Large Cell Neuroendocrine Carcinoma Research Articles

Integrated genomic and transcriptomic characterization of neuroendocrine carcinomas for improved treatment decision-making.

e15138 Background: Neuroendocrine carcinomas (NECs) are poorly characterized due to their innate heterogeneity, thus limiting treatment and clinical trial options for patients. Here, we used whole exome sequencing (WES) and RNA sequencing (RNA-seq) to explore the genetic and microenvironmental landscape of NECs in order to understand the unique features of different NEC types, with the aim of improving treatment modalities. Methods: We analyzed 51 NEC clinical samples morphologically verified by a pathologist: lung NEC (20 small cell NEC and 1 large cell NEC cases), gastroenteropancreatic NEC (GEP, 12 cases), cancer of unknown primary (7 cases), Merkel cell carcinoma (MCC, 5 cases), genitourinary tract NEC (3 cases), and breast NEC (3 cases). Findings on tumor mutational burden (TMB, mut/Mb), microsatellite instability (MSI), gene expression signatures, and tumor microenvironment (TME) profiling were reported. Small cell lung cancer (SCLC) subtyping was performed as reported by Gay et al. on the entire NEC cohort. Results: Half of the patients with lung NEC and 84% of those with extrapulmonary NEC satisfied the molecular inclusion criteria for clinical trials, with the most frequent criterion being KRAS G12X or G13X mutations. Among the extrapulmonary NEC samples, 13.7% were deemed eligible for targeted therapy, specifically for cases with BRAF V600E mutation and/or high TMB (> 10 mut/Mb). We detected varying TMB and distinct gene expression features across the entire cohort. Specifically, we found 2 MCC cases to be Merkel cell polyomavirus-positive with low TMB and devoid of UV-associated mutations. One GEP-NEC case exhibited a high MSI (MSI-high) status. We detected 6 SCLC cases (3 non-smokers, 3 former smokers) with surprisingly low levels of tobacco-associated mutations (<10% of all mutations). Two GEP-NEC cases had high levels of mutations associated with tobacco smoking. While TME profiling showed no significant difference in cell population makeup across all samples, transcriptional SCLC subtyping revealed significant differences among the cases. Inflammatory SCLC (SCLC-I) samples showed statistically significant enrichment of all subpopulations of the immune microenvironment (i.e., B cells, T cells, NK cells), supporting the use of immune checkpoint blockade for treatment. The POU2F3+ SCLC (SCLC-P) samples showed low expression of all neuroendocrine diagnostic markers (i.e., INSM1, NCAM1, SYP, CHGA). Conclusions: Given the heterogeneous molecular features across diverse NEC tumors, a uniform treatment strategy is unlikely to benefit all NEC patients. Hence, our ability to detect these unique molecular features is crucial for matching individual NEC patients with specific clinical trials and targeted therapies that may improve their outcomes. Thus, a concerted effort using in-depth genomic, transcriptomic, and TME profiling for NEC tumors is warranted.

Clinical and Pathologic Differences between Small-Cell Carcinoma and Large-Cell Neuroendocrine Carcinoma of the Lung.

Both small-cell carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) of the lung are often clinically dealt with as being in the same category as neuroendocrine carcinoma, and their clinical differences have not been adequately assessed. The postoperative prognosis was retrospectively analyzed using the data of 196 patients who underwent resection for SCLC or LCNEC. Of the patients included, 99 (50.5%) had SCLC and 97 (49.5%) had LCNEC. The median duration of follow-up was 39 months (interquartile range [IQR] 21-76) and 56 months (IQR 21-87) for SCLC and LCNEC, respectively. The estimated 5-year overall survival (OS) probabilities were 53.7% and 62.7% (p = 0.133) for patients with SCLC and LCNEC, respectively. In the SCLC group, a multivariate analysis showed that adjuvant chemotherapy (hazard ratio 0.54, 95% confidence interval 0.30-0.99, p = 0.04) was the only factor that was significantly associated with OS. In the LCNEC group, univariate analyses demonstrated that pathologic stage I (p = 0.01) was the only factor that was associated with better OS after surgery. We found different clinical features in SCLC and LCNEC; in patients with SCLC, because OS could be expected to significantly improve with postoperative adjuvant chemotherapy, patients with resected SCLC of any pathologic stage should receive adjuvant chemotherapy. For patients with LCNEC, because pathologic stage I LCNEC is related to better prognosis than any other stages, a thorough clinical staging, including invasive staging, according to present guidelines should be performed to identify clinical stage I LCNEC with the highest certainty.

The Effectiveness of Atezolizumab in Metastatic Large Cell Neuroendocrine Carcinoma of the Lungs: Insights from the LANCE Pilot Study.

Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups. Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy (n = 10) or chemotherapy alone (n = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6-100%) and 14.3% (95% CI: 2.33-87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank p = 0.04 and 0.05, respectively). This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC.

Mutational analysis of pulmonary large cell neuroendocrine carcinoma: APC gene mutations identify a good prognostic factor

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm with biological heterogeneity. Mutations in multiple genes have been identified in LCNEC. However, associations between gene alterations, histopathological characteristics, and prognosis remain ambiguous. Here, we investigated the clinicopathologic, immunohistochemical, and genomic characteristics of 19 patients with LCNEC and 9 patients with atypical carcinoid (AC). We revealed high mutation frequencies of TP53 (89.5 %), RB1 (42.1 %), APC (31.6 %), and MCL1 (31.6 %) in LCNEC, while genetic alterations were rarely found in AC. APC alterations mainly occurred to the exon 16 and were only identified in LCNEC with wild-type RB1. The 19 LCNEC were further subgrouped into APC wild-type (LCNEC-APCMT, 6/19) and APC-mutated (LCNEC-APCWT, 13/19) subgroups. In comparison with LCNEC-APCWT, LCNEC-APCMT displayed lower TMB (median: 12.64 vs 4.20, P = 0.045), and relatively mild cytologic atypia. In addition, LCNEC-APCMT distinguished itself from AC and LCNEC-APCWT by obviously downregulated expression of neuroendocrine markers (CD56 and Syn, P < 0.01) and significantly altered expression of genes downstream of APC (β-catenin migrating into the cytoplasm and nucleus, P < 0.001; c-Myc upregulating, P = 0.005). The OS of LCNEC-APCMT was numerically intermediate between AC and LCNEC-APCWT. We first proposed that APC alterations were common in LCNEC with wild-type RB1 and that LCNEC-APCMT was associated with lower TMB and better OS in comparison with LCNEC-APCWT.

Advances in combined neuroendocrine carcinoma of lung cancer.

Lung cancer incidence and mortality rates are increasing worldwide, posing a significant public health challenge and an immense burden to affected families. Lung cancer encompasses distinct subtypes, namely, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). In clinical investigations, researchers have observed that neuroendocrine tumors can be classified into four types: typical carcinoid, atypical carcinoid, small-cell carcinoma, and large-cell neuroendocrine carcinoma based on their unique features. However, there exist combined forms of neuroendocrine cancer. This study focuses specifically on combined pulmonary carcinomas with a neuroendocrine component. In this comprehensive review article, the authors provide an overview of combined lung cancers and present two pathological images to visually depict these distinctive subtypes.

Head-to-head: Should Ki67 proliferation index be included in the formal classification of pulmonary neuroendocrine neoplasms?

The reporting of lung neuroendocrine neoplasms (NENs) according to the 2021 World Health Organisation (WHO) is based on mitotic count per 2 mm2, necrosis assessment and a constellation of cytological and immunohistochemical details. Accordingly, typical carcinoid and atypical carcinoid are low- to intermediate-grade neuroendocrine tumours (NETs), while large-cell neuroendocrine carcinoma (NEC) and small-cell lung carcinoma are high-grade NECs. In small-sized diagnostic material (cytology and biopsy), the noncommittal term of carcinoid tumour/NET not otherwise specified (NOS) and metastatic carcinoid NOS have been introduced with regard to primary and metastatic diagnostic settings, respectively. Ki-67 antigen, a well-known marker of cell proliferation, has been included in the WHO classification as a non-essential but desirable criterion, especially to distinguish NETs from high-grade NECs and to delineate the provisional category of carcinoid tumours/NETs with elevated mitotic counts (> 10 mitoses per mm2) and/or Ki-67 proliferation index (≥ 30%). However, a wider use of this marker in the spectrum of lung NENs continues to be highly reported and debated, thus witnessing a never-subsided attention. Therefore, the arguments for and against incorporating Ki-67 in the classification and clinical practice of these neoplasms are discussed herein in detail.

Laryngeal Neuroendocrine Neoplasms: Analysis of 11 Cases in a Single-Center Study.

Objective: Laryngeal neuroendocrine neoplasms (LNEN) are rare, and there have been previous uncertainties regarding their classification and treatment modalities. This article aims to share our treatment experience, elucidate changes in LNEN classification, and discuss the treatment implications of different types and stages. Methods: A retrospective analysis was conducted on 11 cases of LNEN treated through surgical intervention at the Department of Otolaryngology, Qilu Hospital of Shandong University, Qingdao, from January 2014 to November 2023. Among the 11 cases, there were 9 males and 2 females, with ages ranging from 61 to 77 years. Pathological classifications included neuroendocrine tumors (NET) G1 (1 case), G2 (2 cases), G3 (5 cases), small-cell neuroendocrine carcinoma (2 cases), and large-cell neuroendocrine carcinoma (1 case). The follow-up period ranged from 1 to 115 months. Results: Treatment modalities varied among the cases: 5 patients underwent transoral laser microsurgery (TLM) without neck dissection, 1 patient underwent TLM with unilateral neck lymph node dissection, 1 patient underwent open partial supraglottic laryngectomy (OPSL) with ipsilateral neck lymph node dissection, and 4 patients underwent OPSL with bilateral neck lymph node dissection. Among the 11 patients, 4 died, with 2 succumbing to distant metastasis, 1 to local recurrence, and 1 to other diseases. Conclusion: The prognosis of LNEN is closely associated with the latest pathological classification and TNM staging. For a more detailed and specific clinical staging, further research involving multicenter large-scale data is needed.

Limbic encephalitis associated with large cell neuroendocrine carcinoma mediated by anti SOX1 and GABA B antibodies: A case report

Limbic encephalitis associated with large cell neuroendocrine carcinoma mediated by anti SOX1 and GABA B antibodies: A case report

Association of preexisting anti-thyroid antibodies and body mass index with prognosis of lung cancer patients treated with PD-1/PD-L1 inhibitors

Abstract Objectives Immune checkpoint inhibitors are a new beneficial medication in the treatment of cancer. Whether preexisting TPOAb was related to longer overall survival (OS) is controversial. This retrospective study analyzed the OS and progression-free survival (PFS) of patients with lung cancer, and explored predictive factors associated with the efficacy of PD-1/PD-L1 inhibitors treatment. Methods Patients with lung cancer who were hospitalized in the First Affiliated Hospital of Wenzhou Medical University between January 1, 2020 and December 30, 2020 were enrolled. Thyroid function, TPOAb, TGAb, and prognostic nutritional index levels and body mass index were analyzed. Supervising physicians independently assessed patient staging, OS, and PFS. Demographic data, pathological type, and previous treatment history were also collected. Results In total, this study enrolled 69 patients, with ages of 46–80 years old. Patients with lower weight showed reduced OS and PFS rates relative to those with normal weight and overweight (p&lt;0.05). The single patient with large cell neuroendocrine carcinoma (LCNEC) exhibited a 1-, 1.5- and 2-year OS rate lower than that of the patients diagnosed with squamous cell carcinoma, small cell lung cancer, or adenocarcinoma (p&lt;0.05). This LCNEC patient also had lower 1-, 1.5-, and 2-year PFS rates compared to adenocarcinoma patients (p&lt;0.05). TPOAb and TGAb levels were unrelated to OS or PFS. Multivariate Cox regression analyses revealed a positive association between body mass index, OS, and PFS. Conclusions Patients with lower body weight were predictive of poorer survival outcomes when receiving PD-1/PD-L1 inhibitors treatment as compared to patients with normal weight and overweight. However, positive baseline TGAb and TPOAb levels were not associated with increased OS or PFS in patients with lung cancer.

Clinicopathological Characteristics, Survival and Prognostic Factors in Gastrointestinal Large Cell Neuroendocrine Carcinoma: A Retrospective Cohort Study.

Gastrointestinal large cell neuroendocrine carcinoma (GILCNEC) has a low incidence but high malignancy and poor prognosis. The main purpose of this study was to thoroughly investigate its clinicopathological features, survival and prognostic factors. Information on patients with GILCNEC was extracted from the Surveillance, Epidemiology, and End Result program, and prognostic factors were analyzed by analyzing clinicopathological data and survival functions. Finally, multivariate analysis was applied to identify independent risk factors associated with survival. A total of 531 individuals were screened in our study from the Surveillance, Epidemiology, and End Result database. The primary sites are mainly from the following: esophagus in 39 (7.3%) patients, stomach in 72 (13.6%) patients, hepatobiliary in 51 (9.6%) patients, pancreas in 97 (18.3%) patients, small intestines in 27 (5.1%), and colorectum in 245 (46.1%) patients. Esophagus, stomach, pancreas, and colorectum large cell neuroendocrine carcinoma (LCNEC) were more common in males ( P = 0.001). Esophagus LCNEC had inferior overall survival (OS), whereas small intestine LCNEC was associated with better OS. The results of multivariate analysis showed that the American Joint Committee on Cancer Sixth Edition stage, surgery, and radiotherapy were independent prognostic indicators of OS in patients with GILCNEC ( P < 0.05). The prognosis of patients with GILCNEC varies depending on the primary tumor site. American Joint Committee on Cancer Sixth Edition stage, surgery, and radiotherapy are independent prognostic factors of patients with GILCNEC. Although surgery and radiotherapy can prolong the survival of patients with GILCNEC, their prognosis remains poor, and further prospectively designed multicenter clinical studies are needed to indicate the decision for clinicians.

Neoadjuvant immunochemotherapy for pulmonary large-cell neuroendocrine carcinoma: case report

BackgroundPulmonary large-cell neuroendocrine carcinoma (pLCNEC) represents a rare malignancy characterized by its aggressive behavior and a notably high recurrence rate. Remarkably, there is currently no established standard treatment protocol for this condition.Case descriptionIn this report, we present an intriguing case of pLCNEC diagnosed at clinical-stage IIB. This case involves a 64-year-old man with a smoking history spanning four decades. In our approach, we initiated a course of neoadjuvant chemotherapy in combination with pembrolizumab, administered for two cycles prior to surgical resection. This innovative treatment strategy resulted in a significant pathological response, culminating in a major pathological remission (MPR). As of the time of composing this report, the patient has been diligently monitored for 39 months post-surgery, exhibiting no indications of recurrence, and has demonstrated exceptional tolerance to the entire treatment regimen.ConclusionsWe have first reported a clinically successful case of neoadjuvant combination chemotherapy with pembrolizumab in the treatment of pLCNEC. This case offers promising clinical insights and suggests that this therapeutic approach could be a viable option for managing pLCNEC.

Therapeutic Response to PRRNT in a Rare Case of Metastatic Renal Neuroendocrine Carcinoma

AbstractNeuroendocrine tumors (NETs) are a rare spectrum of neoplasms that are characterized by neuroendocrine and neural differentiation. The treatment can be challenging in view of the heterogeneity in differentiation and behavior. Primary renal origin NETs are rare and only a few cases have been reported in the literature. There is limited knowledge on their presentation and response to various lines of treatment. We report a case of a patient with a metastatic renal NET from a rare histological subtype of large cell neuroendocrine carcinoma, known to cause aggressive disease with poor prognosis. A multimodality treatment approach was followed. In spite of surgical management and second-line chemotherapy, the disease progressed. The patient subsequently received peptide receptor radionuclide therapy (PRRNT) using lutetium-177 DOTATATE, following which the patient demonstrated a remarkable clinical and radiological response and is stable to date. In a rare tumor with poor prognosis, the relevance of theranostics and the efficacy of targeted therapies like PRRNT are noteworthy.

Abstract CT279: DareonTM-5: An open-label phase 2 trial of BI 764532, a DLL3-targeting T-cell engager, in patients (pts) with relapsed/refractory small cell lung cancer or other neuroendocrine carcinomas

Abstract Background: Small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC) of the lung, and extrapulmonary NEC (epNEC) are difficult-to-treat, aggressive tumors with limited treatment options. Purpose: Many pts relapse and have poor outcomes after standard of care platinum-based chemotherapy ± immunotherapy, underscoring the need for better therapies. BI 764532, a humanized IgG-like T-cell engager, binds to delta-like ligand 3 (DLL3) on the cell surface of these tumors and on CD3 on T cells, consequently promoting T-cell-mediated cytotoxicity. In an ongoing first-in-human trial, BI 764532 exhibited efficacy and manageable tolerability in pts with DLL3-positive SCLC, LCNEC of the lung, and epNEC (NCT04429087). We describe a planned phase 2 dose optimization trial to assess safety/efficacy of 2 different doses of BI 764532 monotherapy in pts with progressive/relapsed SCLC, epNEC, or LCNEC of the lung (NCT05882058). Experimental design: The trial will recruit adult pts (n=~120; ~70 sites; ~15 countries) with pathologically confirmed relapsed/refractory SCLC, epNEC, or LCNEC of the lung who have received ≥2 (SCLC) or ≥1 (epNEC/LCNEC) prior lines of therapy, including ≥1 platinum-based regimen. Pts with mixed tumor histology are permitted if the SCLC/NEC component is predominant (≥50% of tumor tissue). Pts will be randomized 1:1 to receive 1 of 2 dose levels of IV BI 764532 (3-week cycles) stratified by tumor type (n=~60/arm). Treatment will continue until disease progression, undue toxicity, withdrawal of consent or any other documented criteria for stopping treatment (maximum treatment duration: 36 months). 2 interim dose-selection analyses are planned after 30 pts per dose have been followed for ≥6 and ≥12 weeks or have stopped treatment. A third interim efficacy analysis will be conducted when 60 pts per dose have been followed for ≥12 weeks or have stopped treatment. Key exclusion criteria: Eastern Cooperative Oncology Group performance status ≥2; untreated/symptomatic brain metastases or leptomeningeal disease; active/history of interstitial lung disease/pneumonitis; previous DLL3-targeting treatment; treatment with other anticancer drugs &amp;lt;4 weeks prior to first administration of BI 764532; unresolved toxicity from prior treatment; immunodeficiency diagnosis; intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: objective response via Response Evaluation Criteria in Solid Tumors v1.1; occurrence of treatment-emergent adverse events (TEAEs). Secondary endpoints: duration of objective response, progression-free survival, disease control, overall survival, patient-reported outcomes, and TEAEs leading to discontinuation. Further endpoints: pharmacokinetics, and prespecified and exploratory biomarker analysis. Citation Format: Valentina Gambardella, Alastair Greystoke, Martin Reck, Meiruo Liu, Martha Mueller, Ulrich Duenzinger, Emily B. Bergsland, Taofeek Owonikoko. DareonTM-5: An open-label phase 2 trial of BI 764532, a DLL3-targeting T-cell engager, in patients (pts) with relapsed/refractory small cell lung cancer or other neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT279.

Abstract CT090: DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas

Abstract Background Neuroendocrine carcinomas (NECs) have limited treatment options. DLL3 is highly expressed in NECs and is a promising treatment target. In an ongoing phase 1 trial (NCT04429087), BI 764532, a DLL3/CD3 IgG-like T-cell engager, was tolerable with clinical activity in patients with DLL3-positive (+) tumors, including those with small cell lung cancer and other NECs. Purpose DAREON™-7 (NCT06132113), a phase 1, open-label, dose-escalation (Part A) and dose-expansion (Part B) trial, aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE)/recommended phase 2 dose (RP2D), and the safety and efficacy of BI 764532 + platinum and etoposide in patients with DLL3+ NEC. Experimental design Part A: ~25 patients will receive intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide (CE) until intolerable toxicity, or progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or for a maximum of 36 months. BI 764532 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Part B: 2 cohorts (~15 patients each) will receive BI 764532 at the RDE/RP2D + CE or cisplatin/etoposide (carboplatin/etoposide or cisplatin/etoposide are the most-used standard of care [SOC] regimens). Key inclusion criteria: patients must have no prior systemic treatment for DLL3+ locally advanced or metastatic NEC (extrapulmonary or unknown primary) or large cell NEC of the lung except for 1 cycle of standard platinum/etoposide regimen as first-line treatment prior to entering the treatment period of the trial; patients with localized NEC or resectable disease who received prior adjuvant therapy can participate in the trial if they experienced a treatment-free interval of &amp;gt;6 months prior to the diagnosis of metastatic disease; and patients must have at least 1 measurable lesion as defined per RECIST v1.1. Patients must be adequate candidates to receive platinum/etoposide as the SOC treatment. Primary endpoints: occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation (Part A) and on-treatment (Part B) periods. Secondary endpoints: occurrence of DLTs and adverse events during the on-treatment period (Part B), and efficacy measured by objective response and duration of response (Part B). Enrollment is ongoing. Citation Format: Jaume Capdevila, Timon Vandamme, Patricia Niccoli, Saori Mishima, Ken Kato, Yiyuan Ma, Ping Sun, Lijiang Geng, Ulrich M. Lauer. DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT090.

Efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647–1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648–1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Prognostic factors and predictive models for patients with lung large cell neuroendocrine carcinoma: Based on SEER database.

Lung Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive, high-grade neuroendocrine carcinoma with a poor prognosis, mainly seen in elderly men. To date, we have found no studies on predictive models for LCNEC. We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database of confirmed LCNEC from 2010 to 2018. Univariate and multivariate Cox proportional risk regression analyses were used to identify independent risk factors, and then we constructed a novel nomogram and assessed the predictive effectiveness by receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). A total of 2546 patients with LCNEC were included, excluding those diagnosed with autopsy or death certificate, tumor, lymph node, metastasis (TNM) stage, tumor grade deficiency, etc., and finally, a total of 743 cases were included in the study. After univariate and multivariate analyses, we concluded that the independent risk factors were N stage, intrapulmonary metastasis, bone metastasis, brain metastasis, and surgical intervention. The results of ROC curves, calibration curves, and DCA in the training and validation groups confirmed that the nomogram could accurately predict the prognosis. The nomogram obtained from our study is expected to be a useful tool for personalized prognostic prediction of LCNEC patients, which may help in clinical decision-making.

Updates on Urinary Bladder Tumors With Neuroendocrine Features.

The most common neuroendocrine tumor in the urinary bladder is small cell carcinoma, which can be pure or mixed with components of urothelial or other histologic subtypes. Large cell neuroendocrine carcinoma of the bladder is rare and remains ill-defined but is increasingly recognized. Well-differentiated neuroendocrine tumor and paraganglioma can arise in the bladder but are very rare in this location. Recent advances in molecular characterization allowed for better classification and may offer improved stratification of these tumors.

Patient-derived tumoroid models of pulmonary large-cell neuroendocrine carcinoma: a promising tool for personalized medicine and developing novel therapeutic strategies

Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine.

Prognostic factors and treatment impact on overall survival in patients with renal neuroendocrine tumour

AbstractBackgroundRenal neuroendocrine neoplasms (R‐NEN) are exceptionally rare tumours characterized by high mortality rates.ObjectiveThe objective of this study is to analyse prognostic factors and treatment impact on overall survival in patients with R‐NEN.Design, setting and participantsWe identified all patients with R‐NEN in the National Cancer Database (NCDB) from 2004 to 2019 and identified prognostic factors for improved survival.Results and limitationsOf 542 R‐NEN cases, 166 (31%) were neuroendocrine tumour grade 1 (NET‐G1), 14 (3%) were neuroendocrine tumour grade 2 (NET‐G2), 169 (31%) were neuroendocrine carcinoma (NEC‐NOS), 18 (3%) were large cell neuroendocrine carcinoma (LC‐NEC) and 175 (32%) were small cell neuroendocrine carcinoma (SC‐NEC). Median overall survival for all patients in the study was 44.88 months (SE, 4.265; 95% CI, 27.57–62.19). Median overall survival was 7.89 months (SE 0.67; 95% CI, 6.58–9.20) for patients without surgical intervention and 136.61 months (SE 16.44; 95% CI, 104.38–168.84, p &lt; 0.001) for patients who underwent surgery. Increased age (HR, 1.05; 95% CI, 1.03–1.06; p &lt; 0.001), T4 stage disease (HR, 3.17; 95% CI, 1.96–5.1; p &lt; 0.001), NEC‐NOS histology (HR, 2.82; 95% CI, 1.64–4.86; p &lt; 0.001), LC‐NEC histology (HR, 2.73; 95% CI, 1.04–7.17; p = 0.041) and SC‐NEC histology (HR, 5.17; 95% CI, 2.95–9.05; p &lt; 0.001) were all positive predictors of worsening overall survival. The main limitation of the study is its retrospective design.ConclusionR‐NEN is an aggressive tumour characterized by high mortality rates. Surgery continues to be the mainstay of treatment and has shown to provide a survival benefit for most patients.Patient SummaryR‐NEN is composed of several tumour histologies that differ based on their aggressiveness with NEC‐NOS and SC‐NEC being the most lethal. Surgery, predominantly through minimally invasive approaches, is the mainstay of treatment and has a clear survival benefit.

245P Age-adjusted trends of pulmonary large cell neuroendocrine carcinoma

245P Age-adjusted trends of pulmonary large cell neuroendocrine carcinoma