Large Cell Neuroendocrine Carcinoma Research Articles

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<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<0.05). This LCNEC patient also had lower 1-, 1.5-, and 2-year PFS rates compared to adenocarcinoma patients (p<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.

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 <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 >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 < 0.001) for patients who underwent surgery. Increased age (HR, 1.05; 95% CI, 1.03–1.06; p < 0.001), T4 stage disease (HR, 3.17; 95% CI, 1.96–5.1; p < 0.001), NEC‐NOS histology (HR, 2.82; 95% CI, 1.64–4.86; p < 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 < 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

Clinical analysis of 12 cases of ovarian neuroendocrine carcinoma.

Neuroendocrine neoplasms of the female genital tract are rare. To enhance our clinical understanding of neuroendocrine carcinoma (NEC) of the ovary. A retrospective review was conducted on 12 patients diagnosed with NEC of the ovary, analyzing clinicopathological characteristics, treatment modalities, and survival status. The median age at diagnosis was 34.5 years (range: 20 to 62 years). Among the 12 cases, 9 were small cell carcinoma of the ovary and 3 were large cell NEC. Five cases were stage I tumors, one case was stage IV, and six cases were stage III. Eleven patients underwent surgery as part of their treatment. All patients received adjuvant chemotherapy. Among the 12 patients, one patient received radiotherapy, and one patient with a BRCA2 mutation was administered PARP inhibitor maintenance after chemotherapy. The median progression-free survival was 13 months, and the median overall survival was 19.5 months. Four cases remained disease-free, while eight cases experienced tumor recurrence, including three cases that resulted in death due to disease recurrence. NEC of the ovary is a rare condition that is more common in women of childbearing age and is associated with aggressive behavior and poor clinical outcomes. Surgical resection remains the mainstay of treatment, with some patients benefiting from adjuvant chemoradiation therapy.

Management of colorectal large cell neuroendocrine carcinoma: case report and literature review

Large cell neuroendocrine carcinoma (LCNEC) of the colorectum is a rare, aggressive subtype of neuroendocrine cancer with a dismal prognosis. Accounting for a mere 0.25% of colorectal cancers, LCNEC is associated with a median overall survival of 4 to 16 months, and nearly all patients succumb within a year. Pure colorectal LCNEC reports are scarce, and this review and case study presents a 40-year-old male, the youngest reported patient, diagnosed with rectal LCNEC. A comprehensive PubMed search for “large cell neuroendocrine carcinoma” and “colorectal” was conducted. Titles were meticulously screened for relevance to the nuanced management of colorectal LCNEC. Despite aggressive therapeutic interventions, including chemotherapy with carboplatin and etoposide, the patient experienced rapid disease progression, emphasizing the challenging nature of LCNEC. The paper discusses the evolving classification of NEC, morphological features, and immunophenotypic characteristics that differentiate LCNEC from other neuroendocrine tumours. Survival rates underscore the aggressive nature of colorectal NEC, and treatment options, primarily relying on retrospective studies, reveal limited efficacy. While surgery remains the preferred approach for localized disease, the optimal chemotherapy regimen for LCNEC is yet to be established. Current evidence suggests platinum-based therapy as a common first-line treatment, but the demand for more effective options persists. The paper highlights the need for additional research, including prospective trials, to elucidate the genuine benefits of adjuvant chemotherapy and to explore emerging therapies, such as immunotherapy, in the context of LCNEC.

[Advances of pathological diagnosis and molecular pathology of lung neuroendocrine neoplasms].

The pathological classification and diagnostic criteria for lung neuroendocrine neoplasms (NENs) in the 2021 World Health Organization (WHO) lung tumor classification are similar to the prior classifications. However, the advances on the molecular studies of lung NENs have shown that both small cell lung carcinoma and large cell neuroendocrine carcinoma are highly heterogeneous tumors with neuroendocrine characteristics and can be subclassified based on the features of genomics or transcriptomics, which are valuable in the diagnosis of lung NENs subtypes and patient treatment. In addition, it is necessary to interpret emerging concepts such as "lung neuroendocrine tumor G3" and "histological transformation" from pathological perspectives, as well as to know the novel neuroendocrine biomarkers such as INSM1 and POU2F3. This article summarized the diagnostic changes and the advances of molecular pathology of lung NENs based on the latest WHO classification and molecular research.

A prognostic nomogram based on least absolute shrinkage and selection operator Cox regression in patients with pulmonary large-cell neuroendocrine carcinoma.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of breast cancer with a poor prognosis. Despite its rarity, it is important to gain a better understanding of the epidemiological, clinical, and prognostic features of pulmonary LCNEC. The purpose of this study was to design, construct, and validate a new nomogram for predicting overall survival (OS) in patients with pulmonary LCNEC. In total, the data of 1,864 LCNEC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, which is maintained by the National Cancer Institute in the United States and serves as a comprehensive source of cancer-related information. Of these patients, 556 served as the validation group and 1,308 served as the training cohort. We constructed a new nomogram with the training cohort that included the independent factors for OS as identified by least absolute shrinkage and selection operator Cox regression. Five independent factors were ultimately selected by the stepwise regression. Every factor of the Cox regression was included in the nomogram. Analyses of the calibration curve, decision curve, area under the curve, and concordance index (C-index) values were performed to assess the effectiveness and discriminative ability of the nomogram. Five optimal predictive factors for OS were selected and merged to construct a 3- and 5-year OS nomogram. The nomogram had C-index values of 0.716 and 0.708 in the training cohort and validation cohort, respectively. The actual OS rates and the calibration curves showing the predictions of the nomogram were in good agreement. The prognostic nomogram may be very helpful in estimating the OS of patients with pulmonary LCNEC.

Prognostic thresholds of fluorine-18 fluorodeoxyglucose-positron emission tomography mean and maximum standardized uptake values for survival and nodal involvement in lung neuroendocrine neoplasms.

The mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose-positron emission tomography are prognostic biomarkers for survival and nodal involvement in non-small-cell lung cancer but their prognostic value in lung neuroendocrine neoplasms (NENs) remains unexplored. In this study, we aimed to examine whether they are also prognostic biomarkers for survival and nodal involvement in lung NENs. We retrospectively studied patients with typical carcinoid, atypical carcinoid or large cell neuroendocrine carcinoma who had been radically resected at our institution between 2008 and 2020. We measured SUVmean and SUVmax on all primary tumours and lymph nodes that were clinically and/or pathologically involved. We dichotomized the patients into groups of high or low SUVmean and SUVmax of the primary tumour using time-dependent receiver operating characteristic curves and compared their overall survival using Kaplan-Meier curves and Cox models. Lastly, we predicted the patients' pathological nodal status with SUVmean and SUVmax of the lymph nodes using binomial logistic models. The study included 245 patients. Patients died earlier if their SUVmean of the primary tumour exceeded 3.9 [hazard ratio 1.97, 95% confidence interval (CI) 1.27-3.04, P = 0.002] or SUVmax exceeded 5.3 (hazard ratio 1.85, 95% CI 1.20-2.87, P = 0.006). Likewise, patients had a higher risk of pathological nodal involvement if their SUVmean of the lymph nodes exceeded 3.3 (odds ratio 10.00, 95% CI 2.59-51.01, P = 0.002) or SUVmax exceeded 4.2 (odds ratio 4.00, 95% CI 1.20-14.65, P = 0.028). The fluorine-18 fluorodeoxyglucose-positron emission tomography SUVmean and SUVmax are strong prognostic biomarkers for survival and nodal involvement in lung NENs and could be important guides for making treatment decisions.

Clinical efficacy of lurbinectedin in metastatic neuroendocrine carcinomas of the genitourinary tract: Multi-institutional real-world experience.

601 Background: Neuroendocrine carcinomas (NEC) of the genitourinary (GU) tract, including small cell (SC) NEC and large cell (LC) NEC, are rare aggressive malignancies. Although highly sensitive to cisplatin-based chemotherapy, GU metastatic NEC (mNEC) have limited data to support next therapies. Lurbinectedin, a marine-derived alkylating drug and a selective inhibitor of oncogenic transcription and DNA repair pathways, is FDA-approved for small cell lung cancer (SCLC) after progression on frontline platinum-based therapy, with a disease control rate (DCR) of 68.6%. It is unknown whether DCR is similar in SCLC and GU mNEC. Methods: We report the first multi-institutional series (n=14) of lurbinectedin in GU mNEC. Imaging-based best overall responses (BOR) were noted as complete (CR), partial (PR), stable (SD), progressive (PD) or non-evaluable (NE). DCR includes CR, PR, and SD. We use the Kaplan-Meier method for overall survival (OS) and progression-free survival (PFS) from lurbinectedin start date. We define duration of response (DoR) from response date to progression or last contact date for patients (pts) with CR or PR. Results: Most pts had a median age at metastasis of 70.5 years (ICR: 64-74.5) [Table]. Primary locations were bladder (7/14, 50%), prostate (5/14, 35.7%) and ureter (2/14, 12.3%). Histology at diagnosis mostly consisted of mixed or pure SCNEC, with one exception of LCNEC. Most pts had visceral disease, prior immunotherapy and at least 2 prior lines of therapy for mNEC before lurbinectedin (8/14, 57.1%). DCR was 6/14 (42.8%), including 5 bladder pts and 1 prostate pt. Among bladder pts, BOR included one CR (1/7, 14.3%) for the LCNEC case, 2 PR (2/7, 28.6%), 2 SD (2/7, 28.6%) and 2 PD (2/7, 28.6%). Most prostate and ureteral pts either progressed on lurbinectedin or were NE (Prostate: 1 PR, 2 PD, and 2 NE; Ureteral: 1 PD and 1 NE). For all 14 pts, median OS was 11.47 months (95% CI: 2.17-13.63) and median PFS was 2.8 mo (1.4-10.9). Median DoR was 7.38 mo (2.3-9.53) for 4 responding pts (CR or PR). Treatment was stopped due to progression (9/14, 64.3%), three adverse events [thrombocytopenia, electrolyte abnormalities, cerebrovascular accident] (3/14, 21.4%), and pt preference (1/14, 7.1%). Conclusions: Lurbinectedin offers encouraging responses (DCR: 5/7, 71.4%) close to those in SCLC, in previously treated bladder mNEC. One CR was noted for a bladder pt with LCNEC. Responses were less appreciated in prostate and ureteral mNEC due to NE responses and limited number. Larger cohorts are needed to confirm survival benefit and genetic analyses are warranted to identify characteristics of responders. [Table: see text]

Efficacy of immune checkpoint inhibitors in advanced large cell neuroendocrine carcinoma of the lung: A single‑institution experience.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and highly invasive lung cancer subtype with an overall poor prognosis. Due to its low incidence rate and unusual pathological features, the clinical management of LCNEC remains controversial. The present study aimed to assess the effect of immune checkpoint inhibitors (ICIs) on treatment response and survival outcomes in patients with advanced LCNEC. The clinical data from 148 patients with LCNEC treated with ICIs at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between January 2019 and September 2021 were retrospectively analyzed. Kaplan-Meier and multivariable Cox regression analyses were used to evaluate associations between clinicopathological variables and patient outcomes. Patients treated with ICIs demonstrated extended median overall survival (mOS) times [23.5 months; 95% confidence interval (CI), 18.524-28.476] compared with patients who did not receive ICIs (11.2 months; 95% CI, 4.530-18.930) (P<0.001). Univariate analysis revealed that histological subtype (P=0.043), lymph node metastases (P=0.032) and number of metastatic organs (P=0.009) were associated with a poor prognosis. The heterogeneity of pathological components was associated with prognosis, and the mOS time was shorter for mixed LCNEC than that for pure LCNEC (P=0.043). The median progression-free survival (mPFS) (9.78 vs. 9.37 months; P=0.82) and mOS (20.70 vs. 25.79 months; P=0.181) times showed no significant association with regard to different regimens of immuno-based combination therapy (chemotherapy combined with ICIs vs. anti-angiogenic agents combined with ICIs). Poor Eastern Cooperative Oncology Group performance status score (P=0.04), multiple organ metastases (P=0.02) and high cancer antigen 125 levels (P=0.01) were independent risk factors of a poor prognosis. The present findings offer valuable insights into potential prognostic markers and highlight the favorable impact of ICIs on OS in advanced LCNEC. Prospective clinical studies are required to validate the therapeutic value of ICIs in LCNEC.

Prognostic scores in pulmonary large cell neuroendocrine carcinoma: A retrospective cohort study

IntroductionPulmonary large cell neuroendocrine carcinoma (PLCNEC) is a rare but aggressive subtype of lung cancer with an incidence of approximately 3 %. Identifying effective prognostic indicators is crucial for guiding treatments. This study examined the relationship between inflammatory markers and PLCNEC patient overall survival (OS) and sought to determine their prognostic significance in PLCNEC. MethodsPatients diagnosed with PLCNEC between 2007 and 2022 at the oncology center, were retrospectively included. Patients who underwent surgery were pathologically re-staged post-surgery. Potential prognostic parameters (neutrophil/lymphocyte ratio, platelet/lymphocyte ratio [PLR], panimmune inflammatory value, prognostic nutritional index and modified Glasgow prognostic score [mGPS]) were calculated at that time of diagnosis. ResultsSixty patients were included. The median follow-up was 23 months. Thirty-eight patients initially diagnosed with early or locally advanced. The mGPS was identified as a poor prognostic factor that influenced disease free survival (DFS) fourfold (p = 0.03). All patients' median OS was 45 months. Evaluating factors affecting OS in all patients, statistically significant relationships were observed between OS and the prognostic nutritional index (p = 0.001), neutrophil/lymphocyte ratio (p = 0.03), platelet/lymphocyte ratio (p = 0.002), and pan-immunoinflammatory value (p = 0.005). Upon multivariate analysis, the platelet/lymphocyte ratio was identified as an independent poor prognostic factor for OS, increasing the mortality risk by 5.4 times (p = 0.002). ConclusionmGPS was significantly linked with prognosis in non-metastatic PLCNEC, with patients with higher mGPS exhibiting poorer long-term DFS. This finding contributes to the evolving understanding of PLCNEC. The multivariable predictive model we employed suggests that PLR is an independent predictor of OS at all stages. A lower PLR was correlated with worse overall survival. Thus, PLR can be a readily accessible and cost-effective prognostic factor in PLCNEC patients.

Strengths and challenges in current lung cancer care: Timeliness and diagnostic procedures in six Dutch hospitals

ObjectivesTimely diagnosis of lung cancer (LC) is crucial to achieve optimal patient care and outcome. Moreover, the number of procedures required to obtain a definitive diagnosis can have a large influence on the life expectancy of a patient. Here, adherence with existing Dutch guidelines for timeliness and type and number of invasive and imaging procedures was assessed. Materials and methods1096 patients with suspected LC were enrolled in this multicenter prospective study (NL9146). The overall survival, time from referral to the first appointment with the pulmonologist, time to diagnosis and treatment, and the number of imaging and invasive procedures were evaluated. Patients were divided into different diagnostic groupsearly- and advanced stage non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC), patients without LC and patients without a definitive diagnosis. ResultsThe majority of patients (66 %) received a definitive diagnosis within 5 weeks, although the time to diagnosis of early-stage LC patients and patients without LC was significantly longer comparted to advanced stage LC. An increase in invasive procedures was seen for early-stage LC compared to advanced stage LC and for 13 % of the advanced stage non-squamous NSCLC patients up to three additional invasive procedures were performed solely to obtain sufficient material for NGS. For patients without a definitive diagnosis, 50 % did undergo at least one invasive procedure, while 11 % did not wish to undergo any invasive procedures. ConclusionThese insights could aid in improved LC diagnostics and efficient implementation of new techniques like liquid biopsy and artificial intelligence. This may lead to more timely LC care, a decreased number of invasive procedures, less variability between the diagnostic trajectory of different patients and aid in obtaining a definitive diagnosis for all patients.