RARE DISEASE
Jejunal neuroendocrine tumor
Jejunal neuroendocrine tumor
Jejunal neuroendocrine tumor
Synonyms: Jejunal neuroendocrine neoplasm
Synonyms: Jejunal neuroendocrine neoplasm
Synonyms: Jejunal neuroendocrine neoplasm
Drug discovery
0
drugs
With orphan designations
Overview
Jejunal neuroendocrine tumors (NETs) are rare, malignant epithelial neoplasms arising from enterochromaffin cells, often presenting with nonspecific abdominal symptoms (cramping, obstruction) or advanced-stage carcinoid syndrome (flushing, diarrhea) [4][9]. These tumors demonstrate variable aggressiveness, with G1/G2 grading in most cases but potential for peritoneal carcinomatosis and distant metastases [1][6][15]. Diagnosis requires histopathology, chromogranin A testing, and somatostatin receptor imaging [10][15].
Categories: rare endocrine diseases, rare gastroenterological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
81 drug discovery papers about Jejunal neuroendocrine tumor, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
81 drug discovery papers about Jejunal neuroendocrine tumor, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-02-22 | Hedgehog signaling drives glial cell plasticity and oncogenic reprogramming in gastroenteropancreatic neuroendocrine neoplasms.
BACKGROUND: Disruption of the Men1 locus in epithelial and endocrine tissues fails to generate the full spectrum of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), raising the possibility of a potential stromal source for these cancers. Neural crest-derived glial cells were previously implicated in neuroendocrine tumors arising in the pituitary and pancreas, yet these studies lacked a clear mechanism for these events. Here, we investigated the hypothesis that Men1-driven Hedgehog (HH) signaling redirects the glial cell fate to give rise to neuroendocrine tumors in the gastrointestinal tract. METHODS: Hyperactivation of the HH signaling pathway in human GEP-NETs was evaluated using immunofluorescent staining and clinicogenomic databases. Men1 was deleted in the glial lineage by expressing Cre recombinase downstream of the human GFAP and Sox10 promoters. Overexpression of HH signaling proteins in mouse GEP-NETs was confirmed by immunofluorescent staining and immunoblot analysis. We generated human and mouse GEP-NET tumoroids and exposed them to agonists and inhibitors of HH signaling. HH activation of Men1-deficient glial cells was blocked by deleting the gene encoding primary ciliary protein KIF3A required for transducing SHH signaling. RESULTS: We demonstrated that human GEP-NETs overexpress HH signaling pathway components, including SHH and its cognate receptor PTCH1. We showed that patient-derived GEP-NET tumoroids proliferate in response to SHH pathway agonists. In contrast, pharmacologic inhibition of GLI1/2, but not inhibition of SMO alone, attenuated tumoroid growth. Genetic deletion of Men1 in GFAP+ and SOX10+ glial cells caused the development of pancreatic and intestinal NETs that overexpress HH proteins. Further use of tdTomato+ mice demonstrated the involvement of GFAP+ and SOX10+ glial cells in these tumors. Tumoroid cultures of mouse pancreatic, duodenal, and jejunal NETs recapitulated the drug response shown by patient-derived tumoroids. Lastly, Men1-deficient enteric glial cultures showed a glial-to-neuroendocrine transition that was alleviated upon HH inhibition, and these events were reproduced in genetic mice harboring GFAP+ cells with impaired primary cilia. CONCLUSIONS: Our study implicates the HH signaling pathway in GEP-NET development and underscores a glial cell of origin for these tumors.
2025-12-08 | Synchronous small bowel neuroendocrine tumour, colonic adenocarcinoma, and non-Hodgkin lymphoma: a rare triad of primary malignancies.
A man in his 70s presented to the Emergency Department with a history of progressive dyspnoea and was found to be anaemic. Endoscopic evaluation revealed a caecal lesion, confirmed histologically as a moderately differentiated adenocarcinoma. Staging computed-tomography imaging demonstrated widespread lymphadenopathy including pelvic, mediastinal and axillary regions, that appeared unlikely to be related to the colonic primary. Surgical resection of the right colon and a palpable axillary node was performed, during which a separate jejunal lesion was incidentally identified and resected. Histopathological analysis confirmed three distinct neoplasms: colonic adenocarcinoma, a small bowel neuroendocrine tumour, and non-Hodgkin lymphoma. Immunohistochemical and molecular profiling confirmed independent origins with no shared clonal relationship. The following case highlights the diagnostic and therapeutic challenges posed by synchronous multiple primary malignancies, particularly across divergent tissue lineages. Accurate histopathological distinction and multidisciplinary coordination are essential to guide management, prioritize treatment, and optimize patient outcomes in such exceptional presentations.
2023-08-22 | Nuclear Imaging and Therapy
This thesis explores new applications of nuclear imaging and therapy in patients with hepatocellular carcinoma (HCC) and neuroendocrine tumors (NET). These diseases are often detected late, making curative therapy not always possible. Developments in positron emission tomography (PET) and radionuclide therapy have led to new nuclear agents. The aim of this thesis is to provide insight into several new applications of current and new tracers in the diagnosis and treatment of HCC and NET.One of the investigated tracers is 18F-DOPA, which is currently used for NET tumors that are negative on 68Ga-labeled somatostatin analog (SSA) PET scans. Our study confirms the equivalent detection of 18F-DOPA in tumor detection compared to 68Ga-SSAs. Selective internal radiation therapy (SIRT) uses yttrium-90 radioactive resin spheres that are intravascularly injected into the liver. Higher than usual dosages (>120 Gy) appear to lead to better results in tumor reduction and the effects not only seem to be greater but also longer lasting.Furthermore, we demonstrated that 11C-Choline and 18F-FDG together find more tumors that are relevant for clinical decision-making in patients suspected of HCC recurrence. The thesis also offers two prospective study protocols, namely a comparison of 68Ga-DOTA-TOC with the new somatostatin tracer 18F-SiTATE in NET and a comparison of ablation with SIRT as a bridge strategy in liver transplantation. These results suggest that broader use of 18F-DOPA in PET diagnosis of NET is possible and that higher tumor-targeted dosages in SIRT can lead to better treatment.
2019-01-15 | Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors.
Small intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs. The analysis was conducted using 40 primary tumors and corresponding 47 metastases. The level of 5hmC, TET1 and TET2 was analyzed by DNA immune-dot blot assay and immunohistochemistry. Other methods included a colony forming assay, western blotting analysis, and quantitative bisulfite pyrosequencing analysis. The effect of the exportin-1 nuclear transport machinery inhibitors on cell proliferation and apoptosis was also explored using two SI-NET cell lines. Variable levels of 5hmC and a mosaic staining appearance with a mixture of positive and negative cell nuclei, regardless of cell number and staining strength, was observed overall both in primary tumors and metastases. Similarly aberrant staining pattern was observed for TET1 and TET2. In a number of tumors (15/32) mosaic pattern together with areas of negative staining was also observed for TET1. Abolished expression of TET1 in the tumors did not seem to involve hypermethylation of the TET1 promoter region. Overexpression of TET1 in a colony forming assay supported a function as cell growth regulator. In contrast to 5hmC and TET1, TET2 was also observed in the cytoplasm of all the analyzed SI-NETs regardless of nuclear localization. Treatment of CNDT2.5 and KRJ-I cells with the exportin-1 (XPO1/CRM1) inhibitor, leptomycin B, induced reduction in the cytoplasm and nuclear retention of TET2. Aberrant partitioning of TET2 from the nucleus to the cytoplasm seemed therefore to involve the exportin-1 nuclear transport machinery. Reduced cell proliferation and induction of apoptosis were observed after treatment of CNDT2.5 and KRJ-I cells with leptomycin B or KPT-330 (selinexor). SI-NETs are epigenetically dysregulated at the level of 5-hydroxymethylcytosine/ TET1/TET2. We suggest that KPT-330/selinexor or future developments should be considered and evaluated for single treatment of patients with SI-NET disease and also in combinations with somatostatin analogues, peptide receptor radiotherapy, or everolimus.
2018-07-16 | Antidepressants appear safe in patients with carcinoid tumor: Results of a retrospective review.
Patients living with neuroendocrine tumors have high rates of depression, often necessitating antidepressants, including selective serotonin reuptake inhibitors (SSRI). Neuroendocrine tumors (NETs) secrete vasoactive substances, including serotonin, which contribute to the cluster of symptoms known as carcinoid syndrome (flushing and diarrhea). Controversy exists over whether or not antidepressants are safe in NET. We aimed to study the safety of antidepressant use in NET patients. We conducted a retrospective chart review of patients with well differentiated NET who were also prescribed antidepressants from January 2008 through April 2015. The study took place at Memorial Sloan Kettering Cancer Center and was approved by the hospital's institutional review board. Ninety-two patients were included. There were 16 (17.4%) patients with carcinoid syndrome (10 ileum, 1 duodenum, 1 jejunum and 4 unknown primary); and 76 (82.6%) patients without (41 lung, 9 pancreas, 8 ileal, 5 duodenum, 5 appendix, 2 unknown primary, 1 jejunum and 5 other). Median duration of antidepressant prescription was 11.6 months (range, 0-121) among those with carcinoid syndrome (N = 16) and 14.3 months (range, 0-172) among those without carcinoid syndrome (n = 76). Antidepressants were stopped in 31 cases (33.7%), though the reason was not specified in the majority of cases (n = 18; 58%). None of the patients developed carcinoid syndrome while being prescribed antidepressants. No patients developed carcinoid crisis. Our findings do not support previous authors' recommendations that SSRIs must be avoided in NET patients. Several classes of antidepressants appeared safe in NET patients with and without carcinoid syndrome.
proteins
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.
2020-01-25 | SOMATOSTATIN ANALOGUES FOR THE TREATMENT OF NEUROENDOCRINE TUMOURS. DOSAGE FORMS AND ROUTES OF ADMINISTRATION (REVIEW)
This review summarises information on drug products Somatostatin Analogues (SSAs), which are included in the algorithm of Neuroendocrine Tumors (NET) treatment. SSAs are the current standard for safe and effective management of NET symptoms and control of tumours growth and are administered in a range of dosage forms for parenteral administration, such as intramuscular, subcutaneous and implant. A search criterion was the therapy of NET with medicines from a group of SSAs. Literature survey has been done in a range of years 1990-2018 to make the review updated and comprehensive and to show the development of SSAs new pharmaceutical dosage forms to improve patient quality of life and side effects decrease. The sources were world-recognized journals. Keywords used as filters were NET, SSAs, octreotide, lanreotide, pasireotide, Somatostatin Receptors (SSTR), dosage form. The current review is created with an intended to focus on the advantage of SSAs modern dosage forms. Literature survey revealed that many studies were carried out to SSAs encapsulation into microspheres that changes the drug bioavailability and allows reducing the number of administration. Also, SSAs delivery systems in particular devices such as auto-injector have been created to control the continuous concentration of the drug and to provide safety guarantee. Besides, studies have been carried out to prepare SSAs formulations for oral administration to improve the quality of life of the NET patients. In this review, SSAs pharmaceutical dosage forms with improved pharmacokinetic and therapeutic characteristics and routes of administration are analyzed.
2019-01-18 | Everolimus in Combination with Octreotide Long-Acting Repeatable in a First-Line Setting for Patients with Neuroendocrine Tumors: A 5-Year Update.
We previously presented data of this multicentric, phase II study showing that everolimus plus octreotide long-acting repeatable (LAR) for advanced neuroendocrine neoplasms (NENs), in the first line setting, is an active and safe treatment. We now present updated data at 5 years. Patients with advanced well-differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg plus everolimus 10 mg/day. The primary endpoint was the objective response rate (ORR). We performed an analysis of "long responder" patients and of time to progression (TTP) and overall survival (OS) at 5 years. Fifty patients were enrolled; the primary tumor site was: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum/duodenum (2 patients), and unknown (14 patients). Seventeen (34%) of these patients have received treatment for more than 2 years. The median exposure to study drugs was 519.5 days (range 48-2,024). Currently 3 patients are still in treatment. The ORR (partial response + complete response) was 18% (95% confidence interval [CI] 7.4-28.6): complete response 1 patient (2%), partial response 8 patients (16%), stable disease 37 patients (74%). The median TTP was 33.6 months (95% CI 18.7-41.2) and the median OS was 61.0 months (95% CI 49.8-not reached). In this update of clinical outcome at 5-year follow-up, everolimus plus octreotide has been shown to be active in advanced NENs. The current analysis showed a further prolongation of TTP and a long exposure to the study drug without major side effects in the long term.
2018-12-01 | The eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience
Metastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT. Patient 1 is a 72 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy. Patient 2 is a 68 year-old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control. Patient 3 is a 63 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET-CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly. Patient 4 is a 72 year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since. Patient 5 is a 61 year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease. NETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients.
2018-02-10 | Clinical experience with indigenous kit-based preparation of 68Ga-DOTATOC using commercial 68Ge/68Ga generator
Pharmaceutical grade DOTATOC kits compliant with all the quality control criteria were formulated and radiolabeled with 68Ga in high yields. Comparison with module-based 68Ga-DOTATOC established product equivalency. Clinical utility was evaluated in patients with histopathologically confirmed well-differentiated neuroendocrine tumors. Kit-based preparation of 68Ga-DOTATOC could identify sites of primary and metastatic disease. PET/CT images of patients conformed to the established criteria for somatostatin imaging agents and clinical expectations. Results of this study emphasize the potential of kit-based 68Ga-DOTATOC for PET imaging of neuroendocrine tumors.
antibodies
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.
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.
2020-03-03 | Analysis of the immune landscape of small bowel neuroendocrine tumors.
Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30-49%) and 14/102 (14%; 95% CI, 8-22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25-44%), mild to moderate in 46/102 samples (45%, 95% CI, 35-55%), intense in 21/102 tumors (21%, 95% CI, 13-30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11-26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.
2019-12-01 | The tumor immune microenvironment in gastroenteropancreatic neuroendocrine neoplasms
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors. Moreover, a comparison between TIMEs among different types of GEP-NENs and the interplay among the TIME, tumor cells, and the stromal microenvironment is described. Novel treatment options for GEP-NENs and potential biomarkers for the immune response are also characterized. We provide a comprehensive generalized review of the TIME that can inform GEP-NEN treatment strategies.
2018-10-16 | Should Ki67 immunohistochemistry be performed on all lesions in multifocal small intestinal neuroendocrine tumours?
Well-differentiated small intestinal neuroendocrine tumours (SI-NETs) are often multifocal, and this has been suggested to impart worse disease-free survival. Practice guidelines have not been established for World Health Organisation (WHO) grading of multiple primary lesions.We identified 68 patients with ileal/jejunal SI-NET for a combined total of 207 primary lesions. Each case was evaluated for patient age and sex; size of all tumours; presence of lymph node metastases, mesenteric tumour deposits or distant metastases; and disease-specific outcome. Ki67 staining was performed on all 207 primary lesions. The relationship between multifocality and clinicopathological factors was compared using Fisher's exact test. Outcome was tested using Cox proportional hazard regression. Forty-two patients had unifocal disease, and 26 had multifocal disease (median five lesions, range = 2-32). Most tumours were WHO grade 1 (201 of 207, 97%). Of the five patients with grades 2/3 tumours, three patients had unifocal disease, one patient had two subcentimetre grade 2 lesions (including the largest) and eight subcentimetre grade 1 lesions, and one patient had one 1.6-cm grade 3 lesion and one subcentimetre grade 1 lesion. There was a positive correlation between tumour size and Ki67 index (coefficient 0.28; 95% confidence interval 0.05-0.52, P = 0.017). There was no significant association between multifocality and nodal metastases, mesenteric tumour deposits, distant metastases or disease-specific survival.In patients with multifocal SI-NET, unless a particular lesion has a high mitotic rate, only staining the largest lesion for Ki67 should serve to grade almost all cases accurately. Multifocality does not appear to significantly impact patient survival.
small molecules
2026-02-22 | Hedgehog signaling drives glial cell plasticity and oncogenic reprogramming in gastroenteropancreatic neuroendocrine neoplasms.
BACKGROUND: Disruption of the Men1 locus in epithelial and endocrine tissues fails to generate the full spectrum of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), raising the possibility of a potential stromal source for these cancers. Neural crest-derived glial cells were previously implicated in neuroendocrine tumors arising in the pituitary and pancreas, yet these studies lacked a clear mechanism for these events. Here, we investigated the hypothesis that Men1-driven Hedgehog (HH) signaling redirects the glial cell fate to give rise to neuroendocrine tumors in the gastrointestinal tract. METHODS: Hyperactivation of the HH signaling pathway in human GEP-NETs was evaluated using immunofluorescent staining and clinicogenomic databases. Men1 was deleted in the glial lineage by expressing Cre recombinase downstream of the human GFAP and Sox10 promoters. Overexpression of HH signaling proteins in mouse GEP-NETs was confirmed by immunofluorescent staining and immunoblot analysis. We generated human and mouse GEP-NET tumoroids and exposed them to agonists and inhibitors of HH signaling. HH activation of Men1-deficient glial cells was blocked by deleting the gene encoding primary ciliary protein KIF3A required for transducing SHH signaling. RESULTS: We demonstrated that human GEP-NETs overexpress HH signaling pathway components, including SHH and its cognate receptor PTCH1. We showed that patient-derived GEP-NET tumoroids proliferate in response to SHH pathway agonists. In contrast, pharmacologic inhibition of GLI1/2, but not inhibition of SMO alone, attenuated tumoroid growth. Genetic deletion of Men1 in GFAP+ and SOX10+ glial cells caused the development of pancreatic and intestinal NETs that overexpress HH proteins. Further use of tdTomato+ mice demonstrated the involvement of GFAP+ and SOX10+ glial cells in these tumors. Tumoroid cultures of mouse pancreatic, duodenal, and jejunal NETs recapitulated the drug response shown by patient-derived tumoroids. Lastly, Men1-deficient enteric glial cultures showed a glial-to-neuroendocrine transition that was alleviated upon HH inhibition, and these events were reproduced in genetic mice harboring GFAP+ cells with impaired primary cilia. CONCLUSIONS: Our study implicates the HH signaling pathway in GEP-NET development and underscores a glial cell of origin for these tumors.
2025-12-08 | Synchronous small bowel neuroendocrine tumour, colonic adenocarcinoma, and non-Hodgkin lymphoma: a rare triad of primary malignancies.
A man in his 70s presented to the Emergency Department with a history of progressive dyspnoea and was found to be anaemic. Endoscopic evaluation revealed a caecal lesion, confirmed histologically as a moderately differentiated adenocarcinoma. Staging computed-tomography imaging demonstrated widespread lymphadenopathy including pelvic, mediastinal and axillary regions, that appeared unlikely to be related to the colonic primary. Surgical resection of the right colon and a palpable axillary node was performed, during which a separate jejunal lesion was incidentally identified and resected. Histopathological analysis confirmed three distinct neoplasms: colonic adenocarcinoma, a small bowel neuroendocrine tumour, and non-Hodgkin lymphoma. Immunohistochemical and molecular profiling confirmed independent origins with no shared clonal relationship. The following case highlights the diagnostic and therapeutic challenges posed by synchronous multiple primary malignancies, particularly across divergent tissue lineages. Accurate histopathological distinction and multidisciplinary coordination are essential to guide management, prioritize treatment, and optimize patient outcomes in such exceptional presentations.
2023-08-22 | Nuclear Imaging and Therapy
This thesis explores new applications of nuclear imaging and therapy in patients with hepatocellular carcinoma (HCC) and neuroendocrine tumors (NET). These diseases are often detected late, making curative therapy not always possible. Developments in positron emission tomography (PET) and radionuclide therapy have led to new nuclear agents. The aim of this thesis is to provide insight into several new applications of current and new tracers in the diagnosis and treatment of HCC and NET.One of the investigated tracers is 18F-DOPA, which is currently used for NET tumors that are negative on 68Ga-labeled somatostatin analog (SSA) PET scans. Our study confirms the equivalent detection of 18F-DOPA in tumor detection compared to 68Ga-SSAs. Selective internal radiation therapy (SIRT) uses yttrium-90 radioactive resin spheres that are intravascularly injected into the liver. Higher than usual dosages (>120 Gy) appear to lead to better results in tumor reduction and the effects not only seem to be greater but also longer lasting.Furthermore, we demonstrated that 11C-Choline and 18F-FDG together find more tumors that are relevant for clinical decision-making in patients suspected of HCC recurrence. The thesis also offers two prospective study protocols, namely a comparison of 68Ga-DOTA-TOC with the new somatostatin tracer 18F-SiTATE in NET and a comparison of ablation with SIRT as a bridge strategy in liver transplantation. These results suggest that broader use of 18F-DOPA in PET diagnosis of NET is possible and that higher tumor-targeted dosages in SIRT can lead to better treatment.
2019-01-15 | Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors.
Small intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs. The analysis was conducted using 40 primary tumors and corresponding 47 metastases. The level of 5hmC, TET1 and TET2 was analyzed by DNA immune-dot blot assay and immunohistochemistry. Other methods included a colony forming assay, western blotting analysis, and quantitative bisulfite pyrosequencing analysis. The effect of the exportin-1 nuclear transport machinery inhibitors on cell proliferation and apoptosis was also explored using two SI-NET cell lines. Variable levels of 5hmC and a mosaic staining appearance with a mixture of positive and negative cell nuclei, regardless of cell number and staining strength, was observed overall both in primary tumors and metastases. Similarly aberrant staining pattern was observed for TET1 and TET2. In a number of tumors (15/32) mosaic pattern together with areas of negative staining was also observed for TET1. Abolished expression of TET1 in the tumors did not seem to involve hypermethylation of the TET1 promoter region. Overexpression of TET1 in a colony forming assay supported a function as cell growth regulator. In contrast to 5hmC and TET1, TET2 was also observed in the cytoplasm of all the analyzed SI-NETs regardless of nuclear localization. Treatment of CNDT2.5 and KRJ-I cells with the exportin-1 (XPO1/CRM1) inhibitor, leptomycin B, induced reduction in the cytoplasm and nuclear retention of TET2. Aberrant partitioning of TET2 from the nucleus to the cytoplasm seemed therefore to involve the exportin-1 nuclear transport machinery. Reduced cell proliferation and induction of apoptosis were observed after treatment of CNDT2.5 and KRJ-I cells with leptomycin B or KPT-330 (selinexor). SI-NETs are epigenetically dysregulated at the level of 5-hydroxymethylcytosine/ TET1/TET2. We suggest that KPT-330/selinexor or future developments should be considered and evaluated for single treatment of patients with SI-NET disease and also in combinations with somatostatin analogues, peptide receptor radiotherapy, or everolimus.
2018-07-16 | Antidepressants appear safe in patients with carcinoid tumor: Results of a retrospective review.
Patients living with neuroendocrine tumors have high rates of depression, often necessitating antidepressants, including selective serotonin reuptake inhibitors (SSRI). Neuroendocrine tumors (NETs) secrete vasoactive substances, including serotonin, which contribute to the cluster of symptoms known as carcinoid syndrome (flushing and diarrhea). Controversy exists over whether or not antidepressants are safe in NET. We aimed to study the safety of antidepressant use in NET patients. We conducted a retrospective chart review of patients with well differentiated NET who were also prescribed antidepressants from January 2008 through April 2015. The study took place at Memorial Sloan Kettering Cancer Center and was approved by the hospital's institutional review board. Ninety-two patients were included. There were 16 (17.4%) patients with carcinoid syndrome (10 ileum, 1 duodenum, 1 jejunum and 4 unknown primary); and 76 (82.6%) patients without (41 lung, 9 pancreas, 8 ileal, 5 duodenum, 5 appendix, 2 unknown primary, 1 jejunum and 5 other). Median duration of antidepressant prescription was 11.6 months (range, 0-121) among those with carcinoid syndrome (N = 16) and 14.3 months (range, 0-172) among those without carcinoid syndrome (n = 76). Antidepressants were stopped in 31 cases (33.7%), though the reason was not specified in the majority of cases (n = 18; 58%). None of the patients developed carcinoid syndrome while being prescribed antidepressants. No patients developed carcinoid crisis. Our findings do not support previous authors' recommendations that SSRIs must be avoided in NET patients. Several classes of antidepressants appeared safe in NET patients with and without carcinoid syndrome.
proteins
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.
2020-01-25 | SOMATOSTATIN ANALOGUES FOR THE TREATMENT OF NEUROENDOCRINE TUMOURS. DOSAGE FORMS AND ROUTES OF ADMINISTRATION (REVIEW)
This review summarises information on drug products Somatostatin Analogues (SSAs), which are included in the algorithm of Neuroendocrine Tumors (NET) treatment. SSAs are the current standard for safe and effective management of NET symptoms and control of tumours growth and are administered in a range of dosage forms for parenteral administration, such as intramuscular, subcutaneous and implant. A search criterion was the therapy of NET with medicines from a group of SSAs. Literature survey has been done in a range of years 1990-2018 to make the review updated and comprehensive and to show the development of SSAs new pharmaceutical dosage forms to improve patient quality of life and side effects decrease. The sources were world-recognized journals. Keywords used as filters were NET, SSAs, octreotide, lanreotide, pasireotide, Somatostatin Receptors (SSTR), dosage form. The current review is created with an intended to focus on the advantage of SSAs modern dosage forms. Literature survey revealed that many studies were carried out to SSAs encapsulation into microspheres that changes the drug bioavailability and allows reducing the number of administration. Also, SSAs delivery systems in particular devices such as auto-injector have been created to control the continuous concentration of the drug and to provide safety guarantee. Besides, studies have been carried out to prepare SSAs formulations for oral administration to improve the quality of life of the NET patients. In this review, SSAs pharmaceutical dosage forms with improved pharmacokinetic and therapeutic characteristics and routes of administration are analyzed.
2019-01-18 | Everolimus in Combination with Octreotide Long-Acting Repeatable in a First-Line Setting for Patients with Neuroendocrine Tumors: A 5-Year Update.
We previously presented data of this multicentric, phase II study showing that everolimus plus octreotide long-acting repeatable (LAR) for advanced neuroendocrine neoplasms (NENs), in the first line setting, is an active and safe treatment. We now present updated data at 5 years. Patients with advanced well-differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg plus everolimus 10 mg/day. The primary endpoint was the objective response rate (ORR). We performed an analysis of "long responder" patients and of time to progression (TTP) and overall survival (OS) at 5 years. Fifty patients were enrolled; the primary tumor site was: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum/duodenum (2 patients), and unknown (14 patients). Seventeen (34%) of these patients have received treatment for more than 2 years. The median exposure to study drugs was 519.5 days (range 48-2,024). Currently 3 patients are still in treatment. The ORR (partial response + complete response) was 18% (95% confidence interval [CI] 7.4-28.6): complete response 1 patient (2%), partial response 8 patients (16%), stable disease 37 patients (74%). The median TTP was 33.6 months (95% CI 18.7-41.2) and the median OS was 61.0 months (95% CI 49.8-not reached). In this update of clinical outcome at 5-year follow-up, everolimus plus octreotide has been shown to be active in advanced NENs. The current analysis showed a further prolongation of TTP and a long exposure to the study drug without major side effects in the long term.
2018-12-01 | The eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience
Metastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT. Patient 1 is a 72 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy. Patient 2 is a 68 year-old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control. Patient 3 is a 63 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET-CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly. Patient 4 is a 72 year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since. Patient 5 is a 61 year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease. NETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients.
2018-02-10 | Clinical experience with indigenous kit-based preparation of 68Ga-DOTATOC using commercial 68Ge/68Ga generator
Pharmaceutical grade DOTATOC kits compliant with all the quality control criteria were formulated and radiolabeled with 68Ga in high yields. Comparison with module-based 68Ga-DOTATOC established product equivalency. Clinical utility was evaluated in patients with histopathologically confirmed well-differentiated neuroendocrine tumors. Kit-based preparation of 68Ga-DOTATOC could identify sites of primary and metastatic disease. PET/CT images of patients conformed to the established criteria for somatostatin imaging agents and clinical expectations. Results of this study emphasize the potential of kit-based 68Ga-DOTATOC for PET imaging of neuroendocrine tumors.
antibodies
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.
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.
2020-03-03 | Analysis of the immune landscape of small bowel neuroendocrine tumors.
Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30-49%) and 14/102 (14%; 95% CI, 8-22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25-44%), mild to moderate in 46/102 samples (45%, 95% CI, 35-55%), intense in 21/102 tumors (21%, 95% CI, 13-30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11-26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.
2019-12-01 | The tumor immune microenvironment in gastroenteropancreatic neuroendocrine neoplasms
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors. Moreover, a comparison between TIMEs among different types of GEP-NENs and the interplay among the TIME, tumor cells, and the stromal microenvironment is described. Novel treatment options for GEP-NENs and potential biomarkers for the immune response are also characterized. We provide a comprehensive generalized review of the TIME that can inform GEP-NEN treatment strategies.
2018-10-16 | Should Ki67 immunohistochemistry be performed on all lesions in multifocal small intestinal neuroendocrine tumours?
Well-differentiated small intestinal neuroendocrine tumours (SI-NETs) are often multifocal, and this has been suggested to impart worse disease-free survival. Practice guidelines have not been established for World Health Organisation (WHO) grading of multiple primary lesions.We identified 68 patients with ileal/jejunal SI-NET for a combined total of 207 primary lesions. Each case was evaluated for patient age and sex; size of all tumours; presence of lymph node metastases, mesenteric tumour deposits or distant metastases; and disease-specific outcome. Ki67 staining was performed on all 207 primary lesions. The relationship between multifocality and clinicopathological factors was compared using Fisher's exact test. Outcome was tested using Cox proportional hazard regression. Forty-two patients had unifocal disease, and 26 had multifocal disease (median five lesions, range = 2-32). Most tumours were WHO grade 1 (201 of 207, 97%). Of the five patients with grades 2/3 tumours, three patients had unifocal disease, one patient had two subcentimetre grade 2 lesions (including the largest) and eight subcentimetre grade 1 lesions, and one patient had one 1.6-cm grade 3 lesion and one subcentimetre grade 1 lesion. There was a positive correlation between tumour size and Ki67 index (coefficient 0.28; 95% confidence interval 0.05-0.52, P = 0.017). There was no significant association between multifocality and nodal metastases, mesenteric tumour deposits, distant metastases or disease-specific survival.In patients with multifocal SI-NET, unless a particular lesion has a high mitotic rate, only staining the largest lesion for Ki67 should serve to grade almost all cases accurately. Multifocality does not appear to significantly impact patient survival.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.