studies and potential selection bias, these results support consideration of surgical consultation for eligible patients as part of a multidisciplinary decision-making process. Prospective studies and inter-institutional collaboration are urgently needed to define optimal treatment strategies in this rare malignancy.

Keywords:  Overall survival; Radiation; Rare malignancy; Small cell neuroendocrine carcinoma of the cervix; Surgery; Systematic review; meta-analysis

DOI:  https://doi.org/10.1016/j.ygyno.2025.11.015
Diagnostics (Basel). 2025 Nov 12. pii: 2865. [Epub ahead of print]15(22):

Gastric Glomus Tumor with Neuroendocrine Features: A Diagnostic Pitfall for Neuroendocrine Tumors.

Dae Hyun Song, Tae-Han Kim, Hyo Jung An.

  A 60-year-old woman with hypertension and hyperlipidemia was referred for an incidentally detected gastric subepithelial mass during screening endoscopy. Esophagogastroduodenoscopy revealed a 10 mm dimple in the antrum, and contrast-enhanced CT showed a 2.5 cm enhancing oval lesion. Laparoscopic partial gastrectomy with intraoperative endoscopic guidance was performed. Gross examination revealed a 3.0 × 2.0 × 1.0 cm pale, firm nodule. Histology showed small round cells arranged in nests and trabeculae within the muscularis propria, with numerous vessels and focal calcification. Immunohistochemistry was negative for CD117, HMB45, and chromogranin A, but demonstrated strong smooth muscle actin positivity, weak synaptophysin reactivity, and focal CD56 staining. The findings confirmed a gastric glomus tumor with neuroendocrine features. Smooth muscle actin immunostaining is essential to distinguish gastric glomus tumors from neuroendocrine tumors when biopsy material is limited, ensuring accurate diagnosis and appropriate management.

Keywords:  gastric submucosal tumor; glomus tumor; neuroendocrine differentiation; smooth muscle actin

DOI:  https://doi.org/10.3390/diagnostics15222865
Pharmaceuticals (Basel). 2025 Oct 31. pii: 1650. [Epub ahead of print]18(11):

Efficacy and Safety of Non-Surgical Treatments for Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis.

Mohammed Saad AlQahtani, Bogdan Miutescu, Ielmina Domilescu, Serban Negru, Dorel Popovici, Eyad Gadour.

  Background: Pancreatic neuroendocrine tumor (pNET) is a rare and complex disease that requires careful management and treatment. Currently, a range of treatments, including surgery, somatostatin analogs (SSA), peptide receptor radionuclide therapy (PRRT), targeted drugs, cytotoxic chemotherapy, and immunotherapy, exist for pNETs. However, determining the optimal treatment strategies remains challenging. Aim: To evaluate the efficacy and safety of non-surgical therapies, such as somatostatin analogs (SSA), peptide receptor radionuclide therapy (PRRT), targeted drugs, cytotoxic chemotherapy, and immunotherapy in treating pNETs. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science databases for relevant studies published from inception until August 2025. Randomized clinical trials (RCTs), non-randomized clinical trials, and prospective studies were included in this meta-analysis if they evaluated the efficacy and safety of any treatment of interest in patients with pNETs. Results: Thirty-three studies involving 2374 pNET patients were analyzed. Targeted therapies showed modest objective response rates (ORRs) but high disease control rates (DCRs): everolimus (ORR 7%, 95% CI: 3-10%; DCR 81%, 95% CI: 75-87%), sunitinib (ORR 12%, 95% CI: 5-19%; DCR 79%, 95% CI: 70-88%), surufatinib (ORR 19%, 95% CI: 12-27%; DCR 81%, 95% CI: 73-89%). Cytotoxic chemotherapy demonstrated higher ORRs: dacarbazine-based (32%, 95% CI: 21-43%), streptozocin-based (40%, 95% CI: 25-54%), temozolomide-based (42%, 95% CI: 29-55%). PRRT showed varying efficacy: 177Lu-DOTATATE (ORR 36%, 95% CI: 27-44%; DCR 84%, 95% CI: 76-92%), 90Y-DOTATOC (ORR 27%, 95% CI: 18-36%; DCR 73%, 95% CI: 63-83%). SSAs had low ORRs but high DCRs: lanreotide (ORR 0%, DCR 67%, 95% CI: 57-77%), octreotide (ORR 23%, 95% CI: 15-31%; DCR 75%, 95% CI: 66-84%). Immunotherapy with pembrolizumab showed limited efficacy (ORR 7%, 95% CI: 0-14%). Treatment-related adverse events were common across therapies, with specific toxicity profiles for each modality. Conclusions: Cytotoxic chemotherapy offers better response rates than other treatment modalities. However, toxicity management is crucial. PRRT also shows robust antitumor activity and disease control, while SSAs and targeted therapies are effective treatment options for disease stabilization. Immunotherapy demonstrated limited antitumor activity, and further research is needed to establish its role in pNET treatment.

Keywords:  cytotoxic chemotherapy; non-surgical treatments; pancreatic neuroendocrine tumor; peptide receptor radionuclide therapy; somatostatin analogs

DOI:  https://doi.org/10.3390/ph18111650
Nuklearmedizin. 2025 Dec;64(6): 341-351

Experimental approach for optimizing dose regimen of 68Ga-DOTATATE PET/CT for neuroendocrine tumor (NET) imaging in current high sensitivity scanners: Phantom and Patient Study.

Abbas Monsef, Fatemeh Saboktakin, Fatemeh Sadeghi, Mohammadreza Elhaie, Mohsen Beheshti, Peyman Sheikhzadeh.

This study aimed to determine the optimized scan time and injected activity regimen for clinical 68Ga DOTATATE PET/CT in neuroendocrine tumor imaging through an experimental approach without using machine learning techniques.A NEMA PET body phantom was used with Ga-68 to simulate a 9:1 sphere-to-background ratio. PET data were acquired on a high-sensitivity scanner at various scan times (15-300 s/bed). For each scan time, coefficient of variation (COV) and contrast-to-noise ratio (CNR) were calculated. The minimum scan time (Tmin) needed to meet the Rose Criterion (CNR > 5) for the smallest sphere was identified. This Tmin was then applied to patient scans with neuroendocrine tumors (originally acquired at 120 s/bed) to evaluate image quality and determine an optimized activity regimen for clinical 68Ga-DOTATATE PET imaging.Phantom experiments showed that a COVmax of 20% is the highest acceptable noise level for detecting the smallest lesions, corresponding to a minimum scan time of about 1 minute per bed position. Patient image analysis confirmed that all tumors visible at routine scan times were still detectable at this minimum duration. This supports the use of a lower activity regimen (~1 MBq/kg), which can reduce patient radiation exposure compared to the standard 1.85 MBq/kg protocol.This work demonstrated that scan time and activity for 68Ga-DOTATATE NET imaging can be significantly minimized without compromising image interpretation and quantification.

DOI: https://doi.org/10.1055/a-2710-7001
Cancers (Basel). 2025 Nov 08. pii: 3604. [Epub ahead of print]17(22):

RBM39 Contributes to MGMT Maintenance in Response to Temozolomide-Induced DNA Damage.

Vahid Khalaj, Jack T Adams, Solmaz AghaAmiri, Servando Hernandez Vargas, Tyler M Bateman, Sukhen C Ghosh, Majid Momeny, Ali Azhdarinia.

  Resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ) is a significant challenge in treating tumors with high MGMT expression, including MGMT-positive glioblastoma and neuroendocrine neoplasms. In this study, we investigated the effect of RNA-binding motif protein 39 (RBM39) downregulation on MGMT protein levels, based on prior observations suggesting an association between these two proteins. Pharmacological depletion or siRNA-mediated knockdown of RBM39 led to a marked reduction in MGMT protein levels in MGMT-expressing cancer cells. We further showed that dual targeting of RBM39 (using indisulam) and MGMT (with O6-benzylguanine) synergistically enhanced MGMT depletion. Functionally, combined indisulam and TMZ treatment significantly increased apoptosis and decreased clonogenic growth in neuroendocrine tumor cells. These findings identify MGMT as a downstream target of RBM39 in MGMT-expressing cancer cells and highlight the therapeutic potential of co-targeting RBM39 and MGMT to overcome resistance to alkylating chemotherapy.

Keywords:  MGMT; RBM39; alkylating chemotherapy; neuroendocrine neoplasms; temozolomide resistance

DOI:  https://doi.org/10.3390/cancers17223604
Front Oncol. 2025 ;15 1692412

Case Report: Diagnostic challenges in cervical small cell neuroendocrine carcinoma of a reproductive-age woman.

Yitong Du, Huiling Yang, Yichen Feng, Zejun Wu, Mengyao Li, Tingting Zhu, Yali Zhuang.

  Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a rare and highly aggressive malignancy with a poor prognosis. We report the case of a 36-year-old nulliparous woman with a history of HPV-18 infection and repeated cytology showing atypical squamous cells of undetermined significance (ASC-US), while multiple biopsies remained negative. She initially underwent surgery for multiple uterine leiomyomas and severe endometriosis. Ten months later, she presented with acute pelvic pain, rectal pressure, and minor vaginal bleeding. Combined hysteroscopy and laparoscopy revealed suspicious lesions, and histopathology with immunohistochemistry confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IVB SCNEC. Postoperatively, she received platinum-based chemotherapy followed by salvage immunotherapy. Despite a transient decline in tumor markers, the disease progressed rapidly, with enlargement and confluence of pelvic lesions and extensive bone metastases, ultimately resulting in death from multiorgan failure. This case highlights the diagnostic challenges, early systemic dissemination, and poor outcomes of SCNEC, underscoring the urgent need for more effective therapeutic strategies.

Keywords:  case report; diagnosis; prognostic factors; small cell neuroendocrine carcinoma; therapy; uterine cervix

DOI:  https://doi.org/10.3389/fonc.2025.1692412
Indian J Nucl Med. 2025 Sep-Oct;40(5):40(5): 301-303

Tissue and Organ-specific Tumor Heterogeneity on dual tracer PET-CT ([68Ga] Ga-PSMA-11 and [18F] FDG) and Dural-based Brain metastasis in Metastatic Prostate Cancer.

Yeshwanth Edamadaka, Rahul V Parghane, Sandip Basu.

  The present report describes a patient of metastatic castration-resistant prostate cancer (mCRPC) with dural-based brain metastasis, discordant and variable [68Ga] Ga-prostate specific membrane antigen (PSMA)-11 and [18F] fluorodeoxyglucose ([18F] FDG) uptake in metastases on dual-tracer positron emission tomography computed tomography (PET/CT), illustrating three important teaching points: (a) Dual-tracer PET/CT demonstrating discordant tumor biology pattern between soft tissue and skeletal metastatic lesions in mCRPC even within the same individual, thereby provides a more comprehensive overview of whole-body tumor status, with implications for personalized patient profiling and treatment selection (b) valuable role of [18F] FDG-PET/CT in identifying PSMA-negative lesions (neuroendocrine transformation) in mCRPC patients, including the possibility of detecting second primary cancer, (c) high metabolic tumor volume on [18F] FDG-PET/CT associated with aggressive biology and adverse prognosis.

Keywords:  [177Lu] Lu-PSMA-617; [18F] fluorodeoxyglucose - positron emission tomography computed tomography; [68Ga] Ga-PSMA-11 positron emission tomography computed tomography; de-differentiation; dual tracer positron emission tomography computed tomography; metastatic castration-resistant prostate cancer; prostate cancer

DOI:  https://doi.org/10.4103/ijnm.ijnm_44_25
Clin Nucl Med. 2025 Oct 29.

First Autopsy-confirmed Complete Remission of Metastatic Neuroendocrine Neoplasm of Tailgut Cyst After a Single Cycle of Alpha-Peptide Receptor Radionuclide Therapy With [225Ac]Ac-DOTA-LM3.

Elisabetta Perrone, Shagufta Shaheen, Pamela L Kunz, Heather C Henri, Richard P Baum.

  A 78-year-old man with neuroendocrine neoplasm (NEN) G2 originating from a presacral tailgut cyst was previously treated with surgery, lanreotide and [177Lu]Lu-DOTATATE peptide receptor radionuclide therapy (PRRT). Due to recurrence, confirmed by [68Ga]Ga-DOTA-LM3 PET/CT, which showed local, hepatic, lymph nodal, soft tissue, and cardiac disease, he received 1 cycle of PRRT with somatostatin receptor (SSTR)-antagonist DOTA-LM3 labeled with alpha-emitting Actinium-225. Due to rising levels of bilirubin 2 months after therapy, an endoscopic retrograde cholangiopancreatography diagnosed bile duct stenosis and gastric adenocarcinoma (cause of death). Autopsy findings did not reveal any residual NEN, indicating complete remission after one cycle of alpha-PRRT.

Keywords:  Actinium-225; SSTR-antagonist; neuroendocrine neoplasm; peptide receptor radionuclide therapy; tailgut cyst

DOI:  https://doi.org/10.1097/RLU.0000000000006201