Overall Survival In Small Cell Lung Cancer Patients Research Articles

Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of small cell lung cancer (SCLC), but only a minority of patients benefit from this therapy. Therefore, it is critical to identify potential risk factors that could predict the efficacy of ICI treatment in SCLC patients and identify patient subgroups who may benefit the most from ICI therapy. Our study included a total of 183 SCLC patients who had received at least one dose of ICI treatment. We utilized both logistic regression and Cox proportional hazard regression to evaluate whether various patient clinical factors and serum biomarkers could serve as predictors of patient response to treatment and overall survival (OS) during ICI therapy. Logistic regression showed that patients with a history of surgery (p=0.003, OR 9.06, 95% CI: (2.17, 37.9)) and no metastasis (p=0.008, OR 7.82, 95% CI: (1.73, 35.4)) exhibited a higher odds of response to ICI treatment. Cox regression analyses demonstrated that pretreatment blood albumin (p=0.003, HR 1.72, 95% CI: (1.21, 2.45)) and derived neutrophil to lymphocyte ratio (dNLR) (p=0.003, HR 1.71, 95% CI: (1.20-2.44)) were independent predictors for OS in SCLC patients. By establishing a pre-treatment prognostic scoring system based on baseline albumin and dNLR, we found that patients with high albumin and low dNLR exhibited a significantly better prognosis than those with low albumin and high dNLR in both the full (P<.0001, HR 0.33, 95% CI: 0.20-0.55) and the metastatic cohort (P<.0001, HR 0.28, 95% CI: 0.15-0.51). The better prognostic group also had younger age, higher BMI and lower systemic inflammatory biomarker values than the unfavorable group (P<.0001). Our data reveals the significant role of metastasis status and treatment history in predicting the initial response of SCLC patients to ICI treatment. However, baseline serum albumin and dNLR provide a more precise prognostic prediction for patient OS. The scoring system based on albumin and dNLR enhances the ability to stratify patient prognosis and holds the potential to guide clinical decision-making for SCLC patients undergoing ICI therapy.

Correlation of Systemic Inflammation Parameters and Serum SLFN11 in Small Cell Lung Cancer-A Prospective Pilot Study.

The objective of this research was to analyze the correlation of the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), soluble programmed cell death ligand 1 (sPD-L1), and Schlafen 11 (SLFN11) with the response to first-line chemotherapy in a cohort of small cell lung cancer (SCLC) patients, and to determine their potential as predictive serum biomarkers. A total of 60 SCLC patients were included. Blood samples were taken to determine CRP, sPD-L1, and SLFN11 levels. The first sampling was performed before the start of chemotherapy, the second after two cycles, and the third after four cycles of chemotherapy. The patients who died earlier during the study had NLR and SLFN11 concentrations significantly higher compared to the survivor group. In the group of survivors, after two cycles of chemotherapy, the NLR ratio decreased significantly (p < 0.01), but after four cycles, the NLR ratio increased (p < 0.05). Their serum SLFN11 concentration increased significantly (p < 0.001) after two cycles of chemotherapy, but after four cycles, the level of SLFN11 fell significantly (p < 0.01). CRP, NLR, and SLFN11 were significant predictors of patient survival according to Kaplan-Meier analysis. The combination of inflammatory parameters and SLFN11 with a cutoff value above the 75th percentile of the predicted probability was associated with significantly lower overall survival in SCLC patients (average survival of 3.6 months vs. 4.8 months). The combination of inflammatory markers and the levels of two specific proteins (sPD-L1, SLFN11) could potentially serve as a non-invasive biomarker for predicting responses to DNA-damaging therapeutic agents in SCLC.

Abstract 7621: Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung cancer

Abstract Background: Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of small cell lung cancer (SCLC), but only a minority of patients benefit from this therapy. Therefore, it is critical to identify potential risk factors that could predict the efficacy of ICI treatment in SCLC patients and identify patient subgroups who may benefit the most from ICI therapy. Methods: Our study included a total of 183 SCLC patients who had received at least one dose of ICI treatment. We utilized both logistic regression and Cox proportional hazard regression to evaluate whether various patient clinical factors and serum biomarkers, could serve as predictors of patient response to treatment and overall survival (OS) during ICI therapy. Results: Logistic regression showed that patients with a history of surgery (p=0.003, OR 9.06, 95% CI: (2.17, 37.9)) and no metastasis (p=0.008, OR 7.82, 95% CI: (1.73, 35.4)) exhibited a higher odds of response to ICI treatment. Cox regression analyses demonstrated that pretreatment blood albumin (p=0.003, HR 1.72, 95% CI: (1.21, 2.45)) and derived neutrophil to lymphocyte ratio (dNLR) (p=0.003, HR 1.71, 95% CI: (1.20-2.44)) were independent predictors for OS in SCLC patients. By establishing a pre-treatment prognostic scoring system based on baseline albumin and dNLR, we found that patients with high albumin and low dNLR exhibited a significantly better prognosis than those with low albumin and high dNLR in both the full (P&amp;lt;.0001, HR 0.33, 95% CI: 0.20-0.55) and the metastatic cohort (P&amp;lt;.0001, HR 0.28, 95% CI: 0.15-0.51). The better prognostic group also had younger age, higher BMI and lower systemic inflammatory biomarker values than the unfavorable group (P&amp;lt;.0001). Conclusion: Our data reveals the significant role of metastasis status and treatment history in predicting the initial response of SCLC patients to ICI treatment. However, baseline serum albumin and dNLR provide a more precise prognostic prediction for patient OS. The scoring system based on albumin and dNLR enhances the ability to stratify patient prognosis and holds the potential to guide clinical decision-making for SCLC patients undergoing ICI therapy. Citation Format: Zhanpeng Kuang, Jessica Miao, Xiaoli Zhang. Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7621.

Development and validation of prognostic models for small cell lung cancer patients with liver metastasis: a SEER population-based study

BackgroundThis study was to establish and validate prediction models to predict the cancer-specific survival (CSS) and overall survival (OS) of small-cell lung cancer (SCLC) patients with liver metastasis.MethodsIn the retrospective cohort study, SCLC patients with liver metastasis between 2010 and 2015 were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly divided into the training group and testing group (3: 1 ratio). The Cox proportional hazards model was used to determine the predictive factors for CSS and OS in SCLC with liver metastasis. The prediction models were conducted based on the predictive factors. The performances of the prediction models were evaluated by concordance indexes (C-index), and calibration plots. The clinical value of the models was evaluated by decision curve analysis (DCA).ResultsIn total, 8,587 patients were included, with 154 patients experiencing CSS and 154 patients experiencing OS. The median follow-up was 3 months. Age, gender, marital status, N stage, lung metastases, multiple metastases surgery of metastatic site, chemotherapy, and radiotherapy were independent predictive factors for the CSS and OS of SCLC patients with liver metastasis. The prediction models presented good performances of CSS and OS among patients with liver metastasis, with the C-index for CSS being 0.724, whereas the C-index for OS was 0.732, in the training set. The calibration curve showed a high degree of consistency between the actual and predicted CSS and OS. DCA suggested that the prediction models provided greater net clinical benefit to these patients.ConclusionOur prediction models showed good predictive performance for the CSS and OS among SCLC patients with liver metastasis. Our developed nomograms may help clinicians predict CSS and OS in SCLC patients with liver metastasis.

A 15-Gene-Based Risk Signature for Predicting Overall Survival in SCLC Patients Who Have Undergone Surgical Resection.

Small cell lung cancer (SCLC) is a malignancy with a poor prognosis whose treatment has not progressed for decades. The survival benefit of surgery and the selection of surgical candidates are still controversial in SCLC. This study is the first report to identify transcriptomic alterations associated with prognosis and propose a gene expression-based risk signature that can be used to predict overall survival (OS) in SCLC patients who have undergone potentially curative surgery. An integrative transcriptome analysis of three gene expression datasets (GSE30219, GSE43346, and GSE149507) revealed 1734 up-regulated and 2907 down-regulated genes. Cox-Mantel test, Cox regression, and Lasso regression analyses were used to identify genes to be included in the risk signature. EGAD00001001244 and GSE60052-cohorts were used for internal and external validation, respectively. Overall survival was significantly poorer in patients with high-risk scores compared to the low-risk group. The discriminatory performance of the risk signature was superior to other parameters. Multivariate analysis showed that the risk signature has the potential to be an independent predictor of prognosis. The prognostic genes were enriched in pathways including regulation of transcription, cell cycle, cell metabolism, and angiogenesis. Determining the roles of the identified prognostic genes in the pathogenesis of SCLC may contribute to the development of new treatment strategies. The risk signature needs to be validated in a larger cohort of patients to test its usefulness in clinical decision-making.

Construction, validation, and visualization of a web-based nomogram to predict overall survival in small-cell lung cancer patients with brain metastasis.

Brain metastasis (BM) is an aggressive complication with an extremely poor prognosis in patients with small-cell lung cancer (SCLC). A well-constructed prognostic model could help in providing timely survival consultation or optimizing treatments. We analyzed clinical data from SCLC patients between 2000 and 2018 based on the Surveillance, Epidemiology, and End Results (SEER) database. We identified significant prognostic factors and integrated them using a multivariable Cox regression approach. Internal validation of the model was performed through a bootstrap resampling procedure. Model performance was evaluated based on the area under the curve (AUC) and calibration curve. A total of 2,454 SCLC patients' clinical data was collected from the database. It was determined that seven clinical parameters were associated with prognosis in SCLC patients with BM. A satisfactory level of discrimination was achieved by the predictive model, with 6-, 12-, and 18-month AUC values of 0.726, 0.707, and 0.737 in the training cohort; and 0.759, 0.742, and 0.744 in the validation cohort. As measured by survival rate probabilities, the calibration curve agreed well with actual observations. Furthermore, prognostic scores were found to significantly alter the survival curves of different risk groups. We then deployed the prognostic model onto a website server so that users can access it easily. In this study, a nomogram and a web-based predictor were developed to predict overall survival in SCLC patients with BM. It may assist physicians in making informed clinical decisions and determining the best treatment plan for each patient.

Prolonged exposure of environmental concentration benzo[a]pyrene promoted cancer stemness through AhR/PKA/SOX2 dependent pathway in small cell lung cancer

Benzo[a]pyrene (BaP) is commonly found in the environment as a result of incomplete combustion of organic materials and cigarette smoke. Epidemiological studies have consistently suggested that elderly smokers are at higher risk for small cell lung cancer (SCLC), with risks and clinical stages increasing with the intensity and duration of smoking. However, the underlying mechanism remains insufficiently investigated. Here, we established a positive correlation between smoking and BaP metabolite 3-hydroxybenzo[a]pyrene (3OH-BaP) in urine. The pooled standardized mean difference of urinary 3OH-BaP concentration for smokers versus nonsmokers was 5.18 (95 % CI 2.86–7.50). Clinical data suggested that smoking led to more lymph node metastasis, higher pathological N-stage, and worse overall survival in SCLC patients. We identified 75 genes that participate in BaP-associated cancer stemness of SCLC from Comparative Toxicogenomics Database and validated the expression of these candidate genes in SCLC patient samples. Protein kinase cAMP-activated catalytic subunit alpha (PRKACA) was found to be most upregulated in SCLC patients and in vitro experiments indicated that long-term exposure of SCLC cells to BaP, at the concentration equivalent to those detected in blood, increased PKA protein level. Further investigation revealed that PKA could directly interact with SOX2 and protect SOX2 from COP1-mediated ubiquitination and degradation. Upregulated SOX2 then contributed to the stemness and metastasis of SCLC cells while inhibition of aryl hydrocarbon receptor (AhR) signaling pathway abolished BaP induced PKA expression and downstream PKA/SOX2 axis. Our findings firstly pinpoint BaP exposure as a high-risk factor for SCLC and worse outcomes in patients, with the underlying mechanism being the activation of cancer stemness of SCLC via the AhR/PKA/SOX2 axis.

The prognostic value of pretreatment albumin-to-fibrinogen ratio in small cell lung cancer patients receiving first-line platinum-based chemotherapy

This study examined the role of pretreatment albumin-to-fibrinogen ratio (AFR) in the prognosis of small-cell lung cancer (SCLC) patients receiving first-line platinum-based chemotherapy. A total of 131 SCLC patients were enrolled. The predictive value of the AFR for progression free survival (PFS) and overall survival (OS) were evaluated by receiver operating characteristic (ROC) curve analysis. The predictive factor of survival was assessed by univariate and multivariate Cox proportional regression analysis. The correlation between OS, PFS and AFR was determined by the log-rank test using the Kaplan-Meier method. AFR was an effective predictor of OS in SCLC patients with a cut-off value of 7.78. AFR was independent risk factors for OS and PFS. Kaplan Meier analysis showed that PFS and OS in patients with high AFR levels were significantly higher than those with low AFR levels. These results suggest that AFR could be an effective predictor of survival in patients with SCLC.

Prognostic significance of Memorial Sloan-Kettering prognostic score in small-cell lung cancer patients.

Aim: To assess the potential factors with predictive value for survival in small-cell lung cancer (SCLC) patients and to develop a nomogram prediction model. Patients & methods: We retrospectively screened and analyzed patients with pathologically confirmed SCLC from April 2015 to December 2021. Results: A total of 167 patients with SCLC were included. According to the Memorial Sloan-Kettering prognostic score (MPS), patients were divided into three groups: group 0 (n=65), group 1 (n=69) and group 2 (n=33). The multivariate analysis showed that MPS was an independent prognostic factor for progression-free and overall survival in SCLC patients (p<0.05). The nomogram showed that MPS was the most influential factor for overall survival. Conclusion: MPS is an independent prognostic factor for overall and progression-free survival in SCLC patients and performed better than other indicators used in this study.

Naples Prognostic Score is an Independent Prognostic Factor in Patients with Small Cell Lung Cancer and Nomogram Predictive Model Established.

BackgroundThe routine clinical nutritional and inflammatory indicators such as serum albumin, total cholesterol and lymphocytes have been widely investigated in the prognosis of small cell lung cancer (SCLC). The Naples prognostic score (NPS), based on nutritional and inflammatory status, has been identified as a prognostic impactor in several malignancies. However, the prognostic role of NPS in SCLC has not been elucidated. This study aims to evaluate the prognostic effect of NPS in SCLC patients.Patients and MethodsPatients with SCLC were recruited at Hebei General Hospital between April 2015 and August 2021. Pretreatment clinical and laboratory data were obtained. Participants were assigned into three groups according to NPS (group 0: NPS=0, group 1: NPS=1 or 2, group 2: NPS=3 or 4). Kaplan-Meier and Cox regression analysis were performed to assess the prognostic significance of NPS. The RMS package in R software was used to draw the nomogram predictive model.ResultsA total of 128 patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) was 7.2 and 12.3 months, respectively. The median PFS and OS was 12.3 vs 19.8 months, 7.6 vs 14.1 months and 6.0 vs 8.45 months for the three groups respectively. There were significant differences in both OS and FPS among the three groups. Survival analysis showed that NPS was significantly correlated with both OS and PFS (P<0.05). Lower NPS is associated with longer OS and PFS. Multivariate analysis showed that NPS has an independent prognostic impact on OS (P<0.05). The nomogram predictive model showed that NPS has good predictive power for survival rates.ConclusionNPS is an independent prognostic factor for OS in SCLC patients. Low NPS may predict longer OS. Therefore NPS plays a vital role in the nomogram predictive model of survival rates in SCLC patients.

Combination of quantitative features from H&amp;E biopsies and CT scans predicts response to chemotherapy and overall survival in small cell lung cancer (SCLC).

8572 Background: Small Cell Lung Cancer (SCLC) is an aggressive malignancy with a rapid growth, and Chemotherapy remains mainstay of treatment. Identifying therapeutic targets in SCLC presents a challenge, partially due to a lack of accurate and consistently predictive biomarkers. In this study we sought to evaluate the utility of a combination of computer-extracted radiographic and pathology features from pretreatment baseline CT and H&amp;E biopsy images to predict sensitivity to platinum-based chemotherapy and overall survival (OS) in SCLC. Methods: Seventy-eight patients with extensive and limited-stage SCLC who received platinum-doublet chemotherapy were selected. Objective response to chemotherapy (RECIST criteria) and overall survival (OS) as clinical endpoints were available for 51 and 78 patients respectively. The patients were divided randomly into two sets (Training (Sd), Validation (Sv)) with a constraint (equal number of responders and nonresponders in Sd)—Sd comprised twenty-one patients with SCLC. Sv included thirty patients. CT scans and digitized Hematoxylin Eosin-stained (H&amp;E) biopsy images were acquired for each patient. A set of CT derived (46%) and tissue derived (53%) image features were captured. These included shape and textural patterns of the tumoral and peritumoral regions from CT scans and of tumor regions on H&amp;E images. A random forest feature selection and linear regression model were used to identify the most predictive CT and H&amp;E derived image features associated with chemotherapy response from Sd. A Cox proportional hazard regression model was used with these features to compute a risk score for each patients in Sd. Patients in Sv were stratified into high and low-risk groups based on the median risk score. Kaplan-Meier survival analysis was used to assess the prognostic ability of the risk score on Sv. Results: The risk score comprised nine CT (intra and peri-tumoral texture) and six H&amp;E derived (cancer cell texture and shape) features. A linear regression model in conjunction with these 15 features was significantly associated with chemo-sensitivity in Sv (AUC = 0.76, PRC = 0.81). A multivariable model with these 15 features was significantly associated with OS in Sv (HR = 2.5, 95% CI: 1.3-4.9, P = 0.0043). Kaplan-Meier survival analysis revealed a significantly reduced OS in the high-risk group compared to the low-risk group. Conclusions: A combined CT and H&amp;E tissue derived image signature model predicted response to chemotherapy and improved OS in SCLC patients. Image features from baseline CT scans and H&amp;E tissue slide images may help in better risk stratification of SCLC patients. Additional independent validation of these quantitative image-based biomarkers is warranted.

Small cell lung cancer: Real-world data from two institutions in Lebanon for patients receiving carboplatin etoposide or atezolizumab in first line of treatment.

e20578 Background: Small-cell lung cancer (SCLC), accounts for approximately 15% to 17% of all diagnosed lung cancers. It is an aggressive high-grade neuroendocrine carcinoma, diagnosed during advanced stages in the majority of patients. Despite the fact that first line treatment provides response rates of up to 80%, the majority of patients relapse within 6 months after completion of initial treatment. Few advances have been made in the management of recurrent disease and treatments patterns are poor and limited in each line of the disease. The aim of this study is to present real world data regards survival outcomes such as progression free survival and overall survival in SCLC patients receiving carboplatine etoposide or tecentriq carboplatin etoposide regimens as first line of treatment. Methods: This is a retrospective (descriptive) study on 56 patients aged ≥ 18 years and with confirmed histological SCLC. Patients with extensive stage of SCLC were enrolled in this cohort study from 2 health institutions in Lebanon from July 2007 to December 2019 and followed up until progression or death. Primary end points were overall survival (time from randomization to death from any cause) and progression free survival at 6 and 12 months (time from randomization to disease progression). Secondary endpoints included objective response rate and the duration of response. Exploratory analyses included the assessment of survival outcomes of each type of treatment according to liver and brain metastasis. Results: Overall, 56 SCLC patients, diagnosed between 2003 and 2019, were observed (age &lt;65: (27.0%, 10 patients); ≥65 (73.0%, 41 patients)). Most often prescribed treatment were etoposide-carboplatyl (80.8%, 42 patients) and atezolizumab (19.2%10 patients). Regarding metastasis at diagnosis, liver and brain metastasis were respectively (26.8%, 11 patients) and (17.1%, 7 patients). 27patients (71.1%) were alive at 6 months without progressive disease and 13 patients (34.21 %) alive at 12 months without PD. Median progression free survival incidence since diagnosis was 8.8 months. Overall survival was 10.86 months. Objective response rate after first line was 84.2%. In a cox regression analysis, liver metastasis, brain metastasis, survival at 6 or 12 months without progressive disease did not decrease significantly PFS or OS since diagnosis. Conclusions: To our knowledge, this is the first real world clinical data on SCLC in Lebanon. This study showed limited treatment options and short survival outcomes with PFS= 8.8months and OS= 10.86 months respectively for carboplatin etoposide regimen and tecentriq carboplatin etoposide regimen. There is an essential needs for clinical comparative studies in real world practicing between treatments at each line, specially for novel treatment like atezolizumab that may present new hope and directions for SCLC.

Albumin-bound paclitaxel plus PD-1/PD-L1 inhibitor versus second-line chemotherapy for patients with recurrent small cell lung cancer.

e20591 Background: The main aim of this study was to evaluate the efficiency of albumin-bound paclitaxel (nab-PTX) plus PD-1/PD-L1 inhibitor versus second-line chemotherapy in small cell lung cancer (SCLC) patients who have failure to the first-line standard treatment. Methods: We retrospectively collected patients’ data from medical records between January 2015 to July 2020 in Shandong Cancer Hospital and Institute. Consecutive 42 patients who were treated with nab-PTX plus PD-1/PD-L1 inhibitor were enrolled and compared with, 126 patients who received second-line chemotherapy (1:3 matched with patient and tumor characteristics). Progress free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were evaluated for each group. Results: Patients treated with nab-PTX plus immunotherapy group and second-line chemotherapy group achieved the median PFS of 5.6 months and 3.3 months ( p = 0.043), respectively. The median OS were 7.7 months and 6.3 months ( p = 0.021), respectively. The ORR and DCR were also higher in nab-PTX plus PD-1/PD-L1 inhibitor group (ORR: 33.3% vs 20.6%, p = 0.094; DCR: 61.9% vs 41.3%, p = 0.020, respectively). The most common incidences of grade ≥3 adverse events were leukopenia and neutropenia, there were no significance difference between the two groups. Conclusions: Albumin-bound paclitaxel plus PD-1/PD-L1 inhibitor conferred higher ORR and DCR, and improved PFS and OS in SCLC patients failed with first-line treatment. Further prospective and randomized trial that directly compares the treatments is urgently warranted.

RADI-07. GAMMA KNIFE RADIOSURGERY FOR SMALL CELL LUNG CANCER: PROGNOSTIC FACTORS INCLUDING ADDITIONAL LESIONS IDENTIFIED ON THE DAY OF RADIOSURGERY

OBJECTIVES: Prophylactic cranial irradiation (PCI) and whole brain radiation (WBRT) are standard of care for intracranial disease in small cell lung cancer (SCLC) patients. We sought to identify predictors of overall survival (OS) in SCLC patients treated with salvage Gamma Knife radiosurgery (GKRS) for brain metastases after prior WBRT or PCI. METHODS: Retrospective analyses were conducted on 26 SCLC patients treated with GKRS at one institution between May 2010 and June 2018. Factors predictive of OS were analyzed using Cox proportional hazards regression and Wilcoxon sum-rank testing. RESULTS: Median follow-up and median OS following GKRS was 6.6 mos (range 0.7–24.2 mos). Median OS was 21.4 mos from initial diagnosis (range 7.3–49.3 mos). Presence of extracranial metastases at the time of GKRS was not significantly associated with median OS after GKRS (5.8 mos for patients with extracranial metastases vs 7.2 mos for patients without, p=0.425). Mean number of lesions was 2.7 (range 1–10) on diagnostic brain MRIs and 4.1 (range 1–12) on GKRS planning MRIs. Eleven patients (42%) had the same number of lesions between diagnostic MRI and GKRS MRI, and 15 patients (58%) had additional lesions on the GKRS MRI. Number of lesions treated and total tumor volume were not associated with median OS. Patients who had additional lesions on GKRS MRI compared to diagnostic MRI had lower median OS from initial diagnosis of SCLC (29.9 mos vs 18.1 mos, p=0.0182) and a trend toward lower median OS from time of GKRS (7.3 mos vs 4.8 mos, p=0.0547) compared to patients who did not have additional lesions. CONCLUSIONS: Finding additional brain metastases on GKRS planning MRIs is associated with decreased OS in SCLC patients treated with salvage GKRS. Presence of extracranial metastases at the time of GKRS and number or total volume of brain metastases were not associated with OS.

KRAS Exon 3 and PTEN Exon 7 Mutations in Small-cell Lung Cancer.

Small cell lung cancer (SCLC) is recognized as one of the most aggressive and fatal malignant tumors. No significant improvement has been made to prolong the survival of SCLC patients. This study aimed to examine the mutation status of K-Ras (KRAS) and phosphatase and tensin homolog (PTEN) in SCLC patients in order to identify potential therapeutic targets for SCLC. Nineteen primary SCLC tumor specimens were enrolled in the study. Direct sequencing was performed to detect the mutations of KRAS exon 3 and PTEN exon 7 in the specimens. Kaplan- Meier and Cox regression analysis was performed to determine the overall survival (OS) of these SCLC patients. KRAS exon 3 mutation was found in 4 (21%) SCLC patients, and PTEN exon 7 mutation in only 1 (5%) SCLC patient. Kaplan Meier analysis showed that clinical stage and brain metastasis were significantly associated with OS (both P<0.05), but neither KRAS exon 3 mutation nor PTEN exon 7 mutation was significantly associated with OS (P>0.05). Cox proportional hazards regression model indicated that extensive stage of disease was the only independent negative prognostic factor for OS in SCLC patients. In conclusion, KRAS exon 3 and PTEN exon 7 mutations had no significant impact on OS of SCLC patients. Further study is still necessary to validate the molecular profiles of SCLC.

DLL3 is regulated by LIN28B and miR-518d-5p and regulates cell proliferation, migration and chemotherapy response in advanced small cell lung cancer

Delta-like protein 3 (DLL3) has been reported as a biomarker in various human tumors. However, the biological function and mechanism of it in advanced small cell lung cancer (SCLC) is rarely reported. This study was devised innovatively to explore the role of DLL3 in the progression of SCLC. Immunohistochemistry (IHC) analysis was used to examine DLL3 expression in paraffin-embedded SCLC tumor samples. Upregulation of DLL3 reduced chemotherapy sensitivity. Kaplan-Meier analysis was used to analyze the progression-free survival or overall survival of SCLC patients with high or low level of DLL3. The negative association between DLL3 expression and the PFS or OS rate of SCLC patients was identified. Relative high level of DLL3 was determined in SCLC cell lines by using qRT-PCR analysis. Loss-of function assays were performed to detect the biological functions of the silencing of DLL3 in SCLC. As a result, silencing of DLL3 led to the proliferative and migratory inhibition of SCLC cells and reversed EMT process. Mechanistically, DLL3 mRNA was stabilized by the RNA-binding protein lin-28 homolog B (LIN28B). Further mechanism investigation revealed that LIN28B and DLL3 are two downstream targets of miR-518d-5p. Finally, rescue assays demonstrated that LIN28B and miR-518d-5p could regulate DLL3-mediated cell proliferation and migration. Collectively, our present study revealed a novel molecular pathway in SCLC, which providing a new insight in exploring the therapeutic strategy for SCLC.

SBF2-AS1: An oncogenic lncRNA in small-cell lung cancer.

The long noncoding RNAs (lncRNAs) SBF2 antisense RNA 1 (SBF2-AS1) was found to act as an oncogenic lncRNA in non-small-cell lung cancer (NSCLC), but the role of SBF2-AS1 in small-cell lung cancer (SCLC) was still unclear. The purpose of this study was to provide the clinical significance and biological function of SBF2-AS1 in SCLC. In our results, SBF2-AS1 was found to be upregulated in SCLC tissues compared with NSCLC tissues or adjacent normal lung tissues. Besides, SBF2-AS1 expression was also elevated in SCLC cell lines compared with the normal bronchial epithelial cell line or NSCLC lines. Moreover, high expression of SBF2-AS1 was associated with clinical stage, tumor size, lymph node metastasis and distant metastasis in SCLC patients. Survival analysis showed SCLC patients with high expression of SBF2-AS1 had shorter overall survival than patients with low expression of SBF2-AS1, and high expression of SBF2-AS1 acted as an independent poor prognostic factor for overall survival in SCLC patients. The study in vitro suggested inhibition of SBF2-AS1 obviously depressed cell proliferation, migration, and invasion in SCLC. In conclusion, SBF2-AS1 acts as a novel oncogenic lncRNA in SCLC.

Functional role of CyclinD1 polymorphism (G870A) in modifying susceptibility and overall survival of North Indian lung cancer patients.

The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Functional Role of CyclinD1 Polymorphism (G870A) in Modifying Susceptibility and Overall Survival of North Indian Lung Cancer Patients.

Purpose The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. Methods The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. Results The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). Conclusions Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial

BackgroundCoagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well-defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients.Patients and methodsWe carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), incidence of VTE and hemorrhagic events.ResultsIn RASTEN, 390 patients were randomized over an 8-year period (2008–2016), of whom 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin [hazard ratio (HR), 1.11; 95% confidence interval (CI) 0.89–1.38; P = 0.36 and HR, 1.18; 95% CI 0.95–1.46; P = 0.14, respectively]. Subgroup analysis of patients with limited and extensive disease did not show reduced mortality by enoxaparin. The incidence of VTE was significantly reduced in the LMWH arm (HR, 0.31; 95% CI 0.11–0.84; P = 0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms.ConclusionLMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Addition of LMWH cannot be generally recommended in the management of SCLC patients, and predictive biomarkers of VTE and LMWH-associated bleeding in cancer patients are warranted.