RARE DISEASE
Ileal neuroendocrine tumor
Ileal neuroendocrine tumor
Ileal neuroendocrine tumor
Synonyms: Ileal neuroendocrine neoplasm
Synonyms: Ileal neuroendocrine neoplasm
Synonyms: Ileal neuroendocrine neoplasm
Drug discovery
1
drug
With orphan designation
Overview
Ileal neuroendocrine tumors (I-NETs), the most common small bowel NETs, arise from serotonin-producing enterochromaffin cells. These tumors frequently present at advanced stages (71% with metastases) due to nonspecific symptoms like abdominal pain or obstruction. Surgical resection remains first-line for localized disease, while systemic therapies—somatostatin analogs, peptide receptor radionuclide therapy (PRRT), and mTOR inhibitors—manage advanced/metastatic cases. Prognosis correlates with tumor grade and stage, with 5-year survival rates exceeding 88% for localized disease but declining with metastasis [1][2][4][12].
Burden
Metastatic spread: 40-64% present with distant metastases (commonly liver) [1][12][17]
Survival: 5-year cancer-specific survival 95% (localized) vs. 54% (distant) [1][17]
Comorbidities: Carcinoid syndrome (6-30% with liver metastases), cardiac fibrosis, and bowel obstruction [4][12][13]
Quality of life: Chronic diarrhea, flushing, and treatment-related side effects (e.g., interferon-induced fatigue) [3][14]
Therapies
Localized disease: Surgical resection (e.g., right hemicolectomy) with lymph node dissection [1][16][17]
Advanced disease:
- First-line: Somatostatin analogs (octreotide/lanreotide) for tumor control and symptom management [3][13][16]
- Second-line: PRRT (177Lu-DOTATATE), mTOR inhibitors (everolimus), or interferon-α [3][13][20]Metastatic liver disease: Hepatic resection, ablation, or embolization [3][16]
Categories: rare endocrine diseases, rare gastroenterological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
331 drug discovery papers about Ileal neuroendocrine tumor, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
331 drug discovery papers about Ileal neuroendocrine tumor, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-16 | Malignant Small Bowel Neoplasms: A 20-Year Retrospective Analysis in a Tertiary Center.
Malignant small bowel neoplasms are rare entities, and knowledge about them remains limited due to their histological diversity and the challenges associated with their investigation. However, their rising incidence has generated increasing clinical and research interest. This study aimed to describe the demographic and clinical characteristics of patients with malignant neoplasms of small bowel and the evolution in their diagnosis over 20 years in a tertiary center. Single-center retrospective study of data of patients with malignant small bowel neoplasms diagnosed between 2001 and 2020 in a tertiary hospital was performed. Statistical analysis was performed with SPSS version 29.0 (significance level ≤0.05). Out of 135 patients included, 57% were male. Eighty-nine neoplasms (65.9%) were found in the jejunum/ileum. Adenocarcinomas were the most frequently diagnosed neoplasms (31.1%), followed by neuroendocrine tumors (28.1%). At the time of diagnosis, the majority of patients (80.7%) were symptomatic, with severe complications - including obstruction, hemorrhage, or perforation - occurring in 55.4% of cases. Diagnosis typically involved CT scan (40.7%) or upper digestive endoscopy (22.2%); notably, 22.2% patients still required surgery for diagnosis. Diagnoses were mainly made between 2011 and 2020 (65.9%). Between 2001 and 2010, the most common diagnosed tumors were adenocarcinomas (37.0%), whereas between 2011 and 2020, the most frequently diagnosed malignant neoplasms were neuroendocrine tumors (37.1%). The distribution of histological types differed significantly over the years (p = 0.016). Adenocarcinoma had a higher mortality rate (54.8%) compared to neuroendocrine tumors (7.9%). Given the rarity of these tumors, the cohort of malignant small bowel neoplasms collected at this tertiary center over a 20-year period represents a substantial sample. More than half of patients were symptomatic at diagnosis, despite diagnostic advances over the years. In the last 10 years of the study, there has been an increase in incidence as well as in 5-year survival rates, possibly due to the higher incidence of neuroendocrine tumors and the lower incidence of adenocarcinomas. Notably, the diagnosis of each histological neoplasm type differed significantly statistically over the years, with neuroendocrine tumors being the most diagnosed in recent years.
2026-03-13 | Multivalvular Cardiac Involvement from Giant Hepatic Metastases of an Ileal Neuroendocrine Tumor.
Intestinal neuroendocrine tumors (NETs) are rare, slow-growing neoplasms arising from enterochromaffin cells, capable of secreting vasoactive substances that may cause carcinoid syndrome (CS) and clinically significant valvular heart disease. These tumors are often diagnosed at advanced stages due to nonspecific gastrointestinal symptoms, and distant metastases, particularly to the liver and lymph nodes, are common at presentation. Hormonal dysregulation can lead to chronic diarrhea, flushing, and bronchospasm, while carcinoid heart disease (CHD) contributes substantially to morbidity and mortality, typically affecting right-sided valves, with left-sided involvement being uncommon and more frequently associated with intracardiac shunts than exceptionally high serotonin exposure. Recent advances in management emphasize a multidisciplinary approach integrating systemic therapy, surgery, and targeted radionuclide treatment. Somatostatin analog therapy remains the cornerstone for controlling hormonal symptoms and slowing tumor progression. Aggressive cytoreductive surgery to achieve hormonal stabilization prior to surgical valve replacement has been associated with improved survival, symptomatic relief, and cardiac function. Targeted peptide receptor radionuclide therapy provides additional treatment for residual or metastatic disease, enhancing biochemical and radiological control. We report the case of a 61-year-old woman with chronic diarrhea, weight loss, and recurrent flushing, diagnosed with a well-differentiated ileal NET with extensive hepatic metastases and severe right-sided valvular disease with mild left-sided involvement. She underwent somatostatin analog therapy to control hormonal symptoms, cytoreductive surgery, and surgical replacement of the pulmonary and tricuspid valves. Subsequent targeted peptide receptor radionuclide therapy further reduced tumor burden and stabilized biochemical markers. This combined multimodal strategy resulted in sustained clinical improvement, normalization of neuroendocrine markers, and long-term oncologic stability, as the patient remains asymptomatic and oncologically stable after four years of follow-up from initial presentation. This case highlights the importance of early recognition, comprehensive evaluation, and a multidisciplinary strategy in advanced NETs. Coordinated care integrating endocrinology, oncology, cardiology, nuclear medicine, and surgery can significantly improve survival, hormonal control, and quality of life in patients with complex metastatic disease.
2025-11-10 | High incidence and poor prognosis of bone metastases in functioning small intestinal neuroendocrine tumors.
The prevalence and clinical relevance of bone metastases (BM) in advanced small intestinal neuroendocrine tumors (siNETs) is not well-documented. We analyzed data from 458 patients (54% male, median age 58 years) with histologically confirmed siNETs treated at the ENETS Center of Excellence Essen from 2003 to 2023. BM occurrence and their impact on skeletal-related events (SREs) and overall survival (OS) were assessed using standardized DOTATOC-PET/CT within a consistent "one-stop shop" multidisciplinary care model. At diagnosis, 305/458 patients (66.6%) had stage IV disease; BM were detected in 105/305 (34.4%). Functioning tumors were more frequent in BM patients (73%) than in the total cohort (40%). In 48.6% of patients, BM were initially visible on SSTR imaging only, becoming morphologically detectable after a median of 16 months. Most BM were osteoblastic (58%). During a median follow-up of 36 months, SREs occurred in 12.4% of BM patients, predominantly in those with osteolytic disease. SREs occurred in 27% of patients without antiresorptive therapy, but in none with treatment (p < 0.0001). Median OS was significantly shorter in patients with BM (127 vs. 170 months, p = 0.023), independent of age, sex or tumor grade. BM are frequent in siNET, particularly in functioning tumors, and are associated with reduced survival. BM may initially be detectable only by functional imaging but becomes morphologically visible within less than 1.5 years. Antiresorptive therapy may reduce SREs. Whether adapting NET treatment algorithm for BM improves OS needs to be tested in clinical trials.
2024-12-16 | Temozolomide and capecitabine regimen as first-line treatment in advanced gastroenteropancreatic neuroendocrine tumors at a Latin American reference center.
Numerous studies have indicated that the temozolomide and capecitabine regimen (TEMCAP) exhibits a certain level of efficacy in treating advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET). However, published data from Peru are limited. We hypothesize that this regimen could be a viable therapeutic option for advanced GEP-NET in the Peruvian population. To evaluate overall survival (OS) in patients diagnosed with advanced GEP-NET treated with TEMCAP at the Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima-Perú. A retrospective review was conducted to identify patients with GEP-NEN treated with the TEMCAP regimen between 2011 and 2021 at the INEN. A total of thirty-eight patients were included in the final analysis: Thirty-five received TEMCAP as a first-line treatment, and three as a second-line treatment. The primary objective was to evaluate OS. The efficacy and safety of TEMCAP were assessed until the occurrence of unacceptable toxicity or disease progression. Survival outcomes were estimated using the Kaplan-Meier method. The median age of the patients was 52 years (range 24-77 years), and 53.3% were female. The most common symptoms at diagnosis were abdominal pain in 31 patients (81.6%). Primary tumors included 12 in the rectum (31.6%), 11 in the pancreas (28.9%), 3 in the ileum (7.9%), 2 in the mesentery (5.3%), 2 in the small intestine (5.3%), 1 in the appendix (2.6%), 1 in the stomach (2.6%) and 6 cases of liver metastasis of unknown primary (15.8%). Five were neuroendocrine tumors (NET) G1 (13.2%), 33 were NET G2 (86.8%), five had Ki67 < 3% (13.2%), and 33 had Ki67 between 3% and 20% (86.8%). TEMCAP was administered to 35 (92.1%) patients as first-line treatment. OS at 12, 36, and 60 months was estimated in 80%, 66%, and 42%, respectively, with a median OS of 49 months. TEMCAP therapy is a viable first-line option regarding efficacy and tolerability in areas where standard therapy is inaccessible.
2024-11-20 | SUNLAND: a randomized, double-blinded phase II GERCOR trial of sunitinib versus placebo and lanreotide in patients with advanced progressive midgut neuroendocrine tumors.
Sunitinib, a multitarget tyrosine kinase inhibitor, showed encouraging antitumor activity and manageable toxicity in patients with advanced midgut neuroendocrine tumors (NETs) in earlier results from phase I and II trials. In this phase II trial, patients with a nonresectable grade 1 or 2 midgut progressive NET and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned 1:1 to receive 37.5 mg sunitinib or a placebo, combined with 120 mg lanreotide autogel every 28 days. The planned sample size was 104 patients. The primary outcome was investigator-assessed progression-free survival (PFS). The study was stopped early because of insufficient patient recruitment. Between January 2013 and December 2016, 44 patients were enrolled and received sunitinib (n = 22) or placebo (n = 22). The median age was 63.7 years (Q1-Q3 range, 56.6-68.1) and 26 patients (59.1%) were male. The main localization was ileum (N = 37, 84.1%) and the majority were grade 2 (n = 25, 56.8%). The median follow-up was 36.7 months (95% confidence interval (CI) 34.6-48.2). The median PFS was 9.84 months (95% CI 6.8-23.3) with sunitinib and 11.47 months (95% CI 5.4-15.3) with placebo (hazard ratio (HR) = 0.80, 95% CI 0.41-1.56, p = 0.51). There was no difference in overall survival between treatment arms (HR = 0.81, (95% CI 0.32-2.01), p = 0.64). The objective response rate was 9.1% with sunitinib and 0.0% with placebo, and 19 patients (86.4%) had stable disease. Thirty-nine patients (88.6%) completed the baseline QLQ-C30 questionnaire. Baseline health-related quality of life level was similar between treatment arms, except for physical and emotional functioning which were higher (p = 0.089) and lower (p = 0.023) in the sunitinib arm, respectively. Trends toward longer time until a definitive deterioration in favor of the sunitinib arm were observed for 10 out of 15 dimensions (HRs < 1), with a significant result for financial difficulties (HR = 0.31, (90% CI 0.10-0.94)). Twenty-seven patients (61.4%) had at least one adverse event grade ⩾3 (sunitinib: 72.7%, placebo: 50.0%), with only one patient grade 4 for hypertension and vomiting. Eleven deaths non-related to treatment occurred (sunitinib arm: n = 5, placebo arm: n = 6). Our study does not provide enough evidence to conclude the role of sunitinib in advanced midgut NETs, primarily due to a lower-than-expected number of enrolled patients. While we cannot entirely rule out the efficacy of sunitinib, lanreotide alone may play a significant role. EudraCT: 2012-001098-94.
antibodies
2025-07-23 | Expression of DLL3 and SEZ6 in the Spectrum of Neuroendocrine Neoplasia.
Delta-like protein 3 (DLL3), a Notch ligand, has been identified in high-grade small- and large-cell lung carcinomas and prostate neuroendocrine carcinomas (NECs). SEZ6 (Seizure-related 6 homolog), a membrane-associated protein, has also been identified neuroendocrine neoplasms (NENs). Both DLL3 and SEZ6 are targets of novel antibody-drug conjugates (ADCs). Their expression in the broader family of NENs remains to be clarified. We examined a series of NENs of all types as well as several non-neuroendocrine neoplasms using immunohistochemistry for DLL3 and SEZ6. Staining was scored with the semi-quantitative assessment of intensity and percentage of stained cells that yields a histoscore (H-score from 0 to 300). We identified strong expression of DLL3 in all lung NECs (average H-score 180) and SEZ6 in 1 of 3 (H-score 70). Merkel cell carcinomas (n = 13) expressed DLL3 strongly and diffusely (H-score 178, range 10-300) and 10 of 13 had positivity for SEZ6 (H-score 128). Both DLL3 and SEZ6 were expressed in medullary thyroid carcinomas (10 of 11 cases, H-scores 199 for DLL3 and 224 for SEZ6). Two thymic neuroendocrine tumors (NETs) had weak expression of DLL3 (H-score 20) and SEZ6 (H-score 70). Nine of 11 lung NETs expressed DLL3 (H-score 191), while only two had focal weak staining for SEZ6 (H-score 45). DLL3 was negative in nine of 11 pancreatic NETs; two grade 3 pancreatic NETs had variable weak positivity (H-score 5). In contrast, seven of 11 pancreatic NETs expressed SEZ6 (H-score 45). DLL3 was positive in two pancreatic NECs (H-score 197), and SEZ6 was positive in 1 (H-score 60). One of 13 gastric NETs, a metastatic grade 3 tumor, expressed both DLL3 and SEZ6 (H-score 200 for each) and one other expressed SEZ6 at lower levels. A gastric NEC was weakly positive for both markers (H-scores 50 and 40). All 10 duodenal, 10 ileal, and nine rectal NETs were negative for DLL3; eight duodenal, six ileal, and four rectal NETs expressed SEZ6 (average H-scores 206, 78 and 45, respectively). Among 10 appendiceal NETs, two expressed DLL3 focally and weakly (H-score 45); eight were positive for SEZ6 (H score 109). Duodenal NECS (n = 2) were negative for DLL3; one duodenal NEC expressed SEZ6 (H-score 110). Among five colonic NECs, two expressed DLL3 (H-score 50) and one expressed SEZ6 (H-score 40). Pituitary NETs also expressed DLL3 with eight of 18 positive (H-scores from 10 to 180), and 11 of 18 expressed SEZ6 (average H-score 65). Three of 20 paragangliomas expressed DLL3 weakly (H-score 43), and six expressed SEZ6 (H-score 73). One of four parathyroid carcinomas expressed DLL3 weakly (H-score 30), and all four were negative for SEZ6; five parathyroid adenomas were negative for both. In 43 non-neuroendocrine neoplasms of the GI tract, pancreas, and liver and 10 non-neuroendocrine thyroid carcinomas, there was only weak focal reactivity for DLL3 in three and two cases, respectively, and for SEZ6 in one case each. These results suggest that expression of DLL3 and SEZ6 varies among NENs of almost all types. Expression appears to be limited primarily to NENs and is rarely seen only focally and weakly in non-NENs. The presence of one or both of these antigens offers a novel approach to the treatment of patients with neuroendocrine neoplasms across the entire spectrum.
2022-10-18 | Potential new applications of immunotherapy for neuroendocrine neoplasms: immune landscape, current status and future perspectives
Neuroendocrine neoplasms (NENs) are a highly heterogeneous class of tumors arising from neuroendocrine cells and peptidergic neurons. After failure of first-line treatment, patients have poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICIs) may be a powerful means of increasing therapeutic efficacy for such patients, but ICIs alone have low response rates and short disease control durations in most NENs and may be effective for only a portion of the population. ICIs combined with other immunotherapies, targeted therapies, or cytotoxic drugs have achieved some efficacy in patients with NENs and are worthy of further exploration to assess their benefits to the population. In addition, accumulating experimental and clinical evidence supports that the interaction between neuroendocrine and immune systems is essential to maintain homeostasis, and assessment of this broad neuroendocrine-immune correlation is essential for NEN treatment. In this review, we summarize the immune microenvironment characteristics, advances in immunotherapy, predictive biomarkers of ICI efficacy for NENs, and the effects of common endocrine hormones on the immune system, highlighting possible new application areas for this promising treatment in neglected NENs.
2022-06-13 | The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms
Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.
2021-06-24 | Prognostic Factors in Curative Resected Locoregional Small Intestine Neuroendocrine Neoplasms.
Small intestinal neuroendocrine neoplasms (SI-NEN) are rare, and only about 40% of patients are diagnosed without distant metastases. Aim of the study was to identify prognostic factors in patients with potentially curative resected locoregional SI-NEN. Patients with curative resected locoregional SI-NEN (ENETS stages I-III) were retrieved from a prospective data base. Demographic, surgical and pathological data of patients with and without disease recurrence were retrospectively analyzed using univariate and multivariate analysis. In a 20-year period, 65 of 203 (32%) patients with SI-NEN were operated for stages I-III disease. Thirty-eight (58.5%) patients were men, and the median age at surgery was 59 (range 37-87) years. After median follow-up of 65 months, 14 patients experienced disease relapse median 28.5 (range 6-122) months after initial surgery, of which 2 died due to their disease. Multivariate analysis revealed age ≥ 60 years (HR = 6.41, 95% CI 1.38-29.67, p = 0.017), tumor size ≥ 2 cm (HR = 26.54, 95% CI 4.46-157.62, p < 0.001), lymph node ratio > 0.5 (HR 7.18, 95% CI 1.74-29.74, p = 0.007) and multifocal tumor growth (HR = 6.98, 95% CI 1.66-29.39, p = 0.008) as independent negative prognostic factors and right hemicolectomy compared to segmental small bowel resection (HR = 0.04, 95% CI 0.01-0.24, p < 0.001) as independent protector against recurrence. Patients with locoregional SI-NEN with an age ≥ 60 years, tumor size ≥ 2 cm, lymph node ratio > 0.5 and multiple small bowel tumor foci have an increased risk for recurrence and might benefit from adjuvant treatment. In contrast, right hemicolectomy of ileal SI-NEN seems to reduce the risk of recurrence.
2020-06-25 | Oncological management of advanced neuroendocrine tumours (Review)
The oncological principles of managing patients with gastroenteropancreatic neuroendocrine tumours (GEP‑NETs) depends on a number of factors and requires a multidisciplinary approach. Recent data have provided additional therapeutic options, including biotherapy, traditional chemotherapy and novel targeted agents. Somatostatin analogues (SSAs) inhibit multiple cellular functions, including secretion, motility and proliferation. Interferon appears to act through several mechanisms, with antisecretory effects, immunomodulatory effects and antiproliferative functions, the latter inhibiting direct growth or attenuating angiogenesis. Opinions on when to commence chemotherapy for well differentiated GEP‑NETs varies among experts. In previous years, reserving chemotherapy for patients with progressive disease (well differentiated, inoperable and/or metastatic GEP‑NETs) was reasonably well argued for. Most well differentiated endocrine tumours are richly vascular and many express vascular endothelial growth factor (VEGF) receptors. In a xenograft model of a human carcinoid, treatment with an anti‑VEGF monoclonal antibody was revealed to inhibit tumour growth and metastasis. As the role of angiogenesis and hypoxic‑associated factors appears to be associated with tumour aggressiveness, strategies using agents which target angiogenesis have been developed. Mammalian target of rapamycin (mTOR) is a conserved serine‑threonine kinase that regulates the cell cycle and metabolism in response to environmental factors. In addition, mTOR inhibition suppression was demonstrated to suppress NET growth. Each patient requires an individual approach to the choice of therapy, which should be selected depending on the severity of disease.
proteins
2026-04-22 | Real-world presentation and outcomes of gastroenteropancreatic neuroendocrine neoplasms in Italy: findings from the nationwide Itanet prospective database.
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is increasing, but population registries seldom capture detailed clinical data. The Italian Association for Neuroendocrine Tumours (Itanet) established a nationwide prospective database to describe presentation, diagnostic pathways, management, and outcomes of newly diagnosed GEP-NENs in Italy. This multicentre prospective observational study enrolled 2138 consecutive patients with newly diagnosed GEP-NENs across 38 Italian centres (2019-2024). Clinical, pathological, imaging, and treatment data were prospectively collected and centrally validated. Descriptive and survival analyses were performed; Ki-67 was modelled as a continuous variable. Median age was 60.6 years, and 55.9% (1195/2138) were male. Tumours were well-differentiated NETs in 90.8% of patients (1942/2138), mainly of pancreatic (41.4%, 886/2138) or ileal (19.7%, 422/2138) origin. Median Ki-67 was 2%. An incidental diagnosis occurred in 58.6% (1254/2138) of cases. Among symptomatic patients, the mean diagnostic delay was 197 days (224 for pancreatic vs 184 for small bowel; p = 0.039). 68Ga-DOTA-peptide PET showed higher diagnostic yield than CT or MRI in small-bowel primaries (93.7% vs 83.1% vs 67.4%), whereas performance was similar in pancreatic tumours. Data on first-line treatment were available for 2050 patients. Initial management included surgery in 36.4% (746/2050), watchful waiting in 19.7% (404/2050), endoscopic resection in 7.7% (158/2050). Overall, 30.6% (627/2050) of patients received systemic therapy, most commonly somatostatin analogues in 23.7% (487/2050). Over a median follow-up of 271 days (IQR 121-530), 62 deaths were observed (event rate 4.9%). Overall survival differed markedly according to metastatic status and tumour grade. Ki-67 was prognostic when modelled continuously (p < 0.001), and a 15% cutoff identified poorer outcomes. This nationwide prospective study delineates real-world diagnostic and therapeutic patterns of GEP-NENs in Italy, confirms Ki-67 as a continuous prognostic biomarker, and identifies a 15% threshold associated with worse survival, providing a benchmark for outcome assessment and future clinical research. None.
2025-12-30 | Cardiac Metastases in Neuroendocrine Neoplasms: A Single-Center Experience of Clinical Characteristics and Outcomes.
Background/Objectives: Cardiac metastases (CM) represent a rare manifestation of neuroendocrine neoplasms (NEN). Detailed clinical characteristics and significance remain understudied. Methods: We retrospectively evaluated 1201 patients with NEN treated at an ENETS Center of Excellence to determine prevalence, clinical features, and outcomes of cardiac metastases. CM were identified in 15 patients (prevalence 1.25%) through multimodal imaging, incorporating somatostatin receptor positron emission tomography/computed tomography (SSTR PET/CT). Metachronous CM occurrence accounted for 93% of cases. Results: The majority of patients showed well-differentiated tumors (G1/G2), with ileum being the most frequent site of origin. Clinical symptoms attributable to CM were observed in 27% of affected patients. Following CM detection, therapeutic management was adjusted in 73% of cases, most frequently by initiating peptide receptor radionuclide therapy (PRRT) n = 8, 53%. Median overall survival (OS) from CM diagnosis was 95 months, with an estimated 5-year survival rate of 77%, with a 5-year OS from NEN diagnosis of 87%. Conclusions: CM in NEN are rare and often clinically silent, with SSTR PET/CT proving essential for detection. While treatment adjustments were frequently observed, particularly with PRRT, OS remained favorable, indicating that the presence of CM in NEN serves as an indicator of metastatic spread rather than a standalone diagnostic determinant of survival. Larger, prospective studies are needed to further validate these findings and to better define the clinical implications of CM in NEN.
2025-10-01 | S6037 Well-Differentiated Ileal Neuroendocrine Tumor Presenting With Nonspecific GI Symptoms and Iron Deficiency Anemia
Introduction: Neuroendocrine tumors (NETs) are rare malignancies arising from neuroendocrine cells with an annual incidence of 6.98 per 100,000 persons, a steadily increasing. NETs most commonly occur in the small intestine (44.7%), rectum (19.6%), appendix (16.7%), and colon (10.6%). Clinical presentation is variable and nonspecific with many patients being asymptomatic or with vague symptoms, such as fatigue or abdominal pain. NETs can be indolent with metastatic disease found at time of diagnosis. Case Description/Methods: A 44-year-old woman with asthma, hypertension, and chronic heavy alcohol use presented to an outpatient GI clinic with several months of intermittent, non-radiating epigastric pain, new onset constipation, and intermittent nausea and vomiting. Lab work showed severe iron deficiency anemia. She underwent esophagogastroduodenoscopy and colonoscopy, which showed a solitary nonbleeding ulcer in the terminal ileum (TI) that was unable to be biopsied, an 11 mm polypoid lesion with congestion at the ileocecal valve, and a 6 mm cecal polyp. Immunohistochemical stain of the cecal polyp and abnormal TI mucosa revealed a well-differentiated NET G2 positive for synaptophysin, chromogranin, CD56, AE1/AE3, and Ki-67 = ∼10% nuclear positivity. Computed tomography enterogram showed mural thickening of the TI, cecum, and ascending colon consistent with enterocolitis, along with segmental bowel wall thickening concerning for inflammation. Ga-68 DOTATATE scan showed hypermetabolic uptake in the ileocecal region at the known NET site and metastasis to a right ileal mesenteric node, central liver, and duodenum/periduodenal node: with overall grade 4 uptake by Krening score. The ileocecal tumor was resected with a right hemicolectomy. Intraoperatively, all 5 lesions were localized to segment 4B and removed via hepatic segment 4B wedge resection. Surgical pathology confirmed well differentiated NET G2 at the ileocecal valve, in 1 liver fragment, and in local lymph nodes with extranodal extension. After discharge, she recovered well and will continue with surveillance computed tomography imaging to determine future need for systemic therapies. Discussion: This case illustrates the indolent nature of NETs and the critical importance of a careful endoscopic examination. Approximately 30% of patients with small bowel NETs have metastatic disease at the time of diagnosis. Timely workup and treatment are key as small intestine NETs with distant metastasis have a median overall survival of about 6 years, and incomplete tumor resection is associated with worse survival.
2025-04-21 | Abstract 4000: The significance of GLP-1R and its agonist in neuroendocrine neoplasms
Abstract Neuroendocrine neoplasms (NENs) are rare cancers originating from neuroendocrine cells that are found throughout the body. NENs are subdivided into 2 categories: Well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Both NET and NEC are highly metastatic and difficult to treat. NEN cases are on the rise and yet the etiology remains unclear. Commonly used drugs such as proton pump inhibitors can promote NET growth and result in poor prognosis for NET patients. Nowadays, the diabetes and weight loss drug semaglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, has gain extensive popularity and are currently being taken by over 15 million people in the USA. Semaglutide is contraindicated for NET patients with medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) since some of these cancers express the GLP-1R. However, this area of research remains understudied. Little is known about the expression levels of GLP-1R in NEN from different anatomical locations and their response to semaglutide since these are rare cancers and few NET models are available for drug testing. We recently identified 2 human NET cell lines (GOT1 and NT-3) that express the GLP-1R and showed that semaglutide promotes tumor cell growth both in vitro and in vivo. In this study, we aim to investigate the levels of GLP-1R expression in a large collection of NEN tissue microarrays and determine the effects of semaglutide in novel GLP-1R positive NET patient-derived spheroid cultures. We stained for GLP-1R expression by immunohistochemistry in 357 NET tissue microarrays covering 7 classes of NEN: 78 pancreas NET, 62 duodenum NET, 33 ileal NET, 42 lung NET, 10 small cell lung NEC, 12 extrapulmonary visceral NEC, 29 thyroid NET, 12 gastric NET, 6 appendix NET, 6 rectum NET, 22 pheochromocytoma, 22 paraganglioma, and 23 Merkel cell carcinoma. Furthermore, we generated GLP-1R positive pancreas, ileal, and duodenal NET spheroids for drug testing. Our data showed 45% of duodenum NET, 17% of gastric NET, and 14% of pancreas NET stained positive for GLP-1R expression. Less than 2% of other classes NET or NEC stained positive for GLP-1R expression. Using newly established NET patient-derived spheroid models, we demonstrated that 100 nM of semaglutide accelerates tumor cell growth by 1.4 to 2-fold. Surprisingly, duodenum NET is the class of NET that frequently express GLP-1R and should be highly cautioned for the semaglutide usage. Citation Format: Sophia A. Hueser, Reese E. Townsend, Casandro J. Chan, Leona Rupp, Leopaul J. Chan, Dawn E. Quelle, Joseph S. Dillon, Andrew M. Bellizzi, James R. Howe, Po Hien H. Ear. The significance of GLP-1R and its agonist in neuroendocrine neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4000.
2024-12-23 | Analysis of dosimetry and clinical variables in treatments of neuroendocrine tumours with [177Lu]Lu-DOTA-TATE.
The main objectives were to study differences between the first and the fourth cycle in dosimetry variables in patients treated for neuroendocrine tumours with four cycles of [177Lu]Lu-DOTA-TATE, as well as to look for absorbed dose-effect correlations aiming to help individualise and optimise this therapy for future patients. SPECT/CT based dosimetry of tumour lesions and kidneys was performed in the first and the fourth cycles of the [177Lu]Lu-DOTA-TATE treatments for 17 patients from 2020 to 2023. Clinical variables of interest were collected in order to look for correlations with some dosimetry variables. Statistical analysis was performed using the R software. Regarding dosimetry variables, for lesions a significant decrease in absorbed dose, mass and initial activity between the first and fourth cycles was observed. For kidneys, a significant increase in absorbed dose was observed. Effective decay constants did not significantly change neither for lesions nor for kidneys. The relative decrease in lesion masses correlated with their total absorbed dose. Total absorbed doses to kidneys were well below the toxicity limits mostly used in this therapy. Relative decrease in lesion absorbed doses was significantly lower for tumour primary sites in ileum and jejunum compared to those in pancreas. Moreover, radiological response correlated with clinical response. The results seem to indicate that the current treatment scheme could be optimised in order to obtain better treatment outcomes.
oligonucleotides
2022-11-24 | The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities
Neuroendocrine neoplasms (NENs) comprise a highly heterogeneous group of tumors arising from the diffuse neuroendocrine system. NENs mainly originate in gastrointestinal, pancreatic, and pulmonary tissues, and despite being rare, show rising incidence. The molecular mechanisms underlying NEN development are still poorly understood, although recent studies are unveiling their genomic, epigenomic and transcriptomic landscapes. RNA was originally considered as an intermediary between DNA and protein. Today, compelling evidence underscores the regulatory relevance of RNA processing, while new RNA molecules emerge with key functional roles in core cell processes. Indeed, correct functioning of the interrelated complementary processes comprising RNA biology, its processing, transport, and surveillance, is essential to ensure adequate cell homeostasis, and its misfunction is related to cancer at multiple levels. This review is focused on the dysregulation of RNA biology in NENs. In particular, we survey alterations in the splicing process and available information implicating the main RNA species and processes in NENs pathology, including their role as biomarkers, and their functionality and targetability. Understanding how NENs precisely (mis)behave requires a profound knowledge at every layer of their heterogeneity, to help improve NEN management. RNA biology provides a wide spectrum of previously unexplored processes and molecules that open new avenues for NEN detection, classification and treatment. The current molecular biology era is rapidly evolving to facilitate a detailed comprehension of cancer biology and is enabling the arrival of personalized, predictive and precision medicine to rare tumors like NENs.
2021-07-26 | IGF2 drives formation of ileal neuroendocrine tumors in patients and mice.
By the strictest of definitions, a genetic driver of tumorigenesis should fulfill two criteria: it should be altered in a high percentage of patient tumors, and it should also be able to cause the same type of tumor to form in mice. No gene that fits either of these criteria has ever been found for ileal neuroendocrine tumors (I-NETs), which in humans are known for an unusual lack of recurrently mutated genes, and which have never been detected in mice. In the following report, we show that I-NETs can be generated by transgenic RT2 mice, which is a classic model for a genetically unrelated disease, pancreatic neuroendocrine tumors (PNETs). The ability of RT2 mice to generate I-NETs depended upon genetic background. I-NETs appeared in a B6AF1 genetic background, but not in a B6 background nor even in an AB6F1 background. AB6F1 and B6AF1 have identical nuclear DNA but can potentially express different allelic forms of imprinted genes. This led us to test human I-NETs for loss of imprinting, and we discovered that the IGF2 gene showed loss of imprinting and increased expression in the I-NETs of 57% of patients. By increasing IGF2 activity genetically, I-NETs could be produced by RT2 mice in a B6 genetic background, which otherwise never developed I-NETs. The facts that IGF2 is altered in a high percentage of patients with I-NETs and that I-NETs can form in mice that have elevated IGF2 activity, define IGF2 as the first genetic driver of ileal neuroendocrine tumorigenesis.
2017-02-06 | Osteotropism of neuroendocrine tumors: role of the CXCL12/ CXCR4 pathway in promoting EMT in vitro.
// Mauro Cives 1 , Davide Quaresmini 1 , Francesca Maria Rizzo 1 , Claudia Felici 1 , Stella D'Oronzo 1 , Valeria Simone 1 , Franco Silvestris 1 1 Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro", Bari, Italy Correspondence to: Franco Silvestris, email: francesco.silvestris@uniba.it Keywords: carcinoid, bone metastasis, SDF-1, epithelial-mesenchymal transition, GPCR nuclear translocation Received: August 31, 2016 Accepted: January 24, 2017 Published: February 06, 2017 ABSTRACT Neuroendocrine tumors (NETs) metastasize to the skeleton in approximately 20% of patients. We have previously shown that the epithelial-mesenchymal transition (EMT) regulates the NET osteotropism and that CXCR4 overexpression predicts bone spreading. Here, we unravel the molecular mechanisms linking the activation of the CXCL12/CXCR4 axis to the bone colonization of NETs using cell lines representative of pancreatic (BON1, CM, QGP1), intestinal (CNDT 2.5), and bronchial origin (H727). By combining flow cytometry and ELISA, BON1, CM and QGP1 cells were defined as CXCR4 high /CXCL12 low , while H727 and CNDT 2.5 were CXCR4 low /CXCL12 high . CXCL12 was inert on cell proliferation, but significantly increased the in vitro osteotropism of CXCR4 high /CXCL12 low cells, as assessed by transwell assays with or without Matrigel membranes. In these cells, CXCL12 induced in vitro a marked EMT-like transcriptional shift with acquirement of a mesenchymal shape. The nuclei of CXCR4 high /CXCL12 low NET cells were typically enriched in non-phosphorylated CXCR4, particularly upon agonist stimulation. Silencing of CXCR4 via siRNA prevented the CXCL12-induced EMT in CXCR4 high /CXCL12 low NET cell lines resulting in the abrogation of both migration and transcriptional mesenchymal patterns. Our data suggest that CXCL12 conveys EMT-promoting signals in NET cells through CXCR4, which in turn regulates transcriptional, morphologic and functional modifications resulting in enhanced in vitro osteotropism of NET cells. Unique functions of CXCR4 may be segregated in relation to its subcellular localization and may acquire potential relevance in future in vivo studies.
small molecules
2026-03-16 | Malignant Small Bowel Neoplasms: A 20-Year Retrospective Analysis in a Tertiary Center.
Malignant small bowel neoplasms are rare entities, and knowledge about them remains limited due to their histological diversity and the challenges associated with their investigation. However, their rising incidence has generated increasing clinical and research interest. This study aimed to describe the demographic and clinical characteristics of patients with malignant neoplasms of small bowel and the evolution in their diagnosis over 20 years in a tertiary center. Single-center retrospective study of data of patients with malignant small bowel neoplasms diagnosed between 2001 and 2020 in a tertiary hospital was performed. Statistical analysis was performed with SPSS version 29.0 (significance level ≤0.05). Out of 135 patients included, 57% were male. Eighty-nine neoplasms (65.9%) were found in the jejunum/ileum. Adenocarcinomas were the most frequently diagnosed neoplasms (31.1%), followed by neuroendocrine tumors (28.1%). At the time of diagnosis, the majority of patients (80.7%) were symptomatic, with severe complications - including obstruction, hemorrhage, or perforation - occurring in 55.4% of cases. Diagnosis typically involved CT scan (40.7%) or upper digestive endoscopy (22.2%); notably, 22.2% patients still required surgery for diagnosis. Diagnoses were mainly made between 2011 and 2020 (65.9%). Between 2001 and 2010, the most common diagnosed tumors were adenocarcinomas (37.0%), whereas between 2011 and 2020, the most frequently diagnosed malignant neoplasms were neuroendocrine tumors (37.1%). The distribution of histological types differed significantly over the years (p = 0.016). Adenocarcinoma had a higher mortality rate (54.8%) compared to neuroendocrine tumors (7.9%). Given the rarity of these tumors, the cohort of malignant small bowel neoplasms collected at this tertiary center over a 20-year period represents a substantial sample. More than half of patients were symptomatic at diagnosis, despite diagnostic advances over the years. In the last 10 years of the study, there has been an increase in incidence as well as in 5-year survival rates, possibly due to the higher incidence of neuroendocrine tumors and the lower incidence of adenocarcinomas. Notably, the diagnosis of each histological neoplasm type differed significantly statistically over the years, with neuroendocrine tumors being the most diagnosed in recent years.
2026-03-13 | Multivalvular Cardiac Involvement from Giant Hepatic Metastases of an Ileal Neuroendocrine Tumor.
Intestinal neuroendocrine tumors (NETs) are rare, slow-growing neoplasms arising from enterochromaffin cells, capable of secreting vasoactive substances that may cause carcinoid syndrome (CS) and clinically significant valvular heart disease. These tumors are often diagnosed at advanced stages due to nonspecific gastrointestinal symptoms, and distant metastases, particularly to the liver and lymph nodes, are common at presentation. Hormonal dysregulation can lead to chronic diarrhea, flushing, and bronchospasm, while carcinoid heart disease (CHD) contributes substantially to morbidity and mortality, typically affecting right-sided valves, with left-sided involvement being uncommon and more frequently associated with intracardiac shunts than exceptionally high serotonin exposure. Recent advances in management emphasize a multidisciplinary approach integrating systemic therapy, surgery, and targeted radionuclide treatment. Somatostatin analog therapy remains the cornerstone for controlling hormonal symptoms and slowing tumor progression. Aggressive cytoreductive surgery to achieve hormonal stabilization prior to surgical valve replacement has been associated with improved survival, symptomatic relief, and cardiac function. Targeted peptide receptor radionuclide therapy provides additional treatment for residual or metastatic disease, enhancing biochemical and radiological control. We report the case of a 61-year-old woman with chronic diarrhea, weight loss, and recurrent flushing, diagnosed with a well-differentiated ileal NET with extensive hepatic metastases and severe right-sided valvular disease with mild left-sided involvement. She underwent somatostatin analog therapy to control hormonal symptoms, cytoreductive surgery, and surgical replacement of the pulmonary and tricuspid valves. Subsequent targeted peptide receptor radionuclide therapy further reduced tumor burden and stabilized biochemical markers. This combined multimodal strategy resulted in sustained clinical improvement, normalization of neuroendocrine markers, and long-term oncologic stability, as the patient remains asymptomatic and oncologically stable after four years of follow-up from initial presentation. This case highlights the importance of early recognition, comprehensive evaluation, and a multidisciplinary strategy in advanced NETs. Coordinated care integrating endocrinology, oncology, cardiology, nuclear medicine, and surgery can significantly improve survival, hormonal control, and quality of life in patients with complex metastatic disease.
2025-11-10 | High incidence and poor prognosis of bone metastases in functioning small intestinal neuroendocrine tumors.
The prevalence and clinical relevance of bone metastases (BM) in advanced small intestinal neuroendocrine tumors (siNETs) is not well-documented. We analyzed data from 458 patients (54% male, median age 58 years) with histologically confirmed siNETs treated at the ENETS Center of Excellence Essen from 2003 to 2023. BM occurrence and their impact on skeletal-related events (SREs) and overall survival (OS) were assessed using standardized DOTATOC-PET/CT within a consistent "one-stop shop" multidisciplinary care model. At diagnosis, 305/458 patients (66.6%) had stage IV disease; BM were detected in 105/305 (34.4%). Functioning tumors were more frequent in BM patients (73%) than in the total cohort (40%). In 48.6% of patients, BM were initially visible on SSTR imaging only, becoming morphologically detectable after a median of 16 months. Most BM were osteoblastic (58%). During a median follow-up of 36 months, SREs occurred in 12.4% of BM patients, predominantly in those with osteolytic disease. SREs occurred in 27% of patients without antiresorptive therapy, but in none with treatment (p < 0.0001). Median OS was significantly shorter in patients with BM (127 vs. 170 months, p = 0.023), independent of age, sex or tumor grade. BM are frequent in siNET, particularly in functioning tumors, and are associated with reduced survival. BM may initially be detectable only by functional imaging but becomes morphologically visible within less than 1.5 years. Antiresorptive therapy may reduce SREs. Whether adapting NET treatment algorithm for BM improves OS needs to be tested in clinical trials.
2024-12-16 | Temozolomide and capecitabine regimen as first-line treatment in advanced gastroenteropancreatic neuroendocrine tumors at a Latin American reference center.
Numerous studies have indicated that the temozolomide and capecitabine regimen (TEMCAP) exhibits a certain level of efficacy in treating advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET). However, published data from Peru are limited. We hypothesize that this regimen could be a viable therapeutic option for advanced GEP-NET in the Peruvian population. To evaluate overall survival (OS) in patients diagnosed with advanced GEP-NET treated with TEMCAP at the Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima-Perú. A retrospective review was conducted to identify patients with GEP-NEN treated with the TEMCAP regimen between 2011 and 2021 at the INEN. A total of thirty-eight patients were included in the final analysis: Thirty-five received TEMCAP as a first-line treatment, and three as a second-line treatment. The primary objective was to evaluate OS. The efficacy and safety of TEMCAP were assessed until the occurrence of unacceptable toxicity or disease progression. Survival outcomes were estimated using the Kaplan-Meier method. The median age of the patients was 52 years (range 24-77 years), and 53.3% were female. The most common symptoms at diagnosis were abdominal pain in 31 patients (81.6%). Primary tumors included 12 in the rectum (31.6%), 11 in the pancreas (28.9%), 3 in the ileum (7.9%), 2 in the mesentery (5.3%), 2 in the small intestine (5.3%), 1 in the appendix (2.6%), 1 in the stomach (2.6%) and 6 cases of liver metastasis of unknown primary (15.8%). Five were neuroendocrine tumors (NET) G1 (13.2%), 33 were NET G2 (86.8%), five had Ki67 < 3% (13.2%), and 33 had Ki67 between 3% and 20% (86.8%). TEMCAP was administered to 35 (92.1%) patients as first-line treatment. OS at 12, 36, and 60 months was estimated in 80%, 66%, and 42%, respectively, with a median OS of 49 months. TEMCAP therapy is a viable first-line option regarding efficacy and tolerability in areas where standard therapy is inaccessible.
2024-11-20 | SUNLAND: a randomized, double-blinded phase II GERCOR trial of sunitinib versus placebo and lanreotide in patients with advanced progressive midgut neuroendocrine tumors.
Sunitinib, a multitarget tyrosine kinase inhibitor, showed encouraging antitumor activity and manageable toxicity in patients with advanced midgut neuroendocrine tumors (NETs) in earlier results from phase I and II trials. In this phase II trial, patients with a nonresectable grade 1 or 2 midgut progressive NET and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned 1:1 to receive 37.5 mg sunitinib or a placebo, combined with 120 mg lanreotide autogel every 28 days. The planned sample size was 104 patients. The primary outcome was investigator-assessed progression-free survival (PFS). The study was stopped early because of insufficient patient recruitment. Between January 2013 and December 2016, 44 patients were enrolled and received sunitinib (n = 22) or placebo (n = 22). The median age was 63.7 years (Q1-Q3 range, 56.6-68.1) and 26 patients (59.1%) were male. The main localization was ileum (N = 37, 84.1%) and the majority were grade 2 (n = 25, 56.8%). The median follow-up was 36.7 months (95% confidence interval (CI) 34.6-48.2). The median PFS was 9.84 months (95% CI 6.8-23.3) with sunitinib and 11.47 months (95% CI 5.4-15.3) with placebo (hazard ratio (HR) = 0.80, 95% CI 0.41-1.56, p = 0.51). There was no difference in overall survival between treatment arms (HR = 0.81, (95% CI 0.32-2.01), p = 0.64). The objective response rate was 9.1% with sunitinib and 0.0% with placebo, and 19 patients (86.4%) had stable disease. Thirty-nine patients (88.6%) completed the baseline QLQ-C30 questionnaire. Baseline health-related quality of life level was similar between treatment arms, except for physical and emotional functioning which were higher (p = 0.089) and lower (p = 0.023) in the sunitinib arm, respectively. Trends toward longer time until a definitive deterioration in favor of the sunitinib arm were observed for 10 out of 15 dimensions (HRs < 1), with a significant result for financial difficulties (HR = 0.31, (90% CI 0.10-0.94)). Twenty-seven patients (61.4%) had at least one adverse event grade ⩾3 (sunitinib: 72.7%, placebo: 50.0%), with only one patient grade 4 for hypertension and vomiting. Eleven deaths non-related to treatment occurred (sunitinib arm: n = 5, placebo arm: n = 6). Our study does not provide enough evidence to conclude the role of sunitinib in advanced midgut NETs, primarily due to a lower-than-expected number of enrolled patients. While we cannot entirely rule out the efficacy of sunitinib, lanreotide alone may play a significant role. EudraCT: 2012-001098-94.
antibodies
2025-07-23 | Expression of DLL3 and SEZ6 in the Spectrum of Neuroendocrine Neoplasia.
Delta-like protein 3 (DLL3), a Notch ligand, has been identified in high-grade small- and large-cell lung carcinomas and prostate neuroendocrine carcinomas (NECs). SEZ6 (Seizure-related 6 homolog), a membrane-associated protein, has also been identified neuroendocrine neoplasms (NENs). Both DLL3 and SEZ6 are targets of novel antibody-drug conjugates (ADCs). Their expression in the broader family of NENs remains to be clarified. We examined a series of NENs of all types as well as several non-neuroendocrine neoplasms using immunohistochemistry for DLL3 and SEZ6. Staining was scored with the semi-quantitative assessment of intensity and percentage of stained cells that yields a histoscore (H-score from 0 to 300). We identified strong expression of DLL3 in all lung NECs (average H-score 180) and SEZ6 in 1 of 3 (H-score 70). Merkel cell carcinomas (n = 13) expressed DLL3 strongly and diffusely (H-score 178, range 10-300) and 10 of 13 had positivity for SEZ6 (H-score 128). Both DLL3 and SEZ6 were expressed in medullary thyroid carcinomas (10 of 11 cases, H-scores 199 for DLL3 and 224 for SEZ6). Two thymic neuroendocrine tumors (NETs) had weak expression of DLL3 (H-score 20) and SEZ6 (H-score 70). Nine of 11 lung NETs expressed DLL3 (H-score 191), while only two had focal weak staining for SEZ6 (H-score 45). DLL3 was negative in nine of 11 pancreatic NETs; two grade 3 pancreatic NETs had variable weak positivity (H-score 5). In contrast, seven of 11 pancreatic NETs expressed SEZ6 (H-score 45). DLL3 was positive in two pancreatic NECs (H-score 197), and SEZ6 was positive in 1 (H-score 60). One of 13 gastric NETs, a metastatic grade 3 tumor, expressed both DLL3 and SEZ6 (H-score 200 for each) and one other expressed SEZ6 at lower levels. A gastric NEC was weakly positive for both markers (H-scores 50 and 40). All 10 duodenal, 10 ileal, and nine rectal NETs were negative for DLL3; eight duodenal, six ileal, and four rectal NETs expressed SEZ6 (average H-scores 206, 78 and 45, respectively). Among 10 appendiceal NETs, two expressed DLL3 focally and weakly (H-score 45); eight were positive for SEZ6 (H score 109). Duodenal NECS (n = 2) were negative for DLL3; one duodenal NEC expressed SEZ6 (H-score 110). Among five colonic NECs, two expressed DLL3 (H-score 50) and one expressed SEZ6 (H-score 40). Pituitary NETs also expressed DLL3 with eight of 18 positive (H-scores from 10 to 180), and 11 of 18 expressed SEZ6 (average H-score 65). Three of 20 paragangliomas expressed DLL3 weakly (H-score 43), and six expressed SEZ6 (H-score 73). One of four parathyroid carcinomas expressed DLL3 weakly (H-score 30), and all four were negative for SEZ6; five parathyroid adenomas were negative for both. In 43 non-neuroendocrine neoplasms of the GI tract, pancreas, and liver and 10 non-neuroendocrine thyroid carcinomas, there was only weak focal reactivity for DLL3 in three and two cases, respectively, and for SEZ6 in one case each. These results suggest that expression of DLL3 and SEZ6 varies among NENs of almost all types. Expression appears to be limited primarily to NENs and is rarely seen only focally and weakly in non-NENs. The presence of one or both of these antigens offers a novel approach to the treatment of patients with neuroendocrine neoplasms across the entire spectrum.
2022-10-18 | Potential new applications of immunotherapy for neuroendocrine neoplasms: immune landscape, current status and future perspectives
Neuroendocrine neoplasms (NENs) are a highly heterogeneous class of tumors arising from neuroendocrine cells and peptidergic neurons. After failure of first-line treatment, patients have poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICIs) may be a powerful means of increasing therapeutic efficacy for such patients, but ICIs alone have low response rates and short disease control durations in most NENs and may be effective for only a portion of the population. ICIs combined with other immunotherapies, targeted therapies, or cytotoxic drugs have achieved some efficacy in patients with NENs and are worthy of further exploration to assess their benefits to the population. In addition, accumulating experimental and clinical evidence supports that the interaction between neuroendocrine and immune systems is essential to maintain homeostasis, and assessment of this broad neuroendocrine-immune correlation is essential for NEN treatment. In this review, we summarize the immune microenvironment characteristics, advances in immunotherapy, predictive biomarkers of ICI efficacy for NENs, and the effects of common endocrine hormones on the immune system, highlighting possible new application areas for this promising treatment in neglected NENs.
2022-06-13 | The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms
Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.
2021-06-24 | Prognostic Factors in Curative Resected Locoregional Small Intestine Neuroendocrine Neoplasms.
Small intestinal neuroendocrine neoplasms (SI-NEN) are rare, and only about 40% of patients are diagnosed without distant metastases. Aim of the study was to identify prognostic factors in patients with potentially curative resected locoregional SI-NEN. Patients with curative resected locoregional SI-NEN (ENETS stages I-III) were retrieved from a prospective data base. Demographic, surgical and pathological data of patients with and without disease recurrence were retrospectively analyzed using univariate and multivariate analysis. In a 20-year period, 65 of 203 (32%) patients with SI-NEN were operated for stages I-III disease. Thirty-eight (58.5%) patients were men, and the median age at surgery was 59 (range 37-87) years. After median follow-up of 65 months, 14 patients experienced disease relapse median 28.5 (range 6-122) months after initial surgery, of which 2 died due to their disease. Multivariate analysis revealed age ≥ 60 years (HR = 6.41, 95% CI 1.38-29.67, p = 0.017), tumor size ≥ 2 cm (HR = 26.54, 95% CI 4.46-157.62, p < 0.001), lymph node ratio > 0.5 (HR 7.18, 95% CI 1.74-29.74, p = 0.007) and multifocal tumor growth (HR = 6.98, 95% CI 1.66-29.39, p = 0.008) as independent negative prognostic factors and right hemicolectomy compared to segmental small bowel resection (HR = 0.04, 95% CI 0.01-0.24, p < 0.001) as independent protector against recurrence. Patients with locoregional SI-NEN with an age ≥ 60 years, tumor size ≥ 2 cm, lymph node ratio > 0.5 and multiple small bowel tumor foci have an increased risk for recurrence and might benefit from adjuvant treatment. In contrast, right hemicolectomy of ileal SI-NEN seems to reduce the risk of recurrence.
2020-06-25 | Oncological management of advanced neuroendocrine tumours (Review)
The oncological principles of managing patients with gastroenteropancreatic neuroendocrine tumours (GEP‑NETs) depends on a number of factors and requires a multidisciplinary approach. Recent data have provided additional therapeutic options, including biotherapy, traditional chemotherapy and novel targeted agents. Somatostatin analogues (SSAs) inhibit multiple cellular functions, including secretion, motility and proliferation. Interferon appears to act through several mechanisms, with antisecretory effects, immunomodulatory effects and antiproliferative functions, the latter inhibiting direct growth or attenuating angiogenesis. Opinions on when to commence chemotherapy for well differentiated GEP‑NETs varies among experts. In previous years, reserving chemotherapy for patients with progressive disease (well differentiated, inoperable and/or metastatic GEP‑NETs) was reasonably well argued for. Most well differentiated endocrine tumours are richly vascular and many express vascular endothelial growth factor (VEGF) receptors. In a xenograft model of a human carcinoid, treatment with an anti‑VEGF monoclonal antibody was revealed to inhibit tumour growth and metastasis. As the role of angiogenesis and hypoxic‑associated factors appears to be associated with tumour aggressiveness, strategies using agents which target angiogenesis have been developed. Mammalian target of rapamycin (mTOR) is a conserved serine‑threonine kinase that regulates the cell cycle and metabolism in response to environmental factors. In addition, mTOR inhibition suppression was demonstrated to suppress NET growth. Each patient requires an individual approach to the choice of therapy, which should be selected depending on the severity of disease.
proteins
2026-04-22 | Real-world presentation and outcomes of gastroenteropancreatic neuroendocrine neoplasms in Italy: findings from the nationwide Itanet prospective database.
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is increasing, but population registries seldom capture detailed clinical data. The Italian Association for Neuroendocrine Tumours (Itanet) established a nationwide prospective database to describe presentation, diagnostic pathways, management, and outcomes of newly diagnosed GEP-NENs in Italy. This multicentre prospective observational study enrolled 2138 consecutive patients with newly diagnosed GEP-NENs across 38 Italian centres (2019-2024). Clinical, pathological, imaging, and treatment data were prospectively collected and centrally validated. Descriptive and survival analyses were performed; Ki-67 was modelled as a continuous variable. Median age was 60.6 years, and 55.9% (1195/2138) were male. Tumours were well-differentiated NETs in 90.8% of patients (1942/2138), mainly of pancreatic (41.4%, 886/2138) or ileal (19.7%, 422/2138) origin. Median Ki-67 was 2%. An incidental diagnosis occurred in 58.6% (1254/2138) of cases. Among symptomatic patients, the mean diagnostic delay was 197 days (224 for pancreatic vs 184 for small bowel; p = 0.039). 68Ga-DOTA-peptide PET showed higher diagnostic yield than CT or MRI in small-bowel primaries (93.7% vs 83.1% vs 67.4%), whereas performance was similar in pancreatic tumours. Data on first-line treatment were available for 2050 patients. Initial management included surgery in 36.4% (746/2050), watchful waiting in 19.7% (404/2050), endoscopic resection in 7.7% (158/2050). Overall, 30.6% (627/2050) of patients received systemic therapy, most commonly somatostatin analogues in 23.7% (487/2050). Over a median follow-up of 271 days (IQR 121-530), 62 deaths were observed (event rate 4.9%). Overall survival differed markedly according to metastatic status and tumour grade. Ki-67 was prognostic when modelled continuously (p < 0.001), and a 15% cutoff identified poorer outcomes. This nationwide prospective study delineates real-world diagnostic and therapeutic patterns of GEP-NENs in Italy, confirms Ki-67 as a continuous prognostic biomarker, and identifies a 15% threshold associated with worse survival, providing a benchmark for outcome assessment and future clinical research. None.
2025-12-30 | Cardiac Metastases in Neuroendocrine Neoplasms: A Single-Center Experience of Clinical Characteristics and Outcomes.
Background/Objectives: Cardiac metastases (CM) represent a rare manifestation of neuroendocrine neoplasms (NEN). Detailed clinical characteristics and significance remain understudied. Methods: We retrospectively evaluated 1201 patients with NEN treated at an ENETS Center of Excellence to determine prevalence, clinical features, and outcomes of cardiac metastases. CM were identified in 15 patients (prevalence 1.25%) through multimodal imaging, incorporating somatostatin receptor positron emission tomography/computed tomography (SSTR PET/CT). Metachronous CM occurrence accounted for 93% of cases. Results: The majority of patients showed well-differentiated tumors (G1/G2), with ileum being the most frequent site of origin. Clinical symptoms attributable to CM were observed in 27% of affected patients. Following CM detection, therapeutic management was adjusted in 73% of cases, most frequently by initiating peptide receptor radionuclide therapy (PRRT) n = 8, 53%. Median overall survival (OS) from CM diagnosis was 95 months, with an estimated 5-year survival rate of 77%, with a 5-year OS from NEN diagnosis of 87%. Conclusions: CM in NEN are rare and often clinically silent, with SSTR PET/CT proving essential for detection. While treatment adjustments were frequently observed, particularly with PRRT, OS remained favorable, indicating that the presence of CM in NEN serves as an indicator of metastatic spread rather than a standalone diagnostic determinant of survival. Larger, prospective studies are needed to further validate these findings and to better define the clinical implications of CM in NEN.
2025-10-01 | S6037 Well-Differentiated Ileal Neuroendocrine Tumor Presenting With Nonspecific GI Symptoms and Iron Deficiency Anemia
Introduction: Neuroendocrine tumors (NETs) are rare malignancies arising from neuroendocrine cells with an annual incidence of 6.98 per 100,000 persons, a steadily increasing. NETs most commonly occur in the small intestine (44.7%), rectum (19.6%), appendix (16.7%), and colon (10.6%). Clinical presentation is variable and nonspecific with many patients being asymptomatic or with vague symptoms, such as fatigue or abdominal pain. NETs can be indolent with metastatic disease found at time of diagnosis. Case Description/Methods: A 44-year-old woman with asthma, hypertension, and chronic heavy alcohol use presented to an outpatient GI clinic with several months of intermittent, non-radiating epigastric pain, new onset constipation, and intermittent nausea and vomiting. Lab work showed severe iron deficiency anemia. She underwent esophagogastroduodenoscopy and colonoscopy, which showed a solitary nonbleeding ulcer in the terminal ileum (TI) that was unable to be biopsied, an 11 mm polypoid lesion with congestion at the ileocecal valve, and a 6 mm cecal polyp. Immunohistochemical stain of the cecal polyp and abnormal TI mucosa revealed a well-differentiated NET G2 positive for synaptophysin, chromogranin, CD56, AE1/AE3, and Ki-67 = ∼10% nuclear positivity. Computed tomography enterogram showed mural thickening of the TI, cecum, and ascending colon consistent with enterocolitis, along with segmental bowel wall thickening concerning for inflammation. Ga-68 DOTATATE scan showed hypermetabolic uptake in the ileocecal region at the known NET site and metastasis to a right ileal mesenteric node, central liver, and duodenum/periduodenal node: with overall grade 4 uptake by Krening score. The ileocecal tumor was resected with a right hemicolectomy. Intraoperatively, all 5 lesions were localized to segment 4B and removed via hepatic segment 4B wedge resection. Surgical pathology confirmed well differentiated NET G2 at the ileocecal valve, in 1 liver fragment, and in local lymph nodes with extranodal extension. After discharge, she recovered well and will continue with surveillance computed tomography imaging to determine future need for systemic therapies. Discussion: This case illustrates the indolent nature of NETs and the critical importance of a careful endoscopic examination. Approximately 30% of patients with small bowel NETs have metastatic disease at the time of diagnosis. Timely workup and treatment are key as small intestine NETs with distant metastasis have a median overall survival of about 6 years, and incomplete tumor resection is associated with worse survival.
2025-04-21 | Abstract 4000: The significance of GLP-1R and its agonist in neuroendocrine neoplasms
Abstract Neuroendocrine neoplasms (NENs) are rare cancers originating from neuroendocrine cells that are found throughout the body. NENs are subdivided into 2 categories: Well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Both NET and NEC are highly metastatic and difficult to treat. NEN cases are on the rise and yet the etiology remains unclear. Commonly used drugs such as proton pump inhibitors can promote NET growth and result in poor prognosis for NET patients. Nowadays, the diabetes and weight loss drug semaglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, has gain extensive popularity and are currently being taken by over 15 million people in the USA. Semaglutide is contraindicated for NET patients with medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) since some of these cancers express the GLP-1R. However, this area of research remains understudied. Little is known about the expression levels of GLP-1R in NEN from different anatomical locations and their response to semaglutide since these are rare cancers and few NET models are available for drug testing. We recently identified 2 human NET cell lines (GOT1 and NT-3) that express the GLP-1R and showed that semaglutide promotes tumor cell growth both in vitro and in vivo. In this study, we aim to investigate the levels of GLP-1R expression in a large collection of NEN tissue microarrays and determine the effects of semaglutide in novel GLP-1R positive NET patient-derived spheroid cultures. We stained for GLP-1R expression by immunohistochemistry in 357 NET tissue microarrays covering 7 classes of NEN: 78 pancreas NET, 62 duodenum NET, 33 ileal NET, 42 lung NET, 10 small cell lung NEC, 12 extrapulmonary visceral NEC, 29 thyroid NET, 12 gastric NET, 6 appendix NET, 6 rectum NET, 22 pheochromocytoma, 22 paraganglioma, and 23 Merkel cell carcinoma. Furthermore, we generated GLP-1R positive pancreas, ileal, and duodenal NET spheroids for drug testing. Our data showed 45% of duodenum NET, 17% of gastric NET, and 14% of pancreas NET stained positive for GLP-1R expression. Less than 2% of other classes NET or NEC stained positive for GLP-1R expression. Using newly established NET patient-derived spheroid models, we demonstrated that 100 nM of semaglutide accelerates tumor cell growth by 1.4 to 2-fold. Surprisingly, duodenum NET is the class of NET that frequently express GLP-1R and should be highly cautioned for the semaglutide usage. Citation Format: Sophia A. Hueser, Reese E. Townsend, Casandro J. Chan, Leona Rupp, Leopaul J. Chan, Dawn E. Quelle, Joseph S. Dillon, Andrew M. Bellizzi, James R. Howe, Po Hien H. Ear. The significance of GLP-1R and its agonist in neuroendocrine neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4000.
2024-12-23 | Analysis of dosimetry and clinical variables in treatments of neuroendocrine tumours with [177Lu]Lu-DOTA-TATE.
The main objectives were to study differences between the first and the fourth cycle in dosimetry variables in patients treated for neuroendocrine tumours with four cycles of [177Lu]Lu-DOTA-TATE, as well as to look for absorbed dose-effect correlations aiming to help individualise and optimise this therapy for future patients. SPECT/CT based dosimetry of tumour lesions and kidneys was performed in the first and the fourth cycles of the [177Lu]Lu-DOTA-TATE treatments for 17 patients from 2020 to 2023. Clinical variables of interest were collected in order to look for correlations with some dosimetry variables. Statistical analysis was performed using the R software. Regarding dosimetry variables, for lesions a significant decrease in absorbed dose, mass and initial activity between the first and fourth cycles was observed. For kidneys, a significant increase in absorbed dose was observed. Effective decay constants did not significantly change neither for lesions nor for kidneys. The relative decrease in lesion masses correlated with their total absorbed dose. Total absorbed doses to kidneys were well below the toxicity limits mostly used in this therapy. Relative decrease in lesion absorbed doses was significantly lower for tumour primary sites in ileum and jejunum compared to those in pancreas. Moreover, radiological response correlated with clinical response. The results seem to indicate that the current treatment scheme could be optimised in order to obtain better treatment outcomes.
oligonucleotides
2022-11-24 | The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities
Neuroendocrine neoplasms (NENs) comprise a highly heterogeneous group of tumors arising from the diffuse neuroendocrine system. NENs mainly originate in gastrointestinal, pancreatic, and pulmonary tissues, and despite being rare, show rising incidence. The molecular mechanisms underlying NEN development are still poorly understood, although recent studies are unveiling their genomic, epigenomic and transcriptomic landscapes. RNA was originally considered as an intermediary between DNA and protein. Today, compelling evidence underscores the regulatory relevance of RNA processing, while new RNA molecules emerge with key functional roles in core cell processes. Indeed, correct functioning of the interrelated complementary processes comprising RNA biology, its processing, transport, and surveillance, is essential to ensure adequate cell homeostasis, and its misfunction is related to cancer at multiple levels. This review is focused on the dysregulation of RNA biology in NENs. In particular, we survey alterations in the splicing process and available information implicating the main RNA species and processes in NENs pathology, including their role as biomarkers, and their functionality and targetability. Understanding how NENs precisely (mis)behave requires a profound knowledge at every layer of their heterogeneity, to help improve NEN management. RNA biology provides a wide spectrum of previously unexplored processes and molecules that open new avenues for NEN detection, classification and treatment. The current molecular biology era is rapidly evolving to facilitate a detailed comprehension of cancer biology and is enabling the arrival of personalized, predictive and precision medicine to rare tumors like NENs.
2021-07-26 | IGF2 drives formation of ileal neuroendocrine tumors in patients and mice.
By the strictest of definitions, a genetic driver of tumorigenesis should fulfill two criteria: it should be altered in a high percentage of patient tumors, and it should also be able to cause the same type of tumor to form in mice. No gene that fits either of these criteria has ever been found for ileal neuroendocrine tumors (I-NETs), which in humans are known for an unusual lack of recurrently mutated genes, and which have never been detected in mice. In the following report, we show that I-NETs can be generated by transgenic RT2 mice, which is a classic model for a genetically unrelated disease, pancreatic neuroendocrine tumors (PNETs). The ability of RT2 mice to generate I-NETs depended upon genetic background. I-NETs appeared in a B6AF1 genetic background, but not in a B6 background nor even in an AB6F1 background. AB6F1 and B6AF1 have identical nuclear DNA but can potentially express different allelic forms of imprinted genes. This led us to test human I-NETs for loss of imprinting, and we discovered that the IGF2 gene showed loss of imprinting and increased expression in the I-NETs of 57% of patients. By increasing IGF2 activity genetically, I-NETs could be produced by RT2 mice in a B6 genetic background, which otherwise never developed I-NETs. The facts that IGF2 is altered in a high percentage of patients with I-NETs and that I-NETs can form in mice that have elevated IGF2 activity, define IGF2 as the first genetic driver of ileal neuroendocrine tumorigenesis.
2017-02-06 | Osteotropism of neuroendocrine tumors: role of the CXCL12/ CXCR4 pathway in promoting EMT in vitro.
// Mauro Cives 1 , Davide Quaresmini 1 , Francesca Maria Rizzo 1 , Claudia Felici 1 , Stella D'Oronzo 1 , Valeria Simone 1 , Franco Silvestris 1 1 Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro", Bari, Italy Correspondence to: Franco Silvestris, email: francesco.silvestris@uniba.it Keywords: carcinoid, bone metastasis, SDF-1, epithelial-mesenchymal transition, GPCR nuclear translocation Received: August 31, 2016 Accepted: January 24, 2017 Published: February 06, 2017 ABSTRACT Neuroendocrine tumors (NETs) metastasize to the skeleton in approximately 20% of patients. We have previously shown that the epithelial-mesenchymal transition (EMT) regulates the NET osteotropism and that CXCR4 overexpression predicts bone spreading. Here, we unravel the molecular mechanisms linking the activation of the CXCL12/CXCR4 axis to the bone colonization of NETs using cell lines representative of pancreatic (BON1, CM, QGP1), intestinal (CNDT 2.5), and bronchial origin (H727). By combining flow cytometry and ELISA, BON1, CM and QGP1 cells were defined as CXCR4 high /CXCL12 low , while H727 and CNDT 2.5 were CXCR4 low /CXCL12 high . CXCL12 was inert on cell proliferation, but significantly increased the in vitro osteotropism of CXCR4 high /CXCL12 low cells, as assessed by transwell assays with or without Matrigel membranes. In these cells, CXCL12 induced in vitro a marked EMT-like transcriptional shift with acquirement of a mesenchymal shape. The nuclei of CXCR4 high /CXCL12 low NET cells were typically enriched in non-phosphorylated CXCR4, particularly upon agonist stimulation. Silencing of CXCR4 via siRNA prevented the CXCL12-induced EMT in CXCR4 high /CXCL12 low NET cell lines resulting in the abrogation of both migration and transcriptional mesenchymal patterns. Our data suggest that CXCL12 conveys EMT-promoting signals in NET cells through CXCR4, which in turn regulates transcriptional, morphologic and functional modifications resulting in enhanced in vitro osteotropism of NET cells. Unique functions of CXCR4 may be segregated in relation to its subcellular localization and may acquire potential relevance in future in vivo studies.
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Drug Discovery Landscape
1 orphan drug designation for Ileal neuroendocrine tumor.
1 orphan drug designation for Ileal neuroendocrine tumor.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
human adenovirus C serotype 5 with E1 gene controlled by chromogranin A promoter and hexon modified with protein transduction domain motif | gene therapies | FDA | 2024-12-18 | — | Elicera Therapeutics AB |
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