Search Results (1,442)

Integrins are heterodimeric transmembrane receptors that mediate bidirectional signaling and regulate cell–cell and cell–extracellular matrix interactions. Integrin αvβ6 is an epithelial-associated integrin that has emerged as a promising molecular target for PET/CT imaging using integrin αvβ6-directed radiotracers such as ⁶⁸Ga-Trivehexin, and, most recently, for antibody–drug conjugate therapy in epithelial malignancies. Unexpected physiological and incidental uptake within the pituitary gland has been reported in integrin αvβ6-targeted PET studies, including uptake in morphologically normal pituitary glands and pituitary neuroendocrine tumors (PitNETs). However, the histological basis of integrin αvβ6 expression in the human pituitary gland remains poorly understood. The aim of this study is to characterize the immunohistochemical expression of integrin αvβ6 in normal human pituitary tissue and PitNETs and to evaluate its potential implications for integrin αvβ6-targeted imaging and theranostic applications. Five complete adult pituitary glands obtained at autopsy and 28 PitNETs were examined by immunohistochemistry for integrin αvβ6. Staining distribution, intensity, and cellular localization were assessed in the adenohypophysis, neurohypophysis, and Rathke’s cleft remnants. PitNETs were classified according to transcription factor expression (PIT1, TPIT, and SF1). Among the 28 PitNETs, 17 were SF1-lineage (60.7%), three were PIT1-lineage (10.7), two were TPIT-lineage (7.1%), three lacked a dominant transcription factor (10.7%), and three showed plurilineage expression (10.7%). Integrin αvβ6 expression was evaluated semiquantitatively according to staining intensity and the percentage of positive tumor cells. In normal pituitary glands, integrin αvβ6 immunoreactivity was predominantly membranous and localized to larger adenohypophyseal cells irrespective of transcription factor lineage or hormone phenotype. Strong expression was also observed in the epithelial lining cells of Rathke’s cleft remnants, whereas the neurohypophysis lacked detectable integrin αvβ6 expression. Among the 28 PitNETs, integrin αvβ6 expression was detected in 20 cases (71.4%). Positive tumors demonstrated variable staining intensity and extent, ranging from 20% to 100% positive tumor cells. By lineage, integrin αvβ6 expression was detected in 13 of 17 SF1-lineage tumors (76.5%), one of three PIT1-lineage tumors (33.3%), and zero of two TPIT-lineage tumors (0%). Additionally, all three tumors lacking a dominant transcription factor (100%) and all three plurilineage tumors (100%) demonstrated integrin αvβ6 expression. Eleven integrin αvβ6-positive tumors showed expression in ≥50% of tumor cells, and six exhibited strong or diffuse immunoreactivity. Integrin αvβ6 expression in adenohypophyseal cells and Rathke’s cleft remnants provides a histological explanation for physiological pituitary uptake observed on αvβ6-targeted PET/CT imaging. The high prevalence of integrin αvβ6 expression in PitNETs, particularly in a subset demonstrating strong and diffuse immunoreactivity, suggests potential applicability of integrin αvβ6-targeted molecular imaging and theranostic approaches, including both radioligand- and antibody-based strategies. However, these applications remain investigational and require further validation in preclinical and clinical studies. At the same time, physiological integrin αvβ6 expression in normal anterior pituitary tissue may limit imaging specificity and should be considered when developing integrin αvβ6-targeted radioligand therapies. Further clinicopathological and imaging correlation studies are warranted to define the diagnostic and therapeutic role of integrin αvβ6-targeted approaches in PitNETs. Full article

Background and Clinical Significance: Oropharyngeal squamous cell carcinoma (OPSCC) and small-cell neuroendocrine carcinoma (SCNEC) are biologically distinct entities with markedly different prognostic and therapeutic implications. While HPV-negative OPSCC carries worse outcomes than HPV-positive disease, SCNEC is exceedingly rare, highly aggressive, and prone to early systemic dissemination. Their synchronous occurrence in the head and neck (HN) is exceptional and poses major diagnostic and therapeutic challenges. Case Presentation: A 54-year-old male, smoker and alcohol consumer, presented with a left tonsillar lesion and cervical lymphadenopathy. Biopsy confirmed p16-negative OPSCC. He underwent transoral robotic surgery with modified radical neck dissection. Histopathology unexpectedly revealed two distinct malignancies: keratinizing OPSCC in the tonsil and high-grade SCNEC in a cervical lymph node, confirmed by immunohistochemistry (synaptophysin, CD56, Ki-67 80%). Postoperative FDG-PET/CT performed within two months showed rapid systemic spread, including paravertebral, pulmonary, and pelvic nodal metastases. Despite recommendation for systemic therapy, the patient deteriorated quickly and died shortly thereafter. Conclusions: This study reports coexistence of p16-negative OPSCC and high-grade SCNEC in the HN. It highlights the diagnostic complexity, staging limitations, and therapeutic dilemmas of discordant histologies, while illustrating the fulminant clinical course typical of SCNEC of unknown origin. Early recognition, comprehensive pathology, and multidisciplinary management are essential, although prognosis remains dominated by the aggressive neuroendocrine component. Full article

Background/Objectives: Paragangliomas (PGLs) are rare neuroendocrine tumors, and data describing them from a medical oncology perspective are limited. We characterized clinicopathological features, tumor localization, and treatment outcomes. Methods: We retrospectively analyzed 43 patients with PGL at a single medical oncology department. The primary endpoint was recurrence-free survival (RFS), defined as time to first recurrence or death from any cause; overall survival (OS), objective response rate (ORR), disease control rate (DCR), and prognostic associations were secondary. Results: Median age was 44 years, 60.5% were female, and tumors were sympathetic (extra-adrenal) in 55.8% and parasympathetic (head and neck) in 39.5%. After a median follow-up of 116.8 months, 40 patients (93.0%) underwent resection, among whom 14 RFS events occurred (13 recurrences, 1 unrelated death). Median RFS and OS were not reached (60-month RFS, 67.1%; 120-month OS, 83.3%). Among nine patients receiving first-line systemic therapy (eight response-evaluable), ORR was 12.5% and DCR 37.5%. In exploratory univariable analysis, a Ki-67 index ≥ 3% correlated with recurrence (time-averaged hazard ratio, 4.53; 95% CI, 1.55–13.19; p = 0.006), alongside an R1 resection margin (not significant after Bonferroni correction). Conclusions: These findings may support further evaluation of Ki-67 within risk-adapted surveillance but do not replace germline testing. Full article

Pituitary neuroendocrine tumors (PitNETs) represent one of the most common intracranial lesions. The pharmacological approach to PitNETs is mainly based on the use of somatostatin (SS) receptor ligands (SRLs) and dopamine agonists (DAs), although resistance or poor efficacy occurs in a percentage of patients. SS receptors (SSTs) and dopamine receptor type 2 (DRD2) represent the principal targets of SRLs and DAs, respectively, in PitNET therapy. Over the years, SSTs and DRD2-related activated pathways have been characterized. Different factors that might play a role in affecting intracellular signaling transduction have been studied, including splicing machinery and its related factors. A severe dysregulation of splicing machinery components in all PitNET subtypes compared to normal pituitary was observed, and possible alterations that might underlie pharmacological resistance or intracellular pathway alterations were investigated. The detection of these alterations presented the opportunity to investigate small molecules that regulate splicing components as an alternative approach for PitNETs treatment. A systematic literature search was conducted in the PubMed database and supplemented by screening the references of the identified articles. A narrative synthesis of the research findings was provided, including relevant studies from 2015 up to date. It aimed to summarize the emerging role of splicing machinery, focusing on different splicing factors shown to be altered in different PitNET subtypes that might affect responsiveness to pharmacological treatment. Different ways to target splicing machinery and its mechanism of action have been described, with the goal of developing novel therapies for PitNETs. Full article

Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare malignant tumor arising from the olfactory epithelium of the sinonasal tract. Surgery combined with radiotherapy remains the standard treatment for localized disease, whereas chemotherapy is mainly used in advanced or recurrent cases. However, recurrent and metastatic ONB continues to present major therapeutic challenges, and traditional staging and histological grading systems cannot fully explain the marked differences in clinical behavior among patients. The primary objective of this review is to summarize recent advances in the molecular pathology, tumor microenvironment (TME), and emerging targeted therapeutic strategies in ONB. Emerging genomic and transcriptomic studies suggest that ONB comprises biologically heterogeneous tumors with distinct molecular and transcriptional programs associated with proliferation, neuroendocrine differentiation, angiogenesis, and stromal remodeling. Furthermore, we explore the increasing attention directed toward the TME, including immune-cell infiltration, angiogenic signaling, and immune checkpoint expression, which may influence therapeutic response. These molecular findings have generated interest in several potential targeted treatment strategies, including peptide receptor radionuclide therapy (PRRT), anti-angiogenic therapy, epigenetic-targeted therapy, immunotherapy, and DNA-damage-response-targeted approaches. Ultimately, although the current evidence remains limited because of the rarity of the disease, novel therapeutic strategies for ONB are emerging. In addition to summarizing the current landscape, this review discusses the translational challenges and future directions for precision oncology and biomarker-driven therapy, aiming to provide insights for improving individualized patient management. Full article

In 2010, the World Health Organization (WHO) standardized neuroendocrine neoplasm terminology, dividing these tumors by differentiation into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Registries such as the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database (NCDB) store legacy codes predating this framework, raising concern that registry-based research carries nomenclature errors into the clinical literature. We performed a scoping review of research published in 2012–2022 that used SEER and/or the NCDB to study gastroenteropancreatic neuroendocrine tumors, charting 170 articles (from 1079 citations) against the 2010 classification, with forward citation analysis (OpenAlex, Semantic Scholar) measuring downstream citation exposure. Of 141 assessable studies, 88% (n = 124) applied the nomenclature inaccurately: 82.3% included poorly or undifferentiated neoplasms within neuroendocrine tumor cohorts (mean 18.7% of the cohort) and 9.9% conflated database differentiation grade with WHO proliferation grade; appropriate usage did not improve over time. These discordant studies accumulated 7323 citations across 5145 works, with 87.9% cited by at least one review (1075 distinct reviews) and six cited by major guidelines (NCCN, ESMO, ENETS). Across research published from 2012 to 2022, nomenclature discordance was widespread, persistent throughout the study period, and present in studies frequently cited by the secondary and guideline literature. Because these cohorts incorporate more aggressive and poorly or undifferentiated neoplasms, their aggregate outcome estimates are likely biased toward a poorer prognosis, potentially overstating the aggressiveness of well-differentiated neuroendocrine tumors, particularly for prognostic estimates; this review characterized cohort composition rather than quantifying the effect on any individual study’s outcomes, and whether this bias has, in turn, affected clinical decision-making was not assessed here and remains a hypothesis for future work. Journals and guideline panels should require explicit alignment with current WHO definitions for registry-based studies. Full article

Prostate cancer remains one of the most frequently diagnosed malignancies in men worldwide, and despite favorable outcomes for localized disease, progression to castration-resistant prostate cancer (CRPC) represents a major clinical challenge associated with poor prognosis. CRPC is characterized by disease progression despite castrate levels of circulating testosterone and is most commonly diagnosed in the metastatic setting. Although the introduction of second-generation androgen receptor-targeted therapies has improved survival, resistance inevitably emerges. This review overviews the most recent findings in the field of CRPC with particular emphasis on the current understanding of the biological mechanisms of hormone-resistant cancer as well as the evidence on treatment strategies. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, focusing mainly on studies published between 2015 and 2025 that investigated molecular and cellular mechanisms of resistance to androgen deprivation therapy and androgen receptor (AR)-targeted treatments. Seventy-eight relevant articles were included in the final synthesis. The reviewed evidence highlights four major categories of resistance mechanisms. First, AR-dependent alterations remain predominant, including AR gene amplification, activating mutations, dysregulation of co-regulators, and expression of constitutively active AR splice variants such as AR-V7. Second, AR-independent or bypass pathways, most notably PI3K/AKT/mTOR, Wnt/β-catenin, MAPK, and glucocorticoid receptor signaling, enable tumor survival despite AR blockade. Third, lineage plasticity and transdifferentiation to neuroendocrine prostate cancer represent a distinct and increasingly recognized resistance mechanism driven by loss of TP53 and RB1 and epigenetic reprogramming. Finally, additional contributors, including intratumoral androgen synthesis, metabolic reprogramming, and tumor microenvironment interactions, further support disease progression. Together, these interconnected mechanisms underscore the biological complexity of CRPC and emphasize the need for biomarker-guided, combination-based therapeutic strategies to overcome resistance and improve patient outcomes. Full article

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA–WSB1–PSMA axis as a therapeutic vulnerability in refractory prostate cancer. Full article

Background/Objectives: Primary renal NETs are exceptionally rare neoplasms that occur disproportionately in horseshoe kidneys. Their rarity and non-specific clinical and radiological features make preoperative diagnosis particularly challenging. Methods: Herein, we report the case of a 60-year-old woman presenting with a painful left lumbar mass associated with dysuria and pollakiuria. Results: Computed tomography revealed a large heterogeneous tumor arising from the left moiety of a horseshoe kidney. Histopathological examination of the resected specimen demonstrated a 14 cm well-differentiated NET (grade 1) with diffuse chromogranin A and synaptophysin expression, a mitotic count of 1 per 2 mm², and a Ki-67 proliferation index of <1%. The histopathological and immunohistochemical findings, together with the absence of an extrarenal primary site on staging investigations, supported the diagnosis of a primary renal NET. The postoperative course was uneventful, and the patient remained disease-free after two years of follow-up. Conclusions: This case highlights the diagnostic challenges posed by this rare entity and underscores the importance of including primary renal neuroendocrine tumors in the differential diagnosis of renal masses arising in horseshoe kidneys. Full article

Background/Objectives: Pituitary neuroendocrine tumors (PitNETs) frequently exhibit invasive behaviors that complicate clinical treatment. While cyclin-dependent kinase 5 (CDK5) and lymphokine-activated killer T-cell-originated protein kinase (PBK, also known as PDZ-binding kinase) are implicated in tumor progression, their reciprocal regulatory mechanism remains unclear. This study aims to elucidate the CDK5-PBK interaction in PitNETs and identify potential therapeutic agents targeting this pathway. Methods: We utilized proximity labeling and phospho-specific assays to characterize the CDK5 and PBK interaction in PitNET cell lines. Immunohistochemical analysis was performed on patient tumor tissues to evaluate clinical relevance. Artificial intelligence (AI)-based virtual screening was employed to discover dual-target inhibitors. The therapeutic efficacy of the identified compound, proguanil hydrochloride, was subsequently evaluated using in vitro functional assays, alongside in vivo xenograft animal models. Results: We identified a mutual phosphorylation loop between CDK5 (at S159) and PBK (at T9) that activates insulin signaling, thereby promoting cellular proliferation and invasion in PitNETs. Patient tumor analysis revealed that the co-expression of phosphorylated CDK5 (S159) and PBK (T9) significantly correlates with tumor invasiveness (p < 0.001). Through AI screening, proguanil hydrochloride was identified as a candidate dual-target inhibitor. In vitro assays confirmed that it effectively reduces tumor cell growth, while in vivo xenograft studies validated its capacity to inhibit tumor progression. Conclusions: The CDK5-PBK mutual phosphorylation axis serves as a key driver of invasiveness in PitNETs. Proguanil hydrochloride represents a promising candidate dual-target therapeutic agent capable of disrupting this pathway to suppress tumor growth. Full article

Liver transplantation (LT) has evolved from a treatment for end-stage benign liver disease into a therapeutic strategy for selected oncological indications, including hepatocellular carcinoma (HCC), unresectable colorectal liver metastases (CRLM), hepatoblastoma, neuroendocrine tumor hepatic metastases, and hepatic epithelioid hemangioendothelioma. As the indications for LT expand and post-transplant survival improves, pulmonary recurrence has emerged as the predominant pattern of extrahepatic relapse across histologies. Yet no standardized surgical guidelines exist for managing lung metastases in the post-transplant patient. This narrative review synthesizes the available evidence on pulmonary metastasectomy following LT, addressing the incidence and tumor-specific patterns of pulmonary recurrence, the influence of immunosuppression on metastatic biology, surgical indications and contraindications, approach and timing considerations, and patient selection across primary histologies. We propose a practical decision-making framework integrating primary tumor biology, disease-free interval, lesion characteristics, immunosuppression regimen, and systemic therapy response. With the recent regulatory recognition of CRLM as a standard transplant indication and the ongoing SECA-III randomized trial, the downstream surgical management of pulmonary recurrence in LT recipients requires urgent evidence-based codification. Full article

An 8-year-old, 3.3 kg spayed female Korean Shorthair cat presented with chronic vomiting, waxing and waning hyporexia, and weight loss. Ultrasonography revealed a 1.5 × 1.6 cm ileocecocolic junction (ICCJ) mass and multiple colonic nodules. Fine-needle aspiration biopsy yielded predominantly oval cells with loosely cohesive clustering, and an intestinal neuroendocrine tumor (NET) was favored. Segmental resection of the distal ileum, ICCJ, and proximal colon with stapled side-to-side ileocolic anastomosis was performed. Histopathology also favored NET because the lesion consisted of relatively monomorphic round-to-polygonal cells with eosinophilic to chromophobic granular cytoplasm. Neoplastic cells showed strong CD20 immunoreactivity and nuclear PAX5 labeling but lacked CD3 immunoreactivity, with CD3-positive lymphocytes mainly peripheral to the neoplastic population. Labeling for chromogranin A, synaptophysin, and NSE was absent. These findings led to reclassification as B-cell lymphoma with NET-like morphology, most consistent with an intermediate-cell type. Postoperatively, vomiting improved and resolved after cyclophosphamide, doxorubicin, vincristine, and prednisolone-based chemotherapy was initiated. At approximately 6 months after surgery, body weight remained stable, no postoperative complications were identified, and no discrete recurrent mass was detected. This case demonstrates that feline enteric B-cell lymphoma may rarely exhibit NET-like morphology and be misclassified on cytology and routine histopathology without immunophenotypic confirmation. Full article

Background: Vitamin D deficiency is common in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Whether vitamin D status influences tumor aggressiveness and clinical outcomes remains uncertain. This review examines current evidence on the prevalence, determinants, clinical associations, and clinical relevance of vitamin D deficiency in GEP-NENs. Methods: A narrative and critical review of the literature was conducted using the PubMed/MEDLINE, Scopus, and Web of Science databases. Clinical studies, observational cohorts, translational research, selected mechanistic studies, and current clinical guidelines addressing vitamin D metabolism and neuroendocrine neoplasms were evaluated. Results: Vitamin D deficiency has been reported in approximately 60–80% of patients with GEP-NENs. Low serum 25-hydroxyvitamin D concentrations likely reflect multiple disease-related factors, including malabsorption, pancreatic exocrine insufficiency, chronic diarrhea, previous gastrointestinal surgery, and nutritional impairment. Several observational studies have linked lower vitamin D status with markers of more aggressive disease, including higher Ki-67 proliferation index values and shorter progression-free survival. Nevertheless, the available data are heterogeneous, predominantly observational, and do not support a causal relationship between vitamin D deficiency and tumor progression. At present, the main clinical rationale for assessing vitamin D status is to support metabolic care, preserve bone health, and prevent osteoporosis. Conclusions: Vitamin D deficiency is a frequent and clinically relevant comorbidity in patients with GEP-NENs. Although lower vitamin D status has been associated with markers of more aggressive disease, current findings do not support vitamin D supplementation as an anticancer treatment strategy. Prospective clinical and translational studies are needed to clarify the biological and clinical significance of vitamin D signaling in GEP-NENs. Full article

Gastrinoma is a rare neuroendocrine tumor in dogs that arises from functional pancreatic non-β cells and secretes excessive gastrin. Gastrinoma in dogs has a high metastasis rate at diagnosis, and curative treatment is often difficult. There are few reports describing the long-term outcomes of surgical treatment in dogs with gastrinoma, and no established method for monitoring disease progression has been reported. We report here the cases of two adult dogs with pancreatic gastrinoma treated with surgical resection. Pharmacological therapy using proton pump inhibitors was administered to control gastrointestinal symptoms caused by hypergastrinemia. Multiple surgeries were performed to reduce the volume of primary and metastatic gastrinoma lesions. Serial serum gastrin concentrations were used as an adjunctive monitoring marker during follow-up. Changes in serum gastrin concentrations were used to support decisions regarding further imaging. Additional surgery was performed based on serum gastrin concentrations, clinical signs, and diagnostic imaging findings. A total of four surgeries were performed in Case 1 and three surgeries in Case 2. Both dogs maintained well-controlled gastrointestinal symptoms and showed long-term survival. The changes in serum gastrin concentrations in these cases suggest that serial serum gastrin measurement may be useful for monitoring recurrence or tumor progression in canine gastrinoma. Full article

Background: Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE has become a cornerstone in the management of neuroendocrine tumors (NETs). However, the efficiency of this targeted therapy is highly dependent on the radiopharmaceutical drug delivery system and its infusion kinetics, which influence systemic biodistribution and therapeutic efficacy. This study evaluates various gravity-based infusion fluid dynamics to optimize the drug delivery profile, ensuring standardized delivery while minimizing residual activity. Methods: A retrospective analysis of 127 administrations of ¹⁷⁷Lu-DOTATATE (7.4 GBq per cycle) was conducted across 35 patients with NETs to assess vial dilution kinetics. Four distinct infusion rate (IR) strategies were compared to evaluate mass balance and delivery efficiency: constant infusion rate (1-IR); a single rate increase at 10 min (2-IR); two rate increases at 10 and 30 min (3-IR); and three rate increases at 10, 30, and 40 min (4-IR). Results: Stepwise increases in the IR significantly accelerated the vial clearance kinetics and reduced radiopharmaceutical stagnation within the infusion lines. Successful delivery of the target dose (98% of the pre-infusion activity measured in each specific vial) was achieved in 56% of cases with the 1-IR protocol (9 injections) and increased to 87% with 2-IR (45 injections), 97% with 3-IR (60 injections), and 100% with 4-IR (13 injections). Conclusions: Modulating fluid dynamics through stepwise IR protocols significantly enhances radiopharmaceutical delivery efficiency. The 3-IR protocol offers a favorable balance between procedural efficiency and clinical safety. Full article