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Small cell lung cancer (SCLC) is a particular subtype of lung cancer with high mortality. Recent advances in understanding SCLC genomics and breakthroughs of immunotherapy have substantially expanded existing knowledge and treatment modalities. However, challenges associated with SCLC remain enigmatic and elusive. Most of the conventional drug discovery approaches targeting altered signaling pathways in SCLC end up in the ‘grave-yard of drug discovery’, which mandates exploring novel approaches beyond inhibiting cell signaling pathways. Epigenetic modifications have long been documented as the key contributors to the tumorigenesis of almost all types of cancer, including SCLC. The last decade witnessed an exponential increase in our understanding of epigenetic modifications for SCLC. The present review highlights the central role of epigenetic regulations in acquiring neoplastic phenotype, metastasis, aggressiveness, resistance to chemotherapy, and immunotherapeutic approaches of SCLC. Different types of epigenetic modifications (DNA/histone methylation or acetylation) that can serve as predictive biomarkers for prognostication, treatment stratification, neuroendocrine lineage determination, and development of potential SCLC therapies are also discussed. We also review the utility of epigenetic targets/epidrugs in combination with first-line chemotherapy and immunotherapy that are currently under investigation in preclinical and clinical studies. Altogether, the information presents the inclusive landscape of SCLC epigenetics and epidrugs that will help translate the knowledge of epigenetics to improve SCLC outcomes.

Background The United Kingdom National Institute for Health and Care Excellence guidelines recommend that patients and professionals make shared decisions between surgery and stereotactic ablative radiotherapy (SABR) when treating early stage non-small cell lung cancer (NSCLC). Variation by centre suggests treatment decisions may be disproportionately influenced by clinician judgment and treatment availability rather than patient preference. This systematic review critically evaluates studies of patient and clinician preferences for treatment of early stage NSCLC. Methods Primary empirical research up to 30 April 2020 was identified from searches of MEDLINE, EMBASE, PsycInfo and Web of Science databases. Data extracted included: study characteristics and methods, preferences for NSCLC treatment and involvement in decision-making and risk of bias using the Mixed Methods Appraisal Tool. Findings were synthesized using descriptive data and narrative synthesis. Results 23 studies were included in the review; 18 measured patient preferences, 4 clinician preferences and 1 both clinician and patient preferences. Patients and clinicians were both most likely to prefer a collaborative role in treatment decisions. Most patients did not recall there being a choice between surgery or SABR options, and thus experienced minimal decisional conflict. Conclusions For professionals to support patients in making informed, value based decisions about NSCLC treatments, better quality evidence is needed of the clinical and quality of life trade offs for both surgery and SABR.

Purpose Histologic change is a resistant mechanism in lung cancer. The most common histological change is the switch from adenocarcinoma (AdenoCa) to small cell carcinoma (SCC) against to tyrosine kinase inhibitor (TKI) inhibitors. However, it is not clear whether other treatment modalities are involved in the histologic changes. Materials and methods We investigated histological changes in eight cases, after various treatments, and compared the molecular profiles between primary tumors and changed tumors using exome sequencing where tissue was available. Results Three cases of AdenoCa that were changed into SCC retained the initial mutations after TKI and/or surgical treatment. After treatment with TKI and immunotherapy, an EGFR-mutant AdenoCa changed to squamous cell carcinoma (SqCa). SqCa in a patient treated with surgery was changed into combined adenoCa and SqCa. These two cases showed the same genetic variations between the two distinct non-small cell carcinomas. Only surgical treatment might induce histologic change. Three patients experienced two histologic changes, which the changed tumors returned to its original state or changed to a combined tumor after treatments. Four cases showed combined histology in first or second change. Two SqCas were changed to SCC. Conclusion The histology of non-small cell carcinoma can be changed to a single pattern or combined subtypes after various treatment modalities, and the phenotypic changes seem not fixed. Therefore, additional morphologic changes may occurred regardless of their genetic status and types of treatments. To refine the new treatment strategy, consecutive repeated biopsies in progressive disease or recurrent tumor are necessary.

For patients with resectable, early-stage non-small-cell lung cancer (NSCLC), surgery is the primary treatment; however, 5-year survival rates remain poor. Postoperative adjuvant platinum-doublet chemotherapy is associated with a statistically significant but modest improvement in survival of ∼5% at 5 years and is widely accepted as standard of care in patients with resectable, Stage II-III NSCLC. Neoadjuvant chemotherapy has been associated with similar improvements in overall survival to adjuvant therapy in this setting. Durvalumab, a high-affinity PD-L1 inhibitor, has become the standard of care for patients with unresectable, Stage III NSCLC following chemoradiotherapy based on improved progression-free and overall survival in the phase III PACIFIC trial. AEGEAN is a phase III, double-blind, placebo-controlled, international study that will assess pathological and clinical outcomes of durvalumab plus chemotherapy prior to surgery, followed by durvalumab monotherapy after surgery in adults with resectable, Stage II-III NSCLC. Approximately 800 patients will be randomized (1:1) to receive durvalumab or placebo every 3 weeks (q3w) alongside platinum-based chemotherapy (≤4 cycles) prior to surgery, followed by durvalumab or placebo monotherapy q4w, for an additional 12 cycles post surgery, stratified by disease stage (IASLC 8th Edition, Stage II vs. Stage III) and PD-L1 tumor cell expression levels (

BackgroundPatients undergoing surgery for early stage non-small cell lung cancer (NSCLC) may be at high risk for postoperative mortality. Access to stereotactic body radiation therapy (SBRT) may facilitate more appropriate patient selection for surgery.Research questionIs postoperative mortality associated with early stage NSCLC lower at facilities with higher use of SBRT?Study design and methodsPatients with early stage NSCLC reported to the National Cancer Database between 2004 and 2015 were included. Use of SBRT was defined by each facility's SBRT experience (in years) and SBRT to surgery volume ratios. Multivariate logistic regression was used to test for the associations between SBRT use and postoperative mortality.ResultsThe study cohort consisted of 202,542 patients who underwent surgical resection of cT1-T2N0M0 NSCLC tumors. The 90-day postoperative mortality rate declined during the study period from 4.6%to 2.6%(P< .001), the proportion of facilities that used SBRT increased from 4.6%to 77.5%(P< .001), and the proportion of patients treated with SBRT increased from 0.7%to 15.4%(P< .001). On multivariate analysis, lower 90-day postoperative mortality rates were observed at facilities with > 6 years of SBRT experience (OR, 0.84; 95% CI, 0.76-0.94; P= .003) and SBRT to surgery volume ratios of more than 17%(OR, 0.85; 95% CI, 0.79-0.92; P< .001). Ninety-day mortality also was associated with surgical volume, region, year, age, sex, and race, among other covariates. Interaction testing between these covariates showed negative results.InterpretationPatients who underwent resection for early stage NSCLC at facilities with higher SBRT use showed lower rates of postoperative mortality. These findings suggest that the availability and use of SBRT may improve the selection of patients for surgery who are predicted to be at high risk of postoperative mortality.

Background Video-assisted thoracic surgery (VATS) has been widely used in the surgical treatment of thoracic diseases, and it suggested surgical and oncological advantages compared with open surgery. However, reports on the application of VATS in surgery of small cell lung cancer (SCLC) are scarce. This study aimed to explore the advantages and disadvantages of different surgical approaches in the treatment of pathological stage T1(pT1) SCLC in terms of safety, clinical outcomes, and lymph node dissection. Patients and Methods Patients who underwent lobectomy for pT1 SCLC between January 2014 and September 2017 were identified from the National Collaborative Lung Cancer Database (LinkDoc Database). The patients were stratified based on the surgery approach (VATS or open lobectomy). Perioperative outcomes and long-term survival were analyzed using SPSS software. Results A total of 169 patients with pT1 SCLC met the criteria and were enrolled for this study, including 110 cases of VATS lobectomies and 59 cases of open lobectomies. VATS lobectomy was associated with less blood loss than open surgery (168.1 ± 237.4 vs. 340.0 ± 509.8 mL, P = .002). Open lobectomy harvested more N2 LNs (11.8 ± 8.2 vs. 8.4 ± 5.8, P = .048) and identified more metastasis positive LNs (3.1 ± 6.0 vs. 1.4 ± 3.0, P = .050). Open lobectomy associated with longer overall survival (OS) but has no statistical difference (23.4 ± 13.2 vs. 20.2 ± 10.9, P = .070). Conclusion Open lobectomy had better lymph node dissection results, and comparable postoperative complications, postoperative hospital stay, and OS to VATS lobectomy. Further studies may still be needed to confirm the recommendation of thoracoscopic approach as a routine surgical procedure for operable SCLC, and until then, open surgery should still be considered.

Recent advances in small cell lung cancer (SCLC) treatments necessitate a better understanding of real-world health utility scores (HUS) in patients treated under current standards to facilitate robust pharmaco-economic assessments.In this single institution cohort observational study, HUS were evaluated in patients with SCLC through EQ-5D questionnaires at outpatient visits (encounters). In addition, patients completed questionnaires relating to treatment toxicities and cancer symptoms. Clinical and pathological variables were abstracted from electronic medical records and disease status at each patient visit was documented. The impact of these variables on HUS were explored.There were 282 clinical encounters (12% newly diagnosed; 37% stable on treatment; 22% progressing on treatment; 29% stable off therapy/other) in 111 SCLC patients (58% male; 64% extensive stage (ES) SCLC). At the first encounter 29% of patients had an ECOG performance status (PS) ≥ 2. ES-SCLC, bone metastases, female sex, progressive disease and/or PS were each significantly associated with decreased HUS in multivariable analyses. Patients clinically stable on first line therapy had generally steady HUS longitudinally, with differences in HUS between limited disease (LD) and ES patients emerging as treatment progressed. Decreased HUS were associated with increased severity of the majority of measured symptoms (fatigue/tiredness, loss of appetite, pain, drowsiness, shortness of breath, anxiety, depression, and overall well-being; each p0.001), supporting the value of EQ-5D-derived HUS in assessing health utility.Our HUS values in chemotherapy-treated SCLC are clinically relevant and are associated with specific clinico-demographic, symptom and toxicity factors.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis and extreme lethality. The backbone of SCLC treatment over the past several decades has been platinum-based doublet chemotherapy, with the recent addition of immunotherapy providing modest benefits in a subset of patients. However, nearly all patients treated with systemic therapy quickly develop resistant disease, and there is an absence of effective therapies for recurrent and progressive disease. Here we conducted CRISPR-Cas9 screens using a druggable genome library in multiple SCLC cell lines representing distinct molecular subtypes. This screen nominated exportin-1, encoded by XPO1, as a therapeutic target. XPO1 was highly and ubiquitously expressed in SCLC relative to other lung cancer histologies and other tumor types. XPO1 knockout enhanced chemosensitivity, and exportin-1 inhibition demonstrated synergy with both first- and second-line chemotherapy. The small molecule exportin-1 inhibitor selinexor in combination with cisplatin or irinotecan dramatically inhibited tumor growth in chemonaïve and chemorelapsed SCLC patient-derived xenografts, respectively. Together these data identify exportin-1 as a promising therapeutic target in SCLC, with the potential to markedly augment the efficacy of cytotoxic agents commonly used in treating this disease. Significance: CRISPR-Cas9 screening nominates exportin-1 as a therapeutic target in SCLC, and exportin-1 inhibition enhances chemotherapy efficacy in patient-derived xenografts, providing a novel therapeutic opportunity in this disease.

Introduction Notwithstanding the diagnostic and therapeutic advancements, the incidence of cardiac metastases has increased in recent decades. Lung cancers are the most common primary malignant neoplasms with cardiac metastasis potential. The clinical presentation of cardiac metastases is either silent or vague, and largely depends on the infiltrated location and tumor burden. Although arrhythmias are not uncommon in metastatic cardiac tumors, complete heart block is relatively a rare manifestation. We present a case of complete heart block due to a metastatic small cell carcinoma in a 67-year-old male of African origin. Case presentation A 67-year-old male of African origin from rural Tanzania was referred to us for expert management. He is a retired agromechanic with over 30 years exposure to asbestos-containing brake linings. His past medical history was unremarkable, but the family-social history was evident for a heavy alcohol intake and chronic cigarette smoking. He presented with a 24-week history of progressive shortness of breath and an 8-week history of recurrent syncopal attacks coupled with a significant weight loss. He had normal echocardiographic findings, however, the electrocardiogram showed features of complete heart block. Chest X-ray showed a homogeneous opacification on the right side and computed tomography scan revealed a solid right lung mass with metastases to the liver, heart, bowels, and bone. He underwent bronchoscopy, which revealed an endobronchial mass obstructing the bronchus intermedius. Histological examination of a section of lung biopsy taken during bronchoscopy confirmed the diagnosis of a small cell carcinoma. The patient underwent dual chamber pacemaker implantation with successful sinus rhythm restoration. He made an informed refusal of chemotherapy and inevitably died 18 months post pacing. Conclusions Despite the advancements in medical diagnostics and management, lung cancers are often diagnosed in advanced stages, with an inevitable grave prognosis. Small cell carcinoma has the potential to metastasize to the heart, resulting in complete heart block.

Purpose K-MASTER project is a Korean national precision medicine platform that screened actionable mutations by analyzing next-generation sequencing (NGS) of solid tumor patients. We compared gene analyses between NGS panel from the K-MASTER project and orthogonal methods.Materials and Methods Colorectal, breast, non–small cell lung, and gastric cancer patients were included. We compared NGS results from K-MASTER projects with those of non-NGS orthogonal methods (KRAS, NRAS, and BRAF mutations in colorectal cancer [CRC]; epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] fusion, and reactive oxygen species 1 [ROS1] fusion in non–small cell lung cancer [NSCLC], and Erb-B2 receptor tyrosine kinase 2 (ERBB2) positivity in breast and gastric cancers).Results In the CRC cohort (n=225), the sensitivity and specificity of NGS were 87.4% and 79.3% (KRAS); 88.9% and 98.9% (NRAS); and 77.8% and 100.0% (BRAF), respectively. In the NSCLC cohort (n=109), the sensitivity and specificity of NGS for EGFR were 86.2% and 97.5%, respectively. The concordance rate for ALK fusion was 100%, but ROS1 fusion was positive in only one of three cases that were positive in orthogonal tests. In the breast cancer cohort (n=260), ERBB2 amplification was detected in 45 by NGS. Compared with orthogonal methods that integrated immunohistochemistry and in situ hybridization, sensitivity and specificity were 53.7% and 99.4%, respectively. In the gastric cancer cohort (n=64), ERBB2 amplification was detected in six by NGS. Compared with orthogonal methods, sensitivity and specificity were 62.5% and 98.2%, respectively.Conclusion The results of the K-MASTER NGS panel and orthogonal methods showed a different degree of agreement for each genetic alteration, but generally showed a high agreement rate.

Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% to 25% of SCLCs harbor loss-of-function (LOF) NOTCH mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive nonneuroendocrine plasticity to support SCLC growth. Given the dual functionality of NOTCH, it is not understood why SCLCs select for LOF NOTCH mutations and how these mutations affect SCLC tumorigenesis. In a CRISPR-based genetically engineered mouse model of SCLC, genetic loss of Notch1 or Notch2 modestly accelerated SCLC tumorigenesis. Interestingly, Notch-mutant SCLCs still formed nonneuroendocrine subpopulations, and these Notch-independent, nonneuroendocrine subpopulations were driven by Runx2-mediated regulation of Rest. Notch2-mutant nonneuroendocrine cells highly express innate immune signaling genes including stimulator of interferon genes (STING) and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote nonneuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations. Significance: A genetically engineered mouse model of NOTCH-mutant SCLC reveals that nonneuroendocrine plasticity persists in the absence of NOTCH, driven by a RUNX2-REST–dependent pathway and innate immune signaling.

Introduction Although precursor lesions of pulmonary squamous carcinoma, adenocarcinoma, and carcinoid tumor are well known and accepted entities, precursor lesions of pulmonary neuroendocrine carcinomas, i.e., small cell lung carcinoma and large cell neuroendocrine carcinoma, have never been identified. A small body of literature documenting intraepithelial involvement in cases of pulmonary neuroendocrine carcinomas begs the question of whether the intraepithelial lesion represents de novo intraepithelial neoplasia or invasion by underlying tumour. Methods and materials The literature on cases of invasive neuroendocrine carcinomas with an intraepithelial component exhibiting a neuroendocrine immunophenotype was thoroughly and critically reviewed. Results The authors of the publications of cases of coexisting invasive and intraepithelial neuroendocrine carcinoma generally favour invasion as the explanation for the intraepithelial component. However, in practice, it is difficult or impossible to determine the direction of migration of tumor cells when there is both an invasive and intraepithelial component. Pulmonary neuroendocrine carcinomas in situ have been produced in genetically engineered mouse models. Conclusions Based on the illustrations in the literature of human cases and the production of pulmonary neuroendocrine carcinomas in situ in genetically engineered mice, it seems likely that these tumours also exist in humans. However, their existence and acceptance require definitive proof. Studies should be undertaken to identify bronchial and other lung biopsies with in situ carcinoma exhibiting a neuroendocrine immunophenotype and a subsequent negative resection specimen and no follow-up evidence of invasive carcinoma. Documenting such cases would provide definitive proof for the existence pulmonary neuroendocrine carcinomas in situ in humans.

Bioinformatics methods are used to construct an immune gene prognosis assessment model for patients with non-small cell lung cancer (NSCLC), and to screen biomarkers that affect the occurrence and prognosis of NSCLC. The transcriptomic data and clinicopathological data of NSCLC and cancer-adjacent normal tissues were downloaded from the Cancer Genome Atlas (TCGA) database and the immune-related genes were obtained from the IMMPORT database (http://www.immport.org/); then, the differentially expressed immune genes were screened out. Based on these genes, an immune gene prognosis model was constructed. The Cox proportional hazards regression model was used for univariate and multivariate analyses. Further, the correlations among the risk score, clinicopathological characteristics, tumor microenvironment, and the prognosis of NSCLC were analyzed. A total of 193 differentially expressed immune genes related to NSCLC were screened based on the "wilcox.test" in R language, and Cox single factor analysis showed that 19 differentially expressed immune genes were associated with the prognosis of NSCLC (P P

This review summarizes key recent developments relevant to the pathologic diagnosis of lung neuroendocrine neoplasms, including carcinoids, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC). Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. Highlighted topics include highly proliferative carcinoids and their distinction from small cell and large cell neuroendocrine carcinomas (NECs), the evolving role of Ki67, the update on the differential diagnosis of NEC to include thoracic SMARCA4-deficient undifferentiated tumors, the recent data on SCLC transcriptional subtypes with the emergence of POU2F3 as a novel marker for the diagnosis of SCLC with low/negative expression of standard neuroendocrine markers, and the update on the diagnosis of LCNEC, particularly in biopsies. There has been remarkable recent progress in the understanding of the genetic and expression-based profiles within each type of lung neuroendocrine neoplasm, and it is hoped that these insights will enable the development of novel diagnostic, prognostic, and predictive biomarkers to aid in the pathologic assessment of these tumors in the future.

A 62-year-old Filipino woman came in for a primary symptom of insidious-onset blurring of vision on the right eye. The medical history revealed hypertension but no other comorbid illnesses. There were no other problems on review of systems. Eye examination revealed a best corrected visual acuity of

Objective: To investigate whether age or other factors are determinants of distant metastasis in patients with lung cancer. Study Design: Observational study. Place and Duration of Study: Department of Nuclear Medicine, Recep Tayyip Erdogan University, Rize, Turkey between December, 2018 and February, 2019. Methodology: A total of 152 patients with lung cancer, who underwent positron emission tomography/computed tomography (PET/CT) for staging, were included in this study. Patients were grouped according to age (>65 and 66 pack-years (p = 0.047/p = 0.047) were independent factors for the presence of distant metastasis. Conclusion: Although age is not a risk factor for distant metastasis in lung cancer, female gender, T3/4 tumour, SCLC subtype, and smoking history of >66 pack-years are high-risk factors. PET/CT is recommended as the first-choice imaging technique in patients with lung cancer indicated for distant metastasis scanning.

High‐grade neuroendocrine carcinoma of gynecologic origin (NEC‐GYN) is a highly aggressive cancer that often affects young women. The clinical management of NEC‐GYN is typically extrapolated from its counterpart, small cell carcinoma of the lung (SCLC), but, unfortunately, available therapies have limited benefit. In our NEC‐GYN cohort, median progression‐free survival (PFS) and overall survival (OS) were 1 and 12 months, respectively, indicating the highly lethal nature of this cancer. Our comprehensive genomic analyses unveiled that NEC‐GYN harbors a higher mutational burden with distinct mutational landscapes from SCLC. We identified 14 cancer driver genes, including the most frequently altered KMT2C (100%), KNL1 (100%), NCOR2 (100%), and CCDC6 (93%) genes. Transcriptomic analysis identified several novel gene fusions; astonishingly, the MALAT1 lincRNA gene was found in ˜ 20% of all fusion events in NEC‐GYN. Furthermore, NEC‐GYN exhibited a highly immunosuppressive state, intact RB1 expression, and was uniquely enriched with the YAP1 high molecular subtype. Our study identifies several potential therapeutic targets and suggests an urgent need to re‐evaluate the treatment options for NEC‐GYN., The neuroendocrine carcinoma of gynecologic origin (NEC‐GYN) is a deadly cancer that often affects young women. Treatment of NEC‐GYN is typically extrapolated from small cell lung cancer (SCLC), but, unfortunately, available treatments are inadequate. We report that NEC‐GYN is genomically distinct from SCLC, identify several potential therapeutic targets, and suggest an urgent need to re‐evaluate the treatment options for NEC‐GYN.

Objective Patients with very early stage small cell lung cancer (SCLC) can benefit from surgery. However, the role of surgery in local advanced SCLC patients remains controversial. We designed this study to investigate the role of surgery on survival of this subset population. Methods The included patients were identified from the Surveillance, Epidemiology, and End Results SEER database from 1998 to 2016 and Shanghai Chest Hospital of China from 2009 to 2016. Propensity score matching(PSM) was used to balance clinical bias. The overall survival (OS) and lung cancer-specific survival (LCSS) were compared by the Kaplan–Meier analysis. Cox proportional hazards regression was used to identify factors associated with survival. Results Among the 3005 stage Ⅲ patients, 570 (18.97%) patients underwent surgery. Compared with non-surgical group, patients undergoing surgery were more likely to be male, had smaller tumor size, mediastinal lymph node involvement and lower pathologic stage. The Kaplan-Meier analysis showed that surgical patients had a better OS and LCSS before and after PSM. 418 surgical patients were well matched with non-surgical patients. In matched surgical group, there were 224 (53.59%) patients who underwent lobectomy (LB), 147 (35.17%) patients who received sublobectomy (SLB), 31 (7.41%) patients who underwent pneumonectomy and 16 (3.83%) patients with unknown surgery type. The 5-year OS of the 4 subgroups were 28.80%, 12.50%, 8.70% and 13.50%, respectively (P = 0.002). In a multivariable Cox model, SLB (hazard ratio, 1.53; 95%CI, 1.20–1.96; P = 0.001) and pneumonectomy (hazard ratio, 1.72; 95%CI, 1.12–2.65; P = 0.013) were associated with worse OS compared with LB. Conclusion Surgical resection significantly improved OS and LCSS of stage Ⅲ SCLC patients in our study. Furthermore, LB had advantage over other surgery type but further exploration in larger prospective clinical trials is needed.

As a novel antiangiogenic multi-target tyrosine kinase inhibitor recently approved in China, anlotinib has exhibited promising anticancer efficacy and acceptable safety profile in the salvage treatment of small cell lung cancer (SCLC) in clinical trials. Here we retrospectively investigated the efficacy and safety of anlotinib as third- or further-line treatment in patients with refractory SCLC. A total of 40 patients with refractory SCLC treated with anlotinib monotherapy were included in this study. The clinicopathological data, treatment information, survival data and safety data were retrospectively collected. Survival curves were constructed using the Kaplan–Meier method. Univariate analysis was performed by log-rank testing. Altogether, 40 patients of extensive-stage SCLC or progressive limited-stage SCLC received anlotinib monotherapy as third- or further-line treatment from July 2018 to June 2020. Four patients achieved partial response (PR), 14 patients achieved stable disease (SD), no complete response (CR) was recorded, and 22 patients experienced progressive disease (PD). The disease control rate (DCR) was 45.0%. The median progression-free survival (PFS) was 3.0 months (95% CI 2.241–3.759), and the median overall survival (OS) was 7.8 months (95% CI 3.190–12.410). The common adverse effects (AEs) included hypertension, fatigue, anorexia, cough, rash and nausea. Grade 3 treatment-related AEs occurred in 3 (7.5%) patients. One patient interrupted anlotinib treatment due to repeated grade 1 epistaxis. Univariate analysis revealed that patients without liver metastases, previously treated with radiotherapy or with Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1 had longer OS with anlotinib treatment. Cox regression analysis demonstrated that patients without liver metastases and patients with ECOG score ≤ 1 had longer PFS, while patients without liver metastases had longer OS. Anlotinib is beneficial to refractory SCLC as third- or further-line treatment, especially in patients without liver metastasis and with better physical status. Related adverse effects are tolerable and manageable.

Purpose These exposure–response (E–R) analyses integrated lurbinectedin effects on key efficacy and safety variables in relapsed SCLC to determine the adequacy of the dose regimen of 3.2 mg/m2 1-h intravenous infusion every 3 weeks (q3wk). Methods Logistic models and Cox regression analyses were applied to correlate lurbinectedin exposure metrics (AUCtot and AUCu) with efficacy and safety endpoints: objective response rate (ORR) and overall survival (OS) in SCLC patients (n = 99) treated in study B-005 with 3.2 mg/m2 q3wk, and incidence of grade 4 (G4) neutropenia and grade 3–4 (G ≥ 3) thrombocytopenia in a pool of cancer patients from single-agent phase I to III studies (n = 692) treated at a wide range of doses. A clinical utility index was used to assess the appropriateness of the selected dose. Results Effect of lurbinectedin AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUCu. An Emax logistic model for G4 neutropenia and a linear logistic model for G ≥ 3 thrombocytopenia, which retained platelets and albumin at baseline and body surface area, best fitted to AUCtot and AUCu. AUCu between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m2 provided median AUCu of 1400 ng·h/L, thus maximizing the proportion of patients within that lurbinectedin target exposure range. Conclusions The relationships evidenced in this integrated E–R analysis support a favorable benefit-risk profile for lurbinectedin 3.2 mg/m2 q3wk. Trial registration Clinicaltrials.gov: NCT02454972; registered May 27, 2015.

Small cell lung cancer (SCLC) is known for its rapid clinical progression and poor prognosis. In this study, we sought to establish a prognostic nomogram among SCLC patients who received chemotherapy. We obtained 4971 SCLC patients’ clinical information from the Surveillance, Epidemiology, and End Results (SEER) database for the period between 2004 and 2015. Patients were divided into training and validation sets. Two nomograms were established based on limited stage (LS) and extensive stage (ES) SCLC patients to predict 1-, 2-, and 3-year overall survival (OS) incorporating superior parameters from multivariate Cox regression. Receiver-operating characteristic curves (ROCs) were applied to assess the discrimination ability of the nomogram while the calibration plots were applied to verify the model. Kaplan-Meier method was applied to find survival curves. Decision curve analysis (DCA) was applied to compare OS between the nomograms and 7th American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) staging system. Four and six clinical parameters were identified as significant prognostic factors for LS-SCLC and ES-SCLC patient’s OS, respectively. The ROC curves indicated satisfactory discrimination capacity of the nomogram, with 1-, 2-, and 3-year area under curve (AUC) values of 0.89, 0.81, and 0.79 in LS-SCLC patients and 0.71, 0.66, and 0.66 in ES-SCLC patients, respectively. Calibration curves indicated that the nomogram showed good agreement with actual observations in survival rate probability. The survival curves among the LS-SCLC and ES-SCLC cohorts were consistent with the high-risk group having a worse prognosis than the low-risk group. Moreover, ROC and DCA curves showed our nomograms had more benefits than the 7th AJCC-TNM staging system. We established two nomograms that can present individual predictions of OS among LS-SCLC and ES-SCLC patients who received chemotherapy. These proposed nomograms may aid clinicians in treatment strategy and design of clinical trials.

Background Human epidermal growth factor receptor 2 (HER2) is tyrosine kinase receptor that belongs to the ErbB family and is overexpressed on the membrane surface of various cancer cells, including small cell lung cancer (SCLC); however, no HER2 targeted therapy for SCLC have yet been established. Near‐infrared photoimmunotherapy (NIR‐PIT) is a novel cancer therapy based on photo‐absorber, IRDye‐700DX (IR700), ‐antibody conjugates, and near‐infrared (NIR) light. Methods We used HER2‐positive SCLC parental cell lines (SBC‐3) and its chemoresistant cell lines, and examined therapeutic efficacy of HER2 targeting NIR‐PIT using anti HER2 antibody trastuzumab. Results We found that HER2 expression was upregulated on chemoresistant cell lines, especially cisplatin‐resistance (SBC‐3/CDDP). In vitro, the rate of cell death increased with the amount of NIR‐light irradiation, and it was significantly higher in SBC‐3/CDDP than in SBC‐3. In vivo, tumor growth was more suppressed in SBC‐3/CDDP group than in SBC‐3 group, and survival period tended to be prolonged. Conclusion In this study, we demonstrated that HER2 targeting NIR‐PIT using trastuzumab is promising therapy for HER2‐positive SCLC, and is more effective when HER2 expression is upregulated due to CDDP resistance, suggesting that the HER2 expression level positively corelated with the efficacy of NIR‐PIT., We found that human epidermal growth factor receptor 2 (HER2) was expressed in small‐cell lung cancer (SCLC) parental cell lines (SBC‐3) and its chemoresistant cell lines, and HER2 was upregulated in chemoresistant SCLC cells, especially CDDP‐resistant cells (SBC‐3/CDDP). The HER2‐targeting near‐infrared photoimmunotherapy (NIR‐PIT) using an anti‐HER2 antibody, trastuzumab, induced HER2‐expressing SCLC cells death, and efficacy of this therapy was significantly higher in SBC‐3/CDDP than in SBC‐3 in vitro and in vivo. These findings suggest a positive correlation between the cancer antigen expression level and the NIR‐PIT effect. Implications of all the available evidence. Our finding suggests that NIR‐PIT targeting HER2 using trastuzumab is a novel therapeutic approach for HER2‐positive SCLC when SCLC acquired CDDP‐based chemotherapy resistance and HER2 expression was upregulated.

Purpose The objective of this study was to evaluate the safety and efficacy of immune checkpoint inhibitor (ICI) plus anlotinib as third-line treatment in extensive-stage small cell lung cancer (ES-SCLC). Methods A total of 120 patients with ES-SCLC who were admitted to Shandong Cancer Hospital between January 2019 and December 2020 were retrospectively analyzed. They were divided into the observation group (n = 62) and the control group (n = 58) according to their different treatment plans. The observation group was given ICI plus anlotinib, while the control group was given anlotinib alone. The primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and disease control rate (DCR). An efficacy evaluation was carried out every 6 weeks. Univariate and multivariate analyses were performed to identify the prognostic factors. The main treatment-related adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Results In the observation group and the control group, the DCRs were 87.1% and 72.4% (p = 0.044), and the ORRs were 19.4% and 6.9% (p = 0.045), respectively. The median PFS was longer in the observation group (7.5 months) than in the control group (4.6 months) (p = 0.0033). In Cox regression analysis, the Eastern Cooperative Oncology Group performance status score, brain metastases and metastatic sites were prognostic factors of ICI plus anlotinib. Compared with the control group, grade 1–2 immune-related pneumonia and hypothyroidism of patients in the observation group were significantly increased (p p > 0.05). Conclusion ICI plus anlotinib showed promising efficacy and manageable toxicity in third-line treatment of ES-SCLC.

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC., Small-cell lung cancer (SCLC) is an aggressive disease with limited therapeutic options. Here the authors perform an immunogenomic analysis of limited-stage SCLC, revealing a homogeneous mutational landscape, but limited T-cell infiltration and a cold and heterogeneous T cell repertoire.

Poorly differentiated pancreatic neuroendocrine carcinomas (NECs) are rare and aggressive malignancies with rapid disease progression and early widespread metastasis. Given histology similarity, they are commonly treated with platinum-based chemotherapy as small cell lung cancer (SCLC). However, no standard treatment has been established for recurrent or progressive disease. We present an Asian patient with recurrent poorly differentiated pancreatic NEC after curative surgery and adjuvant chemotherapy with cisplatin and etoposide. The tumor mutational burden (TMB) was high. The patient received chemotherapy combined with maintenance immunotherapy with nivolumab and achieved promising and durable response, suggesting TMB could be a biomarker to identify NEC patients for immune checkpoint inhibitor (ICI) treatment.

Background/aim LUCAS is a clinical lung cancer registry (ClinicalTrials.gov identifier is NCT04228237), prospectively collecting data from newly diagnosed lung cancer patients in seven pneumooncology centers in the Czech Republic, since June 1, 2018. The aim of the study was to assess the stage of the disease at the time of diagnosis, percentage of morphological types, survival, percentage of driving mutations, eligibility for radical surgery, and percentage of patients who undergo radical surgery, in the non-smoking population in comparison with smokers and former smokers. Patients and methods The total number of patients in the registry at the time of the analysis was 2,743. Only 2,439 patients with complete records (smoking status, stage, and type of tumor) were included in this study. Results The analysis indicated that non-smokers are diagnosed at a later stage of the disease but they have a better survival rate than smokers. Fewer smokers with stage III disease who are eligible for radical surgery will undergo surgery compared to non-smokers with the same clinical stage. Driving mutations are more common in non-smokers, even after adjustment for the more frequent occurrence of adenocarcinoma in the group of non-smokers. Conclusion The data from LUCAS registry are consistent with already known facts, suggesting that the LUCAS registry is a useful clinical tool.

Durvalumab (IMFINZI®), a fully human monoclonal antibody against programmed cell death-ligand 1 (PD-L1), is approved for use in combination with etoposide and either carboplatin or cisplatin for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). In the pivotal phase III CASPIAN trial in previously untreated adults with ES-SCLC, the addition of durvalumab to chemotherapy for up to 4 cycles followed by maintenance durvalumab was associated with a significantly longer overall survival and a favourable hazard ratio for progression-free survival compared with chemotherapy alone for up to 6 cycles. A higher proportion of patients in the durvalumab plus chemotherapy group had an objective response compared with the chemotherapy alone group. The efficacy of durvalumab was also sustained with longer follow-up. Durvalumab in combination with etoposide and either carboplatin or cisplatin had a manageable tolerability profile in patients with ES-SCLC. Given the available evidence, durvalumab in combination with etoposide and either carboplatin or cisplatin represents a valuable treatment option for the first-line treatment of patients with ES-SCLC, and is an accepted standard of care option in this setting. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00843-0., Plain Language Summary Small cell lung cancer (SCLC) is the most aggressive form of lung cancer; extensive-stage (ES) disease, which accounts for about two-thirds of all SCLC, is associated with high relapse rates and a poor prognosis. Expression of programmed cell death-ligand 1 (PD-L1) on both tumour cells and tumour-associated immune cells is an adaptive immune response that helps tumour cells avoid detection and subsequent elimination by the immune system. Durvalumab (IMFINZI®) is a fully human monoclonal antibody against PD-L1, which blocks the interaction of PD-L1 with its receptors, thus enhancing anti-tumour immune responses. When used in combination with chemotherapy (etoposide and either carboplatin or cisplatin) in adults with untreated ES-SCLC, durvalumab prolonged overall survival compared with chemotherapy alone; the improvements in overall survival were also maintained with additional follow-up. The tolerability profile of durvalumab in combination with chemotherapy was manageable in patients with ES-SCLC. Durvalumab in combination with chemotherapy is an effective and valuable treatment option for previously untreated patients with ES-SCLC. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00843-0.

Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133+ cancer stem cells and PD-L1+CD73+ myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease.

Background Conflicting data exists regarding the benefit of prophylactic cranial irradiation (PCI) in patients with extensive-stage small-cell lung cancer (ES-SCLC). We sought to retrospectively review outcomes of patients within our network with ES-SCLC treated with and without PCI between 2009 and 2020. Methods Endpoints assessed using the Kaplan-Meier estimator were overall survival (OS), freedom from death with uncontrolled intracranial disease (UI-DFS), brain metastasis-free survival (BMFS), and symptomatic BMFS (SBMFS). Log-rank test was performed for univariate comparison of outcomes, with Cox regression performed for univariate and multivariable analysis of OS and UI-DFS. Results Some 250 patients were determined to be eligible for PCI based on any response to upfront chemotherapy, with 46 patients excluded owing to lack of negative staging brain magnetic resonance imaging (MRI). Brain MRI was performed both at diagnosis and near completion of chemotherapy in 108 patients, with brain metastases identified near completion of chemotherapy in 17 patients (15.7%), excluding them from further analysis. Median OS in remaining eligible 187 patients was 9.0 months, with 2-year Kaplan-Meier estimate of OS of 21.9%. PCI was associated with improved UI-DFS, BMFS, and SBMFS. However, PCI was not associated with improved OS in the entire cohort or the propensity matched cohort. Conclusion Our study suggests screening with MRI following chemotherapy is important because of the identification of unsuspected brain metastases in nearly 16% of patients with response to chemotherapy. PCI is associated with reduction in brain metastases, without a demonstrable impact on OS in the era of MRI screening.

Background The current study aimed to evaluate the serum pretreatment lactate dehydrogenase (LDH) and overall survival (OS) in small cell lung cancer (SCLC) patients who received first‐line platinum‐containing chemotherapy. Methods A total of 234 SCLC patients, who received first‐line platinum‐based chemotherapy between 2013 and 2018, were retrospectively analyzed. The data of hematological characteristics, age, gender, ECOG score, staging, metastatic site, smoking history, chemotherapy cycle, thoracic radiotherapy and hyponatremia were collected. Overall survival was calculated using the Kaplan‐Meier method. The statistically significant factors in the univariate analysis were selected for the multivariate COX model analysis. Results Age, ECOG score, stage, thoracic radiotherapy, hyponatremia, liver metastasis, brain metastasis, bone metastasis, LDH, NSE and neutrophil‐to‐lymphocyte ratio (NLR) were closely correlated to OS in the univariate analysis. Furthermore, the multivariate analysis revealed that age (, The current study aimed to evaluate the serum pretreatment lactate dehydrogenase (LDH) and overall survival (OS) in small‐cell lung cancer (SCLC) patients who received first‐line platinum‐containing chemotherapy. A total of 234 SCLC patients, who received first‐line platinum‐based chemotherapy between 2013 and 2018, were retrospectively analyzed. Age

Objectives: Circulating levels of activin A (ActA) and follistatin (FST) have been investigated in various disorders including malignancies. However, to date, their diagnostic and prognostic relevance is largely unknown in small cell lung cancer (SCLC). Our aim was to evaluate circulating ActA and FST levels as potential biomarkers in this devastating disease. Methods: Seventy-nine Caucasian SCLC patients and 67 age- and sex-matched healthy volunteers were included in this study. Circulating ActA and FST concentrations were measured by ELISA and correlated with clinicopathological parameters and long-term outcomes. Results: Plasma ActA and FST concentrations were significantly elevated in SCLC patients when compared to healthy volunteers (p < 0.0001). Furthermore, extensive-stage SCLC patients had significantly higher circulating ActA levels than those with limited-stage disease (p = 0.0179). Circulating FST concentration was not associated with disease stage (p = 0.6859). Notably, patients with high (≥548.8 pg/ml) plasma ActA concentration exhibited significantly worse median overall survival (OS) compared to those with low (

Background The majority of patients with small‐cell lung cancer (SCLC) show a good response in the early stages of treatment, but more than 90% of patients will develop drug resistance. Therefore, biomarkers are urgently needed to identify patients who can benefit from systemic treatment. Methods We prospectively enrolled 52 extensive‐stage SCLC patients before treatment from a local hospital to identify mutations related to patient prognosis, and verified them in the published Jiang's cohort and George's cohort. Results We found that patients with high mutations (mut‐high) in the fatty acid (FA) metabolism pathway had a longer progression‐free survival (PFS) in the local hospital cohort (HR = 0.446, 95% CI, 0.207–0.959, p = 0.0387) and a longer overall survival (OS) in Jiang's cohort (HR = 0.549, 95% CI, 0.314–0.960, p = 0.0351) than patients with low mutations (mut‐low). Multivariate analysis suggested that mut‐high status was an independent prognostic factor in both cohorts. George's cohort verified that mut‐high status was associated with a longer OS than mut‐low status (HR = 0.730, 95% CI 0.440–1.220, p = 0.2277). The possible mechanisms were as follows: the frequency of mutated FA synthase (FASN) in the mut‐high group was greater than that in the mut‐low group, and pathways related to the cell cycle, DNA repair, and oxidative phosphorylation were enriched in the mut‐high group. Conclusions The prognosis of SCLC patients treated with chemotherapy was better among patients with more mutations in the FA metabolism pathway, and the underlying mechanisms could be found at the genome and transcriptome levels., We prospectively enrolled 52 extensive‐stage SCLC patients before treatment from local hospital to identify mutations related to patient prognosis. We found that the patients with high mutations (mut‐high) in the fatty acid (FA) metabolism pathway had better prognosis in the local hospital cohort and the Jiang's cohort than patients with low mutations (mut‐low). Then it was verified in George's cohort that mut‐high status was associated with a longer OS than mut‐low status. Finally, the possible mechanisms were explored from the genome and transcriptome levels.

Introduction: In patients with limited disease small cell lung cancer (LD-SCLC) treated with concurrent chemoradiotherapy (CCRT), long-term survival data have not been fully evaluated. Moreover, the association between long-term prognosis and prognostic factors has not been sufficiently investigated. Methods: In this retrospective study, we evaluated the efficacy of CCRT in 120 patients with LD-SCLC with a plan for curative CRT using concurrent accelerated hyperfractionated radiotherapy. Results: The patients had a median age of 65.5 years, predominantly male (73%), and had clinical stage III disease (80%). The median follow-up time for overall survival (OS) was 72.2 months, median OS was 42.5 months, and the 3-year and 5-year survival rates were 52.4% and 41.8%, respectively. The median progression-free survival (PFS) was 12.5 months, and the 3-year and 5-year PFS rates were 37.6% and 33.6%, respectively. The 5-year OS rates of patients who achieved PFS at each time point were 70.9%, 83.6%, and 91.9% at 12, 24, and 36 months, respectively. The gradual increase in the 5-year OS rate following PFS extension and initial depression of the Kaplan–Meier curve showed disease progression frequently occurred in the first 2 years after initiation of CCRT. The Cox proportional hazards model showed no significant factors correlated with long-term survival through univariate and multivariate analyses. Although the prognostic factors associated with long-term prognosis in LD-SCLC were not identified, the 5-year survival rate was 41.8%, and among patients without disease progression at 2 years, the 5-year survival rate was 83.6%. Conclusion: These data suggested that the prognosis of patients with LD-SCLC was improving.

BACKGROUND Large Cell Neuroendocrine Carcinoma of the Lung (L-LCNEC) is a rare type of neuroendocrine lung cancer that is increasingly diagnosed. However, the optimal management regarding the advanced stage is unclear. The purpose of this article is to present and compare our experience when L-LCNEC is treated as Small Cell Lung Cancer (SCLC). PATIENTS AND METHODS Overall, eight cases of L-LCNEC were included. We retrospectively reviewed medical files and reports by accessing the Institution's Data of patients diagnosed with L-LCNEC from April 2019 until December 2020 and evaluated their response to the combination of Platinum - Etoposide - Atezolizumab as first-line chemotherapy. RESULTS The overall observed response rate (ORR) of 75%. The median PFS was 6.85 months. The median response duration was 5.5 months. CONCLUSIONS Comparing our findings with other retrospective and prospective studies, it seems that the systematic treatment of choice and management in L-LCNEC of the lung should be that of a small cell carcinoma of the lung.

Purpose: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. Methods: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. Results: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. Conclusions: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

In advanced lung cancer treatment, immunotherapy provides durable responses in some patients. However, other patients experience progressive disease and the resistance mechanisms to immunotherapy have yet been fully elucidated. Small cell transformation of non‐small cell lung cancer (NSCLC) is commonly recognized as one of the resistance mechanisms to epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors in EGFR‐mutant NSCLC treatment. As a resistant mechanism for immunotherapy, we report the first case of small cell transformation in 2017. Since then, eight similar cases have been reported and the concept of small cell transformation is now becoming more prevalent as a mechanism of immunotherapy resistance. In our facility, we have experienced four cases of small cell transformation after immunotherapy (including the reported case in 2017). The histology of each primary tumor was squamous cell carcinoma, large cell type neuroendocrine carcinoma, or poorly differentiated NSCLC. None had driver gene mutations. Nivolumab was administered in all four cases and atezolizumab was administered as a next line to nivolumab treatment in one case. The best response to immunotherapy was partial response or stable disease. There was a wide range of periods from the start of immunotherapy to confirmation of small cell transformation (from 2 weeks to almost 3 years). In conclusion, small cell transformation is an important resistance mechanism in cancer immunotherapy. When NSCLC progresses after immunotherapy, the possibility of small cell transformation and rebiopsy should always be encouraged, as it leads to clarification of the resistance mechanisms and frequency., Small cell transformation is an important resistance mechanism in cancer immunotherapy. When non‐small cell lung cancers progress after immunotherapy, we should always consider the possibility of small cell transformation and rebiopsy should be encouraged. Herein, we report four cases of tumor transformation from non‐small cell lung cancer to small cell cancer under immunotherapy.

Long non-coding RNA (lncRNA) FOXD3-AS1 expression is upregulated in lung cancer; however, its effect and mechanism on 5-fluorouracil (5-FU) resistance remain unclear. In this study, we determined the effects of FOXD3-AS1-enriched exosomes derived from lung cancer cells on the proliferation, invasion, and 5-FU resistance of lung cancer cells. Online bioinformatics database analysis showed that FOXD3-AS1 was upregulated in lung cancer progression. Real-time quantitative PCR results confirmed that FOXD3-AS1 expression was upregulated in lung cancer tissues and cell lines, and FOXD3-AS1 was greatly enriched in lung cancer cell-derived exosomes. ELAV-like RNA-binding protein 1 (ELAVL1) was identified as an RNA-binding protein of FOXD3-AS1. The lung cancer cell-derived exosomes promoted A549 cell proliferation and invasion and inhibited apoptosis caused by 5-FU, and transfection of si-FOXD3-AS1 or si-ELAVL1 in exosome-incubated A549 cells reversed these effects. Moreover, exosome-incubated A549 cells were co-transfected with si-FOXD3-AS1 and pcDNA-ELAVL1, showing the same cell proliferation, invasion, and 5-FU resistance as those of A549 cells treated with lung cancer cell-derived exosomes alone. Mechanistic studies identified that lung cancer cell-derived exosomes activated the PI3K/Akt pathway, and transfection of si-FOXD3-AS1 or treatment with the PI3K inhibitor LY294002 reversed the activation of the PI3K/Akt axis induced by exosomes. In conclusion, our study revealed that lung cancer cell-derived exosomal FOXD3-AS1 upregulated ELAVL1 expression and activated the PI3K/Akt pathway to promote lung cancer progression. Our findings provide a new strategy for lung cancer treatment.

Introduction Immune cells and molecules are considered as clinical biomarkers and potential targets for immunotherapy. Analyses of the composition of peripheral blood cells hold promise for providing a basis for diagnosing and prognosis lung cancer. In this study, we assessed correlations between immune cell subset profiles in peripheral blood and disease prognosis in patients with lung cancer. Methods One hundred and thirteen patients with lung cancer and 99 age‐matched healthy people were enrolled in this study. The percentage and cell count of monocytes, neutrophils, T cells, B cells, natural killer (NK), and NKT cells in peripheral blood were analyzed by flow cytometry or peripheral blood analyzer. Serum cytokines and colony‐stimulating factors were detected by enzyme‐linked immunosorbent assay (ELISA). Results A reduction in antitumor NK cells (p, One hundred and thirteen patients with lung cancer and 99 age‐matched healthy people were enrolled for analysis of immune cell profiles, cytokines, and colony‐stimulating factors in peripheral blood. Monocyte and neutrophil counts were higher in lung cancer patients with histories of smoking, drinking, and liver metastasis. Serum levels of granulocyte colony‐stimulating factor (G‐CSF) and granulocyte‐macrophage colony‐stimulating factor were higher in lung cancer patients, and G‐CSF levels positively correlated with disease severity.

Background The aim of the study was to define the clinical significance of circulating tumor cells (CTCs)/circulating tumor endothelial cells (CTECs) and their subtypes in small cell lung cancer (SCLC) patients. Methods CTCs/CTECs and their subtypes were determined using SE‐iFISH technology in 33 SCLC patients before initial treatment (B1), after two cycles of chemotherapy (B2), at the completion of chemotherapy (B3), and disease progression (B4). The correlations with clinical characteristics, progression‐free survival (PFS), and overall survival (OS) were analyzed. Results CTCs and CTECs were detected in 96.6% and 65.5% of patients, respectively. Patients had higher levels of CTCs compared with CTECs in circulation (p, It has been proved in many studies that CTCs can be used as a prognostic biomarker in SCLC patients. Here, we report that CTC‐WBC clusters may also be a valuable predictor for SCLC prognosis. In this study, patients with CTC‐WBC clusters before chemotherapy (17.3 vs. 22.6 months, p = 0.041) and after two cycles of treatment (19.9 vs. 25.2 months, p = 0.018) tended to have a significantly shorter overall survival duration.