Search Results (193)

Background: Lung carcinoids—typical and atypical—are rare neuroendocrine tumors (NETs) representing 1–2% of lung cancers. Despite clinicopathological differences, their clinical management often mirrors lung cancer protocols rather than NET-specific recommendations. Objectives: Portray a 12-year real-world experience with lung carcinoids at a Comprehensive Cancer Center, identifying gaps in diagnostic work-up, treatment decision-making, and follow-up. Methods: Retrospective observational cohort study of adult patients with histologically confirmed lung carcinoids diagnosed at IPO Porto between January 2013 and December 2024. Demographic, clinical, imaging, and treatment data were collected from electronic patient records. Analyses were descriptive. Results: Among 179 identified cases, 129 met eligibility criteria. Median age was 62 years (range 18–84); 53.6% were women and 53.5% were non-smokers; 84.5% had ECOG-PS 0–1. The most frequent presentation was respiratory symptoms (34.1%), followed by incidental findings (43.4%, of which ~20% were during staging or surveillance of other cancers). Typical carcinoids accounted for 49.6% and atypical for 43.4%. FDG-PET/CT was requested in 70.9% of cases, including many with typical carcinoid, and SSTR-PET/CT in 64.6% (dual PET in 38.8%). Most patients (65.1%) presented with stage I disease; 17.1% were stage IV. Mean time-to-first treatment was 83 days (range 1–259). Surgery was the first treatment option for 78.3% of patients. Conclusions: This real-world series highlights heterogeneity in diagnostic pathways, excessive FDG-PET use in typical carcinoids, and non-standardized follow-up. Dedicated multidisciplinary lung-NET boards and national reference centers are needed to homogenize and streamline patient management. Full article

Background: Neuroblastoma is the most common extracranial solid malignancy in infants and children. High-risk neuroblastoma patients are commonly treated with temozolomide (TMZ), which typically exhibits a poor therapeutic response. Serotonin, also known as 5-hydroxytryptamine (5-HT), plays various essential functions in the human body. In the central nervous system, it serves as a neurotransmitter. Beyond its physiological roles, 5-HT has recently been identified as a potential growth factor for several human tumors, including gliomas and carcinoid tumors. Recent literature has demonstrated that 5-HT receptor antagonists can inhibit the growth of cancer cells. Furthermore, both 5-HT receptors and their antagonists have been identified as potential anticancer agents, suggesting their significance in the development of new treatment strategies. Objectives: The primary aim of this study was to examine the effects of 5-HT and 5-HT antagonists on tumor (neuroblastoma (SH-SY5Y)) and healthy cells (microglia (HMC3)) and determine the impact of their interaction with the anticancer agent TMZ on cell proliferation/viability and migration. Methods: The study explored the interaction between 5-HT, the 5-HT antagonist granisetron (GRN), the anticancer agent TMZ, and their combinations, specifically assessing their influence on cell proliferation, viability, and migration. Results: As a result, the single and combined applications of 5-HT, TMZ, and GRN, a 5-HT antagonist, inhibited cell growth and proliferation in SH-SY5Y, causing decreased cell viability. Additionally, the combination of 5-HT and GRN increased the efficacy of TMZ. Conclusions: The study findings revealed that 5-HT and 5-HT antagonists may have therapeutic effects by exhibiting antiproliferative effects in SH-SY5Y cells at high concentrations. Full article

Background: Ovarian neuroendocrine neoplasms (O-NENs) are extremely rare, representing less than 1% of all ovarian neoplasms and under 5% of all neuroendocrine tumors (NETs). They encompass two primary histological subtypes: well-differentiated carcinoids and poorly differentiated neuroendocrine carcinomas, which display distinct biological behaviors and prognoses. The ovary can also be a site of metastasis from extra-ovarian NETs. Owing to their rarity, clinical management lacks standardization, and diagnosis is often incidental following surgery for presumed epithelial ovarian neoplasms. Objectives: This review aims to provide an updated synthesis of current evidence on the epidemiology, pathogenesis, clinical presentation, diagnosis, treatment strategies, and prognosis of O-NENs, highlighting unmet clinical needs. Methods: A literature search was performed on PubMed for the years 2014–2024 using the keywords: “ovarian neuroendocrine tumor”, “ovarian neuroendocrine neoplasm”, “ovarian neuroendocrine carcinoma”, and “ovarian carcinoid”. Only articles published in English were considered. Given the rarity of the disease, in addition to meta-analyses and systematic reviews, relevant case reports and case series were also included to provide a comprehensive clinical picture, yielding 32 eligible articles. Results: Evidence indicates that O-NENs remain understudied, with most data derived from case reports and small series. Clinical presentations vary from asymptomatic masses to hormone-related syndromes, often mimicking other ovarian pathologies. Diagnostic work-up typically follows the same protocol as epithelial ovarian cancer, with the neuroendocrine nature only recognized postoperatively. Treatment strategies are empirical and largely extrapolated from extra-ovarian NETs due to the absence of specific guidelines. Prognosis varies widely depending on histotype, stage, and secretory activity. Conclusions: O-NENs pose significant diagnostic and therapeutic challenges due to their rarity and heterogeneity. Greater clinical awareness, multidisciplinary management, and multicenter research are essential to establish evidence-based protocols and improve patient outcomes. Full article

Purpose: Zollinger–Ellison syndrome (ZES) is the most frequent, functional, malignant pancreatic neuroendocrine tumor syndrome (pNET), which is due to ectopic secretion of gastrin by a pNET/NET (i.e., gastrinomas) resulting in severe, refractory acid-peptic disease (ulcer, GERD). ZES has several unique management features, which lead to a number of unresolved controversies. Areas covered: Whereas both medical and surgical controversies exist, they have not been examined in detail for some time. This review contains an analysis of a number of the main current, medical controversies that are unresolved in ZES patients, including insights into the basis of these controversies and possible insights into their resolution from recent studies in patients with gastrinomas or from recent studies in other pNET syndromes or other neuroendocrine tumors (NETs). These include the following: controversies in the long-term control of acid secretion and acid antisecretory drug side-effects; controversies related to the difficulty in making the diagnosis of ZES; nonsurgical MEN1/ZES controversies related to the management of gastric carcinoids (Type II); nonsurgical MEN1/ZES controversies related to whether genotype–phenotype correlations exist in MEN1 patients including MEN1/ZES patients; nonsurgical MEN1/ZES controversies related to the roles of imaging/tumor localization in MEN1 patients for gastrinomas/pNETs in their initial/follow-up management; controversies related to the role of non-surgical tumor ablation for treatment of ZES/gastrinomas; and controversies related to medical treatment selection for advanced, metastatic disease in patients with ZES/gastrinomas/other malignant pNETs. Conclusions: In this paper, the basis for the development of each of these unique ZES-related controversies is discussed and insights into progress that could lead to their resolution are reviewed. Full article

Background/Objectives: Thymic neuroendocrine neoplasms (t-NENs) are rare, biologically aggressive malignancies of the anterior mediastinum. Due to their low incidence, clinical evidence remains limited, and treatment recommendations are primarily based on expert opinion and extrapolation from other neuroendocrine tumors. This study aimed to analyze the clinicopathological features, treatment patterns, and survival outcomes of patients with t-NENs treated at a single comprehensive cancer center over 25 years. Methods: A retrospective review was performed on 19 adult patients diagnosed with t-NENs between 2000 and 2024. Data on demographics, histology, treatment intent, modalities used, and outcomes were collected. Survival analyses—of overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS)—were conducted using the Kaplan–Meier method. Results: The median age was 52 years; 63% of patients were male. Atypical carcinoid was the most common histologic subtype (52.6%), followed by large cell neuroendocrine carcinoma (31.6%). Paraneoplastic syndromes, including Cushing’s syndrome, were observed in 26.3% of cases. Radical surgery was performed for 8 patients, but R0 resection was achieved in only 25% of them. Postoperative radiotherapy and chemotherapy were used for 36.8% and 15.8% of patients, respectively. Disease recurrence occurred in 44.4% of curatively treated patients. The median OS for the entire cohort was 127 months; patients treated with curative intent had a significantly longer OS (170 months) compared to those after palliative treatment (33 months). Median PFS in the palliative group was 11 months. Conclusions: t-NENs are aggressive tumors with high risk of recurrence and limited systemic treatment efficacy. Complete surgical resection remains the cornerstone of curative therapy. However, the overall prognosis remains poor, emphasizing the need for novel therapeutic strategies and prospective multicenter studies. Full article

Background/Objectives: Neuroendocrine tumors (NETs) of the lung account for about 30% of NETs. In localized and locally advanced forms, radical surgical resection is the standard of care. Although considered indolent tumors, they appear to be susceptible to post-surgical recurrence, with rates differing between typical and atypical carcinoid. Although still debated, several clinicopathologic factors are potentially associated with recurrence. The aim of this retrospective/prospective observational study is to evaluate the predictive role of clinicopathological factors and radiomics features in patients with NET of the lung. Methods: From January 2021 to April 2024, 45 consecutive patients who underwent radical (R0) surgery for lung NET at the ENETS Center of Excellence of the Sant’Andrea Hospital were enrolled, all with at least 12 months of postoperative follow-up and availability of preoperative unenhanced chest CT. Clinicopathologic and radiomic factors were considered (107 radiomic features). Of the individual characteristics, the impact on recurrence was assessed by univariate logistic regression. Results: Among the 45 patients included, 4 patients (8.9%) experienced disease recurrence. Among the clinicopathological features, major age at diagnosis (p = 0.020), atypical carcinoid (p = 0.010), presence of functional syndrome (p = 0.002), advanced stage at diagnosis (p = 0.013), necrosis (p = 0.017) higher Ki-67 (p = 0.001), higher mitotic count (p = 0.006), and pathologic lymph node (p = 0.006) were associated with disease recurrence. Three radiomic features were found to predict recurrence: DependenceEntropy (p = 0.049), DependenceNonUniformityNormalized (p = 0.024), and Elongation (p = 0.039). In this preliminary analysis, multivariate analysis was not performed due to the small sample size. Conclusions: This study has shown that radiomics can be a valuable tool in predicting recurrence. Currently, to our knowledge, no other studies on the possible application of radiomics as prognostic factors in patients with lung NET have been published. These encouraging findings warrant further investigations with larger, multicenter cohorts to validate these results and implement them by constructing a predictive model of recurrence. Full article

Neuroendocrine tumors (NETs) are heterogeneous neoplasms with different molecular characteristics and prognosis. Although slow-growing, NETs are often diagnosed at an advanced stage. The treatment choice depends on primary site, extent, grade, growth rate, somatostatin receptor status, functional status, performance status, and comorbidities. Precise knowledge of the biological and molecular features of NETs has led to the development of novel therapies. Therapeutic options include somatostatin analogs, multi-targeted tyrosine kinase inhibitors (e.g., sunitinib), or mammalian targets of rapamycin (mTOR) inhibitors (e.g., everolimus), telotristat ethyl, chemotherapy, and peptide-receptor radionuclide therapy. Pivotal studies that led to approval, treatment-related adverse events, and safety concerns, as demonstrated in clinical trials and real-world clinical practice. Questions, such as the optimal timing, selection, and sequence of therapies, and biomarkers that predict response to the novel agents in an individual patient, remain to be answered. We propose a stepwise approach for the management of advanced Gastro-entero-pancreatic (GEP)-NETs that utilizes a multidisciplinary team of experts. Biomarkers may assist in both the diagnosis and post-treatment follow-up in patients with GEP-NETs. The next decade of research on GEP-NETs is promising and should provide new insights into the molecular underpinnings of this disease, therapy selection, and the sequencing of the available therapies, along with the potential role of AL in NET pharmacotherapy. Full article

Objectives: Lung neuroendocrine tumors (LNETs) are rare, comprising 1–2% of lung cancers. This study aimed to compare overall survival (OS) and recurrence-free survival (RFS) after lobar resection versus sublobar resection for LNETs and to identify factors associated with prognosis and resection extent. Methods: We retrospectively analyzed patients with clinical stage I (T ≤ 4 cm, N0M0) typical or atypical carcinoid who underwent curative resection at Hadassah Medical Center and Kaplan medical Center between 2010 and 2024. Results: Seventy patients (mean age 56.8 ± 16 years; 63% female) were included. Lobar resection was performed in 40 (57%) and sublobar resection in 30 (43%; 15 segmentectomies, 15 wedge resections). Pathology revealed 50 typical carcinoid (71.43%) and 20 atypical carcinoid (28.57%). Final pathological stage was I in 57 patients (81.42%), II in 9 (12.86%), and III in 4 (5.71%), reflecting surgical upstaging in 13 patients (18.57%), all due to nodal involvement. Atypical carcinoid was associated with worse RFS, nodal upstaging, and adjuvant therapy (all p < 0.01). Patients undergoing sublobar resection were older, had higher comorbidity scores, more frequently presented with peripheral tumors, and underwent less frequent lymph node assessment (all p < 0.01). At a median follow-up of 3.8 years for OS and 2.0 years for RFS, survival rates were 95.7% for both. Neither OS, RFS, nor postoperative normalization of plasma pro-gastrin-releasing peptide (ProGRPp) levels differed significantly between lobar resection and sublobar resection (p = 0.94, p = 0.42, and p = 0.205, respectively). Conclusions: Sublobar resection may represent an acceptable surgical option for selected patients with clinical stage I LNETs, particularly for peripheral tumors ≤ 2 cm in older or comorbid patients. The high rate of nodal upstaging underscores the need for lymph node assessment, irrespective of resection extent. Full article

Introduction: Appendiceal neuroendocrine neoplasms (aNENs) are the most common malignant appendiceal neoplasms. Localized aNENs are typically managed with an appendectomy; however, right colectomy may be necessary in patients with a high risk of nodal disease. However, the role of right hemicolectomy and the optimal surveillance strategy, particularly for tumors between 1 and 2 cm, remains controversial. Material and Methods: This retrospective, observational study evaluated patients diagnosed with aNENs between January 1995 and July 2015 at two tertiary centers in Ireland and Italy. Data were extracted from a prospectively maintained registry and included clinical, pathological, and therapeutic variables, as well as follow-up outcomes. Results: Forty-three patients (41.8% male; median age 27.5 years) were included, with a median follow-up of 49 months. The median tumor size was 6.4 mm (range: 0.6–40 mm). The majority were G1 tumors (58%), and staging distribution was predominantly Stage I (60%). While no significant differences in demographics or tumor features were observed between centers, completion right hemicolectomies were more frequent in the Irish cohort (p = 0.04). Follow-up practices varied, with more intensive imaging and biochemical monitoring observed in the Italian cohort. Overall prognosis was excellent, with a single case of recurrence during the study period. Conclusions: Most aNENs are effectively managed with appendectomy alone, and routine follow-up may be unnecessary in the absence of adverse pathological features. Accurate risk stratification, driven by comprehensive histopathological assessment, is critical for optimizing management and surveillance strategies. Full article

Primary tricuspid regurgitation (TR) is an underrecognized valve disease characterized by structural abnormalities of the tricuspid valve (TV) apparatus, including leaflet prolapse, flail, rheumatic degeneration, carcinoid involvement and congenital malformations such as Ebstein’s anomaly. Historically neglected and often misclassified as functional, primary TR has recently gained attention due to advances in multimodality imaging and increased awareness of its pathophysiological complexity and adverse outcomes. A major challenge that remains is the accurate diagnosis of primary TR, as well as the optimal timing for intervention, particularly in asymptomatic patients. While surgical repair or replacement has been the traditional approach, recent developments in transcatheter therapies, such as tricuspid edge-to-edge repair, have broadened the therapeutic landscape for patients considered at high surgical risk. In this context, personalized medicine has emerged as a central paradigm in the management of this valvular disease. Tailored therapeutic decisions should include anatomical, functional, and clinical parameters, as well as patient-specific risk factors such as age and comorbidities. Advanced imaging modalities, including 3D echocardiography and cardiac magnetic resonance, are essential for guiding this individualized approach. This review summarizes the current understanding of the etiology, pathophysiology, diagnostic tools, and treatment strategies for primary TR, highlighting the critical role of personalized treatment pathways in optimizing clinical outcomes. Full article

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

Objective: Early-signet-ring cell carcinoma has a low malignancy and good prognosis, while advanced signet-ring cell carcinoma has high malignancy and high mortality. So, we need to understand the risk factors of early-signet-ring cell carcinoma, analyze the relationship between early gastric signet-ring cell carcinoma and non-Signet-ring cell carcinoma, and between pure signet-ring cell carcinoma and mixed signet-ring cell carcinoma, in order to provide the basis for the early diagnosis and treatment of signet-ring cell carcinoma. Methods: In this study, a retrospective analysis of 424 cases of early gastric cancer that underwent endoscopic submucosal dissection and surgical treatment between March 2019 and March 2023 in Shanghai Oriental Hospital was carried out. Among the cases, the two groups, namely, the signet-ring cell carcinoma and non-signet-ring cell carcinoma group, and the pure signet-ring cell carcinoma and mixed signet-ring cell carcinoma group, were compared and analyzed. With the help of logistic regression analysis, gender, age, smoking history, alcohol consumption history, tumor site, pathological characteristics, disease progression, tumor size, infiltration depth, and H. pylori infection were investigated between the two groups. Result: The results of the univariate regression analyses in the signet-ring cell carcinoma and non-signet-ring cell carcinoma groups showed that being female (p = 0.001), age < 60 years (p = 0.001), with cancer foci in the middle part of the stomach (p = 0.001), and with a mixed type of cancer foci (p = 0.007) were the risk factors for signet-ring cell carcinoma. In the multifactorial regression analysis, age < 60 years (OR = 1.037, CL = 1.008–1.067, p = 0.012), cancer foci in the middle part of the stomach (OR = 2.094, CL = 1.488–2.948, p = 0.001), mixed-type patients (OR = 0.702, CL = 0.519–0.951, p = 0.022), and women (OR = 0.421, CL = 0.254–0.698, p = 0.001) were the risk factors for signet-ring cell cancer. These are independent risk factors for signet-ring cell carcinoids. Univariate regression analysis on the pure and mixed signet-ring cell carcinoma groups showed that Helicobacter pylori infection (p = 0.001), Kimura–Takemoto classification O1–O3 (p = 0.013), flat and concave types (p = 0.004), and age < 60 years (p = 0.013) were risk factors affecting the development of pure signet-ring cell carcinoma. In the multifactorial regression analysis, age (OR = 0.233, CL = 0.059–0.930, p = 0.039) was the main independent risk factor for pure signet-ring cell carcinoma. Conclusions: Age < 60 years, cancer foci located in the middle of the stomach, mixed type, and female are associated with the development of early gastric signet-ring cell carcinoma; age < 60 years is related to the development of pure signet-ring cell carcinoma, so we need to pay attention to these clinical and pathological factors to prevent the growth of ring cell carcinoma. Full article

Efforts by the World Health Organization (WHO) have clarified the descriptive nomenclature and histologic grading of neuroendocrine neoplasms (NENs) in human medicine. Employing a standardized stratification scheme in conjunction with specific immunohistochemical markers, such as gastrin, enhances prognostic accuracy and guides treatment recommendations. Yet, this classification system has yet to be applied consistently in veterinary pathology. Histopathologic features and gastrin expression were analyzed in a group of canine gallbladder (GB) NENs. Based on the human WHO histologic system, which stratifies grade based on proliferative indices (mitotic count and Ki67%), all gradable GB NENs were classified as neuroendocrine tumors (NETs) rather than neuroendocrine carcinomas (NECs). Only one GB NET was positive for gastrin using immunohistochemical staining. Collectively, our data suggest that canine GB NENs have a lower grade than most human GB NENs and rarely express gastrin. The use of proliferative indices in the histologic characterization of canine GB NENs is likely to improve prognostic information. Given the limited expression of gastrin in these neoplasms in dogs, this marker is unlikely to be widely applicable as a druggable target. Full article

Pulmonary neuroendocrine tumors (PULMONARY NETs) are heterogeneous tumors ranging from well-differentiated to highly aggressive neoplasms. The aim of this study is to prospectively test pre-operative circulating free DNA (cfDNA) in PULMONARY NET patients undergoing surgery and evaluate its relationship to clinicopathological features. From February to December 2024, 136 patients with suspected primary lung cancer underwent pre-operative blood sampling, of whom 21 were diagnosed with PULMONARY NETs. Total cell-free nucleic acid extraction was performed using the Genexus Purification System (Thermofisher). cfDNA was quantified using a fluorometric assay with the Qubit dsDNA HS Assay kit (Thermofisher) and a capillary electrophoresis-based assay (cell-free DNA ScreenTape kit) on the Tape Station 4200 systems (Agilent). A cfDNA quality assessment was also obtained (cfDNA sizing and % cfDNA). Most patients had Stage I (18/21.85.7%) typical carcinoids (16/21.76.2%). Nodal involvement was detected in one patient (0.5%). Six months after surgery, all patients were alive without recurrence. Larger tumors presented higher levels of cfDNA. The mean tumor size in patients with cfDNA > 40 ng was 266 mm (±16.7 mm), compared to 13.2 mm (±7.3 mm) for cfDNA < 40 ng (p-value = 0.018). Higher levels of cfDNA were observed in patients with pStages greater than IA (p-value = 0.007). Although limited by a small sample group and biases of a surgical series, we observed that larger/advanced PULMONARY NETs presented higher cfDNA levels pre-operatively. Full article

Background: Cardiotoxicity remains a concern across cancer therapies. To date, there is a lack of extensive studies evaluating the potential impact of radioligand therapy (RLT) on myocardial injury in patients with neuroendocrine tumors (NETs), particularly in subgroups with increased susceptibility to such injury. This study aimed to assess the potential cardiotoxic effects and myocardial dysfunction associated with RLT using both [¹⁷⁷Lu]Lu-DOTA-TATE and tandem therapy with [¹⁷⁷Lu]Lu-DOTA-TATE/[⁹⁰Y]Y-DOTA-TATE in patients with NETs, including specific high-risk subgroups such as patients with pre-existing heart failure, carcinoid heart disease or those previously treated with chemotherapy, by monitoring serum concentration of troponin I, CK-MB, and NT-proBNP before and after RLT. Methods: We conducted a retrospective observational analysis of 60 consecutive NET patients who underwent 228 RLT courses. A comprehensive cardiac assessment, including a detailed medical history, was performed. Additionally, serum troponin I, CKMB and NT-proBNP concentrations were measured prior to treatment and 48 h post-therapy. Fifty-two patients received [¹⁷⁷Lu]Lu-DOTA-TATE monotherapy, while eight patients were treated with tandem therapy. Results: No increase in cardiotoxicity markers was observed in the overall study population following RLT administration (ΔTroponin −0.2 [−1.4–0.3]ng/L, p = 0.007; ∆CKMB 0.0 [−4.0–3.0]U/L, p = 0.90; ΔNT-proBNP 4.0 [−45.6–33.6]pg/mL) as well as in the subgroup receiving tandem therapy (ΔTroponin 0.7 [−1.7–013]ng/L, p = 0.68; ΔCKMB −0.5 [−10.7–3.0]U/L, p = 0.21; ΔNT-proBNP −21.6 [−44.1–16.7]pg/mL). Furthermore, none of the predefined patient subgroups exhibited signs of cardiotoxicity or evidence of myocardial dysfunction. Conclusions: RLT is a safe anticancer treatment option for patients with NETs in terms of cardiotoxicity and cardiac dysfunction, including those at higher risk of cardiovascular complications. Full article