Small Cell Lung Cancer Patients:Prognostic Model Building,Dynamic Recurrence Pattern,and Immunophenotype And RNA Modification Related Molecular Biomarkers

Background:Small cell lung cancer(SCLC)is a highly aggressive subtype of lung cancer with poor prognosis.In this study,we developed and validated a nomogram for predicting survival in surgically resected limited-stage SCLC patients.Methods:The SCLC patients extracted from the Surveillance,Epidemiology,and End Results database between 2000 and 2014 were reviewed.Significant prognostic factors were identified and integrated to develop the nomogram using multivariable Cox regression.The model was then validated internally by bootstrap resampling and externally using an independent SCLC cohort diagnosed between 2000 and 2015 at our institution.The prognostic performance was measured by the concordance index(C-index),and calibrate curve.Results:A total of 1006 resected limited-stage SCLC patients were included in the training cohort.444 cases from our institution constituted the validation cohort.Seven prognostic factors were identified and entered into the nomogram construction.The C-indexes of this model in the training cohort were 0.723,0.722,0.746 for predicting 1-,3-and 5-year overall survival(OS),respectively,and 0.816,0.710,0.693 in the validation cohort.The calibration curve showed optimal agreement between nomogram predicted survival and actual observed survival.Additionally,significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed.The proposed nomogram was then deployed into a website server for convenient appliance.Conclusions:We developed and validated a novel nomogram for individual prediction of survival in resected limited-stage SCLC patients.This model performs better than the previously widely used staging system and may offer clinicians instructions for strategy-making and design of clinical trials.Background:Small cell lung cancer(SCLC)is characterized with high malignancy,rapid progress,high recurrence rate and rapid resistance to the traditional chemotherapy.For patients with SCLC who received surgical resection as the initial treatment,the postoperative recurrence pattern is still unclear.In this study,we systematically analyzed the postoperative recurrence pattern and its dynamic changes based on those patients who received surgical resection for limited-stage SCLC.Methods:This study retrospectively reviewed the patients who underwent radical resection for limited-stage SCLC in Cancer Hospital,Chinese Academy of Medical Sciences from 2000 to 2018.This temporal and spatial distribution of postoperative recurrence were analyzed.The annual recurrence risk dynamic curve was estimated and shown by Kernel smoothing method.The risk factors of postoperative recurrence were analyzed through Fine-Gray competitive risk model,and the restricted cubic spline method based on multivariate Cox regression model was used to flexibly model the functional association of those significant variables with survival.Results:This study cohort included 576 patients of resected limited-stage SCLC in our institution.By the end of this study period,265(46.0%)patients experienced post-operative recurrence,in which 48(18.1%)was locoregional recurrence,172(64.9%)was distant recurrence,and 45(17.0%)had both,and the 3-year cumulative incidence of recurrence rate were 44.0%(95%CI,40.0-48.1).After multivariate Fine and Gray's analysis,age(HR,1.35;P=0.017),Brinkman index(HR,1.36;P=0.017),lymphvascular invasion(HR,1.31;P=0.042),and LN ratio(HR,2.73;P=0.005)were finally identified as independent predictors for recurrence.The smoothed annual hazard curve for recurrence of all patients showed a unimodal distribution pattern,in which the hazard ratio for recurrence peaks within 12 months.The distribution pattern was consistent in the subgroups with different recurrence risk factors.After multivariate Cox analysis,elder age(HR,4.30;P=0.014)and combined SCLC(HR,1.98;P=0.004)were revealed to be independent prognostic variables for post-recurrence survival.Conclusion:Based on the largest cohort of patients with surgically resected SCLC to date,this study analyzed and demonstrated the detailed recurrence pattern and its time-dependent dynamic changes.In addition,this study found that age,smoking index,lymph nodes ratio,and lymphvascular invasion were independent risk factors for postoperative recurrence,suggesting that it is necessary to formulate stricter postoperative follow-up strategy for those SCLC patients with high-risk factors.Background:Small cell lung cancer(SCLC)is a rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis.So far,there is still a lack of effective treatment regime.The advent of immune checkpoint inhibitors has renewed hope to the treatment of malignant tumor;however,few relevant studies have been reported in SCLC.In this study,we explored the expression profile and clinical significance of PD-L1 and CD8+T-cell in SCLC.Methods:Based on the resected specimens of 301 SCLC cases from the Cancer Hospital,Chinese Academy of Medical Sciences,we systematically analyzed the expression profile of PD-L1 and CD8+T-cell density through immunohistochemistry.The correlation of PD-L1,CD8+T-cell density and patients' clinicopathological characteristics and survival.Results:The results showed that 169 cases were PD-L1 positive(with 5% as the cut-off value),and the average density of CD8+T cells was 34.03 cells/mm2 in 301 cases of SCLC.The positive expression of PD-L1 was significantly correlated with the CD8+T cells density(P<0.001).PD-L1 expression was found to be correlated with TNM stage(P=0.015),T stage(P=0.006),N stage(P=0.006)and pleural invasion(P=0.001);CD8+T cell density was correlated with T stage(P=0.042).Multivariate Cox regression analysis showed that PD-L1 expression and CD8+T cell density were independent risk factors for overall survival(PD-L1,HR,0.50,P<0.001:CD8+T cell density,HR,0.52,P=0.005)and disease-free survival(PD-L1,HR,0.63,P=0.007;CD8+T cell density,HR,0.66,P=0.035).Significant differences were observed in the prognosis between patients stratified by the·combination of PD-L1 and CD8,namely the groups of Type ?(PD-L1+CD8+),Type ?(PD-L1-CD8-),Type ?(PD-L1+CD8-)and Type ?(PD-L1-CD8+).Conclusion:This study preliminarily revealed that PD-L1 and CD8 status are novel prognostic biomarkers for SCLC and may inform the implementation of risk-related therapeutic strategies.This study also supported the assertion that PD-L1/PD-1 inhibitors should be investigated in this rare malignancy.Background:Small-cell lung cancer(SCLC)is a devastating subtype of lung cancer with few therapeutic options.Despite the advent of immunotherapy,only a minority of SCLCs respond to immune checkpoint inhibitors.N6-methyladenosine(m6A)is a novel epigenetic decisive factor in cancer biology and tumor immunotherapy.The m6A modification in SCLC is still unknown.Methods:Based on the expression profiles of 125 SCLC samples from the International and Domestic cohorts,the expression patterns of 30 widely reported m6A regulators between SCLC and normal tissues were systematically analyzed.Through survival analysis,the prognosis-related m6A regulators were selected and enrolled into the construction of a m6A risk score system for SCLC patients.Results:Our results showed that there were abnormal mutations of m6A regulators in SCLC specimens,and the expression patterns of m6A regulators was significantly different between SCLC and normal tissue.Through survival analysis,21 prognosis-related m6A regulators were identified.Based on the LASSO regression,11 m6A regulators were selected and enrolled into the construction of a m6A risk score system:m6A risk score=(PRRC2A×-0.1627)+(IGF2BP1×-0.0702)+(METTL5×0.4571)+(METTL14×0.151)+(G3BP1×0.1318)+(ZCCHC4 × 0.1609)+(IGF2BP3×-0.1672)+(RBM15B ×-0.2846)+(ALKBH5×-0.2664)+(YTHDC2×0.0212)+(IGF2BP2×0.0184).According to the median value of m6A risk score,the SCLC patients in the International and Domestic cohorts were divided into high-risk group and low-risk group..Kaplan-Meier survival curves showed significant differences between the high-risk group and low-risk group.The multivariate Cox regression analysis showed that m6A risk score was an independent risk factor for prognosis in SCLC patients,whether in the International and Domestic cohorts.Conclusion:This study preliminarily revealed the significance of m6A modification in SCLC patients,and showed the potential of m6A to be a novel prognostic biomarker for SCLC patients.