bims-necame 2026-02-01 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–02–01
sixteen papers selected by
Grigor Varuzhanyan, UCLA

ISL1: A Novel Neuroendocrine Subtype in Small Cell Lung Cancer Predicts Durable Response to Lurbinectedin.
OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.
Case Report: Analysis of colposcopic image features in a case of early-stage small cell neuroendocrine carcinoma of the cervix.
Clonal selection of pre-existing neuroendocrine component in prostate cancer during androgen receptor signaling inhibitor therapy: A case report.
Characterization of POU2F3-expressing large cell neuroendocrine carcinoma of the lung: A comprehensive analysis of morphology, immunohistochemistry, and genomic alterations.
Paving the Way for CCK2R-Targeted Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-MGS5 in Patients with Small Cell Lung Cancer.
Targeted precision Strike in Extensive-Stage small cell lung Cancer: Current advances and future Perspectives for Antibody-Drug conjugates.
Targeting GNG4 inhibits tumor progression and restores enzalutamide sensitivity in prostate cancer by suppressing autophagy.
Novel ImmunoPET Probes [64Cu]Cu-NOTA-GGB02-F9 for Small-Cell Lung Cancer Derived from a SEZ6-Targeting Antibody.
A multicenter phase II randomized controlled trial comparing 177Lu-Dotatate/capecitabine combination treatment with 177Lu-Dotatate monotherapy in patients with neuroendocrine tumors.
Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC.
Thymic Neuroendocrine Tumors: Evolving Insights and Innovative Approaches.
Rectal neuroendocrine tumors: Update.
Atezolizumab plus platinum-based chemotherapy and etoposide as first-line treatment for metastatic small cell lung cancer: a retrospective multicenter observational study.
Early emergence of neuroendocrine prostate cancer during triplet therapy for high-volume metastatic castration-sensitive prostate cancer.
Vitamin D Deficiency and Replacement Challenges in Type 1 Gastric Neuroendocrine Tumors: A Comparative Study.

Mol Cancer Ther. 2026 Jan 26.

ISL1: A Novel Neuroendocrine Subtype in Small Cell Lung Cancer Predicts Durable Response to Lurbinectedin.

Misty D Shields, Katherine G Minton, Hilal Ozakinci, Tianhao Zhou, Olivia C Terry, Paresh Kumar, Reem Akel, Luc Girard, John D Minna, Theresa A Boyle, John M Koomen, Michael Shafique.

Small cell lung cancer (SCLC) is a recalcitrant thoracic malignancy known for acquired chemoresistance, early metastatic spread, and poor overall survival. Lurbinectedin, a DNA minor groove alkylating agent, provides durable efficacy in a minority. Predictive biomarkers for lurbinectedin are needed. Patients with relapsed SCLC who received lurbinectedin (n=16) were classified by cycles received, including eight durable responders defined as ≥8 cycles (average, 14.75 cycles; median PFS, 9.8 months). Pretreatment specimens were analyzed by immunohistochemistry (IHC) for SLFN11 and tandem mass tag (TMT)-labeled expression proteomics. Top candidates were confirmed by IHC and functionally validated in SCLC cell lines. SLFN11 failed to predict lurbinectedin response (P = 0.40). Proteomics highlighted a primitive neuroendocrine pathway (ISL1, SOX5, SIX1, SIX4). ISL1 expression significantly correlated with lurbinectedin response (r = 0.65, P = 0.0351). IHC confirmed lurbinectedin reduced ISL1 post-treatment. Lurbinectedin preferentially induced DNA damage in ISL1 "high" SCLC (P <0.0001) without causing neuroendocrine subtype switching. RNA sequencing showed downregulation of ISL1, RBMS3, ASCL1, SOX5, SIX1, and upregulation of ATF3. ISL1 "high" SCLC demonstrated cellular dependency on ISL1; ISL1 knockdown reduced lurbinectedin sensitivity. L-MYC positively regulated ISL1, while ISL1 positively regulated ASCL1 and SOX5. This is the first comprehensive investigation of predictive biomarkers for lurbinectedin. Proteomics identified ISL1 as defining a novel SCLC subtype with enhanced lurbinectedin sensitivity. ISL1 serves as both a predictive biomarker and functional dependency, as evidenced by essentiality for cell survival and loss following treatment. Prospective studies using ISL1 as a predictive biomarker for lurbinectedin are planned.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0663
Mol Cancer Res. 2026 Jan 27.

OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.

Matthew J Bernard, Andrea Gallardo, Angel Ruiz, Johnny A Diaz, Nicholas M Nunley, Rachel N Dove, Shile Zhang, Ernie Lee, Kylie Y Heering, Grigor Varuzhanyan, Sachi Bopardikar, Takao Hashimoto, Raag Agrawal, Chad M Smith, Blake R Wilde, Nedas Matulionis, Helen M Richards, Sandy Che-Eun S Lee, Marina N Sharifi, Joshua M Lang, Shuang G Zhao, Owen N Witte, Michael C Haffner, David B Shackelford, Paul C Boutros, Heather R Christofk, Andrew S Goldstein.

As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL reduces nucleotide synthesis, induces accumulation of the DNA damage response marker ƔH2AX, and alters Androgen Receptor inhibition-induced plasticity. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer, and that knockdown of OGDHL impairs growth of cell line models of neuroendocrine prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer. Implications: OGDHL emerged as an unexpected metabolic dependency associated with lineage plasticity and neuroendocrine differentiation, implicating poorly studied metabolic enzymes as potential targets for treatment-resistant prostate cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0913
Front Oncol. 2025 ;16 1653318

Case Report: Analysis of colposcopic image features in a case of early-stage small cell neuroendocrine carcinoma of the cervix.

Leilei Yuan, Kejie Liu.

  This study analyzes the colposcopy findings of an early-stage cervical small cell neuroendocrine carcinoma with ectopic kidney in a patient treated at Fuyang Peoples Hospital in October 2023. The colposcopic findings primarily included a well-defined, dense, thickened cervix with atypical and fragile blood vessels, along with irregular stromal infiltration. Pathological examination confirmed cervical small cell neuroendocrine carcinoma. The patient underwent a transabdominal radical hysterectomy with bilateral salpingectomy, pelvic lymph node dissection, and bilateral ovarian repositioning on October 5, 2023. No adjuvant therapy was administered postoperatively, and follow-up over 15 months showed no evidence of disease recurrence or metastasis. The study highlights the critical role of colposcopy in early detection of cervical small cell neuroendocrine carcinoma and its significant impact on improving patient outcomes.

Keywords:  cervical cancer; cervical small cell neuroendocrine carcinoma; colposcopy images; early-stage; renal ectopia

DOI:  https://doi.org/10.3389/fonc.2025.1653318
Urol Case Rep. 2026 Mar;65 103347

Clonal selection of pre-existing neuroendocrine component in prostate cancer during androgen receptor signaling inhibitor therapy: A case report.

Haruka Kubota, Toshiki Kijima, Hadzki Matsuda, Toshitaka Uematsu, Kohei Takei, Masahiro Yashi, Kazuyuki Ishida, Takao Kamai.

  Neuroendocrine prostate cancer (NEPC) is often considered treatment-induced. We report a case with pre-existing neuroendocrine differentiation that became evident during androgen receptor signaling inhibitor (ARSI) therapy. A 79-year-old man with metastatic prostate cancer received degarelix plus apalutamide. Prostate-specific antigen (PSA) decreased to <0.01 ng/mL. Subsequently, lung and liver metastases developed while PSA remained low, with neuron-specific enolase rising to 584 ng/mL. Liver biopsy revealed PSA-negative, neuroendocrine marker-positive carcinoma. Re-evaluation of initial biopsy demonstrated positivity for both PSA and neuroendocrine markers, indicating pre-existing neuroendocrine differentiation.

Keywords:  Androgen receptor signaling inhibitor; Clonal selection; Neuroendocrine prostate cancer; PSA-imaging discordance

DOI:  https://doi.org/10.1016/j.eucr.2026.103347
Cancer Treat Res Commun. 2026 Jan 22. pii: S2468-2942(26)00022-5. [Epub ahead of print]46 101113

Characterization of POU2F3-expressing large cell neuroendocrine carcinoma of the lung: A comprehensive analysis of morphology, immunohistochemistry, and genomic alterations.

Ryota Matsuoka, Kei Asayama, Tomoki Nakagawa, Yoshihiko Murata, Ayako Suzuki, Yutaka Suzuki, Naohiro Kobayashi, Yukio Sato, Nobuyuki Hizawa, Hiroyoshi Tsubochi, Shunsuke Endo, Koichi Hagiwara, Toshiro Niki, Noriyoshi Fukushima, Kentaro Inamura, Daisuke Matsubara.

  Large cell neuroendocrine carcinoma (LCNEC) is a neuroendocrine carcinoma (NEC) of the lung that is characterized by its heterogeneous morphology, diverse immunophenotypes, and complex genomic profiles. Among LCNECs, a subset expressing the transcription factor POU2F3 (LCNEC-P) has been suggested to share similarities with small cell lung carcinoma (SCLC)-P, a subtype of SCLC defined by POU2F3 expression. However, the specific characteristics of LCNEC-P have not been fully elucidated. Therefore, the aim of the present study is to clarify the clinicopathological, immunohistochemical, and genetic characteristics of LCNEC-P. Fifty-six LCNEC cases were analyzed, including 12 LCNEC-P and 44 LCNEC-non-P cases. Morphologically, LCNEC-P exhibited significantly lower cytomorphology scores, indicating a resemblance to SCLC. Immunohistochemically, LCNEC-P showed the lower expression of neuroendocrine markers (SYP, CHGA, and INSM1), but the higher expression of C-MYC than LCNEC-non-P. A strong mutually exclusive expression pattern was observed between POU2F3 and ASCL1/NEUROD1. Whole-genome sequencing of 20 cases revealed that LCNEC-P harbored RB1 mutations in 100 % of cases, which was significantly higher than in LCNEC-non-P (40 %). FGFR1 amplification was observed in 60 % of LCNEC-P cases, representing a higher prevalence than previously reported for LCNEC. In addition, LCNEC-P showed a distinct copy number alteration profile, including frequent 20q13 amplification, compared with LCNEC-non-P. These results demonstrate that LCNEC-P represents a distinct subgroup of LCNEC that is characterized by a specific morphological, immunohistochemical, and genetic profile, closely resembling SCLC-P. This study provides insights into the biology of LCNEC-P and supports its classification as a unique entity within LCNEC.

Keywords:  Large cell neuroendocrine carcinoma; Neuroendocrine carcinoma; POU2F3; Small cell carcinoma

DOI:  https://doi.org/10.1016/j.ctarc.2026.101113
Pharmaceutics. 2026 Jan 22. pii: 138. [Epub ahead of print]18(1):

Paving the Way for CCK2R-Targeted Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-MGS5 in Patients with Small Cell Lung Cancer.

Taraneh Sadat Zavvar, Giulia Santo, Leonhard Gruber, Ariane Kronthaler, Judith Hagenbuchner, Ira Skvortsova, Inken Piro, Katja Steiger, Vladan Martinovic, Danijela Minasch, Judith Löffler-Ragg, Gianpaolo di Santo, Irene J Virgolini, Elisabeth von Guggenberg.

  Background/Objectives: Peptide receptor radionuclide therapy (PRRT) is an established treatment for neuroendocrine tumors (NETs), enabling targeted radiation delivery via radiolabeled peptides. Small cell lung cancer (SCLC) remains a major therapeutic challenge due to its aggressive nature and poor prognosis. Despite advances, relapse rates are high and effective therapies are limited. We previously demonstrated the diagnostic potential of the cholecystokinin-2 receptor (CCK2R)-targeting minigastrin analog [68Ga]Ga-DOTA-MGS5 in PET/CT imaging of different NETs. Building on this, we developed and evaluated [177Lu]Lu-DOTA-MGS5 as a therapeutic PRRT agent. Methods: Preclinical studies investigating the receptor-mediated cellular internalization and intracellular distribution over time in A431 cells with and without CCK2R expression were performed using the fluorescent tracer ATTO-488-MGS5. Short- and long-term cytotoxic effects of [177Lu]Lu-DOTA-MGS5 were evaluated on the same cell line using trypan blue exclusion and clonogenic survival assays. CCK2R expression was assessed by immunohistochemistry in 42 SCLC tissue specimens. In addition, the first PRRT with [177Lu]Lu-DOTA-MGS5 was conducted in a patient with extensive disease SCLC (ED-SCLC) after confirming CCK2R-positive uptake in [68Ga]Ga-DOTA-MGS5 PET/CT. Results: Rapid binding and internalization into A431-CCK2R cells, with progressive accumulation in intracellular compartments, was observed for ATTO-488-MGS5. Short-term irradiation effects of [177Lu]Lu-DOTA-MGS5 were comparable for 4 h and 24 h incubation and were between the effects obtained with 2 and 4 Gy of external beam radiotherapy (EBRT). Clonogenic survival of A431-CCK2R cells incubated with increasing activity of [177Lu]Lu-DOTA-MGS5 decreased in a dose-dependent manner. Immunohistochemistry on SCLC specimens confirmed moderate to high CCK2R expression in 16 out of 42 SCLC samples. In the first patient with SCLC treated with four cycles of [177Lu]Lu-DOTA-MGS5 with a total activity of 17.2 GBq, an improvement in clinical symptoms was observed. Conclusions: The preclinical and clinical results confirm the feasibility of [177Lu]Lu-DOTA-MGS5 PRRT in patients with SCLC and support further clinical studies investigating the therapeutic value and clinical applicability of this new CCK2R-targeted theranostic approach in larger patient cohorts.

Keywords:  SPECT/CT imaging; cholecystokinin-2 receptor; first-in-human; minigastrin; peptide receptor radionuclide therapy

DOI:  https://doi.org/10.3390/pharmaceutics18010138
Cancer Treat Rev. 2026 Jan 11. pii: S0305-7372(26)00005-8. [Epub ahead of print]143 103091

Targeted precision Strike in Extensive-Stage small cell lung Cancer: Current advances and future Perspectives for Antibody-Drug conjugates.

Yuwei Li, Kaiyan Chen, Hui Li, Yun Fan.

  Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumour with a poor prognosis. Although treatment regimens such as first-line immunochemotherapy have shown clinical benefits in extensive stage SCLC (ES-SCLC), patients still face disease recurrence and drug resistance. Antibody-drug conjugates (ADCs) are new therapeutic compounds made up of a monoclonal antibody (mAb) attached to a cytotoxic drug (payload) using a linker. They achieve precise killing of tumour cells by conjugating highly cytotoxic drugs with monoclonal antibodies targeting specific tumour antigens. In recent years, antigens such as B7-H3, Trop-2, SEZ6, DLL3, and EGFR-HER3 have become primary targets for ADC development in ES-SCLC. Although some ADCs have been limited due to toxicity-related issues, numerous other ADCs have entered clinical trial phases and demonstrated encouraging efficacy, with ORRs of 33.3 %-68.0 % and median PFS of 4.0-7.6 months. In this review, we systematically summarize ADCs currently in clinical trials and preclinical research for SCLC, and comprehensively discuss their pharmacodynamic characteristics, therapeutic effects, adverse effects, and strategies for optimising treatment.

Keywords:  Antibody–drug conjugates; B7-H3; SEZ6; Small-cell lung cancer; Trop-2

DOI:  https://doi.org/10.1016/j.ctrv.2026.103091
Cell Death Dis. 2026 Jan 28.

Targeting GNG4 inhibits tumor progression and restores enzalutamide sensitivity in prostate cancer by suppressing autophagy.

Lei Chen, Jingyan Zhang, Yanshuo Hu, Xufeng Peng, Hong Wang, Binghua Chen, Jun Xia, Wei Xue, Chun-Wu Pan.

Prostate cancer (PCa) is the most prevalent malignancy among men worldwide. Advanced prostate cancer is characterized by aggressive progression, limited therapeutic response, and poor prognosis. Elucidating its oncogenic mechanisms may provide new opportunities for targeted intervention. Increasing evidence suggests that modulating cytoprotective autophagy represents a promising strategy for improving cancer treatment efficacy and overcoming drug resistance. Here, we identified the G protein subunit GNG4 as a crucial regulator of prostate cancer development. GNG4 expression was markedly elevated in advanced prostate cancer phenotypes and positively correlated with tumor survival, apoptosis, and migration. Further analysis demonstrated that GNG4 depletion suppressed autophagy and enhanced cellular sensitivity to enzalutamide. Mechanistically, GNG4 interacts with GNB1 to stabilize the downstream effector protein GNAI3 through the ubiquitination-proteasome pathway. These three distinct G protein subunits form a functional complex that regulates intracellular autophagy and subsequently influences the malignant behavior of prostate cancer. Furthermore, inhibition of autophagy or GNG4 knockdown significantly increased the antitumor efficacy of enzalutamide both in vitro and in vivo. Our findings identified GNG4 as a pivotal modulator of prostate cancer progression and proposed it as a promising therapeutic target to enhance the clinical response to enzalutamide.GNG4 interacts with GNB1 to stabilize GNAI3 via the ubiquitination-proteasome pathway, thereby activating autophagy. This process promotes prostate cancer progression and resistance to androgen receptor signaling inhibitors (ARSis). In contrast, GNG4 knockdown or pharmacological inhibition of autophagy restores ARSI sensitivity and suppresses tumor growth.

DOI: https://doi.org/10.1038/s41419-026-08421-w
J Med Chem. 2026 Jan 27.

Novel ImmunoPET Probes [64Cu]Cu-NOTA-GGB02-F9 for Small-Cell Lung Cancer Derived from a SEZ6-Targeting Antibody.

Guanyun Wang, Lingling Zheng, Xu Yang, Xiaoya Wang, Zi'ang Zhou, Ying Kan, Wei Wang, Jianhua Gong, Jigang Yang.

Seizure-related 6 homologue (SEZ6) is a highly expressed transmembrane protein that has emerged as a promising therapeutic target for small-cell lung cancer (SCLC). In this study, we developed a novel immuno-positron emission tomography probe ([64Cu]Cu-NOTA-GGB02-F9) based on the SEZ6-targeting antibody, GGB02-F9, for use in preclinical mouse models of SCLC. The diagnostic potential of [64Cu]Cu-NOTA-GGB02-F9 was evaluated in preclinical SCLC models with varying levels of SEZ6 expression. The H69 tumors exhibited a distinct accumulation of tracer uptake in the tumor xenograft mice, reaching a maximum uptake at 72 h postinjection, which was significantly higher than that in the H69 GGB02-F9-blocked and H460 groups (P < 0.01) at 24, 48, and 72 h postinjection. The uptake of the tumor tracer in mice was found to be associated with SEZ6 expression, as determined by immunohistochemical analysis. Our study demonstrated that [64Cu]Cu-NOTA-GGB02-F9 can noninvasively evaluate SEZ6 expression in preclinical SCLC mouse models.

DOI: https://doi.org/10.1021/acs.jmedchem.5c02806
Clin Cancer Res. 2026 Jan 27.

A multicenter phase II randomized controlled trial comparing 177Lu-Dotatate/capecitabine combination treatment with 177Lu-Dotatate monotherapy in patients with neuroendocrine tumors.

Morticia N Becx, Johannes Hofland, Eric P Krenning, David K Wyld, Julie Nonnekens, Frederik A Verburg, Tessa Brabander, Jan J V van Busschbach, Wouter W de Herder.

INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-[DOTA0,Tyr3]octreotate (177Lu-Dotatate) is an effective and safe treatment for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP NET). While 177Lu-Dotatate prolongs progression-free survival (PFS) and preserves quality of life (QoL), objective response rates (ORR) remain limited. Capecitabine, as radiosensitizer, could increase efficacy without increasing 177Lu-Dotatate activity. This phase II randomized controlled trial investigated the additional cytotoxic or radiosensitizing effect of capecitabine in combination with 177Lu-Dotatate.
METHODS: Patients with advanced somatostatin receptor positive GEP NET or bronchopulmonary NET were scheduled for four cycles of 7.4 GBq 177Lu-Dotatate and capecitabine or 177Lu-Dotatate alone. Capecitabine (1650 mg/m2/day) was administered for two weeks from the start of each PRRT cycle. Primary endpoints were ORR, PFS and median overall survival (OS). Secondary endpoints included biochemical response, adverse events and QoL.
RESULTS: 111 of the 200 predefined patients were randomized for 177Lu-Dotatate/capecitabine (n=50) or 177Lu-Dotatate (n=61). According to the intention-to-treat analysis, ORR was 32% for 177Lu-Dotatate/capecitabine group versus 46% for 177Lu-Dotatate group (p=0.348). Treatment with 177Lu-Dotatate/capecitabine did not prolong median PFS (45.7 versus 31.7 months, p=0.629) or median OS (75.8 versus 61.4 months, p=0.530). Quality-adjusted life years (QALYs) were lower in the 177Lu-Dotatate/capecitabine group (1.30±0.48 versus 1.47±0.48, p=0.014).
CONCLUSION: In this prematurely closed phase II study, 177Lu-Dotatate/capecitabine did not improve ORR or prolong PFS and OS in advanced NET patients compared to 177Lu-Dotatate alone and was associated with reduced QALYs.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1884
Front Oncol. 2025 ;15 1748527

Coactivator networks orchestrating noncanonical AR programs in enzalutamide-resistant CRPC.

Ephraim J Gardner, Sasikumar Ponnusamy, Remi Adelaiye-Ogala.

  Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in the treatment of castration-resistant prostate cancer (CRPC). Emerging evidence suggests that Enzalutamide resistance is not solely due to the loss of AR dependency but can also arise from epigenomic reprogramming of the AR cistrome toward noncanonical gene networks. Recent studies have revealed that this reprogramming is mediated by previously unrecognized coactivators, including CXXC5, TET2, and EZH2, which cooperate with AR to establish a transcriptional landscape that supports lineage plasticity and therapeutic evasion. These noncanonical AR transcriptional programs enable CRPC cells to survive under continued AR blockade, acting as a transitional state towards neuroendocrine differentiation. Pharmacologic disruption of these coactivators abrogates noncanonical AR activity and suppresses tumor growth, highlighting a tractable vulnerability. These findings redefine AR signaling in advanced disease, suggesting that targeting noncanonical AR coactivators could offer a novel therapeutic paradigm to overcome resistance. Advances in single-cell and epigenomic profiling are poised to delineate further the heterogeneity and dynamics of AR cistrome remodeling in treatment-refractory prostate cancer.

Keywords:  AR cistrome; advanced prostate cancer; androgen receptor; canonical and noncanonical AR cistrome; enzalutamide resistance; lineage plasticity; noncanonical AR coactivator; therapeutic strategies

DOI:  https://doi.org/10.3389/fonc.2025.1748527
JTO Clin Res Rep. 2026 Feb;7(2): 100935

Thymic Neuroendocrine Tumors: Evolving Insights and Innovative Approaches.

Erica Pietroluongo, Christine M Bestvina, Rachel Brattin, Pietro De Placido, Anna Di Lello, Waqas Haque, Alessandra Esposito, Roberto Bianco, Noura Choudhury, Marina Chiara Garassino.

   Introduction: Thymic neuroendocrine tumors (TNENs) are exceptionally rare and a clinically heterogeneous malignancy, often diagnosed at an advanced stage and lacking standardized treatment algorithms. Due to the scarcity of dedicated evidence, most therapeutic strategies are extrapolated from other neuroendocrine neoplasms.
Methods: This narrative review provides an updated overview of current and emerging treatment approaches for TNENs, focusing on histology-driven strategies and the evolving role of targeted and radionuclide therapies. A comprehensive literature search was conducted through PubMed/MEDLINE and Embase from January 1, 2000, up to May 31, 2025, integrating retrospective series, real-world data, and ongoing clinical trials.
Results: Surgical resection remains the cornerstone of treatment whenever feasible. The benefit of adjuvant therapy in well-differentiated tumors is unclear, whereas thymic neuroendocrine carcinomas often require multimodal approaches, including platinum-etoposide chemotherapy and radiotherapy. Retrospective evidence suggests that even well-differentiated, high-grade tumors may respond to cytotoxic agents. Somatostatin analogues are widely used in indolent or peptide receptor-positive tumors, whereas everolimus and, more recently, cabozantinib represent options for progressive disease. Peptide receptor radionuclide therapy has demonstrated encouraging results in somatostatin receptor-positive tumors and is currently under further investigation in prospective trials involving thymic primaries. However, the 5-year overall survival rate varies significantly (approximately 28%-80%), underlining an urgent need for prospective, subtype-specific studies.
Conclusions: The management of TNENs requires a multidisciplinary and individualized approach based on histologic subtype, somatostatin receptor status, and disease aggressiveness. Despite promising therapeutic options, robust prospective data remain limited. The integration of TNENs into basket trials, the molecular refinement of prognostic subgroups (e.g., NET G3), and the conduct of dedicated multicenter prospective studies are urgently needed to define optimal treatment algorithms and improve clinical outcomes in these rare entities.

Keywords:  PRRT; Somatostatin analogs; Targeted therapy; Thymic neuroendocrine tumors

DOI:  https://doi.org/10.1016/j.jtocrr.2025.100935
World J Gastrointest Oncol. 2026 Jan 15. 18(1): 114818

Rectal neuroendocrine tumors: Update.

Mohammed Khayyat, Yasir M Khayyat.

  Rectal neuroendocrine tumors (NETs) are increasingly detected and are the most common gastrointestinal NET sites. Often discovered incidentally during endoscopy, most are small, well differentiated, and have an excellent prognosis. Local resection is typically considered curative. Several guidelines, namely the European Neuroendocrine Tumor Society guidelines 2023, National Comprehensive Cancer network 2025, and the Polish Network of Neuroendocrine Tumors (2017) emphasize the use of endoscopic and endoscopic ultrasound staging to select the appropriate therapy, ranging from resection to advanced techniques for larger or metastatic diseases, highlighting the need for an accurate initial assessment.

Keywords:  Endoscopic ultrasound; Metastasis; Neuroendocrine; Rectum; Transanal

DOI:  https://doi.org/10.4251/wjgo.v18.i1.114818
Farm Hosp. 2026 Jan 28. pii: S1130-6343(25)00178-3. [Epub ahead of print]

Atezolizumab plus platinum-based chemotherapy and etoposide as first-line treatment for metastatic small cell lung cancer: a retrospective multicenter observational study.

Laura Moñino Domínguez, Laura Amaro Álvarez, Alicia Aguado Paredes, Isabel María Carrión Madroñal.

   INTRODUCTION: The standard first-line treatment for metastatic small-cell lung cancer (SCLC) is platinum-based chemotherapy in combination with etoposide. The aim of this study was to evaluate the real-world effectiveness and safety of atezolizumab plus chemotherapy in SCLC and to explore factors associated with survival.
METHODS: A retrospective, observational, multicenter study was conducted in patients diagnosed with SCLC who received first-line treatment with atezolizumab in combination with platinum-etoposide chemotherapy between November 2021 and March 2025. Treatment effectiveness was evaluated by assessing the objective response rate (ORR), treatment duration, progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox models were used to explore associations between clinical variables and survival outcomes.
RESULTS: A total of 76 patients with SCLC were included. Median age was 65 years, and 17.1% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. The median duration of the treatment was 4.43 months (Interquartile range: 0.4-6.2). The ORR was 81.67% (95% CI: 70.08-89.44%). The median PFS was 7.2 months (95% CI: 6.5-8.6), and the median OS was 9.4 months (95% CI: 7.0-13.06). Patients with ECOG ≥2, hepatic metastases, and age ≥ 65 years were associated with a poor survival prognosis. Sex and the presence of brain metastases were not significantly associated with survival. Grade ≥ 3 treatment-related adverse events were observed in 44.7% patients, with no treatment-related deaths.
CONCLUSIONS: In this real-world cohort, atezolizumab plus platinum-etoposide achieved high response rates and acceptable survival with a manageable safety profile in extensive-stage SCLC. Baseline ECOG performance status, hepatic metastases, and older age were associated with worse survival, underscoring the prognostic value of clinical factors. These observational data complement, but do not validate, the results of IMpower133, as no randomized control group or formal trial emulation methods were used.

Keywords:  Análisis de supervivencia; Atezolizumab; Carcinoma de pulmón microcítico; Metastatic; Metastásico; Small cell lung carcinoma; Survival analysis

DOI:  https://doi.org/10.1016/j.farma.2025.12.001
Int Cancer Conf J. 2026 Jan;15(1): 41-47

Early emergence of neuroendocrine prostate cancer during triplet therapy for high-volume metastatic castration-sensitive prostate cancer.

Yuichiro Nakamura, Hajime Fukushima, Hiroki Kurata, Junki Harada, Kyohei Araki, Kensuke Mitsunari, Tomohiro Matsuo, Kojiro Ohba, Yasushi Mochizuki, Ryoichi Imamura.

  This case highlights the potential for early emergence of neuroendocrine differentiation in patients with metastatic castration-sensitive prostate cancer undergoing triplet therapy with androgen deprivation therapy, darolutamide, and docetaxel, even with marked prostate-specific antigen (PSA) suppression. In this patient, although some lesions initially responded to treatment, new metastases and radiological progression were observed early after triplet therapy was initiated. These atypical progression patterns raised the suspicion of neuroendocrine prostate cancer (NEPC), confirmed by percutaneous biopsy of an enlarged right external iliac lymph node. This enabled the timely modification of the treatment strategy. Furthermore, retrospective immunohistochemical reevaluation of the diagnostic prostate biopsy specimen obtained at the referring hospital using only four cores revealed focal neuroendocrine differentiation within the poorly differentiated Gleason pattern 5 areas, suggesting that de novo NEPC features may have been present at the time of diagnosis. As triplet therapy has become more widespread, the incidence of NEPC may increase. Clinicians should maintain a high level of vigilance for discordant PSA progression and consider early biopsy of metastatic lesions to ensure accurate diagnosis and appropriate therapeutic decision-making.

Keywords:  Metastatic castration-sensitive prostate cancer; Metastatic lesion biopsy; Neuroendocrine prostate cancer; Triplet therapy

DOI:  https://doi.org/10.1007/s13691-025-00812-8
Nutrients. 2026 Jan 15. pii: 281. [Epub ahead of print]18(2):

Vitamin D Deficiency and Replacement Challenges in Type 1 Gastric Neuroendocrine Tumors: A Comparative Study.

Elio Benevento, Michele Coletta, Alessia Liccardi, Roberto Minotta, Gianfranco Di Iasi, Massimo Di Nola, Annamaria Colao, Roberta Modica.

  Background/Objectives: Type 1 gastric neuroendocrine tumors (gNET) arise in the setting of autoimmune chronic atrophic gastritis and secondary hypergastrinemia. Vitamin D deficiency (VDD) has been associated with bone impairment and adverse outcomes in patients with neuroendocrine tumor (NET); however, data specifically addressing gNET remain limited. This study aimed to evaluate vitamin D status, supplementation requirements, and bone involvement in patients with type 1 gNET compared with those with entero-pancreatic NET (EP-NET). Methods: This retrospective study included patients with type 1 gNET followed at a tertiary referral center between 2010 and 2025 and an age- and sex-matched EP-NET cohort. VDD prevalence, time and dose required for normalization, supplementation formulations, bone status, and dietary habits were analyzed. Results: Twenty-six patients were included (thirteen gNET and thirteen EP-NET). VDD was significantly more prevalent in the gNET group compared with the EP-NET group (92.3% vs. 46.2%, p = 0.03, OR: 14). gNET required significantly higher daily cholecalciferol doses (3198.9 ± 1629 vs. 1580 ± 1121 IU/day, p = 0.008) and more frequently required multiple supplementation formulations (38.5% vs. 0%, p = 0.04). Multivariable linear regression analysis restricted to VDD patients confirmed that gNET was independently associated with higher daily cholecalciferol dose requirements (p = 0.037). Bone impairment, defined as osteoporosis or osteopenia, was significantly more common in the gNET group (61.5% vs. 15.4%, p = 0.04, OR: 8.8). Dietary adherence did not differ between groups. Conclusions: Type 1 gNET show a higher burden of VDD, increased vitamin D supplementation requirements, and a higher prevalence of bone impairment compared with EP-NET, irrespective of dietary habits. These findings suggest disease-specific mechanisms and support the need for tailored management in these patients.

Keywords:  entero-pancreatic neuroendocrine tumor; gastric neuroendocrine tumors; vitamin D

DOI:  https://doi.org/10.3390/nu18020281