RESUMEN
Introduction: Lung carcinoids (LCs) are a type of neuroendocrine tumor (NET) that originate in the bronchopulmonary tract. LCs account for 20-25% of all NETs and approximately 1-2% of lung cancers. Given the highly vascularized nature of NETs and their tendency to overexpress vascular growth factor receptors (VEGFR), inhibiting angiogenesis appears as a potential therapeutic target in slowing down tumor growth and spread. This study evaluated the long-term antitumor activity and related mechanisms of axitinib (AXI), a VEGFR-targeting drug, in LC cell lines. Methods: Three LC cell lines (NCI-H727, UMC-11 and NCI-H835) were incubated with their respective EC50 AXI concentrations for 6 days. At the end of the incubation, FACS experiments and Western blot analyses were performed to examine changes in the cell cycle and the activation of apoptosis. Microscopy analyses were added to describe the mechanisms of senescence and mitotic catastrophe when present. Results: The primary effect of AXI on LC cell lines is to arrest tumor growth through an indirect DNA damage. Notably, AXI triggers this response in diverse manners among the cell lines, such as inducing senescence or mitotic catastrophe. The drug seems to lose its efficacy when the DNA damage is mitigated, as observed in NCI-H835 cells. Conclusion: The ability of AXI to affect cell viability and proliferation in LC tumor cells highlights its potential as a therapeutic agent. The role of DNA damage and the consequent activation of senescence seem to be a prerequisite for AXI to exert its function.
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Apoptosis , Axitinib , Tumor Carcinoide , Proliferación Celular , Neoplasias Pulmonares , Humanos , Axitinib/farmacología , Axitinib/uso terapéutico , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ciclo Celular/efectos de los fármacosAsunto(s)
Octreótido , Vasoconstrictores , Humanos , Octreótido/uso terapéutico , Vasoconstrictores/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Complicaciones Intraoperatorias/prevención & control , Tumor Carcinoide/cirugía , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Síndrome Carcinoide Maligno/tratamiento farmacológico , Síndrome Carcinoide Maligno/cirugíaRESUMEN
Pulmonary atypical carcinoid (AC) is an extremely rare neuroendocrine tumor. The neurotrophic tropomyosin receptor kinase (NTRK) fusions are reported in only 0.5% of nonsmall cell lung cancer, and are more rare in AC with only one previously reported case. Currently, there is little established evidence on the optimal therapeutic strategies and prognosis for advanced cases. We present a female patient with metastatic AC after complete resection. Due to low expression of somatostatin receptor in this case, somatostatin analogs and peptide receptor radionuclide therapy were not available. After pursuing other alternative treatments, including chemotherapy (ie, carboplatin, etoposide, capecitabine, temozolomide, and paclitaxel), everolimus, and atezolizumab, she returned with significant progression, including innumerable subcutaneous nodules, left pleura metastasis, multiple bone metastases, and brain metastases. New biopsy analysis revealed an ETV6-NTRK2 fusion. She was immediately administered the first-generation tropomyosin receptor kinase inhibitor entrectinib at a dose of 600 mg q.d. A subsequent month of treatment resulted in a complete response in all of the metastatic lung lesions. To date, she has maintained sustained benefit for at least 1 year from initiation of entrectinib. Here, we present the first case of a female patient with metastatic AC harboring the ETV6-NTRK2 fusion, and successfully treated with entrectinib, providing evidence for the application of entrectinib in patients with NTRK-positive AC, and underscoring the critical role of molecular profiling for such cases.
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Benzamidas , Tumor Carcinoide , Indazoles , Neoplasias Pulmonares , Proteínas de Fusión Oncogénica , Humanos , Femenino , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Tumor Carcinoide/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Proteínas de Fusión Oncogénica/genética , Indazoles/uso terapéutico , Benzamidas/uso terapéutico , Persona de Mediana Edad , Receptor trkB/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Glicoproteínas de MembranaAsunto(s)
Octreótido , Vasoconstrictores , Humanos , Octreótido/uso terapéutico , Vasoconstrictores/uso terapéutico , Tumor Carcinoide/cirugía , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Complicaciones Intraoperatorias , Antineoplásicos Hormonales/uso terapéutico , Síndrome Carcinoide Maligno/tratamiento farmacológico , Síndrome Carcinoide Maligno/cirugía , PronósticoRESUMEN
BACKGROUND: Intraoperative carcinoid crisis is typically sudden onset of profound hypotension during operations on patients with neuroendocrine tumors. The crisis was thought to be due to massive release of hormones, and perioperative octreotide was recommended as a prophylaxis against the crisis and as first-line treatment. Recent studies show that octreotide does not prevent the crisis and that no massive release of hormones occurs. Therefore, the authors hypothesized that octreotide is not effective for treating the crisis. METHODS: A prospective carcinoid anesthesia database was analyzed for occurrences of crisis. Outcomes were compared between protocols when first-line therapy was bolus octreotide and when it was vasopressors without octreotide. Significance was determined by Student's t test, the Mann-Whitney U test, and Fisher's exact test. RESULTS: Among operations performed with octreotide as first-line treatment (n = 150), crisis occurred for 45 (30 %) patients, the median crisis duration was 6 min, 12 (27 %) patients had crises longer than 10 min, 42 patients (93 %) required subsequent vasopressor administration to resolve the crisis, and 3 (2 %) operations were aborted. Among operations performed with vasopressors as the first-line treatment (n = 195), crisis occurred for 49 (25 %) patients (p = 0.31), the median crisis duration was 3 min (p < 0.001), and no crisis lasted longer than 10 min (p = 0.001). Patients treated with vasopressors were less likely to have multiple crises and had a shorter total time in crisis, a shorter anesthesia time, and no aborted operations (p < 0.05 for all). CONCLUSIONS: First-line octreotide was ineffective treatment for carcinoid crisis, with patients requiring vasopressors to resolve the crisis, and many crises lasting longer than 10 min. First-line vasopressor treatment resulted in significantly shorter crisis durations, fewer crises and aborted operations, and shorter anesthesia times. Vasopressors should be used as first-line treatment for intraoperative crisis, and treatment guidelines should be changed.
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Tumor Carcinoide , Síndrome Carcinoide Maligno , Humanos , Octreótido/uso terapéutico , Estudios Prospectivos , Síndrome Carcinoide Maligno/tratamiento farmacológico , Síndrome Carcinoide Maligno/cirugía , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/cirugía , Vasoconstrictores/uso terapéutico , HormonasRESUMEN
We report a rare case involving a 52-year-old female diagnosed with an atypical bronchial carcinoid tumor with metastases to the mediastinum, hilar lymph nodes, breast, and pancreas. In additional, the patient had metastases to the iris and ciliary body, resulting in progressive vision loss in her left eye. Treatment was successful by intravitreal injections of anti-vascular endothelial growth factor.
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Tumor Carcinoide , Factores de Crecimiento Endotelial , Humanos , Femenino , Persona de Mediana Edad , Inyecciones Intravítreas , Manejo de Caso , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/patologíaRESUMEN
The mTOR-inhibitor everolimus has been approved for the treatment of advanced neuroendocrine tumors (NETs) but is associated with relevant toxicities in clinical practice. Hence, optimal treatment sequencing and the impact of dose reductions have yet to be clarified. This retrospective analysis assessed patients with advanced, well-differentiated NET treated with everolimus at the Medical University of Vienna. The primary objective was to evaluate the efficacy of everolimus in a real-world cohort. A total of 52 patients treated with everolimus for advanced NET grade 1 (G1) or G2 (or typical or atypical carcinoid) 2010-2021 were included in this analysis. The most common sites of origin were pancreas (44%) and lung (29%). The initial dose was decided by the treating physician based on clinical assessment and 25 patients (48%) each were started at 10 mg/day and 5 mg/day. Median progression-free survival (PFS) following everolimus in the overall cohort was 9.8 months (95% CI: 4.3-15.3), with a statistically significant PFS difference (p = .03) between NET G1/typical carcinoids (42.9 months) and NET G2/atypical carcinoids (8.9 months). PFS was numerically but not significantly shorter in patients treated with a reduced dose (7.5 months vs. 12.4 months, p = .359). Even in this mixed full/half dose cohort, 93% developed treatment-related side effects (mostly grade I, no grade IV), 63% had dose reductions or interruptions, and five stopped due to toxicity. Median survival following treatment was 40.9 months (95% CI: 21.5-60.3) and no difference with regard to dosing was observed (p = .517). These data from an unselected patient cohort show long-term outcomes similar to those reported in the pivotal studies. Comparing everolimus starting dose, median PFS did not significantly differ for patients treated at a lower dose. While this finding is limited by the sample size and warrants prospective verification, initiating therapy at a reduced dose might be practicable and safe in a distinct subset of patients.
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Antineoplásicos , Tumor Carcinoide , Tumores Neuroendocrinos , Humanos , Everolimus/efectos adversos , Tumores Neuroendocrinos/patología , Antineoplásicos/efectos adversos , Centros de Atención Terciaria , Estudios Retrospectivos , Estudios Prospectivos , Tumor Carcinoide/inducido químicamente , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patologíaRESUMEN
Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.
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Cardiopatía Carcinoide , Tumor Carcinoide , Síndrome Carcinoide Maligno , Tumores Neuroendocrinos , Humanos , Cardiopatía Carcinoide/diagnóstico , Cardiopatía Carcinoide/terapia , Tumor Carcinoide/tratamiento farmacológico , Síndrome Carcinoide Maligno/tratamiento farmacológico , Tumores Neuroendocrinos/terapia , Tumores Neuroendocrinos/tratamiento farmacológico , Everolimus/uso terapéuticoRESUMEN
Thymic atypical carcinoids are extremely rare tumors and have a poor prognosis owing to their aggressive clinical course. The efficacy of treatments other than complete surgical resection is unclear. We herein report a postoperative recurrent case of thymic atypical carcinoid treated with everolimus and octreotide long-acting repeatable (LAR). A 75-year-old woman was admitted to our department because a nodule was detected in the right lobe of thymus by annual computed tomography. The patient underwent thymothymectomy, and a diagnosis of thymic atypical carcinoid was made. One year and seven months after surgery, she developed multiple metastases in the lung, hilar and mediastinal lymph nodes, liver, and bone. Everolimus 10 mg/day was administered; however, the dose had to be reduced to 5 mg/day due to grade 3 hyperglycemia and grade 3 interstitial lung disease. Metastatic lesions other than liver metastasis markedly responded to everolimus, although the liver metastases gradually progressed. Three years and six months after surgery, she was administered octreotide LAR 30 mg per month in combination with everolimus. She has maintained stable disease for 8 months after the application of this combination therapy.
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Tumor Carcinoide , Neoplasias del Timo , Femenino , Humanos , Anciano , Everolimus/uso terapéutico , Octreótido/uso terapéutico , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Mediastino/patología , Neoplasias del Timo/tratamiento farmacológico , Neoplasias del Timo/patologíaRESUMEN
Clinical experience is herein reported with somatostatin analogues (octreotide and lanreotide) in the management of 10 CS out of a series of 14 collected cases of carcinoid syndrome (CS).
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Tumor Carcinoide , Síndrome Carcinoide Maligno , Humanos , Tumor Carcinoide/tratamiento farmacológico , Somatostatina/uso terapéutico , Octreótido/uso terapéutico , Síndrome Carcinoide Maligno/tratamiento farmacológicoRESUMEN
Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.
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Tumor Carcinoide , Carcinoma Neuroendocrino , Neoplasias Pulmonares , Animales , Tumor Carcinoide/tratamiento farmacológico , Carcinoma Neuroendocrino/patología , Xenoinjertos , Humanos , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Pez CebraRESUMEN
PURPOSE OF REVIEW: Lung neuroendocrine tumors (NETs)-typical carcinoids and atypical carcinoids-have unique molecular alterations that are distinct from neuroendocrine carcinomas of the lung and non-small cell lung cancers. Here, we review the role of molecular profiling in the prognosis and treatment of lung NETs. RECENT FINDINGS: There have been no recently identified molecular prognostic factors for lung NETs and none that have been routinely used to guide management of patients with lung NETs. Previous findings suggest that patients with loss of chromosome 11q may have a worse prognosis along with upregulation of anti-apoptotic pathways (e.g., loss of CD44 and OTP protein expression). Lung NETs rarely harbor driver mutations commonly found in non-small cell lung cancer (NSCLC) or TP53/RB1 mutations found universally in small cell lung cancer. Lung NETs also have low tumor mutation burden and low PD-L1 expression. Everolimus, an mTOR inhibitor and the only FDA approved therapy for unresectable lung NETs, is an effective treatment but the presence of a molecular alteration in the PI3K/AKT/mTOR pathway is not known to predict treatment response. The predominant mutations in lung NETs occur in genes regulating chromatin remodeling and histone modification, with potential targeted therapies emerging in clinical trials. Lung NETs have recurring alterations in genes that regulate the epigenome. Future targeted therapy interfering with epigenetic pathways may hold promise.
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Antineoplásicos , Tumor Carcinoide , Carcinoma Neuroendocrino , Carcinoma de Pulmón de Células no Pequeñas , Everolimus , Neoplasias Pulmonares , Tumores Neuroendocrinos , Antineoplásicos/uso terapéutico , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/genética , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Everolimus/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Recurrencia Local de Neoplasia/metabolismo , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
Lung carcinoids are neuroendocrine tumors representing 1 to 2% of lung cancers. This study outlines the case of a patient with a metastatic lung atypical carcinoid who presented with a pleural effusion and progression of liver metastases after developing resistance to conventional treatments. Personalized functional profiling (PFP), i.e. drug screening, was performed in ex-vivo spheroids obtained from the patient's liver metastasis to identify potential therapeutic options. The drug screening results revealed cediranib, an antiangiogenic drug, as a hit drug for this patient, from a library of 66 Food and Drug Administration (FDA)-approved and investigational drugs. Based on the PFP results and the reported evidence of clinical efficacy of bevacizumab and capecitabine combination in gastro-intestinal neuroendocrine tumors, this combination was given to the patient. Four months later, the pleural effusion and pleura carcinosis regressed and the liver metastasis did not progress. The patient experienced 2 years of a stable disease under the PFP-guided personalized treatment.
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Tumor Carcinoide , Carcinoma Neuroendocrino , Neoplasias Hepáticas , Neoplasias Pulmonares , Neoplasias Primarias Secundarias , Tumores Neuroendocrinos , Derrame Pleural , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/patología , Carcinoma Neuroendocrino/patología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Pulmón/patología , Neoplasias Pulmonares/patología , Neoplasias Primarias Secundarias/patología , Tumores Neuroendocrinos/patología , Derrame Pleural/patologíaRESUMEN
Carcinoid syndrome, a paraneoplastic condition linked with the release of multiple humoral factors, affects around 30-40% of patients with well-differentiated neuroendocrine tumours. Carcinoid syndrome has a major and unfavourable impact on patients' quality of life; it raises costs when compared to non-functioning neuroendocrine tumours; and it causes patients' lifestyles to alter, such as food, job, physical activity, and social life. Somatostatin analogues have been the first-line therapy for individuals with neuroendocrine tumours and carcinoid disease for decades. While these drugs give considerable relief from carcinoid syndrome symptoms, clinical progression is unavoidable, necessitating further research into newer treatment measures. Carcinoid tumours are sometimes difficult to diagnose because of their vague or nonspecific symptoms. There have been several advancements in all aspects of carcinoid syndrome, as well as novel therapeutics, in the previous few years. New epidemiological studies show that it is becoming more common; increasing insights into the pathogenesis of its various clinical manifestations and its natural history: definition of prognostic factors; new methods to verify its presence; the development of new drugs to treat its various manifestations, both initially and in somatostatin-refractory cases; and an increased understanding of the pathogenesis, natural history, and management of the disease. An all language literature search was conducted on MEDLINE, COCHRANE, EMBASE, and Google Scholar till November 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: "Recent advances", "Carcinoid syndrome", "Neuroendocrine Neoplasms" and "Carcinoid heart disease". We comprehensively reviewed the literature on the pathogenesis, clinical features, and newer treatment modalities for Carcinoid Syndrome. Recent advancements in research and management have resulted from advances in our understanding of the aetiology of carcinoid syndrome. The development of molecular indicators of aggressiveness improved serum tumour markers, and the molecular aetiology of carcinoid heart disease are all possible because of advances in molecular biology. We conducted a comprehensive review to update knowledge regarding the pathophysiology, diagnostic protocols, and current and newer treatments for carcinoid syndrome, which presently requires a multidisciplinary approach, due to the complexity of the illness's aetiology, diagnosis, and therapy.
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Tumor Carcinoide , Síndrome Carcinoide Maligno , Tumores Neuroendocrinos , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/terapia , Humanos , Síndrome Carcinoide Maligno/complicaciones , Síndrome Carcinoide Maligno/diagnóstico , Síndrome Carcinoide Maligno/terapia , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Calidad de Vida , Somatostatina/uso terapéuticoRESUMEN
Peptide receptor radionuclide therapy (PRRT) is a therapeutic option in inoperable or metastatic neuroendocrine tumours (NETs). PRRT proved to be promising in prolonging survival and delaying disease progression in patients with advanced bronchopulmonary carcinoid. However, it may lead to worsening of carcinoid symptoms or even precipitate carcinoid crises. The incidence of PRRT induced carcinoid crisis would be between 1-10%. This usually takes place during the first PRRT cycle, either during the tracer infusion or 12-48 hours' post-administration. We report a 62-year-old man with underlying metastatic lung carcinoid tumour who developed carcinoid crisis at 10 hours after receiving PRRT. The carcinoid crisis was successfully treated with intravenous octreotide infusion, corticosteroid, a selective 5-HT3 receptor antagonist, parenteral ranitidine and chlorpheniramine for H1 and H2 antagonism respectively.
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Tumor Carcinoide , Tumores Neuroendocrinos , Tumor Carcinoide/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Octreótido/uso terapéutico , Radioisótopos/uso terapéutico , Receptores de PéptidosRESUMEN
Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation that arise in most organs of the body. Mediastinal NETs are very rare, and account for no more than 5% of all mediastinal tumors. R0 surgery represents the milestone of treatment. Here, we describe a case of a locally advanced primary atypical carcinoid of the mediastinum. This was initially considered inoperable due to infiltration of a great vessel and was successfully resected after neoadjuvant treatment as a result of very extensive surgery. Only through an accurate preoperative diagnosis and good radiological planning is it possible to obtain satisfactory oncological results.
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Antineoplásicos/uso terapéutico , Tumor Carcinoide/tratamiento farmacológico , Tumor Carcinoide/cirugía , Neoplasias del Mediastino/tratamiento farmacológico , Neoplasias del Mediastino/cirugía , Terapia Neoadyuvante/métodos , Anciano , Terapia Combinada , Humanos , Masculino , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/cirugíaRESUMEN
PURPOSE: Neuroendocrine neoplasia (NEN) of the thymus is a very rare entity with a poor prognosis. None of the treatments was proofed by studies. Usually, therapy protocols for bronchopulmonary carcinoids are used. So far no data exist on the effect of mammalian target of rapamycin (mTOR) inhibitors. We describe our long-term experience with everolimus and give a thorough review of the therapeutic strategies used so far. PATIENTS AND METHODS: Four patients (mean age 46 years, range 37-55) with progressing thymic NEN (t-NEN) (two well-differentiated atypical carcinoids and two atypical carcinoids with large cell characteristics) were treated with everolimus 10 mg/day after the failure of at least one previous medical therapy. Everolimus was applied after a mean interval of 32.4 months (range 5-56) after the first diagnosis. The follow-up included clinical examination, imaging and chromogranin A testing in 3 or 6 monthly intervals. RESULTS: We observed stable disease for a mean of 20.8 months. Both patients with large cell characteristics t-NEN (Ki-67 of 20%) had rapid progress after 7 and 10 months and had more previous therapies (three and six) than the patients with well-differentiated t-NEN (Ki-67 5% and 10%, progress after 24 and 42 months, one and two previous therapies). No severe side effects occurred. In three of four patients, everolimus led to stable disease for the longest compared to the other nonsurgical therapies used. CONCLUSION: Comparing the sparse data available everolimus is a promising treatment for t-NEN at least in second-line therapy. A low Ki-67 index was associated with a better outcome.