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Hodgkin lymphoma (HL) survivors have an increased risk of developing subsequent treatment-related primary malignancies. In the last few decades, advances in knowledge, radiotherapy, chemotherapy and autologous stem cell transplantation have led to the transformation of lethal malignancy into highly curable malignancy, thereby improving outcomes. With prolonged survival, the risk of developing subsequent treatment-related late adverse effects, such as malignancies, steadily increases over time. Herein, we present the first case of a treatment-related second primary stage IV peripheral small cell lung carcinoma in a female HL survivor who was also diagnosed with right breast cancer 13 years after HL treatment and 1 year before her lung cancer diagnosis.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with exceptionally poor prognosis, comprising approximately 15% of lung cancers. Emerging knowledge of the molecular and genomic landscape of SCLC and recent successful clinical applications of new systemic agents have allowed for precision oncology treatment approaches. Imaging is essential for the diagnosis, staging, and treatment monitoring of patients with SCLC. The role of imaging is increasing with the approval of new treatment agents, including immune checkpoint inhibitors, which lead to novel imaging manifestations of response and toxicities. The purpose of this state-of-the-art review is to provide the reader with the latest information about SCLC, focusing on the subtyping of this malignancy (molecular characterization) and the emerging systemic therapeutic approaches and their implications for imaging. The review will also discuss the future directions of SCLC imaging, radiomics and machine learning.

International audience; INTRODUCTION: Molecular profile of resected stage I-II non-small cell lung cancer (NSCLC) would help refine prognosis and personalize induction or adjuvant strategies. We sought to report the molecular profile of resected stage I-II NSCLC and analyzed the impact of epidermal growth factor receptor (EGFR) mutations on outcomes in a Western population. PATIENTS AND METHODS: Surgical cases were identified from Biomarkers France study, a nationwide prospective study including NSCLC patients screened for EGFR, HER2, KRAS, BRAF, PIK3CA, ALK alterations from 2012 to 2013. Among surgical patients, clinical charts of the largest centers were reviewed in order to analyze the prognostic impact of EGFR mutations. RESULTS: In the BMF database (n = 17.636), surgical patients (n = 854) were characterized by a higher proportion of EGFR mutations than nonsurgical patients (12.9% vs. 10.2%, P = .025), while the other molecular alterations did not differ. The proportion of EGFR mutations was 27% in women undergoing surgery. In the study group (n = 293; EGFR wild type, n = 235; usual mutation, n = 50; rare mutation, n = 8), after a median follow-up of 67 months, 215 patients (74.4%) had not relapsed. No difference was found between EGFR-mutant and EGFR-wt tumors regarding recurrence site, disease-free survival, and overall survival. The 5-year disease-free survival and overall survival after surgical resection of stage I-II EGFR-mutated tumors were 65% and 75%, respectively. CONCLUSION: In resected stage I to II NSCLC, EGFR mutations were found in 12.9% of cases, associated with a 5-year overall survival of 75%, with no impact on recurrence site, disease-free survival, and overall survival.

Small cell lung cancer (SCLC) remains a lethal disease with a dismal overall survival rate of 6% despite promising responses to upfront combination chemotherapy. The key drivers of such rapid mortality include early metastatic dissemination in the natural course of the disease and the near guaranteed emergence of chemoresistant disease. Here, we found that we could model the regression and relapse seen in clinical SCLC in vitro. We utilized time-course resolved RNA-sequencing to globally profile transcriptome changes as SCLC cells responded to a combination of cisplatin and etoposide—the standard-of-care in SCLC. Comparisons across time points demonstrated a distinct transient transcriptional state resembling embryonic diapause. Differential gene expression analysis revealed that expression of the PEA3 transcription factors ETV4 and ETV5 were transiently upregulated in the surviving fraction of cells which we determined to be necessary for efficient clonogenic expansion following chemotherapy. The FGFR-PEA3 signaling axis guided the identification of a pan-FGFR inhibitor demonstrating in vitro and in vivo efficacy in delaying progression following combination chemotherapy, observed inhibition of phosphorylation of the FGFR adaptor FRS2 and corresponding downstream MAPK and PI3K-Akt signaling pathways. Taken together, these data nominate PEA3 transcription factors as key mediators of relapse progression in SCLC and identify a clinically actionable small molecule candidate for delaying relapse of SCLC.

The present study investigated the expression and role of ROR2 in small cell lung cancer (SCLC). To examine the expression of ROR2, 27 surgically resected SCLC tissue samples were immunostained for ROR2. Sixteen tissue samples were positive and some showed intratumor heterogeneity in staining intensity. The heterogeneity of ROR2 expression was also observed in tumor tissues from a PDX model of SCLC, in which there were cells with high ROR2 expression (ROR2

Small cell lung cancer (SCLC) is a recalcitrant, relatively immune-cold, and deadly subtype of lung cancer. SCLC has been viewed as a single or homogenous disease that includes deletion or inactivation of the two major tumor suppressor genes (TP53 and RB1) as a key hallmark. However, recent sightings suggest the complexity of SCLC tumors that comprises highly dynamic multiple subtypes contributing to high intratumor heterogeneity. Furthermore, the absence of targeted therapies, the understudied tumor immune microenvironment (TIME), and subtype plasticity are also responsible for therapy resistance. Secretory chemokines play a crucial role in immunomodulation by trafficking immune cells to the tumors. Chemokines and cytokines modulate the anti-tumor immune response and wield a pro-/anti-tumorigenic effect on SCLC cells after binding to cognate receptors. In this review, we summarize and highlight recent findings that establish the role of chemokines in SCLC growth and metastasis, and sophisticated intratumor heterogeneity. We also discuss the chemokine networks that are putative targets or modulators for augmenting the anti-tumor immune responses in targeted or chemo-/immuno-therapeutic strategies, and how these combinations may be utilized to conquer SCLC.

To determine the association of SOX2 with the prognosis in lung cancer, studies providing survival information were selected based on multivariate Cox regression analysis.PubMed, Embase, and Web of Science databases were searched to identify eligible studies before June 19, 2021. The hazard ratios (HR) with 95% confidence intervals (CI) were calculated to assess the prognostic impact of SOX2 based on multivariate Cox regression analysis. Publication bias was used to assess the risk of bias. Functional analysis of SOX2 was also conducted.13 studies with a total of 2008 patients with lung cancer were included. SOX2 expression was not correlated with overall survival in lung cancer (10 studies with 1591 cases). Between-study heterogeneity was noted (ISOX2 may be an independent prognostic factor in time-to-progression and recurrence-free survival and may become a promising therapeutic target. More studies are essential to further our findings.

Severe pneumonitis (≥ grade 3 by Common Terminology Criteria for Adverse Events [CTCAE]) is a toxicity associated with concurrent chemoradiation therapy (CCRT), which is the standard first-line treatment for patients with limited-stage small cell lung cancer (LS-SCLC). We summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT. A systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines. Electronic databases were searched to identify relevant randomized controlled trials (RCTs), observational studies, and non-randomized trials between 2014 to July 16, 2020. The primary outcome was incidence of pneumonitis. Thirteen studies were included in the SLR and 1539 pooled patients from 10 studies were included in the base-case meta-analysis. The pooled incidence of ≥ grade 3 pneumonitis was 3.28% (95% confidence interval [CI]: 1.52%-5.04%) in RCTs, and 6.34% (95% CI: 3.64%-9.04%) in non-RCTs. The pooled incidence risk of grade 5 (fatal) pneumonitis was 0.29% (95% CI: 0.00%-0.62%) in RCTs and 0.88% (95% CI: 0.02%-1.74%) in non-RCT. Results from sensitivity analyses were consistent with the base-case analysis. The results from this analysis show that the incidence of ≥ grade 3 pneumonitis in patients with LS-SCLC was 3.28% to 6.34%. The incidence of pneumonitis was higher in studies conducted in non-RCTs compared to RCTs. These results can be used to understand the safety, with regard to pneumonitis, of novel therapeutic agents when administered with CCRT to treat patients with LS-SCLC. To summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT, a systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines.

Radiation therapy is a mainstay of cancer treatment but does not always lead to complete tumor regression. Here we combine radiotherapy with blockade of the ‘don’t-eat-me’ cell-surface molecule CD47 in small cell lung cancer (SCLC), a highly metastatic form of lung cancer. CD47 blockade potently enhances the local antitumor effects of radiotherapy in preclinical models of SCLC. Notably, CD47 blockade also stimulates off-target ‘abscopal’ effects inhibiting non-irradiated SCLC tumors in mice receiving radiation. These abscopal effects are independent of T cells but require macrophages that migrate into non-irradiated tumor sites in response to inflammatory signals produced by radiation and are locally activated by CD47 blockade to phagocytose cancer cells. Similar abscopal antitumor effects were observed in other cancer models treated with radiation and CD47 blockade. The systemic activation of antitumor macrophages following radiotherapy and CD47 blockade may be particularly important in patients with cancer who suffer from metastatic disease.

Extensive stage small cell lung cancer (ES-SCLC) is associated with poor prognosis. Recently, anlotinib has demonstrated significant clinical activity as a third-line or further on treatment. This study aimed to evaluate the safety and efficacy of a combination of anlotinib and platinum-etoposide as first-line treatment in patients with ES-SCLC.The present multi-center, single-arm, prospective study (NCT04684017) was conducted at three Chinese sites, and included patients with asymptomatic metastasis in the central nervous system. Patients were treated with up to six cycles of chemotherapy comprising etoposide with either carboplatin or cisplatin on day 1 of each cycle. Anlotinib was administered orally once daily on days 1-14 per cycle. The primary end points of the study were safety and investigator assessed objective response rate (ORR).A total of 101 patients were screened from August 2018 to September 2021, of which 86 who had received at least one dose of the treatment were included in the formal analysis. The median follow-up duration was 27.9 months. Complete response and partial response were observed in 2 and 73 patients, respectively, with an ORR of 87.2 % and a disease control rate of 97.7 %. Progression-free survival (PFS) and overall survival (OS) events occurred in 78 and 47 patients, respectively. The median PFS and OS were 9.0 (95 % confidence interval [CI]: 7.5-10.5) and 19 (95 % CI: 16.7-21.3) months, respectively. The incidence of grade 3 or higher adverse events (AEs) was 58.1 % and 24 patients (27.9 %) experienced serious treatment-related AEs. No fatalities consequent to AEs were recorded.Given its promising efficacy, safety profile and durability, anlotinib combined with chemotherapy deserves further investigation as first-line anticancer therapy in ES-SCLC (NCT: 04684017).

Small cell lung cancer (SCLC) is a clinically common malignant tumor originating from the lung neuroendocrine stem cells, which has a poor prognosis and accounts for approximately 15% of all lung cancer cases. However, research on its treatment has been slow, and the 5-year survival rate of patients with SCLC has been 5% for many years. In recent years, the development and popularization of gene sequencing technology have facilitated the understanding of the gene mutation landscape and tumor evolution of SCLC, thereby leading to a more accurate prediction of the prognosis of SCLC and the development of individualized treatment. In this review, we aimed to discuss the mutation evolution of SCLC from the perspective of a tumor evolution theory and described the sequence of mutation evolution in the occurrence and development of SCLC. In addition, we summarized the existing whole-exome sequencing (WES) data of SCLC cases at our center along with relevant publications on sequencing. Thereafter, we discuss the role of different mutated pathways in the occurrence of SCLC to predict its prognosis more accurately and summarized individualized treatment strategies.

Treatment for small cell lung cancer (SCLC) has not changed significantly compared to the overwhelming development of targeted therapies for non-small cell lung cancer. However, recent epigenetic and expressional analyses have revealed that SCLC can be divided into four distinct subtypes, which may lead to precision treatments. The situation appears slightly similar to the "four-color problem," a classic mathematical problem stating that no more than four colors are required to color the regions so that no two adjacent areas have the same color. This review introduces the framework for subtyping SCLC into four molecular subtypes and the promising targeted treatment for each subtype.

Small-cell lung cancer (SCLC) is an aggressive lung cancer subtype and its first-line treatment has remained unchanged for decades. In recent years, immunotherapy has emerged as a therapeutic strategy for tumor treatment, whereas, patients with SCLC exhibit poor overall responses to immunotherapy alone, which highlights the necessity for combinatorial approaches. The tumor microenvironment (TME), an integral component in cancer, is widely implicated in tumorigenesis and tumor metastasis. The interactions of various cells within TME shape the adverse conditions of the tumor microenvironment (characterized by hypoxia, nutrient restriction, and acidity) and are considered responsible for the modest therapeutic responses to immunotherapy. Several studies have suggested that adverse TME can regulate immune cell activation and function. However, the specific regulatory mechanisms and their implications on immunotherapy remain unclear. Thus, it is worth unraveling the characteristics of TME and its impact on antitumor immunity, in the hope of devising novel strategies to reinforce immunotherapeutic effects on SCLC. In this review, we firstly elaborate on the immune landscape of SCLC and the formation of three remarkable characteristics in TME, as well as the interaction among them. Next, we summarize the latest findings regarding the impacts of adverse TME on immune cells and its targeted therapy in SCLC. Finally, we discuss the ongoing trials in combination therapy and potential directions of SCLC therapy. Collectively, the findings combined here are expected to aid the design of trials for combining immunotherapy with therapy targeting the TME of SCLC.

Small cell lung cancer (SCLC), originating from lung neuroendocrine stem cells, is a common pulmonary malignant tumor. SCLC, with poor prognoses, accounts for approximately 13-15% of all lung cancer cases. Due to the slow progress of clinical treatment, the 5-year survival rate of SCLC has remained below 7% for many years. In recent years, with the development and popularity of gene sequencing technologies, we were able to better grasp patterns of gene mutations and tumor evolution in SCLC. Thus, appropriate molecular subtyping strategies have been established to help predict patients' prognoses and develop the treatment regimen for SCLC more accurately. In this narrative review, we aim to summarize the evolution of mutation-based molecular subtyping of SCLC, as well as the trends in molecular targeting and immunotherapeutic for SCLC. Based on the latest sequencing data for SCLC, thereafter, we discuss therapeutic opinions of SCLC from basic to clinic. This review may provide a basis for guiding the development of subsequent individualized precision-targeted therapy for SCLC patients to improve their clinical prognoses.

Small cell lung cancer (SCLC) is an extremely aggressive neuroendocrine tumor, accounting for approximated 13% of all lung cancer cases. SCLC is characterized by rapid growth and early metastasis. Despite marked improvements in the number and efficacy of targeted, therapeutic options and overall survival rates in SCLC have remained nearly unchanged for almost three decades. The lack of significant progress can be attributed to our poor understanding of the biology of SCLC. Although immune checkpoint inhibitors were recently approved as front-line therapies for SCLC, we still need to better understand the mechanisms responsible for the selective vulnerability of some SCLCs to these inhibitors. Recent work utilizing sequencing data and single cell analyses identified four distinct subsets of SCLC, based on the expression levels of the transcription factors ASCL1, NEUROD1, POU2F3 and YAP1. Each subset was found to have its own distinct biology and therapeutic vulnerabilities. However, these subsets appear to be phenotypically unstable, representing snapshots in the gradual evolution of a tumor that exhibits significant plasticity. Tumor evolution, a product of this plasticity, results in the emergence of significant intratumoral heterogeneity which plays an important role in multiple aspects of SCLC development and progression, including cell survival and proliferation, metastasis and angiogenesis. The recent paradigm shifting discoveries in the biology of SCLC are now beginning to inform the design of new therapeutic strategies for the management of this intractable disease.

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with a particularly poor prognosis. For decades, the best available systemic therapy was platinum plus etoposide chemotherapy, which offered frequent but transient responses. Survival gains were finally realized with the addition of immune checkpoint inhibitors to first-line chemotherapy. The phase III IMpower 133 trial showed that the addition of atezolizumab to chemotherapy improved survival. The subsequent CASPIAN trial demonstrated a similar benefit with durvalumab. These results quickly established chemo-immunotherapy as the preferred initial treatment for advanced SCLC, but outcomes remain poor for most patients. Here, we review the current and evolving role of immunotherapy in SCLC and outline emerging strategies poised to further elevate the standard of care.

Weight loss (WL) has been associated with shorter survival in patients with advanced cancer, while obesity has been associated with longer survival. Integrating body mass index (BMI) and WL provides a powerful prognostic tool but has not been well-studied in lung cancer patients, particularly in the setting of clinical trials.We analysed patient data (n = 10 128) from 63 National Cancer Institute sponsored advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) trials. Risk matrices were created using BMI and WL percentage, which were divided into 'grades' based on median survival. Relationships between survival, BMI and WL percentage were examined using Kaplan-Meier estimators and Cox proportional hazards (PH) models with restricted cubic splines.For NSCLC, a twofold difference was noted in median survival between the BMI 28 and WL ≤ 5% group (13.5 months) compared with the BMI 20 and WL 5% group (6.6 months). These associations were less pronounced in SCLC. Kaplan-Meier curves showed significant survival differences between grades for both NSCLC and SCLC (log-rank, P 0.0001). In Stage IV NSCLC, Cox PH analyses with restricted cubic splines demonstrated significant associations between BMI and survival in both WL ≤ 5% (P = 0.0004) and5% (P = 0.0129) groups, as well as in WL 5% in Stage III (P = 0.0306). In SCLC, these relationships were more complex.BMI and WL have strong associations with overall survival in patients with advanced lung cancer, with a greater impact seen in NSCLC compared with SCLC. The integration of a BMI/WL grading scale may provide additional prognostic information and should be included in the evaluation of therapeutic interventions in future clinical trials in advanced lung cancer.

BACKGROUND: Endothelial activation and insult may contribute to the aggressive clinical course of small-cell lung cancer (SCLC); however, no predictive biomarker for this pathogenesis has been identified. OBJECTIVE: To evaluate the clinical impact of the endothelial activation and stress index (EASIX) in SCLC. METHODS: In this retrospective study, the EASIX was calculated from measurements of serum lactate dehydrogenase, creatinine, and platelet levels. A total of 264 patients with SCLC treated with platinum-based chemotherapy were stratified into high and low EASIX groups. RESULTS: Complete and objective response rates in the limited-stage (LD) were 19.5% vs. 33.3% (P= 0.050) and 85.4% vs. 97.9% (P= 0.028) in the high and low EASIX groups, respectively. There was no significant difference in the response rate between the two groups in the extensive-stage (ED). The median overall survival was 9.8 vs. 40.5 months in LD (P< 0.001) and 7.2 vs. 11.9 months in ED (P< 0.001) in the high and low EASIX groups, respectively. In multivariate analyses, a high EASIX level was an independent prognostic factor for worse progression-free and overall survival irrespective of stage. CONCLUSION: EASIX may be a potential predictive biomarker of SCLC.

The application of immune checkpoint inhibitors (ICIs) represents a breakthrough in the current landscape for the treatment of extensive-stage small-cell lung cancer (ES-SCLC), but the real-world outcome is limited. This study aimed to investigate the treatment options and efficacy evaluation of first-line, second-line, and subsequent-line immunotherapy in routine practice.A retrospective analysis of ES-SCLC patients treated with ICIs was conducted between May 2016 and September 2021. Objective response rate, disease control rate, progression-free survival (PFS) and overall survival were assessed between groups to explore the value of ICIs at different treatment time periods. PFS1 and PFS2 were defined as the duration from initial therapy to disease progression or death in first-line or second-line treatment.Ninety-six patients with ES-SCLC were included. PFS1 was prolonged in patients treated with first-line ICIs-combined therapy (median PFS1 7.20 months vs. 5.30 months, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.36-087, p = 0.0085). For patients who progressed after first-line ICIs treatment (N = 22), PFS1 + PFS2 was longer in the second-line ICIs continuation group with no significant difference (median PFS1 + PFS2 11.27 months vs. 7.20 months, HR 0.45, 95% CI 0.14-1.51, p = 0.19). For patients who experienced a progression event after first-line chemotherapy (N = 50), PFS2 and PFS1 + PFS2 were prolonged in patients who accepted second-line ICIs-combined therapy without significant difference (median PFS2 4.00 months vs. 2.43 months, HR 0.59, 95% CI 0.33-1.05, p = 0.070; median PFS1 + PFS2 11.30 months vs. 8.70 months, HR 0.53, 95% CI 0.29-0.98, p = 0.056).First-line ICIs plus chemotherapy should be applied in the clinical practice of ES-SCLC. If patients did not receive ICIs plus chemotherapy in first-line treatment, therapies that include ICIs in second-line treatment should be considered.

Immunotherapy plus etoposide and platinum (EP)-based chemotherapy is the standard of care for patients with extensive stage-small cell lung carcinoma (ES-SCLC). In the era of immunotherapy, the role of thoracic radiotherapy for ES-SCLC remains unclear.We retrospectively included ES-SCLC patients treated with first-line EP-based chemotherapy plus atezolizumab or durvalumab at Taichung Veterans General Hospital to evaluate the prognostic role and safety of thoracic radiotherapy.A total of 22 patients were included. The median age was 64 years and most of them were male and smokers. Sixteen patients (72.7%) received durvalumab, while the other 6 patients (27.3%) underwent atezolizumab treatment. Among these patients, 11 (50.0%) had a history of thoracic radiotherapy. There was no significant difference in baseline characteristics between patients with and without thoracic radiotherapy. In the overall population, the objective response rate to immunotherapy plus chemotherapy was 73.7%. The progression-free survival and overall survival were 6.0 months (95% CI: 4.0-7.9) and 13.8 months (95% CI: 8.0-19.6), respectively. The overall survival was significantly longer in patients with thoracic radiotherapy (not-reached [NR] [95% CI NR-NR] vs. 9.6 months [95% CI 2.5-16.6]), respectively ( P value by log-rank test0.001). Both multivariate analysis and subgroup analysis specifically comparing patients with consolidative thoracic radiotherapy and patients with clinical benefits to systemic therapy who did not undergo thoracic radiotherapy indicated that thoracic radiotherapy improved survival.The real-world efficacy of EP-based chemotherapy plus atezolizumab or durvalumab was comparable with that of clinical trials. Thoracic radiotherapy may improve the outcome of ES-SCLC.

Activating mutations in the epidermal growth factor receptor (EGFR) are predominantly detected in pulmonary adenocarcinoma and have been reported in small cell lung cancer (SCLC) for decades. This retrospective single-center study aimed to determine the frequency and types of EGFR mutations in SCLC in Taiwan.This study comprises a consecutive cohort of 161 patients histologically diagnosed with SCLC between January 1992 and August 2014 at the Department of Pathology in Keelung Chang Gung Memorial Hospital, Taiwan. Archived formalin-fixed paraffin-embedded sections from 71 patients were eligible for molecular analysis. EGFR mutation analysis was performed using a fully-automated IdyllaTM EGFR Mutation Test and confirmed a comparable result through Qiagen Therascreen® EGFR RGQ PCR. In addition, EGFR gene copy number was assessed in EGFR-mutated tumors by fluorescence in situ hybridization (FISH).Mutational status of the EGFR gene was successfully analyzed in 63 specimens by both IdyllaTM and Qiagen platforms. Both methods detected L858R point mutation in exon 21 in an 81-year-old female and a 47-year-old male non-smoker. Both tumors show no concurrent EGFR gene amplification. The overall agreement between results obtained with the Idylla™ EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR was 100% Conclusions. Our results showed that EGFR mutation is a rare mutation type in a consecutive series of de novo SCLC. Furthermore, the performance of Idylla™ EGFR Mutation Test and Qiagen Therascreen® EGFR RGQ PCR on archived paraffin sections of limited quantities is available with the high agreement of results.

WNT signaling represents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers. Here, we characterize WNT pathway activity in small cell lung cancer (SCLC) and determine the functional role of WNT signaling using genetically engineered mouse models. β-Catenin, a master mediator of canonical WNT signaling, was dispensable for SCLC development, and its transcriptional program was largely silenced during tumor development. Conversely, WNT5A, a ligand for β-catenin–independent noncanonical WNT pathways, promoted neoplastic transformation and SCLC cell proliferation, whereas WNT5A deficiency inhibited SCLC development. Loss of p130 in SCLC cells induced expression of WNT5A, which selectively increased Rhoa transcription and activated RHOA protein to drive SCLC. Rhoa knockout suppressed SCLC development in vivo, and chemical perturbation of RHOA selectively inhibited SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A–RHOA axis in SCLC, providing critical insights for the development of novel therapeutic strategies for this recalcitrant cancer. This study also sheds light on the heterogeneity of WNT signaling in cancer and the molecular determinants of its cell-type specificity. Significance: The p130–WNT5A–RHOA pathway drives SCLC progression and is a potential target for the development of therapeutic interventions and biomarkers to improve patient treatment.

The effect of first-line chemotherapy on overall survival (OS) may be significantly influenced by subsequent therapy for patients with extensive disease small cell lung cancer (ED-SCLC). Therefore, we evaluated the relationship between progression-free survival (PFS), post-progression survival (PPS), and OS of ED-SCLC patients treated with atezolizumab plus carboplatin and etoposide as first-line therapy.We analyzed the data of 57 patients with relapsed ED-SCLC treated with atezolizumab plus carboplatin and etoposide (AteCE) as first-line chemotherapy between August 2019 and September 2020. The respective correlations between PFS-OS and PPS-OS following first-line AteCE treatment were examined at the individual patient level.Spearman's rank correlation analysis and linear regression analysis showed that PPS strongly correlated with OS (r = 0.93, p lt; 0.05, Rsup2/sup = 0.85) and that PFS moderately correlated with OS (r = 0.55, p lt; 0.05, Rsup2/sup = 0.28). Performance status at relapse (0-1/≥2), number of cycles of atezolizumab maintenance therapy (lt;3/≥3), and platinum rechallenge chemotherapy all significantly positively correlated with PPS (p lt; 0.05).Upon comparing OS-PFS and OS-PPS in this patient population, OS and PPS were found to have a stronger correlation. These results suggest that performance status at relapse, atezolizumab maintenance, or chemotherapy rechallenge could affect PPS.

Small cell lung cancer (SCLC) is an aggressive tumor, and despite its sensitivity to chemotherapy and radiotherapy, patients usually have a short survival. There are no clinically relevant predictive factors of responses to therapies, and therapeutic options are still limited.Clinical data and somatic mutations of genes included in the MSK-IMPACT panel were retrieved from cBioPortal for 108 SCLCs and analyzed to identify mutated gene networks. Results were validated in an independent cohort of 54 SCLCs, whose information was also available from cBioPortal.Different networks were observed in tumors of short and long survivors. Degree (K) and betweenness (B) are key features that characterize a gene in its network of related mutations. By comparing their B/K ratio, 2 signatures of mutated genes were identified, describing short (IL-7R, NTRK2, HNF-1A) and long survivors (NBN, PTPN-11, IRS-1, INPP-4A, PIK-3CG, HGF, LATS-2, SMARCA-4, FLT-3, EIF-4A2, SPEN, PAX-5, SH2-D1A, ARID-1A, HOXB-13, ERCC-4, FANCA, FH, FGFR-2, MST-1R, SMAD-4, DDR-2, IGF-1R, PIK-3CB). Patients with at least 1 mutated gene of the short signature had a worse median overall survival of 8 versus 28 months (P.001). Patients with at least 1 mutated gene of the long signature had a better median overall survival of 39 versus 20 months (P = .004). The value of the short signature was further confirmed in an independent cohort of SCLCs.The networks of mutated genes could help subclassify SCLCs based on their somatic mutations and aid in identifying a subset of tumors with poor prognosis.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with dismal prognosis. Recently, molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1, and POU2F3 transcription regulators. ASCL1 is essential for neuroendocrine differentiation and is expressed in the majority of SCLC. Although previous studies investigated ASCL1 target genes in SCLC cells, ASCL1-mediated regulation of miRNAs and its relationship to molecular subtypes remain poorly explored. Here, we performed genome-wide profiling of chromatin modifications (H3K27me3, H3K4me3, and H3K27ac) by CUTTag assay and ASCL1 knockdown followed by RNA sequencing and miRNA array analyses in SCLC cells. ASCL1 could preferentially regulate genes associated with super-enhancers (SEs) defined by enrichment of H3K27ac marking. Moreover, ASCL1 positively regulated several SE-associated miRNAs, such as miR-7, miR-375, miR-200b-3p, and miR-429, leading to repression of their targets, whereas ASCL1 suppressed miR-455-3p, an abundant miRNA in other molecular subtypes. We further elucidated unique patterns of SE-associated miRNAs in different SCLC molecular subtypes, highlighting subtype-specific miRNA networks with functional relevance. Notably, we found apparent de-repression of common target genes of different miRNAs following ASCL1 knockdown, suggesting combinatorial action of multiple miRNAs underlying molecular heterogeneity of SCLC (e.g., co-targeting of YAP1 by miR-9 and miR-375). Our comprehensive analyses provide novel insights into SCLC pathogenesis and a clue to understanding subtype-dependent phenotypic differences.

Purpose: Cisplatin-etoposide treatment is recommended as a first line in small cell lung cancer patients (SCLC). However, the prognosis is poor and the dosing is not tailored beyond the body surface area, which is related with indeterminate cisplatin exposure-response relationship. We aimed to evaluate cisplatin pharmacokinetics (PK) and the exposure to unbound cisplatin in SCLC patients using the informative priors, and assess the relationship between the cisplatin exposure and probability of neutropenia. Methods: Observational clinical study was performed including 17 cisplatin-treated SCLC patients. External population cisplatin PK models were identified and NONMEM® software and $PRIOR subroutine were used for the model evaluation. The bias and precision of the model-predicted cisplatin concentrations were evaluated. The best models were combined in a final model including several sets of informative priors, which was used to estimate individual cisplatin exposure, analyze the relationship between the exposure and neutropenia and simulate several cisplatin dosing regimens in a virtual patient cohort. Results: The models by Urien with the informative priors best fitted the data. The individual cisplatin exposure ranged between 2430 and 4560 μg*h/L. There was a trend of increasing probability of neutropenia and febrile neutropenia with increasing cisplatin exposure. Approximately 50%, 75% and 90% of patients receiving 60 mg/m2, 70 mg/m2 and 80 mg/m2, respectively, achieved the previously identified exposure threshold of 2860 μg*h/L. Conclusion: We developed a tool to individualize cisplatin dosing based on the estimated probability of neutropenia. The benefit of more intense dosing regimens in SCLC patients should be further assessed. Bibliografija: str. 311-313. Abstract. ARRS ARRS

Introduction Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis. Methods This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs. Discussion DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN. Conclusions Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.

Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients’ circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.

Purpose Resection is guideline recommended in stage I small-cell lung cancer (SCLC) but not in stage II. In this stage, patients are treated with a non-surgical approach. The aim of this meta-analysis was to assess the role of surgery in both SCLC stages. Surgically treated patients were compared to non-surgical controls. Five-year survival rates were analysed. Methods A systematic literature search was performed on December 01, 2021 in Medline, Embase and Cochrane Library. Studies published since 2004 on the effect of surgery in SCLC were considered and assessed using ROBINS-I. We preformed I2-tests, Q-statistics, DerSimonian-Laird tests and Egger-regression. The meta-analysis was conducted according to PRISMA. Results Out of 6826 records, we identified seven original studies with a total of 15,170 patients that met our inclusion criteria. We found heterogeneity between these studies and ruled out any publication bias. Patient characteristics did not significantly differ between the two groups (p-value > 0.05). The 5-year survival rates in stage I were 47.4 ± 11.6% for the ‘surgery group’ and 21.7 ± 11.3% for the ‘non-surgery group’ (p-value = 0.0006). Our analysis of stage II SCLC revealed a significant survival benefit after surgery (40.2 ± 21.6% versus 21.2 ± 17.3%; p-value = 0.0474). Conclusion Based on our data, the role of surgery in stage I and II SCLC is robust, since it improves the long-term survival in both stages significantly. Hence, feasibility of surgery as a priority treatment should always be evaluated not only in stage I SCLC but also in stage II, for which guideline recommendations might have to be reassessed.

Plasma glucose levels might be associated with the severity of tumor hypoxia in patients with cancer. In our previous study, we found that chronic hyperglycemia significantly increased the risk of locoregional recurrence in patients with non-small cell lung cancer treated with radical radiotherapy (RT). Here, we evaluated the association between plasma glucose levels in terms of hemoglobin A1c (HbA1c) and locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT.We retrospectively analyzed the clinical data of 59 patients with small cell lung cancer. HbA1c levels were measured 1 week before the start of RT. Survival outcomes were analyzed according to HbA1c levels. Multivariable analysis was conducted to identify whether HbA1c level was a significant prognostic factor for survival.The 1-, 2-, and 3-year locoregional recurrence-free survival rates were 90.9, 86.1, and 78.9%, respectively, in the low HbA1c group, and 45.1, 27.1, and 20.3%, respectively, in the high HbA1c group (p 0.001). The 1-, 2-, and 3-year distant metastasis-free survival rates were 67.2, 57, and 57%, respectively, in the low HbA1c group, while it was 56.6, 24.9, and 24.9%, respectively, in the high HbA1c group (p = 0.024). HbA1c level remained a significant prognostic factor for locoregional recurrence-free survival in the multivariable analysis (p = 0.010).Chronic hyperglycemia is a significant prognostic factor for locoregional recurrence-free survival in patients with limited-stage small cell lung cancer treated with radical RT. Routine monitoring of plasma glucose levels and aggressive glycemic control should be conducted to prevent locoregional recurrence.

Purpose: The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically “cold” tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with (i) decreased neuroendocrine characteristics and (ii) activation of NOTCH signaling. We previously showed that inhibition of the lysine-specific demethylase 1a (LSD1) demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD-1 inhibition in SCLC. Experimental Design: We employed a syngeneic immunocompetent model of SCLC, derived from a genetically engineered mouse model harboring Rb1/Trp53 inactivation, to investigate combining the LSD1 inhibitor bomedemstat with anti-PD-1 therapy. In vivo experiments were complemented by cell-based studies in murine and human models. Results: Bomedemstat potentiated responses to PD-1 inhibition in a syngeneic model of SCLC, resulting in increased CD8+ T-cell infiltration and strong tumor growth inhibition. Bomedemstat increased MHC class I expression in mouse SCLC tumor cells in vivo and augmented MHC-I induction by IFNγ and increased killing by tumor-specific T cells in cell culture. Conclusions: LSD1 inhibition increased MHC-I expression and enhanced responses to PD-1 inhibition in vivo, supporting a new clinical trial to combine bomedemstat with standard-of-care PD-1 axis inhibition in SCLC.

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.

T-cell engager; Eeuroendocrine carcinoma; Small-cell lung cancer Acoplador de cèl·lula T; Carcinoma neuroendocrí; Càncer de pulmó de cèl·lules petites Acoplador de célula T; Carcinoma neuroendocrino; Cáncer de pulmón de células pequeñas Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy. This study was funded by Boehringer Ingelheim. M Wermke received honoraria from Novartis, Pfizer, Roche, Lilly; reports consulting or advisory role for Bristol-Myers Squibb, Novartis, Pfizer, Cellex GmbH, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, GEMoaB, Roche, MSD, AstraZeneca, Amgen, Immatics; received research funding from Roche; travel, accommodations, expenses from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche Amgen, GEMoaB. E Felip received personal fees for advisory boards from AbbVie, Guardant Health, Janssen, Medscape, Merck KGaA, GlaxoSmithKline, Bayer; advisory board and speakers' bureau fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; speakers' bureau fees from Prime Oncology, Touchime; research funding from Grant for Oncology Innovation (GOI), Fundacion Merck Salud; Grífols: independent member of the board. Y Kuboki received honoraria from Taiho, ONO, Bayer, Sanofi; consulting fees from Takeda, Boehringer Ingelheim, Taiho; grants or funds from Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GSK, Genmab, Astellas, Daiichi-Sankyo. D Morgensztern received consulting fees from AbbVie, Gilead, PharmaMar, Lilly, Bristol-Myers Squibb, G1 Therapeutics, Mirati, Boehringer Ingelheim. ZO' Hamed, M Liu and M Studeny report employment with Boehringer Ingelheim. TK Owonikoko received consulting fees from Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, XCovery, Bayer, Heron Pharmaceutical, ARMO BioSciences, Merck, Bayer, Jazz Pharmaceuticals; and research funding from Novartis, Astellas Pharma, Bayer, StemCentRx, Regeneron, AstraZeneca/MedImmune, AbbVie, G1 Therapeutics, Bristol-Myers, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Mersana, Turning Point, and Oncorus. V Gambardella reports no conflicts of interest. All authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and did not receive payment related to the development of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The newly released eighth edition of the American Joint Committee on Cancer TNM staging system for lung cancer seeks to improve prognostic accuracy but lacks external validation for small cell lung cancer (SCLC). Moreover, previous studies posed a few questions concerning survival differences for patients with specific site N3 node involvement or single-site metastasis (SSM) in different distant organs. The aim of this study was to validate the eighth edition of the TNM classification for SCLC in an independent multi-institutional cohort from China and answer the questions raised by the previous research.Patients with SCLC from four Chinese cancer centers between 2009 and 2019 were reclassified according to the seventh and eighth edition of the TNM classification. Survival was estimated using the Kaplan-Meier method. Comparisons between adjacent categories and stage groups were performed using Cox proportional hazard regression. R2 statistics were calculated to evaluate the discriminating performance of editions.Of 3384 enrolled cases, 3358 had clinical stage, 537 had pathological stage, and 511 had both. Progressive deterioration of survival was observed with advancing of TNM categories and stages both in the seventh and the eighth edition. The eighth edition stages had a higher R2 statistic than the seventh edition (0.207 versus 0.197). Newly defined categories M1b and M1c and stages IIIC, IVA and IVB in the eighth edition discriminated groups with significantly different prognosis. Patients with N3 contralateral supraclavicular nodes had a significantly worse prognosis than those without (p = 0.032). For patients with single-site metastasis, liver involvement showed a worse prognosis compared to brain involvement (p = 0.030).Our study provided an external validation of the eighth edition of the TNM classification for lung cancer in Chinese patients with SCLC, and confirmed its improved prognostic accuracy compared with the seventh edition. Patients with N3 and M1b might represent heterogeneous populations that warrant further research.

Lobar resection has been the established standard of care for peripheral early-stage non—small cell lung cancer (NSCLC). Over the last few years, surgical lung sparing approach (sublobar resection [SLR]) has been compared with lobar resection in T1N0 NSCLC. Three nonsurgical options are available in those patients who have a prohibitive surgical risk, and those who refuse surgery: stereotactic body radiotherapy (SBRT), percutaneous ablation, and bronchoscopic ablation. Local ablation involves placement of a probe into a tumor, and subsequent application of either heat or cold energy, pulsing electrical fields, or placement of radioactive source under an image guidance to create a zone of cell death that encompasses the targeted lesion and an ablation margin. Despite being in their infancy, the bronchoscopic ablative techniques are undergoing rapid research, as they extrapolate a significant knowledge-base from the percutaneous techniques that have been in the radiologist's armamentarium since 2000. Here, we discuss selected endoscopic and percutaneous thermal and non-thermal therapies with the focus on their efficacy and safety.

Assess Once daily (OD) chemoradiation effectiveness for LS-SCLC compared with twice daily (BID) chemoradiation.Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, eligible randomized clinical trials (RCT) comparing OD and BID were identified on electronic databases. A meta-analysis was performed to compare overall survival (OS), progression-free survival (PFS), and toxicity. A metaregression analysis was conducted to explore the influence of fractionation, biological effective dose (BED), the proportion of patients treated with prophylactic cranial irradiation (PCI), elective nodal irradiation (ENI), and the start of radiotherapy (week 1 or week 4).Five RCTs with a total of 1941 patients (OD vs. BID) were included. The relative risk (RR) for OS and PFS was 0.97 (CI95% 0.8-1.1, p = 0.731) and 0.90 (CI95% 0.7-1.1, p = 0.20) at 3-years. In the metaregression analysis, hypofractionated radiotherapy schedules were associated with an improvement in overall survival (p = 0.03). The start of radiotherapy (W1 or W4), BED, and ENI had no significant effect on OS and PFS. The complete response rate partial response and overall response rate for BID vs OD were 40% vs. 33% (p = 0.97), 50% vs. 57% (p = 0.94), and 89% vs. 93% (p = 0.99). The rate of completed planned RT 96% vs. 94% (p = 0.66), and the % of ≥4 chemotherapy cycles received 74% vs. 74% (p = 0.99), did not differ between OD and BID. The local and distant failure rates were not significantly different between OD and BID 40% vs. 33% (p = 0.88) and 36% vs. 36% (p = 0.99). No difference in grade 2 or grade 3 pneumonitis and esophagitis was observed among the groups (p = NS).For LS-SCLC, OD conventional chemoradiation results in similar outcomes to BID chemoradiation. In contrast, hypofractionated radiotherapy was associated with a better OS and PFS than BID. Additional randomized phase III trials exploring hypofractionation with systemic therapy are warranted to validate our findings.

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.

It has long been thought that small-cell lung cancer (SCLC) is a central type of tumor that is located in the proximal bronchi and the mediastinum. However, several studies reported that SCLC exhibited several types of spread pattern on computed tomography (CT). The aim of this study is to investigate the relationship between CT images and clinical characteristics in patients with SCLC.We retrospectively reviewed the CT images of 92 SCLC patients and classified them into six types of spreading patterns: central, peripheral, lymphangitic spread (LYM), pleural dissemination (PLE), lobar replacement (LOB), and air-space consolidation (AC). We also evaluated the correlation between primary tumor location and the clinical characteristics of patients.The most common type of imaging pattern was peripheral (n = 40, 44%), with the next most common type being central (n = 27, 29%). Atypical types of SCLC, such as LYM (n = 2, 2%), PLE (n = 4, 4%), LOB (n = 8, 9%), and AC (n = 11, 12%), were also recognized in our study. The prevalence of emphysema and interstitial lung disease (ILD) was significantly higher in the peripheral type than in the central type (p = 0.0056 and p = 0.0403, respectively). Meanwhile, no survival difference was seen between the central type and the peripheral type (median months 17.9 vs. 21.9, respectively, p = 0.720).The peripheral type of tumor was correlated with higher prevalence of emphysema and ILD in SCLC. Our result suggests different mechanisms of development and tumor characteristics according to tumor location.

Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti-SCLC mechanisms of pazopanib remain unclear.Cell viability was evaluated by CCK-8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic-related molecules and ER-stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH-HA staining followed by flow cytometry. An NCI-H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI-H446 cell-bearing NOD-SCID mice.Pazopanib dose- and time-dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved-caspase3 and Bax, and decreased Bcl-2. Moreover, the PERK-related ER-stress pathway was potently activated by pazopanib treatment, inhibiting ER-stress by salubrinal significantly reversing pazopanib-mediated apoptosis in SCLC cell lines. Furthermore, pazopanib-induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib-induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI-H446 xenograft growth and decreased Ki67 positive cells in the tumor.Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER-stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated.

Background: Small cell lung cancer (SCLC) is characterized with high risk of brain metastasis and poor survival. This study aimed to assess the prognostic role of LDH in limited stage small-cell lung cancer (LS-SCLC) treated with thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI).Methods: This study retrospectively evaluated 197 consecutive patients who underwent TRT and PCI for LS-SCLC between November 2005 and October 2017. Both pretreatment and maximal serum LDH levels (mLDH) during treatment were checked, increased LDH level was defined as more than 240 IU/ml .Clinical factors were tested for associations with intracranial progression-free survival (IPFS) and overall survival (OS) after PCI. The Kaplan–Meier method was used to calculate survival rates, and multivariate Cox regression analyses were carried out to identify variables associated with survival.Results: Of the total patients, 95 had higher pretreatment LDH levels, and serum LDH levels were increased in 95 patients during treatment. In patients with the normal and elevated mLDH groups, the 1-, 2- and 5-year IPFS rate were 96.7% vs. 90.1%,91.7% vs. 73.8% and 87.8% vs. 61.0% (P < 0.01),respectively. Compared to those with normal LDH level, patients with increased mLDH level had higher cumulative risk of intracranial metastasis [hazard ratio (HR),3.87; 95% confidence interval (CI), 1.73-8.63; P< 0.01], and worse overall survival [HR,2.59; 95% CI, 1.67-4.04; P < 0.01]. The factors of LDH level at baseline or changes between pretreatment level and maximum level during treatment failed to predict BMs or OS with statistical significance.In the multivariate analyses, both mLDH during treatment [HR,3.53; 95% CI, 1.57-7.92; P = 0.002] and age≥60 [HR, 2.46; 95% CI,1.22-4.94; P =0.012] were independently associated with worse IPFS. Factors significantly associated with worse OS included mLDH during treatment [HR, 2.45; 95% CI, 1.56-3.86; P< 0.001], IIIB stage [HR, 1.75; 95% CI,1.06-2.88; P =0.029] and conventional radiotherapy applied in TRT [HR, 1.66; 95% CI,1.04-2.65; P =0.034]. Conclusion: mLDH level during treatment, but not pretreatment level predicts brain metastasis and survival in LS-SCLC patients treated with TRT and PCI, which may provide valuable information for identifying patients with poor survival outcomes.

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.

High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.

Small cell lung cancers (SCLC) are highly aggressive, and currently there are no available targeted therapies. To identify clinically actionable drug combinations, we analyzed our previously reported chemogenomics screens and identified a synergistically cytotoxic combination of the topoisomerase I (TOP1) inhibitor topotecan and cycle-dependent kinase 7 (CDK7) inhibitor THZ1. Topotecan causes cell death by generating TOP1-induced DNA breaks and DNA-protein cross-links (TOP1-DPC) that require proteolysis by the ubiquitin-proteasome pathway for their repair. We find that inhibition of the transcriptional kinase CDK7 by THZ1 induces ubiquitin-mediated proteasomal degradation of RNA polymerase II and prevents the proteasomal degradation of TOP1-DPCs. We provide a mechanistic basis for combinatorial targeting of transcription using selective inhibitors of CDK7 and TOP1 in clinical trials to advance SCLC therapeutics.

Lung cancer is a leading cause of cancer-related mortality worldwide. Imaging is integral in accurate clinical staging to stratify patients into groups to predict survival and determine treatment. The eighth edition of the tumor, node, and metastasis (TNM-8) staging system proposed by the International Association for the Study of Lung Cancer in 2016, accepted by both the Union for International Cancer Control and the American Joint Committee on Cancer, is the current standard method of staging lung cancer. This single TNM staging is used for all histologic subtypes of lung cancer, including nonsmall cell lung cancer, small cell lung cancer, and bronchopulmonary carcinoid tumor, and it addresses both clinical and pathologic staging. Familiarity with the strengths and limitations of imaging modalities used in staging, the nuances of TNM-8, its correct nomenclature, and potential pitfalls are important to optimize patient care. In this article, we discuss the role of computed tomography (CT) and positron emission tomography/CT in lung cancer staging, as well as current imaging recommendations pertaining to TNM-8.

Background. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays a key role in tumorigenesis and tumor progression. Lung cancer is the leading cause of cancer-related death in men and women all over the world. However, the relationship between IGF2BP3 and small-cell lung cancer (SCLC) has not been reported yet. Methods. SCLC and normal samples (GSE19945 and GSE149507) were obtained in the Gene Expression Omnibus (GEO) dataset. Differential genes were screened by R software, and functional analysis and signal pathway enrichment analysis were carried out. In addition, we used the survival analysis database to analyze the relationship between prognosis and gene expression. Besides, immunohistochemistry (IHC) and quantitative real-time PCR (qPCR) were used for further research. Results. Five differentially expressed miRNAs and 9 differentially expressed mRNAs were selected by using R software. Survival analysis database results show that C7, CLIC5, PRDX1, IGF2BP3, and LDB2 were related the overall survival of patients with SCLC. Furthermore, multivariate analysis included that IGF2BP3 was independent risk factors for SCLC patients. Besides, gene function and signal pathway enrichment analysis showed that differentially expressed miRNAs were involved in the process of tumorigenesis and development. Furthermore, IHC and qPCR outcomes showed that the expression level of hsa-miR-182, hsa-miR-183, and IGF2BP3 was differentially expressed in normal lung tissues (NLTs) and SCLC tissues (SCLCTs). Conclusions. Our results concluded that hsa-miR-182, hsa-miR-183, and IGF2BP3 may take part in the development of SCLC.

Purpose: RB1 mutations and loss of retinoblastoma (Rb) expression represent consistent but not entirely invariable hallmarks of small cell lung cancer (SCLC). The prevalence and characteristics of SCLC retaining wild-type Rb are not well-established. Furthermore, the performance of targeted next-generation sequencing (NGS) versus immunohistochemistry for Rb assessment is not well-defined. Experimental Design: A total of 208 clinical SCLC samples were analyzed by comprehensive targeted NGS, covering all exons of RB1, and Rb IHC. On the basis of established coordination of Rb/p16/cyclinD1 expression, p16-high/cyclinD1-low profile was used as a marker of constitutive Rb deficiency. Results: Fourteen of 208 (6%) SCLC expressed wild-type Rb, accompanied by a unique p16-low/cyclinD1-high profile supporting Rb proficiency. Rb-proficient SCLC was associated with neuroendocrine-low phenotype, combined SCLC with non-SCLC (NSCLC) histology and aggressive behavior. These tumors exclusively harbored CCND1 amplification (29%), and were markedly enriched in CDKN2A mutations (50%) and NSCLC-type alterations (KEAP1, STK11, FGFR1). The remaining 194 of 208 SCLC were Rb-deficient (p16-high/cyclinD1-low), including 184 cases with Rb loss (of which 29% lacked detectable RB1 alterations by clinical NGS pipeline), and 10 cases with mutated but expressed Rb. Conclusions: This is the largest study to date to concurrently analyze Rb by NGS and IHC in SCLC, identifying a 6% rate of Rb proficiency. Pathologic-genomic data implicate NSCLC-related progenitors as a putative source of Rb-proficient SCLC. Consistent upstream Rb inactivation via CDKN2A/p16↓ and CCND1/cyclinD1↑ suggests the potential utility of CDK4/6 inhibitors in this aggressive SCLC subset. The study also clarifies technical aspects of Rb status determination in clinical practice, highlighting the limitations of exon-only sequencing for RB1 interrogation. See related commentary by Mahadevan and Sholl, p. 4603

Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high relapse rates and poor prognosis. Anlotinib monotherapy has shown promising efficacy for patients with ES-SCLC and has a non-overlapping toxicity profile with chemotherapy. Therefore, the study aims to assess the efficacy and safety of the addition of anlotinib to platinum-chemotherapy as first-line therapy for patients with ES-SCLC. ES-SCLC patients without systemic chemotherapy and immunotherapy were recruited. Eligible patients received anlotinib (12 mg/day, on day 1-14) of a 21-day cycle, with concomitant etoposide (100 mg/msup2/sup, on day 1-3) plus cisplatin (75 mg/msup2/sup, on day 1) or carboplatin (AUC = 4-5, on day 1) for 4-6 cycles, followed by indefinite anlotinib maintenance therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Between Jan 15, 2019 and Dec 31, 2020, 25 patients were enrolled. At the data cut-off time (November 3, 2021), the median follow-up was 14.3 months. Median PFS was 10.3 months (95% CI: 6.0-14.5) and median OS was 17.1 months (95% CI: 11.1-19.3). The ORR and DCR were 90% and 100%, respectively. The most common grade 3 or worse treatment-related adverse events were neutropenia (50%), leukopenia (35%), thrombocytopenia (25%), fatigue (10%), nausea (10%), hyponatremia (10%), anemia (10%). One patient discontinued treatment due to treatment-related adverse events. No treatment-related death occurred. Anlotinib plus platinum-chemotherapy as first-line therapy for ES-SCLC has anti-tumor activity, and showed acceptable tolerability. These results provide a basis for future randomized controlled trials.