Gender Differences in Lung Neuroendocrine Tumors: A Single-Center Experience.

INTRODUCTION: Gender difference may affect lung neuroendocrine tumor (L-NET) onset, progression, and outcomes as emerged in other cancers. This study aimed to analyze gender difference in L-NET to identify potential prognostic factors, to improve patient follow-up and therapeutic strategies. METHODS: Patients with histologically confirmed L-NEN diagnosis referred to the ENETS CoE of the Endocrinology Unit, Federico II University of Naples, from 2013 to 2023, were retrospectively evaluated. RESULTS: Among 48 patients with L-NEN, 38 (79.2%) with sporadic L-NET were enrolled: 22 typical (57.9%) and 16 atypical (42.1%) carcinoids, 22 (57.9%) female and 16 (42.1%) male, mean age at diagnosis 57.3 years (range 16-84). Median follow-up was 70.5 months (range 12-305). No statistical difference resulted regarding smoking habit, BMI, primary site (left/right and central/peripheral), and histological characteristics, between cohorts. Metastasis at diagnosis was found in 20 patients (52.3%), 10 female (10%) and 10 male (10%) (p: 0.20). Progressive disease (PD) was observed in 14 (36.8%) patients, and male sex developed PD more frequently 9/14 (64.3%) than female 5 (35.7%), p: 0.05. Male sex seemed to show more frequently bone metastasis without reaching statistical difference, 7 male/10 (70%), p: 0.06. Among 9 deaths (23.7%), 7 (77.8%) were men and 7 died for PD, p < 0.03. Male had a poorer prognosis than female regarding progression-free survival (PFS) (p: 0.04) and overall survival (p: 0.001), also when sub-groups of patient metastatic at diagnosis were compared (p: 0.02 and p: 0.02). CONCLUSIONS: This study showed a worse prognosis in male than female with L-NET, despite similar clinical features, tumor type, stage, and treatment, with regard to PFS, OS, and metastatic spread. These findings may suggest a closer follow-up in men, with potential positive impact on outcomes.

Lung Neuroendocrine Tumors: How Does Molecular Profiling Help?

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.

Multiple Assays to Determine Methylguanine-Methyltransferase Status in Lung Carcinoids and Correlation with Clinical and Pathological Features.

BACKGROUND: O6-methylguanine-methyltransferase (MGMT) is a key enzyme for the DNA repair machinery strongly associated with response to alkylating agents in different tumors. Data on its expression and related clinical impact in neuroendocrine tumors are limited to the gastro-entero-pancreatic system, with controversial results in terms of prognostic or predictive value. In lung carcinoids, although clinical efficacy of alkylating agents has been shown in small studies, very few data to date are available on MGMT status. OBJECTIVE: To assess MGMT status in lung carcinoids using multiple assays and to compare data with major clinical and pathological features. METHODS: A retrospective series of 95 lung carcinoids and 51 control cases of high-grade neuroendocrine lung carcinomas was analyzed for MGMT promoter methylation, MGMT gene expression, and MGMT protein expression using pyrosequencing, quantitative real-time PCR, and immunohistochemistry, respectively. RESULTS: MGMT protein expression was inversely correlated with MGMT promoter methylation and positively with MGMT gene expression. MGMT promoter methylation progressively increased from carcinoids to high-grade carcinomas. In the carcinoid group, decreased MGMT gene expression was significantly associated with aggressive features (atypical histotype, grade G2, larger tumor size, higher T stage, and positive nodal status) but not with survival. MGMT promoter methylation was associated with lower stage and negative nodal status. CONCLUSIONS: Our study investigated MGMT status in a large series of lung carcinoids in the attempt to move forward a rational use of alkylating agents in these tumors. Interestingly, low MGMT gene expression defines a subgroup of lung carcinoids with aggressive features.

Treatment Patterns and Clinical Outcomes in Advanced Lung Neuroendocrine Tumors in Real-World Settings: A Multicenter Retrospective Chart Review Study.

BACKGROUND: Using data from four tertiary referral centers in the U.S., we assessed real-world treatment patterns and clinical outcomes of patients with advanced lung neuroendocrine tumors (NETs). SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective chart review of adult patients with locally advanced/metastatic (typical/atypical) lung NETs treated between July 2011 and December 2014. Index date was histologically confirmed typical/atypical carcinoid tumor diagnosis date. Data included baseline characteristics, treatment patterns, progression, death, and lung NET-related health care resource use from index date through last contact/death. Time to treatment discontinuation and first progression, time from first to second progression, and overall survival (OS) were estimated using Kaplan-Meier analysis. RESULTS: We identified 83 patients; 19 (23%) had functional NET. First-line treatments included somatostatin analogs (SSAs) alone (56%) or in combination with other therapies (6%), cytotoxic chemotherapy (20%), external beam radiation therapy (EBRT) (9%), liver-directed therapy (LDT) (4%), and everolimus/other (5%). Sixty patients had second-line therapy including SSA alone (18%) or in combination (40%), cytotoxic chemotherapy (17%), everolimus (12%), LDT (7%), EBRT (3%), and other treatments (3%). Median time (months) to first-line discontinuation were as follows: SSAs, 43.3; cytotoxic chemotherapy, 3.6. Overall median time (months) to investigator-assessed progression following treatment initiation was 12.4. Median OS (months) following treatment initiation was 66.4 for all patients and 81.5 for patients receiving SSAs. CONCLUSION: SSAs, alone and in combination, are common treatments for advanced lung NETs. Patients have additional treatment options and relatively long survival compared with patients with other advanced cancers. Treatment pattern assessment following approval of newer treatments is needed. IMPLICATIONS FOR PRACTICE: Somatostatin analogs (SSAs), cytotoxic chemotherapy, EBRT, liver-directed therapy, and targeted therapies are common treatments for locally advanced/metastatic (typical/atypical) lung neuroendocrine tumors (NETs). SSAs alone or in combination with other treatment modalities were the most common first- and second-line therapy, followed by cytotoxic chemotherapy. Patients continued treatment with SSAs long-term with median treatment duration of 43 months. Median overall survival was 66 months following initiation of first-line therapy for all patients. Treatment pattern assessment beyond the time period of this study is needed given recent U.S. Food and Drug Administration approvals for additional treatments for lung NETs that will likely be incorporated in the treatment landscape.

Treatment of lung large cell neuroendocrine carcinoma.

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: A Blanked Out Pulmonary Neuroendocrine Tumor.

Introduction: Lung neuroendocrine tumors (NETs) are a rare type of pulmonary tumor and represent approximately 2% of all lung cancers. The prevalence of lung NETs is increasing, which may be due to improved diagnostic techniques for asymptomatic tumors. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare and underdiagnosed disease that falls under the spectrum of NETs. Case Presentation: We presented a case of a 59-year-old male who presented with severe coughing spells, flushing, and diarrhea. His computed tomography scan showed innumerable pulmonary nodules and irregular nodular opacities throughout the lungs. He underwent a left upper lobe wedge resection and was eventually diagnosed with neuroendocrine tumorlets via immunohistochemical stains. He was started on a trial of octreotide and reported significant improvement in symptoms after 1 month. Conclusion: DIPNECH is a rare preinvasive lesion characterized by the abnormal proliferation of pulmonary neuroendocrine cells. Patients with DIPNECH can present initially with respiratory symptoms, while other cases are discovered incidentally during the workup of different conditions. Definitive diagnosis of DIPNECH requires histopathological examination of lung tissue. There is limited evidence on DIPNECH management, and an individualized approach is currently advised.

Uncommon Metastasis of a Large-Cell Neuroendocrine Carcinoma From the Lungs to the Buccal Palatal Region.

The metastasis of a primary lung tumor to the mouth cavity is a rare occurrence. In addition, the occurrence of neuroendocrine bronchial carcinoma with large cells is uncommon. When metastases are not possible to surgically remove, the conventional treatment for large-cell neuroendocrine tumors (LCNET) is still used. The etiology of these metastases remains inadequately comprehended, rendering their administration very intricate. The oncologist at this institution must possess a comprehensive comprehension of how to effectively oversee the patient's quality of life to guarantee the uninterrupted progression of therapy. This paper is a case study of a 51-year-old male patient who was hospitalized due to a severe dry cough and dysphonia that began two months prior to seeking medical consultation. Gingival hyperplasia was diagnosed during a clinical examination. The diagnosis of LCNET (carcinoma of the lung) was determined after a thorough etiological investigation utilizing gingival samples and pulmonary tissue. The objective of this study was to provide a description of our case, conduct an analysis of the response to therapy, and make a contribution to the current body of research. The purpose was to encourage more investigation into this type of metastasis, aiming to get a deeper comprehension of the mechanisms behind the metastatic spread and assess its predictive significance in future instances.

Auranofin inhibition of thioredoxin reductase sensitizes lung neuroendocrine tumor cells (NETs) and small cell lung cancer (SCLC) cells to sorafenib as well as inhibiting SCLC xenograft growth.

Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1-5 d. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism.

Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells.

Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed. Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide. Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression. Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone. Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.

Visual analysis of lung neuroendocrine tumors based on CiteSpace knowledge graph.

Objective: The relevant literatures in the field of pulmonary neuroendocrine tumor were analyzed to understand the lineage, hot spots and development trends of research in this tumor. Method: The Web of Science core collection was searched for English-language literature about neuroendocrine tumors of the lung published between 2000 and 2022. CiteSpace software was imported for visualization analysis of countries, institutions, co-cited authors and co-cited journals and sorting of high-frequency keywords, as well as co-cited references and keyword co-occurrence, clustering and bursting display. Results: A total of 594 publications on neuroendocrine tumours of the lung were available, from 2000 to 2022, with an overall upward trend of annual publications in the literature. Authors or institutions from the United States, Italy, Japan and China were more active in this field, but there was little cooperation among the major countries. Co-cited references and keyword co-occurrence and cluster analysis showed that research on diagnostic instruments, pathogenesis, ectopic ACTH signs, staging and prognosis and treatment was a current research hotspot. The keyword bursts suggested that therapeutic approaches might be a key focus of future research into the field for pulmonary neuroendocrine tumors. Conclusion: Over these 20 years, research related to neuroendocrine tumors of the lung has increased in fervour, with research on diagnostic instruments, pathogenesis, ectopic ACTH signs, staging and prognosis, and treatment being the main focus of research. Therapeutic treatments may be the future research trend in this field.

Masquerading as Pneumonia: A Lung Neuroendocrine Tumor Case Report.

The presentation of recurrent pneumonia, particularly in the same lobe, should raise suspicion for possible neuroendocrine tumors of the lung within that respective lobe. Commonly, these types of tumors will have a gastrointestinal origin with a larger incidence of carcinoid syndrome, but they may also originate in the pancreas or lungs. This case illustrates the potential for a masked lung tumor in an otherwise young and healthy 31-year-old patient, with a short history of tobacco dependence and unremarkable family history, who presents with recurrent pneumonia and dyspnea. Although rare in itself, this case was even more unique due to the partial calcification of the neuroendocrine tumor mass along with causing a collapse in the entire right middle lobe.

Heterogeneity of TPIT expression in ACTH-secreting extra-pituitary neuroendocrine tumors (NETs) supports the existence of different cellular programs in pancreatic and pulmonary NETs.

Extra-pituitary ACTH secretion is associated with a variety of neoplastic conditions and may cause the so-called ectopic ACTH-dependent Cushing syndrome (CS). The clarification of the mechanisms of extra-pituitary ACTH expression would provide potential therapeutic targets for this complex and severe disease. In the adenohypophysis, the transcription factor TPIT, co-operating with other molecules, induces POMC expression and ACTH production. However, no data are currently available on the presence and role of TPIT expression in extra-pituitary ACTH-producing neoplasms. This study was designed to explore TPIT expression in a series of pulmonary and pancreatic ACTH-producing tumors, either CS-associated or not. Forty-one extra-pituitary ACTH-producing neuroendocrine tumors (NETs) were included in the study, encompassing 32 NETs of the lung (LuNETs), 7 of the pancreas (PanNETs), and 2 pheochromocytomas. Of these, 9 LuNETs, all PanNETs, and the two pheochromocytomas were CS-associated. For comparison, 6 NETs of the pituitary gland (PitNETs; 3 ACTH-secreting and 3 ACTH-negative) and 35 ACTH-negative extra-pituitary NETs (15 Lu-NETs and 20 PanNETs) were analyzed. Immunohistochemistry with specific anti-TPIT antibodies and quantitative real-time PCR (qRT-PCR) were performed using standard protocols. TPIT expression was completely absent (protein and mRNA) in PanNETs, pheochromocytomas, and all ACTH-negative NETs. In contrast, it was expressed in 16/32 LuNETs, although with lower levels than in PitNETs. No definite relationship was found between immunohistochemistry TPIT expression and NET grade or the presence of Cushing syndrome. This study further highlights the clinical and biological heterogeneity of extra-pituitary ACTH secretion and suggests that the differences between ACTH-secreting PanNETs and LuNETs may mirror distinct molecular mechanisms underlying POMC expression. Our results point towards the recognition of a real corticotroph-like phenotype of ACTH-producing LuNETs, that is not a feature of ACTH-producing PanNETs.

Progressive neuroendocrine tumor of lung with combined categories in metastatic site: a case report.

Background: Both large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) are high-grade neuroendocrine tumors of lung in classification. Combined LCNEC and combined SCLC may comprise up to 25% of the resected cases. However, co-existence of LCNEC and SCLC in lung accompanied with combined LCNEC in extrapulmonary metastatic sites is infrequent. Case Description: In this paper, we report a 58-year-old male with cough, back pain and increased sputum. He was diagnosed as LCNEC and SCLC in his lung successively. His tumor gradually progressed and combined LCNEC was then diagnosed in his cervical lymph node. Regimens of chemotherapy were accordingly adjusted several times, but his lesions were not relieved and he finally died. Conclusions: Both LCNEC and SCLC have high aggressiveness. Some patients may have limited curative effect and poor prognosis when treated with chemotherapy even in combination with immune checkpoint inhibitors. Combined LCNEC may occur in extrapulmonary sites of some patients when the tumor progresses. Timely radiological evaluations are essential to identify changes of pulmonary and extrapulmonary lesions. Histopathological results including morphological features of malignant cells and immunohistochemical features of diseased tissues are more indispensable in establishing a confident diagnosis of lung neuroendocrine tumor and judging corresponding cellular types.

Serum NSE is Early Marker of Transformed Neuroendocrine Tumor After EGFR-TKI Treatment of Lung Adenocarcinoma.

Background: Transformation to a lung neuroendocrine tumor (LNET) is a mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). Serum neuron-specific enolase (NSE) is a useful marker in the detection of LNET. Therefore, we explored the clinical significance of serum NSE levels in the detection of transformed neuroendocrine tumors after EGFR-TKI therapy. Methods: We report a cohort of 5 cases in our treatment group. The characteristics of the patients, pathological diagnoses, immunohistochemistry with molecular detection, laboratory examination, and treatment histories are analyzed. The tumor markers of serum NSE were analyzed. Additionally, we reviewed the publications reporting the tumor markers before and after LNET transformation during EGFR-TKI therapy. Results: Most patients are female (3/5), aged <60 years old (4/5), nonsmokers (4/5) and harbor the EGFR 19 exon deletion (4/5). The median time of LNET transformation was 19 months (range: 12-31 months). The clinical characteristics were similar to those reported in previous studies. Laboratory examination revealed an increased NSE level before the LNET is defined. Sixteen publications were reviewed. Of those, 86.67% (13/15) publications showed an increased level of NSE when the LNET transformation was defined. Conclusion: Adenocarcinoma tumors in non-smokers, young patients harboring the EGFR 19 exon deletion tended to transform to LNETs after EGFR-TKI therapy. Combining our findings and a review of the literature, we suggest that serum NSE may be a useful tumor marker to predict neuroendocrine tumor transformation.

Efficacy and Safety of 177Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter study.

The purpose of this study was to assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR)-positive lung neuroendocrine tumors (NETs). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177Lu-DOTATATE. Concordance between 2 response assessment methods was evaluated by κ statistics. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on Common Terminology Criteria for Adverse Events, version 5. Results: Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted κ of 0.51 (95% CI, 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had a longer OS than those with no response, NR versus 52 mo (95% CI, 28-64), hazard ratio 0.2 (95% CI, 0.1-0.6), P < 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia or leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.

Construction and validation of nomograms based on the log odds of positive lymph nodes to predict the prognosis of lung neuroendocrine tumors.

Background: This research aimed to investigate the predictive performance of log odds of positive lymph nodes (LODDS) for the long-term prognosis of patients with node-positive lung neuroendocrine tumors (LNETs). Methods: We collected 506 eligible patients with resected N1/N2 classification LNETs from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The study cohort was split into derivation cohort (n=300) and external validation cohort (n=206) based on different geographic regions. Nomograms were constructed based on the derivation cohort and validated using the external validation cohort to predict the 1-, 3-, and 5-year cancer-specific survival (CSS) and overall survival (OS) of patients with LNETs. The accuracy and clinical practicability of nomograms were tested by Harrell's concordance index (C-index), integrated discrimination improvement (IDI), net reclassification improvement (NRI), calibration plots, and decision curve analyses. Results: The Cox proportional-hazards model showed the high LODDS group (-0.79≤LODDS) had significantly higher mortality compared to those in the low LODDS group (LODDS<-0.79) for both CSS and OS. In addition, age at diagnosis, sex, histotype, type of surgery, radiotherapy, and chemotherapy were also chosen as predictors in Cox regression analyses using stepwise Akaike information criterion method and included in the nomograms. The values of C-index, NRI, and IDI proved that the established nomograms were better than the conventional eighth edition of the TNM staging system. The calibration plots for predictions of the 1-, 3-, and 5-year CSS/OS were in excellent agreement. Decision curve analyses showed that the nomograms had value in terms of clinical application. Conclusions: We created visualized nomograms for CSS and OS of LNET patients, facilitating clinicians to bring individually tailored risk assessment and therapy.

Low risk for all-cause mortality among patients with lung neuroendocrine tumors co-diagnosed with pituitary adenomas.

PURPOSE: Lung neoplasms often co-occur with pituitary adenoma (PA). However, whether co-diagnosis of lung neuroendocrine tumors (LNETs) and PA constitute a unique entity and the impact of such co-diagnosis on patients' outcome is yet to be defined. The study objective was to compare patients' clinical characteristics with LNET to patients co-diagnosed with PA. METHODS: A Retrospective, case-control study based on the Surveillance, Epidemiology, and End Results (SEER) registry database between 2000 and 2016. A total of 2947 patients with LNET, including 2913 with LNET alone ("Sporadic") and 34 patients with both LNET and PA ("LNET-PA"). RESULTS: PA preceded LNET diagnosis in 85.3% of patients and had higher rates among LNET patients (34/2947) than with any cancer (p < 0.00001) and compared to patients with non-small cell lung cancer (NSCLC) (15/2378, p = 0.047). LNET-PA patients were younger at diagnosis compared with NSCLC patients and PA (p = 0.04). Among patients <60 years with LNET, co-diagnosis with PA was associated with lower all-cause mortality (ACM) risk (Log-rank test, p = 0.03). Adjusted ACM risk of patients with LNET-PA was lower than sporadic LNET (hazard ratio 0.553, 95% confidence interval 0.309-0.99, p = 0.046), especially among Caucasians, and lower overall-mortality risk in patients <60 years with borderline statistical significance (p = 0.071). CONCLUSIONS: Patients with both LNET and PA constitute a distinct morbidity and mortality profile than sporadic LNET, possibly suggesting an undefined MEN syndrome. Additional studies to further investigate patients' natural course and genetic profile with these neoplasms are needed.

The Autophagy Inhibitor Chloroquine, Alone or in Combination with mTOR Inhibitors, Displays Anti-Tumor Effects in In Vitro and In Vivo Lung Carcinoid Models.

(1) Background: Neuroendocrine neoplasms of the lung (LNENs, lung carcinoids) are often diagnosed at an advanced stage when they are not surgically curable, and treatment options are limited. One of the approved options for treating inoperable tumors is everolimus-an mTOR inhibitor (mTORi). Activation of mTOR, among many other effects, inhibits autophagy, which is a cell survival mechanism in general, and in tumor cells in particular. Everolimus may paradoxically encourage cancer cell survival. In practice, the drug inhibits tumor development. Chloroquine (CQ) is a known antimalarial compound that inhibits autophagy. Our research is focused on the hypothesis that autophagy plays a key role in the development of tumor resistance to mTORi, and that the addition of autophagy inhibitors to mTORi exerts a synergistic effect on suppressing tumor cell proliferation. We have recently demonstrated that the combination of CQ with different mTORi increases their potency compared with mTORi alone in both in vitro and in vivo models of pancreatic NENs. In this study, we examined the effects of CQ and mTORi on in vitro and in vivo LNEN models. Aims: Testing the effects of CQ together with mTORi on cell proliferation, apoptosis, and autophagy in in vitro and in vivo LNEN models. (2) Methods: The NCI-H727 LNEN cells were treated with CQ ± mTORi. Cells' viability and proliferation were measured using XTT and Ki-67 FACS staining. The effects of the treatments on the mTOR pathway and autophagy were examined using Western blotting. Cytotoxicity was measured using a cytotoxicity kit; apoptosis was measured by PI FACS staining and Western blotting. We further established an LNEN subcutaneous murine xenograft model and evaluated the effects of the drugs on tumor growth. (3) Results: CQ alone suppressed LNEN cells' viability and proliferation and increased their cytotoxicity and apoptosis; these effects were augmented when CQ was added to an mTORi. We also showed the possible mechanisms for these results: on the one hand we could see a decrease in P62 levels and the absence of LC3-II (both inversely related to autophagy) following treatment with the mTORi, and on the other hand we could demonstrate an increase in their levels when CQ was added. The effect was less apparent in the murine xenograft model. (4) Conclusions: By inhibiting autophagy and inducing apoptosis, CQ suppresses tumor cell growth in LNENs. CQ potentiates mTORi effects, implying that further studies are needed in order to elucidate its possible role in tumor inhibition in patients with LNENs.

Metachronous bilateral breast metastases of a lung neuroendocrine tumor: A case report.

Breast metastases of primary lung neuroendocrine tumors are rarely reported. The current report presents the case of a 41-year old female with no history of smoking who initially underwent surgery for a breast fibroadenoma, during which a neuroendocrine tumor of the right lung was detected via chest X-ray. The patient underwent surgery for the tumor and developed right breast nodules after adjuvant chemotherapy. Histological and immunohistochemical examinations of biopsies from these nodules indicated breast metastasis of the primary lung neuroendocrine tumor. The patient underwent mastectomy of the right breast but subsequently developed metastases in the left breast, for which local radiotherapy was administered. The observed metachronous bilateral breast metastases indicated that the contralateral breast should be considered during an investigation of metastasis.

The Risk of Second Primary Malignancies in Patients With Lung Neuroendocrine Tumors: A Population-Based Study on SEER Database.

PURPOSE: We investigated the at-risk sites of second primary malignancies (SPMs) and evaluate the risk factors of SPMs among lung neuroendocrine tumors (LNETs) survivors by using the surveillance, epidemiology, and end results (SEER) database. METHODS: Propensity-score matching was performed to conduct a case-control study from the surveillance, epidemiology, and end results (SEER) database. Cox regression analysis and multiple primary standardized incidence ratios were performed to investigate the risk factors of occurrence of SPMs among patients with LNETs. RESULTS: Of 3,206 patients with LNETs after matching, 539 developed SPMs. The risk of developing SPMs was higher in older patients (55-74 vs ≦54: hazard ratios [HR] 1.875; age ≧75 vs ≦54: HR 2.713), higher-stage of LNETs (regional vs localized: HR 1.387; distant vs localized: HR 2.732) and recent periods of diagnosis (2004-2014 vs 1984-1993: HR 1.735). Patients with SCLC, TC and LENEC had a higher risk for SPMs compared to general population. Lung and bronchus, larynx and some digestive organs had higher risk for SPMs while some sex hormone related organs like prostate, breast, and female reproductive system had a lower incidence of SPMs. CONCLUSIONS: Patients with LNETs had overall higher risks of SPMs than general population. Different types of second primary malignancies occurred in different periods after LNETs were diagnosed. Further investigations are required to screen different second primary malignancies for those with primary LNETs.