Search Results (1,456)

Long-term psychological stress drives breast cancer progression through neuroendocrine, immune, and gut microbiota (GM) dysbiosis. Preclinical and clinical data link stress-induced depletion of Akkermansia muciniphila and its cross-fed metabolite, butyrate, to the activation of the Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5)-Wnt/β-catenin signaling pathway and increased cancer stemness. However, the current evidence has critical limitations. A. muciniphila does not produce butyrate, and its effects are highly context-dependent. While gut-resident populations are generally beneficial, translocation to mammary tissue can paradoxically induce oxidative stress and promote tumor progression. Therefore, future interventions must move beyond indiscriminate live bacterial supplementation. For the safe management of stress-associated breast cancer, future research should prioritize tissue-context-aware strategies, such as harnessing postbiotics (e.g., purified Amuc_1100, extracellular vesicles) and bacterial metabolites (e.g., targeted butyrate modulation), or utilizing high-fiber diets, integrated with established psycho-oncological care. Full article

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are the most common subtype of NETs, and their incidence continues to increase worldwide. Many NETs express somatostatin receptors (SSTRs), enabling molecular imaging and treatment with radiolabeled somatostatin analogs (SSTAs). [¹⁷⁷Lu]Lu-DOTATATE is an established treatment for advanced SSTR-positive NETs, but complete and durable responses remain uncommon. This review summarizes current clinical experience with [¹⁷⁷Lu]Lu-DOTATATE and emerging SSTR-targeting radiopharmaceuticals and examines strategies to improve PRRT efficacy. Treatment may be enhanced at several interconnected steps, including increasing receptor availability and tumor targeting, improving radiopharmaceutical uptake and absorbed dose, preventing repair of radiation-induced damage, suppressing cellular stress adaptation and survival, and promoting tumor cell elimination. These approaches include radiation priming and fractionation, somatostatin analog pretreatment, epigenetic modifiers, inhibitors of DNA repair and cellular survival pathways, immunotherapy, and chemotherapy-based combinations. PARP, DNA-PK, and HSP90 inhibitors and chemotherapy-based combinations have shown particularly strong preclinical or clinical evidence, whereas mTOR inhibitors, tyrosine kinase inhibitors, Hedgehog inhibitors, immunotherapy, NAMPT inhibitors, p53 stabilization, and epigenetic modifiers remain under investigation. Ongoing development of novel radiopharmaceuticals, personalized dosimetry, retreatment strategies, and rational combinations is expected to refine PRRT and improve outcomes for patients with NETs. Full article

Pancreatic ductal adenocarcinoma (PDAC) is defined by significant desmoplastic reaction composed of cancer-associated fibroblasts (CAFs), pancreatic stellate cells (PSCs), extracellular matrix (ECM), immune cells, and abnormal vascularization. This stromal compartment is by no means a passive fibrotic reaction; rather, it contributes to tumor progression and treatment resistance through physical and biological mechanisms. The accumulation and remodeling of collagen, hyaluronic acid, and other ECM components lead to tissue stiffness and increased tissue pressure, compress intratumoral vessels, impair blood flow, promote hypoxia, and limit homogeneous drug delivery. Simultaneously, heterogeneous CAF populations send out paracrine, metabolic, and immunomodulatory signals that can either promote or inhibit tumor growth. Such opposing features may contribute to the inconsistent or unfavorable outcomes observed in attempts to comprehensively reduce the PDAC stroma. Pancreatic neuroendocrine neoplasms (PanNENs), especially well-differentiated pancreatic neuroendocrine tumors (PanNETs), have typically been considered highly vascularized tumors with a relatively limited stromal component. New findings challenge this simplified view. In subgroups of clinically aggressive PanNETs, fibrosis, reduced microvascular density, and CAF-rich stromal phenotypes have been observed. Recent findings also suggest spatially organized interactions between CAFs and the tumor that may promote epithelial–mesenchymal plasticity, invasion, and metastasis. Nonetheless, it remains unknown whether fibrosis in PanNETs constitutes a mechanically relevant barrier to drug delivery comparable to that observed in PDAC. This mini-review explores the desmoplastic barrier in PDAC as a frame of reference, evaluates new findings on stromal and vascular remodeling in PanNETs, and underscores the need to define tumor-specific stromal and vascular phenotypes rather than assuming a common desmoplastic mechanism across all malignant pancreatic tumors. Full article

Background and Clinical Significance: Carcinoid heart disease remains one of the most serious complications of carcinoid syndrome, yet cardiac involvement may still be recognized late, when valvular damage is already advanced and treatment options are limited. Case Presentation: We report a 70-year-old man with a well-differentiated ileal neuroendocrine tumor (NET G2, Ki-67 up to 5%), diagnosed in December 2019. Over six years, the disease progressed with liver metastases, markedly rising 24 h urinary 5-HIAA levels and clinically active carcinoid syndrome, and was treated sequentially with somatostatin analogues, everolimus and ¹⁷⁷Lu-DOTATOC. Throughout this period, oncological evaluation was frequent, whereas structured cardiac assessment was essentially absent until 2025. When the patient was referred for evaluation for transcatheter tricuspid repair, echocardiography demonstrated advanced carcinoid tricuspid valve disease with severe regurgitation, mild stenosis, marked leaflet thickening and tethering, and a coaptation gap of 17 mm—far beyond the ~7 mm threshold associated with favorable edge-to-edge repair and the >10 mm range associated with poor outcome. Because of the advanced valve remodeling and the overall clinical burden, the patient was not a candidate for transcatheter edge-to-edge repair or surgery and subsequently died. Conclusions: This case illustrates how carcinoid heart disease can progress beyond correctability and supports regular echocardiographic surveillance in patients with carcinoid syndrome, so that valve involvement is identified while intervention is still anatomically feasible. Full article

Somatostatin receptor (SSTR)–targeted imaging and therapy are established approaches for neuroendocrine tumors, but accumulating evidence indicates that SSTRs are also expressed in various non-neuroendocrine tumors. This review aimed to summarize their expression patterns, imaging characteristics, and theranostic potential. Published evidence was reviewed for central nervous system tumors, head and neck cancers, thyroid carcinoma, lung cancer, breast cancer, lymphoma, and melanoma, with particular attention to the cellular localization of SSTR expression and the mechanisms underlying radiotracer uptake. Meningioma, non-keratinizing nasopharyngeal carcinoma, and selected estrogen receptor–positive breast cancers show relatively prominent tumor-cell SSTR expression. In several other malignancies, SSTR expression may predominantly involve tumor-associated macrophages, endothelial cells, fibroblasts, or other stromal components. Imaging findings are heterogeneous across and within tumor types. Preliminary studies suggest that peptide receptor radionuclide therapy may provide clinical benefit in selected patients with SSTR-positive non-neuroendocrine tumors, although the available evidence remains limited and largely non-prospective. Further studies integrating quantitative molecular imaging, spatial pathology, and molecular profiling are needed to clarify receptor biology, establish patient-selection criteria, and define the clinical role of SSTR-targeted theranostics beyond neuroendocrine tumors. Full article

Background: Pulmonary neuroendocrine tumors (lung NETs) comprise a biologically heterogeneous group of neoplasms ranging from indolent typical carcinoids to more aggressive atypical carcinoids. Accurate characterization of tumor biology is essential for optimizing staging, prognostic stratification, and treatment selection. Beyond conventional cross-sectional imaging, functional imaging and emerging quantitative imaging techniques are progressively redefining the diagnostic pathway. Methods: We performed a comprehensive narrative review of the current evidence regarding conventional radiological imaging, somatostatin receptor (SSTR) PET/CT, ¹⁸F-FDG PET/CT, dual-tracer imaging, and radiomics in lung NETs, integrating recent international recommendations from ENETS, ESMO, AIOM, and other major societies. Results: Contrast-enhanced CT remains the cornerstone of anatomical staging, whereas ⁶⁸Ga-labelled somatostatin analogue (SSA) PET/CT provides highly sensitive assessment of receptor expression and patient eligibility for somatostatin analogue therapy and peptide receptor radionuclide therapy (PRRT). Conversely, ¹⁸F-FDG PET/CT identifies metabolically active and biologically aggressive disease, particularly in atypical carcinoids and tumors showing dedifferentiation. Increasing evidence supports the complementary role of dual-tracer PET/CT for non-invasive characterization of tumor heterogeneity, prognostic stratification, and treatment planning. Radiomics further expands this paradigm by extracting quantitative imaging biomarkers that may improve histological prediction, recurrence risk assessment, and individualized management. Although promising, radiomics remains limited by methodological heterogeneity and the lack of prospective validation. Conclusions: The integration of conventional imaging, molecular imaging, and quantitative radiomics supports a shift from lesion detection toward biologically driven precision imaging. Future prospective multicenter studies incorporating imaging biomarkers, artificial intelligence, and clinical-pathological variables may further support personalized management of patients with lung NETs. Full article

Background: Pituitary carcinoma (PC) is a rare and aggressive pituitary neuroendocrine tumor (PitNET) defined by non-contiguous craniospinal or systemic metastatic spread. Evidence guiding treatment is limited to case reports and case series. This systematic review aimed to characterize the clinicopathological features, treatment patterns, and prognostic determinants of PC through pooled individual patient data (IPD) analysis. Methods: A systematic search of PubMed/MEDLINE and Embase (January 1990 to March 2026) was conducted in accordance with PRISMA 2020 guidelines (PROSPERO: CRD420261402665). Individual patient data were extracted for 56 pre-specified variables from the identified literature. Two additional institutional cases were analyzed separately as illustrative clinical examples and are not part of the pooled statistical cohort. Survival was estimated using the Kaplan–Meier method with log-rank tests. Univariate and multivariable Cox proportional hazards regression and binary logistic regression (outcome: long-survivor status, defined as OS > 24 months) were performed on the pooled literature cohort. Results: A total of 111 patients from 93 papers were included (51 males (45.9%); median age at PC diagnosis 54 years (IQR 40–61)), with corticotroph lineage predominating (47.7%). Median OS from PC diagnosis was 19 months (IQR 9.5–46); one-year OS was 67.7% and two-year OS 52.0%. Multimodal treatment was associated with significantly longer OS (median 45 vs. 12 months; log-rank p = 0.004). In multivariable Cox regression (n = 88; C-index 0.725), any objective treatment response (HR 0.245, 95% CI 0.101–0.593, p = 0.002), functional tumor status (HR 2.041, 95% CI 1.017–4.095, p = 0.045), and age at PC diagnosis (HR 1.018/year, p = 0.049) were independently associated with OS. Logistic regression identified multimodal treatment (OR 5.29, p = 0.009), any treatment response (OR 5.47, p = 0.006), and early metastasis (OR 0.18, p = 0.024) as independent predictors of long-survivor status. Ki-67 increased significantly from initial to PC-stage diagnosis (median 7% vs. 12%; Wilcoxon p < 0.001), which is, to our knowledge, the first demonstration of this longitudinal rise in a pooled pituitary carcinoma cohort. Conclusions: PC carries a poor prognosis, with a median OS of 19 months. Multimodal therapy and achievement of objective response are the strongest determinants of prolonged survival. Prospective registries with standardized molecular profiling are needed to advance precision management of this ultra-rare malignancy. Full article

To review the current state of knowledge regarding neuroendocrine tumors (NETs) of the larynx, with a particular focus on their epidemiology, etiopathogenesis, clinico-pathological features, immunohistochemical profile, and differential diagnostics. Narrative review. Diagnostic criteria for laryngeal NETs were recently defined in the 5th edition of the WHO Classification of Head and Neck Tumors, which newly introduces the entity of NET, grade 3 (G3 NET). However, some of these criteria are still considered provisional. The most common NET of the larynx is the G2 NET. These tumors typically affect older men, with the supraglottic region being the most frequent localization. For a definitive diagnosis, it is essential to demonstrate the epithelial origin and neuroendocrine differentiation of these tumors using cytokeratins and neuroendocrine markers (e.g., chromogranin, INSM1, synaptophysin). The differentiation between individual NET types is based on mitotic activity and/or Ki-67 proliferation index, as well as the presence or absence of necrosis. Laryngeal NETs typically exhibit wild-type p53 expression and retained Rb1 and somatostatin receptor 2 expression. This can be utilized in the differential diagnosis from neuroendocrine carcinomas (NECs). Given that laryngeal NETs frequently express calcitonin, they must be differentiated from medullary thyroid carcinoma (MTC), particularly in lymph node metastases. A high frequency of HRAS gene mutations has been recently demonstrated in laryngeal NETs, underlining their distinctness from their gastroenteropancreatic and thoracopulmonary counterparts. By utilizing the proposed diagnostic criteria for individual types of laryngeal NETs, it is anticipated that more precise knowledge regarding the clinico-pathological characteristics of these exceedingly rare tumors will be obtained, particularly with respect to their biological behavior and prognosis. Full article

Background: Pheochromocytoma is a highly vascular neuroendocrine tumor with variable biological behavior. Reliable biomarkers reflecting tumor aggressiveness remain limited. This study evaluated apelin and vascular endothelial growth factor (VEGF) expression in pheochromocytoma and their associations with histopathological prognostic parameters. Methods: This retrospective single-center study included 20 pheochromocytoma patients and 18 normal adrenal medulla controls. Apelin and VEGF expression were evaluated immunohistochemically using the immunoreactivity score (IRS). Associations between IRS values and Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) score, Ki-67 index, tumor size, clinicopathological characteristics, and individual PASS components were analyzed. Results: Apelin IRS was significantly lower in pheochromocytoma than in normal adrenal medulla (median 0 vs. 4, p = 0.001), whereas VEGF IRS was significantly higher (median 6 vs. 2, p < 0.001). Tumors with PASS ≥ 4 had significantly lower apelin IRS than those with PASS < 4 (p = 0.001). Apelin IRS was inversely correlated with PASS (r = −0.874, p < 0.001), GAPP score (r = −0.618, p = 0.004), and Ki-67 (r = −0.560, p = 0.010). Lower apelin expression was also associated with diffuse growth pattern, central/confluent necrosis, and tumor cell spindling. VEGF IRS showed no significant association with PASS, GAPP score, Ki-67, tumor size, or individual PASS components. Conclusions: Reduced apelin immunoreactivity was associated with unfavorable histopathological features in pheochromocytoma, whereas increased VEGF immunoreactivity was not associated with the evaluated histopathological risk parameters. These exploratory findings suggest that apelin may be a candidate tissue marker; however, its clinical and prognostic relevance requires further investigation in larger multicenter studies. Full article

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma in which Merkel cell polyomavirus (MCPyV) oncoproteins and ultraviolet-induced mutations provide distinct sources of tumor immunogenicity. This narrative review examines the biological determinants, immunohistochemical assessment, and prognostic and therapeutic relevance of programmed death ligand 1 (PD-L1) in MCC, linking tumor immunobiology to pathological interpretation. PD-L1 expression on tumor and immune cells is often concentrated at tumor–immune interfaces, consistent with interferon-γ-driven adaptive immune resistance. Reported associations with survival and treatment response vary across studies, partly reflecting differences in tissue sampling, assays, scoring compartments, and treatment context. Immune checkpoint blockade can produce durable responses in both PD-L1-positive and PD-L1-negative tumors, while baseline PD-L1 expression alone is not a validated criterion for treatment selection. Resistance mechanisms and emerging biomarkers are discussed alongside viral status, T-cell architecture, antigen-presentation defects, and alternative immune checkpoints. A reporting framework should emphasize specimen characteristics, assay documentation, separate assessment of PD-L1 expression in tumor and immune cells, and spatial heterogeneity. Interpreting PD-L1 within this biological and pathological context supports informative reporting and highlights the potential of integrated spatial biomarkers to improve understanding of immune responsiveness in MCC. Full article

Gastrointestinal neuroendocrine tumors (GI-NETs) are being diagnosed with increasing frequency and often manifest with liver metastases, presenting considerable therapeutic challenges. This commentary addresses the systematic review by Lai et al., which evaluated liver transplantation (LT) for NET-associated liver metastases (NEN-LM). Although Lai et al. identified LT as a promising intervention for unresectable or liver-confined NETs, we believe that certain aspects warrant further discussion. To begin with, approximately 16% of reported cases had an unknown primary tumor. This not only complicates patient selection and potentially introduces confounding outcomes but also contradicts the notion of “liver-limited disease”. Furthermore, elevated proliferative activity, as indicated by a Ki-67 index of >2%, has been correlated with reduced survival rates. Therefore, LT should ideally be offered to patients with GI-NETs with a Ki-67 index of <2%. This subgroup of patients may also benefit from alternative therapy options, such as cytoreductive surgery/tumor debulking combined with peptide receptor radionuclide therapy (PRRT), which has demonstrated favorable outcomes and deserves greater attention. Finally, advocating LT for patients with NEN-LM based on retrospective data might facilitate its overuse, especially in countries/regions where living donor LT is employed. We believe that this important yet missing point merits an in-depth examination of its advantages and disadvantages. Full article

Background/Objectives: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare biologically heterogeneous neoplasms but with increasing incidence in recent years. Surgery remains the backbone of treatment; however, long-term recurrence is common even after curative resection. Despite expanding treatment options, the optimal perioperative integration of adjunct therapies in conjunction with surgery remains incompletely defined, as available evidence is largely retrospective and heterogeneous. This review critically synthesizes available evidence on the role of perioperative therapies in the surgical management of GEP-NENs, identifies key knowledge gaps, and highlights areas where multidisciplinary decision-making is required. Methods: A targeted narrative literature review was performed in PubMed/MEDLINE (2001–2026), supplemented by ClinicalTrials.gov and major society guidelines. Predefined search terms were used to include “gastroenteropancreatic neuroendocrine tumor”, “GEP-NET”, “pancreatic neuroendocrine tumor”, “surgery”, “palliative surgery”, “neoadjuvant”, “adjuvant”, “PRRT”, “somatostatin analogue”, “chemotherapy”, “targeted therapy”, “immune checkpoint inhibitor”, and “liver-directed therapy”. Studies were selected based on relevance, with emphasis on comprehensive reviews, key clinical studies, and major guideline statements. This approach was chosen due to varied literature and scarce high-quality prospective evidence. Results: Neoadjuvant PRRT and CAPTEM-based chemotherapy demonstrate encouraging activity in selected patients with SSTR-positive or borderline resectable pNETs, though evidence is predominantly retrospective and R0 resection rates are inconsistent across modalities. Adjuvant systemic therapy lacks high-quality evidence of benefit in well-differentiated GEP-NETs whereas platinum-based chemotherapy following resection of NEC represents the only setting where adjuvant treatment is commonly recommended, albeit without randomized trial support. Liver-directed therapies, including thermal ablation, TACE, and TARE, play complementary roles in selected patients with hepatic metastases. The overall evidence base is largely retrospective and heterogenous. Management should be individualized through multidisciplinary discussion. Full article

Background: Gastric carcinoma with coexisting exocrine and neuroendocrine components (GC-EN) is rare and clinically aggressive, but its temporal pattern and prognostic impact remain poorly characterized. Materials and Methods: We retrospectively analyzed 1043 patients who underwent curative gastrectomy at our center between 2008 and 2024. Following tumor–node–metastasis staging and 1:2 pTNM stage matching, 882 patients were included; 294 had GC-EN, of which 175 had GNEC, and 588 had GC. Clinicopathological characteristics were compared, survival outcomes were assessed using Kaplan–Meier estimates and multivariate Cox regression, and the proportion of GNEC cases in our center and the U.S. surveillance, epidemiology, and end results (SEER) database were evaluated. Survival patterns of GNEC were further compared with published international cohorts using Engauge Digitizer software. Results: Among the patients with gastric cancer admitted for treatment, the proportion of NEC fluctuated between 4.01% and 4.38% (2008–2013) and finally dropped to 1.6% (2020–2021), whereas the SEER database showed a modest rise with a late dip (1.67% → 2.72% → 2.44%). The overall survival (OS) of patients with NEC appeared to improve at our center (1-/2-/3-year OS: 85.1%/59.6%/34% in 2008–2012 to 94.1%/87.5%/76.2% in 2021–2024), whereas that in the SEER database declined over the same periods. The 5-year OS of the two databases remained similar (42.7% vs. 41.0%). The 1, 2 and 5-year survival rates of NEC in the external cohorts were higher than those in the SEER and Berlin series; however, the 3-year survival rates were similar, with the Italian multicenter cohort performing the worst. The Kaplan–Meier analysis demonstrated significantly worse OS for GC-EN versus GC (p < 0.001); within GC-EN, the NEC subgroup (NEC ≥ 70%) had the poorest outcomes (p < 0.001), whereas mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) and adenocarcinoma-dominant (AC-dominant) cases had similar outcomes as GC (p = 0.52, p = 0.81). In the multivariable Cox model, GC-EN histology remained independently associated with worse OS (HR = 1.49, 95% CI 1.15–1.92; p < 0.01). Metastatic lymph node burden and higher pTNM stage were associated with worse survival, whereas greater lymph node retrieval and age 40–65 years were protective. After adjustment, vascular invasion, tumor size, and location were not independently significant. Conclusions: Over the past 16 years at the National Cancer Center of China, the proportion of NEC cases decreased, and survival appeared to improve. NEC-dominant disease appeared to be the main driver of poor prognosis within GC-EN, whereas MiNEN and AC-dominant tumors showed survival patterns similar to GC in this cohort. These findings emphasize the need for GC-EN-specific risk stratification and tailored treatment strategies. Full article

Background/Objectives: Retinoic acid receptor γ (RARγ), encoded by RARG, is increasingly recognized as a cancer-associated regulator through aberrant expression in multiple solid tumors and recurrent gene rearrangements in acute myeloid leukemia. While the oncogenic relevance of RARγ is well established, the potential involvement of its N-terminal activation function-1 (AF1) domain in human cancer remains poorly characterized. Previous biochemical studies demonstrated that phosphorylation of Ser66 and Ser68 in RARγ2, corresponding to Ser77 and Ser79 in canonical RARγ1, is required for ligand-dependent receptor activation, ubiquitination, and proteasome-mediated degradation. Methods: To determine whether this experimentally validated phosphoregulatory region is altered in human cancer, we interrogated the Catalogue of Somatic Mutations in Cancer (COSMIC v104, GRCh38) at single-residue resolution. Mutation data were integrated with clinical and pathological information obtained from the corresponding primary publications and public annotation resources. Results: Rare somatic mutations affecting the AF1 phosphoregulatory region were identified, including the missense variants p.S77L and p.S79L, the nonsense variant p.S79*, and the in-frame insertion p.S77_P78insLQ. These alterations occurred in independent epithelial malignancies, including cervical neuroendocrine carcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, bladder carcinoma, and gastric neuroendocrine carcinoma. Notably, the truncating p.S79* mutation was detected in five spatially distinct regions of a single EGFR-mutant lung adenocarcinoma, consistent with an early clonal event during tumor evolution. Rare cancer-associated mutations affect a previously characterized AF1 phosphoregulatory module of RARγ. These findings extend established RARγ regulatory biology into the context of human malignancy and broaden the spectrum of reported cancer-associated RARG alterations. While the functional consequences of these rare variants remain unknown, their occurrence within residues known to regulate receptor activation and turnover highlights the AF1 phosphoregulatory region as a candidate for future mechanistic investigation. Full article