bims-necame 2025-12-14 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–12–14
seventeen papers selected by
Grigor Varuzhanyan, UCLA

Actin dysregulation induces neuroendocrine plasticity and immune evasion: a vulnerability of small cell lung cancer.
ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer.
FAP-targeted Radio-ligand Therapy in Pancreatic Neuroendocrine Tumor: A Potential Alternative to PRRT.
Intra-arterial peptide receptor radionuclide therapy (IA-PRRT) in patients with SSTR-expressing neuroendocrine neoplasms: short- and long-term safety and efficacy for up to 13 years.
A public data-based molecular classification of small cell lung cancer by neuroactive signaling networks unveils distinct microenvironment landscapes and immunotherapy-related prognostic biomarkers.
Prognostic implications of [¹⁸F]FDG PET and metabolic changes in patients with advanced metastatic neuroendocrine tumors undergoing rechallenge PRRT: final results from a multicenter 10-year survival WARMTH study.
Enhancing PRRT Outcome Prediction in Neuroendocrine Tumors: Aggregated Multi-Lesion PET Radiomics Incorporating Inter-Tumor Heterogeneity.
Real-world outcomes of lower lenvatinib doses in advanced neuroendocrine tumors: a multinational retrospective study.
Neuroendocrine tumours of the urinary bladder: recent advances.
High-grade gastro-entero-pancreatic neuroendocrine neoplasms: An overlooked population in interventional clinical trials. A systematic review.
OPRK1 drives SLC9A3R1 progression to neuroendocrine prostate cancer.
Functional Evaluation of Irreversible Electroporation for a Pancreatic Nonfunctioning Neuroendocrine Tumor Using 68Ga-DOTATOC PET/CT.
Prognostic analysis and expression patterns of programmed cell death ligand 1 and BRAF V600E in esophageal neuroendocrine carcinoma.
Comprehensive fecal metagenomic and metabolomic analysis reveals the role of gut microbiota and metabolites in detecting brain metastasis of small cell lung cancer.
Survival Determinants and Treatment Outcomes of Patients with Small Cell Lung Cancer and Brain Metastases: A U.S. National Analysis.
Overall survival according to time-of-day of immunochemotherapy for extensive-stage small cell lung cancer.
Small-cell lung cancer: anatomy of an immune-cold tumor.

Nat Commun. 2025 Dec 06.

Actin dysregulation induces neuroendocrine plasticity and immune evasion: a vulnerability of small cell lung cancer.

Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park.

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit increased cellular heterogeneity and escape from immune surveillance. Conversely, pharmacological inhibition of EZH2 restores MHC-I expression, reactivates antitumor immunity, and suppresses tumor growth. These findings identify CRACD as a tumor suppressor that constrains cell plasticity and immune evasion, highlighting the CRACD-EZH2-MHC-I axis as a potential therapeutic vulnerability in SCLC.

DOI: https://doi.org/10.1038/s41467-025-67078-9
Nat Commun. 2025 Dec 09. 16(1): 10983

ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer.

Lydia Meder, Charlotte I Orschel, Cyrielle L Bouchez, Rahil Gholamipoorfard, Claudia V Orschel, David Stahl, Christoph Kreer, Mirjam Koker, Marieke Nill, Ilayda G Kocak, Ka-Won Noh, Xinlei Zhao, Leon Ullrich, Björn Häupl, Josefine Jakob, Marie-Lisa Eich, Alexandra Florin, Holger Grüll, Jürgen Wolf, Filippo Beleggia, Reinhard Büttner, Thomas Oellerich, Florian Klein, Johannes Brägelmann, H Christian Reinhardt, Nima Abedpour, Roland T Ullrich.

Small cell lung cancer (SCLC) is characterized by its highly aggressive phenotype and dismal outcome. Despite the benefit of adding immune checkpoint blockade to standard chemotherapy, tumors acquire the ability to evade immunosurveillance and develop resistance. To investigate these underlying mechanisms, we perform high-dimensional profiling of human and murine SCLC specimens. In matched primary and metastatic human samples, we observe MHC-I loss in metastases, highlighting its role in immune evasion. Correspondingly, silencing MHC-I in SCLC cells drastically reduces immune infiltration and promotes metastasis in mice. Using mass spectrometry and phospho-tyrosine kinase analyses, we identify ERBB2 signaling as a suppressor of MHC-I and driver of immune-modulatory transcripts. Mechanistically, genetic and pharmacologic blockade of ERBB2 induces MHC-I in a STING-dependent manner and prevents immune evasion in autochthonous murine SCLC. Strikingly, combining ERBB2 inhibition with anti-PD-1 elicits profound synergistic responses in preclinical models, suggesting this combination for future clinical trials in SCLC patients.

DOI: https://doi.org/10.1038/s41467-025-66800-x
Clin Nucl Med. 2025 Nov 17.

FAP-targeted Radio-ligand Therapy in Pancreatic Neuroendocrine Tumor: A Potential Alternative to PRRT.

Farid Jafari Zarrin Ghabaei, Amin Saber Tanha, Nasrin Raeisi, Kamran Aryana, Somaye Barashki.

  A 47-year-old man presented with a grade II well-differentiated metastatic neuroendocrine tumor originating from the pancreas. Initial treatment included trans-arterial embolization, long-acting octreotide, followed by chemotherapy. Despite these interventions, progressive disease was noted, prompting evaluation for peptide receptor radionuclide therapy using 68Ga-DOTATATE PET/CT; however, this imaging revealed nonavid lesions. Subsequently, a 99mTc-FAPI-46 scan was conducted, demonstrating favorable uptake in both the liver metastases and the primary tumor, leading to the administration of 177Lu-FAPI-2286 therapy. This case highlights the potential of FAPI as a novel imaging and therapeutic strategy in the management of neuroendocrine tumors.

Keywords:  DOTATATE; FAPI; neuroendocrine tumor; octreotide; somatostatin receptor; theranostics

DOI:  https://doi.org/10.1097/RLU.0000000000006204
Theranostics. 2026 ;16(4): 1658-1670

Intra-arterial peptide receptor radionuclide therapy (IA-PRRT) in patients with SSTR-expressing neuroendocrine neoplasms: short- and long-term safety and efficacy for up to 13 years.

Jingjing Zhang, Birger Mensel, Richard P Baum.

  Intravenous peptide receptor radionuclide therapy (IV-PRRT) has established its role in the treatment algorithm of somatostatin receptor (SSTR)-expressing neuroendocrine neoplasms (NENs). This study aims to evaluate the safety and efficacy of intra-arterial PRRT (IA-PRRT) in patients with SSTR-expressing NENs. Methods: The radiopharmaceutical was injected by a dedicated radionuclide infusion set via an intra-arterial catheter entering the femoral artery access site, with a microcatheter placed in the common hepatic artery or other selected artery via a standard access using the common femoral artery. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and the EORTC criteria with 68Ga-SSTR PET/CT. Kaplan-Meier survival analysis was performed to calculate median progression-free survival (PFS) and overall survival (OS). Short- and long-term toxicities were documented in accordance with the CTCAE, version 5.0. Results: 52 patients with SSTR-expressing NENs treated with intra-arterial PRRT with 177Lu- or 90Y-DOTATOC/DOTATATE from February 1999 to January 2019 were reviewed. The median follow-up time was 94.4 mo. Safety analysis demonstrated anemia (grade 1, n=4), leukocytopenia (grade 1, n=3; grade 2, n=1; grade 3, n=1), thrombocytopenia (grade 1, n=11) following IA-PRRT compared to baseline. No severe nephrotoxicity or liver dysfunction was observed after IA-PRRT. According to RECIST 1.1, the disease control rate at 3-6 mo after IA-PRRT was 89.4%, and the best objective response rate was 36.2%. For the entire cohort received IA-PRRT (n=52), the median PFS and OS were 29.9 and 68.9 months, respectively. In the subgroup of patients with neuroendocrine liver metastases receiving liver directed IA-PRRT, the median PFS and OS for patients with hepatic only tumor with or without lymph node metastases were significantly longer than those with extrahepatic-tumor (PFS, 35.9 mo vs. 21.6 mo, p=0.0128; OS, 80.1 mo vs. 50.5 mo, p=0.0470). Conclusions: Intra-arterial PRRT is well-tolerated, safe and effective in patients with SSTR-expressing neuroendocrine neoplasms. The median OS and PFS appear promising, particularly in patients with hepatic tumor burden. No additional severe hematotoxicity, nephrotoxicity or hepatotoxicity was observed after IA-PRRT and during long-term follow-up. In particular, this procedure can be considered in patients with neuroendocrine liver metastases only or liver metastases mainly. Prospective studies are warranted to verify these results.

Keywords:  177Lu; 90Y; Peptide receptor radionuclide therapy (PRRT); intra-arterial PRRT (IA-PRRT); neuroendocrine neoplasms (NENs); somatostatin receptor (SSTR)

DOI:  https://doi.org/10.7150/thno.112012
Transl Lung Cancer Res. 2025 Nov 30. 14(11): 4983-4999

A public data-based molecular classification of small cell lung cancer by neuroactive signaling networks unveils distinct microenvironment landscapes and immunotherapy-related prognostic biomarkers.

Wensheng Zhou, Yujie Tang, Jiyuan Zeng, Xiaoyi Zhang, Haotian Meng, Wenhui Guan, Yue Zhu, Huixin Jiang, Yansheng Wang, Xiaohong Xie, Chengzhi Zhou, Ming Liu.

   Background: Small cell lung cancer (SCLC) represents an aggressive malignancy characterized by marked heterogeneity and neuroendocrine differentiation. Despite its clinical significance, the functional landscape of neuroendocrine function, while neuroactive-signaling-related genes (NRGs) in SCLC pathogenesis remains poorly characterized. Therefore, the aim of this study is to classify SCLC based on neuroactive signaling networks and to analyze the characteristics of these classifications in relation to the immune microenvironment.
Methods: Through integrated analysis of bulk transcriptomic profiling from 79 primary SCLC tumors and single-cell transcriptomic profiling from 11 SCLC tumors, we employed a consensus clustering algorithm to deconvolute transcriptional programs underlying neuroactive signaling networks. Molecular functions and tumor-infiltrated immune cells were estimated from bulk transcriptomes using bioinformatics methods. Single-cell transcriptomic analysis was implemented for cross-validation and cellular characterization.
Results: Bulk-seq analyses reported that the transcriptional variability of three major clusters of tumors were associated with different clinical outcomes and biological pathways. Clinical, genomic, and immunological characteristics were observed among three clusters. Furthermore, the key genes module of cluster with the worst survival were identified as neuroactive-signaling-related signature (NRS) and used to classify tumor samples into two distinct intra-tumoral subtypes (H-NRS and L-NRS) with single-cell transcriptomic data. At single-cell level, malignant cells in H-NRS tumor were in later cell state and had more frequent cellular communication. And NRS subsequently was identified as a biomarker correlated with better prognosis for patients receiving chemoimmunotherapy. It was found that Natriuretic Peptide C (NPPC), as one of the key genes in NRS, was overexpressed in SCLC tumor cells and correlated with poor prognosis. Treatment with C-type natriuretic peptide (CNP) facilitates cellular migration and metastatic potential.
Conclusions: This study proposes a novel molecular taxonomy for SCLC grounded in neuroactive signaling networks, suggests a potential prognostic biomarker to aid in therapeutic stratification, and identifies NPPC as a candidate therapeutic target worthy of further investigation in metastatic SCLC. Our findings may help bridge gaps in understanding between neuroendocrine biology and tumor microenvironment (TME) dynamics during SCLC evolution.

Keywords:  Neuroactive signaling; immunotherapy; tumor microenvironment (TME)

DOI:  https://doi.org/10.21037/tlcr-2025-620
Theranostics. 2026 ;16(3): 1227-1237

Prognostic implications of [¹⁸F]FDG PET and metabolic changes in patients with advanced metastatic neuroendocrine tumors undergoing rechallenge PRRT: final results from a multicenter 10-year survival WARMTH study.

Giulia Santo, Margarida Rodrigues, Diana Paez, Olga Morozova, Levent Kabasakal, Kalevi Kairemo, Chiara Maria Grana, Richard P Baum, Gianpaolo di Santo, Irene J Virgolini.

  Rationale: Rechallenge peptide receptor radionuclide therapy (PRRT) is a valid therapeutic option for patients with advanced/metastatic neuroendocrine tumors (NETs) who previously benefited from initial PRRT. In this context, [18F]FDG PET may serve as a prognostic marker. This multicenter 10-year survival study aims to evaluate the prognostic implications of [18F]FDG PET and PRRT-induced changes in NET patients undergoing rechallenge PRRT. Methods: This retrospective multicenter study included 100 patients (median age: 54 years, range: 29-83) treated with rechallenge PRRT. All patients underwent [68Ga]Ga-DOTA-TOC/TATE/NOC and [18F]FDG PET/CT prior to the first PRRT period, 3-4 months after PRRT, and every 6-9 months thereafter. Metabolic status and its changes (no change vs. FDG+/FDG- vs. FDG-/FDG+) before the first PRRT period and at each restaging were recorded and correlated to baseline characteristics, time to progression (TTP), and overall survival (OS). Results: In 43 out of 100 patients, the primary tumor site was the pancreas; the liver was involved in more than 90% of patients. Biopsies revealed G1 NET in 16%, G2 NET in 66%, and G3 NET in 18% of cases. Before the first PRRT period, 50% of patients were FDG-positive. Following the first PRRT period, 27 patients exhibited a change in metabolic status: 20 converted to FDG-negative, whereas 7 became FDG-positive. After the second PRRT period, metabolic status changed in 41 patients, with 25 converting to FDG-negative and 16 to FDG-positive. Metabolic status after the first period was significantly correlated with NET grade (p = 0.009). The correlation persisted also after rechallenge (p < 0.001), suggesting that FDG positivity increased progressively in G3 NET patients (p = 0.020). The presence of bone metastases statistically correlated with FDG positivity before (p < 0.001) and after (p = 0.001) the first PRRT period. Multivariate Cox regression analysis revealed NET G3 and FDG status after the first PRRT course as independent factors for shorter TTP. After a median follow-up time of 117.6 months (range: 38.4-180 months), 37 patients had died. Multivariate Cox regression analysis revealed FDG positivity after the first (p < 0.001) and second (p < 0.001) periods of PRRT as independent predictors of poor OS. Conclusions: Assessing [18F]FDG status before PRRT and during follow-up after treatment enables prediction of TTP and OS, even in patients considered for rechallenge PRRT. Standardizing the use of dual-tracer imaging in patients receiving PRRT seems a valuable approach to improve clinical decision-making in NET patients.

Keywords:  [18F]FDG PET; neuroendocrine tumors; peptide receptor radionuclide therapy; prognosis; rechallenge

DOI:  https://doi.org/10.7150/thno.123273
Cancers (Basel). 2025 Dec 04. pii: 3887. [Epub ahead of print]17(23):

Enhancing PRRT Outcome Prediction in Neuroendocrine Tumors: Aggregated Multi-Lesion PET Radiomics Incorporating Inter-Tumor Heterogeneity.

Maziar Sabouri, Ghasem Hajianfar, Omid Gharibi, Alireza Rafiei Sardouei, Yusuf Menda, Ayca Dundar, Camila Gadens Zamboni, Sanchay Jain, Marc Kruzer, Habib Zaidi, Fereshteh Yousefirizi, Arman Rahmim, Ahmad Shariftabrizi.

   INTRODUCTION: Peptide Receptor Radionuclide Therapy (PRRT) with [177Lu]Lu-DOTA-TATE is effective in treating advanced Neuroendocrine Tumors (NETs), yet predicting individual response in this treatment remains a challenge due to inter-lesion heterogeneity. There is a lack of standardized, effective methods for using multi-lesion radiomics to predict progression and Time to Progression (TTP) in PRRT-treated patients. This study evaluated how aggregating radiomic features from multiple PET-identified lesions can be used to predict disease progression (event [progression and death] vs. event-free) and TTP.
METHODS: Eighty-one NETs patients with multiple lesions underwent pre-treatment PET/CT imaging. Lesions were segmented and ranked by minimum Standard Uptake Value (SUVmin) (both descending and ascending), SUVmean, SUVmax, and volume (descending). From each sorting, the top one, three, and five lesions were selected. For the selected lesions, radiomic features were extracted (using the Pyradiomics library) and lesion aggregation was performed using stacked vs. statistical methods. Eight classification models along with three feature selection methods were used to predict progression, and five survival models and three feature selection methods were used to predict TTP under a nested cross-validation framework.
RESULTS: The overall appraisal showed that sorting lesions based on SUVmin (descending) yields better classification performance in progression prediction. This is in addition to the fact that aggregating features extracted from all the lesions, as well as the top five lesions sorted by SUVmean, lead to the highest overall performance in TTP prediction. The individual appraisal in progression prediction models trained on the single top lesion sorted by SUVmin (descending) showed the highest recall and specificity despite data imbalance. The best-performing model was the Logistic Regression (LR) classifier with Recursive Feature Elimination (RFE) (recall: 0.75, specificity: 0.77). In TTP prediction, the highest concordance index was obtained using a Random Survival Forest (RSF) trained on statistically aggregated features from the top five lesions ranked by SUVmean, selected via Univariate C-Index (UCI) (C-index = 0.68). Across both tasks, features from the Gray Level Size Zone Matrix (GLSZM) family were consistently among the most predictive, highlighting the importance of spatial heterogeneity in treatment response.
CONCLUSIONS: This study demonstrates that informed lesion selection and tailored aggregation strategies significantly impact the predictive performance of radiomics-based models for progression and TTP prediction in PRRT-treated NET patients. These approaches can potentially enhance model accuracy and better capture tumor heterogeneity, supporting more personalized and practical PRRT implementation.

Keywords:  Neuroendocrine Tumors; PET; PRRT; feature aggregation; radiomics

DOI:  https://doi.org/10.3390/cancers17233887
Endocr Oncol. 2025 Jan;5(1): e250076

Real-world outcomes of lower lenvatinib doses in advanced neuroendocrine tumors: a multinational retrospective study.

G R Almeida, G K Zanetta, J M O'Connor, M J Barros, T C Felismino, R F Weschenfelder, A Bel-Ange, S Grozinsky-Glasberg, P R Riechelmann.

   Objective: Neuroendocrine tumors (NET) are heterogeneous neoplasms with increasing incidence and limited treatment options for advanced, progressive disease. Lenvatinib, a multitargeted TKI, demonstrated high efficacy but substantial toxicity at the standard 24 mg/day in the phase II TALENT trial. This study evaluates real-world efficacy and safety of lower-dose lenvatinib in patients with grade 1-3 GEP or thoracic NET.
Design: Retrospective multinational cohort study.
Methods: Twenty-two patients from Brazil, Argentina, and Israel with grade 1-3 NET and radiologic progression received lenvatinib (starting doses per physician discretion) between March 2021 and September 2024. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS) and grade ≥3 adverse events (AEs). Exploratory endpoints included objective response rate (ORR) and disease control rate (DCR). Kaplan-Meier methods estimated time-to-event outcomes; AEs were graded per CTCAE v5.0.
Results: Median age was 60 years (range: 36-81); primary sites were pancreatic (27%), gastrointestinal (54.5%), and thoracic (18.2%). Grades: G1 (23%), G2 (45%), G3 (31.8%). Starting doses ranged 8-24 mg/day, most often 10 mg (32%) or 8 mg (27%); 45% required reductions. Mean daily dose was 11.8 mg (±4.7). After 16.8 months median follow-up, mPFS was 13 months (IQR: 8.8-17.9) and mOS 16 months (IQR: 12.6-18.5). Among 22 evaluable patients, ORR was 31.8% and DCR 90.9%. Grade 3-4 AEs occurred in 22%; most were grade 1-2 (fatigue 31.8%, hypertension 22.7%).
Conclusions: Lenvatinib (average of 10-12 mg/day) showed meaningful antitumor activity and improved tolerability in advanced GEP and thoracic NET, supporting individualized dosing to enhance safety without compromising efficacy.

Keywords:  carcinoids; metastasis; neuroendocrine tumors

DOI:  https://doi.org/10.1530/EO-25-0076
Histopathology. 2026 Jan;88(1): 108-121

Neuroendocrine tumours of the urinary bladder: recent advances.

Dilara Akbulut, Hikmat Al-Ahmadie.

  Small cell carcinoma is the most frequently encountered neuroendocrine tumour (NET) of the urinary bladder, and it may present as either pure or in combination with urothelial carcinoma or other histological subtypes. Large cell neuroendocrine carcinoma is increasingly recognized in this location, but it is not yet fully characterized. Well-differentiated NET and paraganglioma of the bladder are rare neuroendocrine neoplasms. Advances in the molecular characterization of these tumours have enhanced our understanding of their biology and can provide better classification and more accurate risk stratification for clinical decision-making.

Keywords:  ASCL‐1; NEUROD1; POU2F3; large cell neuroendocrine carcinoma; paraganglioma; small cell carcinoma; well‐differentiated neuroendocrine tumour

DOI:  https://doi.org/10.1111/his.70044
Crit Rev Oncol Hematol. 2025 Dec 08. pii: S1040-8428(25)00462-7. [Epub ahead of print]218 105074

High-grade gastro-entero-pancreatic neuroendocrine neoplasms: An overlooked population in interventional clinical trials. A systematic review.

Elettra Merola, Maria Pina Dore, Giovanni Mario Pes, Giuseppe Fanciulli.

   BACKGROUND: High-grade gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of tumors with poor prognosis, including grade 3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), which represent distinct entities with different clinical outcomes. Our aim was to systematically review the available clinical evidence on therapeutic strategies for sporadic, highly proliferative GEP-NENs.
METHODS: A systematic literature search was conducted using PubMed, Scopus, and Web of Science (last update: August 9, 2025). Endpoints included the evaluation of clinical outcomes from interventional trials and subgroup analysis comparing NET G3 with NEC.
RESULTS: A total of 2135 records were retrieved, with a final inclusion of 28 prospective trials (six randomized trials). Twelve trials exclusively enrolled NECs, one trial focused on NET G3, five provided NET G3/NEC subanalyses, ten included mixed populations without morphological stratification. Owing to the high risk of bias, a meta-analysis was not feasible. In NECs, the highest disease control was achieved with the CAPOXIRI-Bevacizumab regimen (disease control rate, DCR 78.9 %; median progression-free survival, PFS 18 months; overall survival, OS 30.5 months), but the cohort was small (n = 19) and toxicity substantial. Immunotherapy yielded disappointing results, either as monotherapy or in combination with a dual checkpoint blockade (median PFS: ∼2 months). Platinum-based chemotherapy proved poor for NET G3, whereas temozolomide/everolimus and peptide receptor radionuclide therapy offered clear benefits (DCR: 96.1 % and 70 %, respectively).
CONCLUSIONS: High-grade GEP-NENs (particularly NET G3) remain an overlooked population in interventional studies. Progress in precision medicine requires the identification of molecular biomarkers to guide individualized therapy.

Keywords:  Clinical outcome; Gastro-entero-pancreatic neuroendocrine neoplasms; High-grade; Interventional trials; Medical therapy; Systematic review

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105074
Cell Death Dis. 2025 Dec 07.

OPRK1 drives SLC9A3R1 progression to neuroendocrine prostate cancer.

Linghui Liang, Zhiyi Shen, Yuwei Zhang, Yifei Cheng, Bing Yao, Ninghan Feng, Ruizhe Zhao.

Neuroendocrine differentiation (NED) plays a critical role in endocrine therapy resistance and dismal outcomes among prostate cancer (PCa) patients. The emergence of treatment-induced neuroendocrine prostate cancers (t-NEPCs) with the utilization of second-generation androgen receptor (AR) pathway inhibitors (ARPIs) poses a significant challenge, as the molecular underpinnings remain elusive. Here, our investigation unveils a close correlation between heightened levels of opioid receptor membrane protein OPRK1 and treatment-induced NED (t-NED), alongside an adverse prognosis in PCa cohorts. Our findings illuminate that AR represses OPRK1 transcription by binding to its promoter, a regulation amenable to reversal via ARPI administration. Further exploration reveals that OPRK1 stimulation triggers autophagic degradation of REST upon up-regulation and interaction with SLC9A3R1, thereby instigating NED. In essence, OPRK1 experiences negative control by AR and emerges as a pivotal instigator of t-NED. Combining JTC-801 with CQ successfully impedes NEPC progression by impacting the OPRK1/SLC9A3R1/autophagy/REST axis. Our study accentuates OPRK1 as a novel therapeutic target for PCa management and furnishes profound insights into the pathogenesis of t-NEPC.

DOI: https://doi.org/10.1038/s41419-025-08279-4
Clin Nucl Med. 2025 Nov 19.

Functional Evaluation of Irreversible Electroporation for a Pancreatic Nonfunctioning Neuroendocrine Tumor Using 68Ga-DOTATOC PET/CT.

Hind Ait Talhiq, Philippe Baltzinger, Michaela Achille, Pietro Addeo, Julien Garnon, Alessio Imperiale.

  Percutaneous irreversible electroporation (IRE) is a nonthermal ablation technique increasingly used for pancreatic malignancies, though rarely reported in pancreatic neuroendocrine tumors (pNETs). We present the case of a 75-year-old man with a well-differentiated grade-1 nonfunctioning pNET treated by percutaneous IRE after refusing surgery. Posttreatment somatostatin receptors PET/CT showed a marked reduction in 68Ga-DOTATOC uptake at 1 month, followed by stable residual activity at 1 year, despite complete devascularization on contrast-enhanced CT. This case illustrates the potential of IRE to achieve durable tumor control and highlights the added value of PET/CT in assessing functional response beyond morphology.

Keywords:  DOTATOC; PET; irreversible electroporation; neuroendocrine tumor; pancreas

DOI:  https://doi.org/10.1097/RLU.0000000000006223
Oncol Lett. 2026 Feb;31(2): 49

Prognostic analysis and expression patterns of programmed cell death ligand 1 and BRAF V600E in esophageal neuroendocrine carcinoma.

Chengcheng Zhang, Li Zheng, Binwen Xu, Guidong Shi, Maoyong Fu.

  Esophageal neuroendocrine carcinoma (ENEC) is a rare and highly aggressive malignancy. The present study investigated the expression of BRAF V600E and programmed death ligand 1 (PD-L1) and analyzed prognostic factors affecting patient outcomes. A total of 56 patients diagnosed with ENEC at the Affiliated Hospital of North Sichuan Medical College between January 2019, and September 2024 were retrospectively analyzed. Among them, 39 patients received surgery and were tested for BRAF V600E and PD-L1 expression using immunohistochemistry. Survival outcomes were estimated using the Kaplan-Meier method, and prognostic factors were assessed using Cox regression models. BRAF V600E mutations were identified in 12.8% (5/39) of cases, and PD-L1 expression was positive in 15.4% (6/39). In the mixed neuroendocrine carcinoma and squamous cell carcinoma (MiNEC-SCC), the positivity rates for both BRAF V600E and PD-L1 were 33.3% (3/9). Across the entire cohort, the 1-year overall survival (OS) and progression-free survival (PFS) rates were 79.7 and 43.1%, respectively, while the 3-year OS and PFS rates were 49.5 and 25.1%, respectively. Clinical lymph node stage and surgery were notably associated with both OS and PFS. Patients with tumor thickness >1 cm and length >3 cm had markedly worse PFS. Multivariate analysis identified surgery as an independent predictor of improved PFS (P=0.015). Among patients who underwent surgery, postoperative adjuvant therapy was independently associated with improved PFS (P=0.026). In conclusion, BRAF V600E and PD-L1 were more frequently expressed in the MiNEC-SCC compared with small cell neuroendocrine carcinoma. Surgery and postoperative adjuvant therapy were notably associated with improved PFS.

Keywords:  BRAF V600E mutation; esophageal neuroendocrine carcinoma; esophageal small cell neuroendocrine carcinoma; prognostic analysis; programmed cell death ligand 1

DOI:  https://doi.org/10.3892/ol.2025.15402
Front Microbiol. 2025 ;16 1673983

Comprehensive fecal metagenomic and metabolomic analysis reveals the role of gut microbiota and metabolites in detecting brain metastasis of small cell lung cancer.

Xu Han, Qiang-Guo Sun, Dan Zang, Jun Chen.

   Background: Brain metastasis (BM) is a common and highly lethal complication in patients with small cell lung cancer (SCLC). People have paid great attention to exploring the relationship between gut microbiota and the occurrence and development of cancer. This study investigated the relationship between brain metastasis, gut microbiota, and their metabolites in SCLC, providing new insights for the prevention and diagnosis of brain metastasis in SCLC.
Methods: Baseline fecal samples were collected from 45 participants, including 15 patients with BM and 30 patients with no distant metastasis who were newly diagnosed with SCLC. The gut microbiota and metabolite levels were analyzed using metagenomics and untargeted metabolomics, and machine learning models were utilized to identify differences and potential biomarkers.
Results: Gut microbiota composition varied significantly between the two groups. Genus such as Alistipes and Streptococcus were more abundant in the brain metastasis group, while Bacteroides and Prevotella predominated in patients without distant spread. Metabolomic profiling identified several metabolites inversely associated with brain metastasis, including leukotriene F4, benzoic acid, velnacrine, piperidine, and an unidentified compound labeled C20916. KEGG pathway analysis linked multiple key physiological processes, such as aminobenzoate degradation, carbapenem biosynthesis, toluene degradation, dioxin degradation, and benzoate degradation, underscoring the complex role of gut microbial metabolites in cancer progression. Furthermore, machine learning models identified key biomarkers, including the genus Marvinbryantia and the metabolites benzoic acid, which showed strong discriminatory ability for brain metastasis. After robust validation, the model demonstrated good performance with excellent discriminative power (AUC = 0.80).
Conclusion: Compared to patients without distant metastasis, SCLC patients with BM exhibit distinctive gut microbial and metabolite profiles. These findings suggest that specific gut microbes and their metabolic products may serve as valuable biomarkers for diagnosing and stratifying treatment in brain metastatic SCLC.

Keywords:  brain metastasis; gut microbiota; metabolomics; metagenomics; small cell lung cancer

DOI:  https://doi.org/10.3389/fmicb.2025.1673983
Cancers (Basel). 2025 Nov 29. pii: 3833. [Epub ahead of print]17(23):

Survival Determinants and Treatment Outcomes of Patients with Small Cell Lung Cancer and Brain Metastases: A U.S. National Analysis.

Khalid Ahmad Qidwai, Zouina Sarfraz, Khalis Mustafayev, Lydia C Hodgson, Arun Maharaj, Triparna Sen, Tulika Ranjan, Manmeet S Ahluwalia.

  Background/Objectives: Brain metastases (BM) are common in small cell lung cancer (SCLC) and portend poor outcomes. Contemporary determinants of survival in the modern treatment era remain incompletely defined. We evaluated factors associated with overall survival (OS) among patients with SCLC and BM using a recent, nationally representative dataset. Methods: We identified adults diagnosed with SCLC and brain metastases between 2018 and 2020 in the National Cancer Database (NCDB). Demographic, clinical, treatment, and survival data were extracted for analysis. Unadjusted OS was estimated using Kaplan-Meier methods. Multivariable Cox proportional hazards models identified factors associated with mortality, with proportional hazards (PH) assessed using scaled Schoenfeld residuals. Complementary Accelerated Failure Time (AFT) modeling was performed to confirm robustness. Results: Of 62,671 SCLC cases, 11,074 (17.7%) had BM, including 32.6% with brain-only disease. Median overall survival (mOS) was 6.6 months (95% CI, 6.47-6.87); patients with brain-only disease had an mOS of 8.8 months (8.38-9.26), compared with 5.95 months (5.75-6.18) for those with concurrent extracranial metastases. In multivariable analysis, age ≥ 65 years (HR 1.13, p < 0.001) was associated with higher mortality, whereas female sex (HR 0.87, p < 0.001), Black (HR 0.88, p = 0.001), Asian (HR 0.80, p = 0.022), and Hispanic (HR 0.87, p = 0.008) patients had lower hazards. Worse outcomes were associated with public or no insurance, lower income, non-academic facilities, and extracranial metastases; educational attainment was not significant. Proportional hazards assumptions were largely met with minor deviations, and AFT modeling confirmed consistent results. Treatment modality remained independently associated with survival in both models. Conclusions: In this contemporary national cohort, survival among patients with SCLC and brain metastases was influenced by multiple clinical, sociodemographic, and treatment factors, including age, sex, insurance status, facility type, and extent of metastatic disease. Treatment modality remained an independent predictor of survival. These results provide updated real-world benchmarks and highlight the need for prospective studies to define optimal management strategies in this high-risk population.

Keywords:  National Cancer Database; brain metastases; overall survival; small cell lung cancer; stereotactic radiosurgery; systemic therapy; treatment patterns

DOI:  https://doi.org/10.3390/cancers17233833
Cancer. 2025 Dec 15. 131(24): e70126

Overall survival according to time-of-day of immunochemotherapy for extensive-stage small cell lung cancer.

Zhe Huang, Zhaohui Ruan, Shidong Xu, Nachuan Zou, Li Deng, Huan Yan, Jiacheng Dai, Jun Deng, Xue Chen, Jing Wang, Hua Xiang, Liang Zeng, Gang Yin, Yongchang Zhang.

   BACKGROUND: Emerging evidence suggests that circadian timing influences the efficacy of immune checkpoint inhibitors (ICI), with morning infusions associated with improved therapeutic outcomes across various malignancies. However, the impact of ICI infusion timing on extensive-stage small cell lung cancer (ES-SCLC), a disease with poor prognosis and limited therapeutic advancements, remains unexplored.
METHOD: This retrospective study (LungTime-R02) analyzed 397 patients with ES-SCLC who received first-line anti-PD-L1 (atezolizumab or durvalumab) plus chemotherapy at our center between May 2019 and October 2023. The time of day of administration (ToDA) was calculated as the median infusion time for each patient's first four ICI treatment cycles. To assess its prognostic relevance, hazard ratios (HRs) of earlier progression or death were estimated across multiple ToDA thresholds (11:00-16:30). Propensity score matching (1:2) was applied to balance baseline characteristics.
RESULT: Of the 397 patients, the optimal ToDA cutoff for maximizing progression-free survival (PFS) benefit was identified as 15:00, with the lowest HR for PFS observed at this threshold. Patients who received immunochemotherapy before 15:00 exhibited significantly longer PFS and overall survival compared to those treated later, with results consistent across pooled and propensity score matching cohorts. Multivariable analysis confirmed early ToDA as an independent prognostic factor for both PFS (adjusted HR, 0.483; 95% CI, 0.357-0.654) and overall survival (adjusted HR, 0.373; 95% CI, 0.265-0.526).
CONCLUSION: This study provides real-world evidence supporting the survival benefit of earlier immunochemotherapy administration in patients with ES-SCLC. These findings add to the growing body of knowledge on the clinical relevance of circadian timing in cancer treatment.
CLINICAL TRIAL REGISTRATION: Not applicable.

Keywords:  anti‐PD‐L1; chronotherapy; extensive‐stage small cell lung cancer; immune checkpoint inhibitors; immunochemotherapy; time‐of‐day infusion

DOI:  https://doi.org/10.1002/cncr.70126
Trends Cancer. 2025 Dec 08. pii: S2405-8033(25)00285-7. [Epub ahead of print]

Small-cell lung cancer: anatomy of an immune-cold tumor.

David Millrine, Kathryn L Simpson, Fiona Blackhall, Caroline Dive.

  Small-cell lung cancer (SCLC) is an aggressive neuroendocrine (NE) tumor and a leading cause of cancer-related morbidity. The introduction of immune checkpoint inhibitors (ICIs) transformed the treatment of many other cancers but has so far failed to benefit all but a minority of SCLC patients who gain a modest increase in overall survival. Although SCLC is often considered to be 'immune-cold', there is no consensus mechanistic view on why most patients fail to respond to ICI therapy. We address this important question by reviewing recent genomic profiling studies that reveal a complex immune landscape. Each molecular subtype is associated with a unique pattern of immune infiltration and a program of cellular plasticity that involves loss of NE traits. This immunobiology presents a rapidly evolving case study in mechanisms of ICI response and resistance. We discuss recent developments, present new hypotheses, and explore future directions for the field.

Keywords:  SCLC; cancer inflammation; immunotherapy

DOI:  https://doi.org/10.1016/j.trecan.2025.11.011