bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salvage radiotherapy after chemotherapy for unresectable locally advanced non-small cell lung cancer in real world.
Authors: Xu Qinghua , Hu Min , Yuan Xiaoshuai , Li Fangjuan , Liu Hui , Xu Yaping 
Published: May 2020

e21052 Background: For patients with unresectable stage III disease, combined modality therapy (chemoradiation) is superior to radiation alone, and concurrent chemoradiotherapy (CCRT) is superior to sequential chemoradiotherapy (SCRT). The current standard of care for unresectable stage III disease is CCRT. Consequently, CCRT is commonly given to patients with minimal or no comorbidities, a good general condition, and who are relatively young. SCRT may be a valuable alternative for patients who are not eligible for CCRT. However, the role of salvage radiotherapy (SRT) after chemotherapy for patients with unresectable stage III disease without CCRT or SCRT is currently unknown. Methods: Patients with unresectable stage III disease receiving chemoradiotherapy were enrolled. All patients were treated with CCRT, SCRT or SRT. Overall survival (OS) was estimated by Kaplan-Meier curves. Results: From May 2014 to September 2018, 216 patients were enrolled, including 65 (30.1%) who received CCRT, 80 (37.0%) who received SCRT, and 71 (32.9%) who received SRT. No significant difference in gender, age, performance status, TNM stage, or EGFR gene status among the three groups. The median OS for the entire cohort was 22.1 (range: 18.4–25.8) months. The median OS in CCRT, SCRT, and SRT group were 29.7, 21.3, and 19.1 months, respectively (P = 0.011). The difference was statistically significant between CCRT group and SCRT or SRT group but was not between SCRT and SRT group. The 1-year survival rate in CCRT, SCRT, and SRT group were 89.2%, 75.0%, and 75.2%, respectively. However, the 3-year survival rate in CCRT, SCRT, and SRT group were 42.7%, 32.7%, and 9.6%, respectively. However, CCRT also has a higher rate of Grade 3 or 4 acute esophagitis and pneumonitis . Conclusions: The current study demonstrated compared with CCRT and SCRT, SRT had reduced patient survival survival time significantly.
The genomic landscape of immune-related genes and its correlations with TMB and PD-L1 expression in Chinese NSCLC.
Authors: Zheng Linxin , Li Weifeng , Xie Wenzhuan , Huang Mengli 
Published: May 2020

e21056 Background: Understanding the genomic landscape of immune-related genes (IRGs) of patient with Non-Small Cell Lung Carcinoma (NSCLC) may provide critical insight and facilitate development of novel strategies for cancer therapy. Methods: Targeted next generation sequencing (NGS) was performed on tissue obtained from patients with NSCLC using a 381-gene panel. The IRGs were mainly based on a published article that summarized the genes related to activated T cells, immune cytolytic activity and IFN-γ release. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations (CNV) and gene fusions were assessed. Mutational profiles of IRGs and its correlations with Tumor mutation burden (TMB) and PD-L1 expression in NSCLC patients were analyzed from the 3D Medicine database. Results: Genomic data of 2,510 patients with NSCLC were analyzed via tissue detection [median age 62 years, (IQR: 54 - 69 years)]. 4.26% (107 / 2,510) of the patients had at least one characterized altered IRGs. The most frequently mutated IRGs identified for all genomic alternations occurred in PDCD1LG2 (40%), FAS (27%), LCK (23%), CD274 (21%), CD74 (3%), and missense mutations were the mainly mutant types of PDCD1LG2 and LCK, and copy number gains were showed in PDCD1LG2 and CD274. TMB levels in NSCLC patients with IRGs mutations were higher than in wild-type patients (mean TMB: 14.17 mut/MB vs 9.27 mut/MB, P < 0.001). 65.42% (70/107, 9.35% for PD-L1 > = 1% and < 5%, 28.97% for PD-L1 > = 5% and < 50%, 27.10% for PD-L1 > = 50%) of patients harboring PD-L1-positive ( > = 1%), and the proportion of patients with mutations in IRGs does not exceed 10% in each subgroup. Results of Pearson Chi-square test showed that the PD-L1 expression had different between two groups ( Χ2 = 13.3774, P = 0.0038), patients harboring IRGs mutation had a significantly higher level of PD-L1 than those wide-type patients (P = 0.001). Conclusions: Genomic landscape of IRGs significantly correlated with that of PD-L1 expression. Further analyses using more precisely IRGs and different stage NSCLC samples are requisite to support a role for IRGs as an target to immune therapy of cancers.
Study of immune regulatory receptor expression upon combination of chemotherapy and immune checkpoint blockade in a murine lung cancer model.
Authors: Ho James C. M. , Yan Sheng , Lam Sze Kwan 
Published: May 2020

e21083 Background: Blockade of inhibitory immune checkpoints namely the programmed cell death protein 1 (PD-1) and the PD-1 ligand (PD-L1) achieved remarkable clinical outcomes in multiple malignant diseases including lung cancer. However, as the dynamic interactions between the cancer cells and the tumor-associated microenvironment evolves, acquired resistance arises. Thus exploration on alternative strategies would be necessary in order to reach long-term tumor suppression. Methods: Murine lung cancer model was established by inoculation of Lewis lung carcinoma cells subcutaneously on the flank of C57BL/6J mice. Chemotherapy (cisplatin or pemetrexed) or anti-PD-1 alone, or in combination started at 7 days post-inoculation as tumor growth was established. Digital caliper was used to measure tumor sizes and survival rates were recorded. Mice were sacrificed upon humane endpoint (tumor size > 17 mm in diameter). Splenocytes and tumor cells were harvested and expression of immune regulatory markers (including PD-L1, PD-1, Tim-3, OX-40, GITR, LAG-3 and CTLA-4) was analyzed by flow cytometry. Results: While PD-1 blockade delayed tumor growth ( p< 0.001), there was no significant difference in overall survival. Systemically, anti-PD-1 immunotherapy induced upregulation of Tim-3, OX-40 and GITR; cisplatin alone and in combination with anti-PD-1 induced upregulation of GITR; OX-40 is upregulated in combinations of chemotherapy and anti-PD-1. Population of tumor-infiltrating T cells were increased in anti-PD-1-treated mice, while combination of pemetrexed and anti-PD-1 prompted augmented expression of co-stimulatory receptors including GITR and OX-40 within tumor. Conclusions: Cisplatin and pemetrexed triggered different systematic and intratumoral immune responses when used alone or in combination with anti-PD-1 treatment. Increased expression of co-stimulatory receptors in the tumor in response to combination therapy provide insights for investigation of synergism on anti-PD-1 and alternative therapeutic targets.
Developing post-treatment PET/CT volumetric prognostic index for non-small cell lung cancer.
Authors: Liu Liu , Zhang Jingmian , Ferguson Mark K. , Appelbaum Daniel E. , Pu Yonglin 
Published: May 2020

e21085 Background: The aim of this study is to model and validate a post-treatment PET/CT volumetric prognostic (ptPVP) index for risk assessment after definitive therapy for NSCLC. Methods: This IRB-approved retrospective cohort study included 1028 NSCLC patients diagnosed between 2004 and 2017. Variables included: pre-treatment whole-body metabolic tumor volume (MTVwb) measured on baseline FDG PET/CT, patient age, clinical TNM stage, ECOG performance status (PS), gender, tumor histology, treatment type, and survival outcomes. Patients were assigned to a modeling cohort (531 patients) for modeling ptPVP index and a clinical index with a multivariate Cox regression model. The ptPVP index was validated with a separate validation cohort (497 patients) by comparing the prognostic value of ptPVP index against its individual independent variables and the clinical index. Results: The ptPVP index generated from the modeling cohort was comprised of 5 variables including treatment type (surgery, no surgery, and no therapy), age, clinical TNM stage (stage I or II, III, and IV), PS ( 0, 1, and ≥ 2) and MTVwb. The clinical index was comprised of above 4 clinical variables without MTVwb. Univariate Cox models showed significant association of the ptPVP index with OS with Hazard ratio (HR) of 2.72 (95% CI = 2.39-3.09, p < 0.001). The C-statistic of ptPVP index (0.71) was significantly greater than that of clinical index (0.68) (p = 0.001). In the validation cohort, univariate Cox models showed significant association of the ptPVP index with OS (HR = 3.09, 95% CI = 2.64-3.61, p < 0.001). The ptPVP index showed greater prognostic power (C-statistic = 0.72) than that of the clinical index (C-statistic = 0.70, p = 0.001), treatment type (C-statistic = 0.66, p < 0.001), MTVwb (C-statistic = 0.67, p < 0.001), age (C-statistic = 0.58, p < 0.001), clinical 9-group TNM staging (C-statistic = 0.66, p < 0.001), and PS (C-statistic = 0.57, p < 0.001). Multivariate Cox regression analysis demonstrated a significant association of ptPVP index with OS (HR = 3.06, 95% CI of 2.60-3.61, p < 0.001) after adjusting gender and NSCLC histology. A better separation of Kaplan-Meier curves of patients grouped by ptPVP index than those grouped by clinical index, MTVwb, or clinical TNM stage was evident. Conclusions: The ptPVP index developed for NSCLC patients demonstrated moderately prognostic power and better prognostic ability than its individual independent variables and clinical index without MTVwb. It provides a practical quantitative risk assessment for the patient follow-up and management after initial treatment.
Role of the total mutation burden (TMB) and tumor-infiltrating lymphocytes (TILs) on the development of second primary cancer after complete resection of non-small cell lung cancer (NSCLC).
Authors: Gauthier Marie-Pier , Karimi Maryam , Michiels Stefan , Seymour Lesley , Brambilla Elisabeth , Le Chevalier Thierry , Soria Jean-Charles , Kratzke Robert Arthur , Graziano Stephen L. , Govindan Ramaswamy , Tsao Ming-Sound , Shepherd Frances A. 
Published: May 2020

e21092 Background: Risk of developing SPC after complete surgical resection of NSCLC has been reported to be 3-6% per person-year. We hypothesized that genomic instability, as assessed by high TMB, and the absence of TILs in the primary tumor might be associated with SPC. Methods: The LACE [Lung Adjuvant Cisplatin Evaluation])-BIO database was used, which includes 3 randomized trials. TMB and TILs were analyzed on FFPE specimens. TMB was categorized into tertiles (high > 7.8 mutations/MB, moderate i.e. > 4 and < = 7.8, low < 4) and TILs as marked vs. other. Associations on competing time-to-event endpoints (SPC, and death without developing SPC) were evaluated using the Fine and Gray model stratified by trail and adjusted on treatment, age, gender, tumor stage, nodal stage, histology, performance status and surgery type. Results: TMB and TILs assessments were available for 879 patients without missing clinical covariates; 85 patients had marked TILs. During follow-up, 47 SPCs had been observed and 392 deaths without developing SPC. Regarding TMB, a significant association was found between low TMB and death without SPC (sub-distribution hazard ratio SHR = 1.36(1.06-1.74), see Table), suggesting a higher risk of death without SPC among patient with low TMB compared to those with moderate TMB; no strong effect was observed for SPC. Regarding TILs, a trend was observed between marked TILS and a lower risk of death (SHR = 0.70 [0.47-1.04]) but to a lesser extent for SPC (SHR = 0.80 [0.28-2.28]). Conclusions: This is the first study of the effect of genomic instability (measured by TMB) and host immune response (measured by TILs) in completely resected NSCLC on competing events of SPC and death, suggesting associations between TMB, TILs and death-without-SPC . There was no statistically significant association with SPC. However, the number of SPCs was small; these findings requires validation in other early stage lung cancer cohorts. [Table: see text]
Marvelous objective response of low dose radiotherapy plus ICIs for extended stage small cell lung cancer.
Authors: Zhou Lin , Yu Min , Chen Lin , Zhang Yan , Jiang Zhu , Liu Yongmei , Gong Youling , Xu Yong , Xue Jianxin , Li Yanying , Huang Meijuan , Lu You 
Published: May 2020

e21097 Background: Immune checkpoint inhibitors (ICIs) has limited efficacy with unsatisfactory objective response for extensive stage small cell lung cancer (ES-SCLC). In this respective study, efficacy and toxicities of low dose radiotherapy (LDRT) plus ICIs for pretreated failure ES-SCLC has been evaluated, and marvelous objective response has been observed. Methods: From March 2018 to Dec 2019, ten pretreated failure ES-SCLC patients received LDRT (8-20Gy/2-10f, BED10 9.5-24Gy) for lesions located in lung or other sites plus ICIs (Nivolumab, Pembrolizumab, Ipilimumab, Durvalumab, and Sintilimab) were enrolled. Two patients received concurrent chemotherapy of etoposide plus cisplatin or albumin-bound paclitaxel monotherapy. ICIs were given within 7 days after LDRT. Efficacy, toxicities, and lung cancer symptom scale (LCSS) scores were evaluated. Results: Thirteen lesions (ten located in lungs, and the others located in adrenal gland, axillary lymph node, and abdomen) received LDRT. The gross tumor volume and planning target volume were 32.56 cc-430.19cc and 73.74 cc-771.41 cc, respectively. Eleven lesions did not receive radiotherapy. The objective response rate (ORR) of whole patients was 90% (9/10). The ORR and disease control rate (DCR) of radiated lesions were 92.3% (12/13) and 100% (13/13), compared to 9.1% (1/11) and 18.2% (2/11) for no radiated lesions. Volume shrinkage rates (VSRs) of radiated lesions were 35.16% to 95.91% (13.75cc-277.02cc), and 61.5% (8/13) of radiated lesions reduced more than 80%. VSRs for radiated lesions with volume > 100cc were 63.07% to 95.91% (122.38cc-277.02cc). LCSS improved significantly after treatment (465±13.02 vs. 380±17.8, p= 0.0013). Lymphocyte declined initially and then recovered in patients with disease not progressed, on the contrary, it declined continuously in patients with disease progressed. The most popular toxicities were lymphopenia (70%) and anemia (60%). Grade 3-4 toxicities included lymphopenia (40%), thrombocytopenia (20%), anemia (20%), and granulocytopenia (10%). Conclusions: LDRT might enhance the effectiveness of ICIs greatly for tumor lesions, and radiotherapy should be considered to be given initially for ES-SCLC received ICIs treatment.
The role of surgery in stage I small-cell lung cancer: A national VA database analysis.
Authors: Azar Ibrahim , Austin Adam , Kim Seongho , Jang Hyejeong , Chopra Amit , Mehdi Syed Arzoo , Mamdani Hirva 
Published: May 2020

e21109 Background: Historically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, real world data regarding the role of surgery in very limited SCLC is lacking. To our knowledge, only one retrospective study has evaluated the role of surgery in stage I SCLC. Methods: Data from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed Stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs lower lobe as delineated by ICD-10 codes C34.1 and C34.3. Results: Four-hundred and forty-two patients received concurrent CRT; while 219 underwent treatment that contained surgery (92 surgery only, 84 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.25-4.60) while median OS for the CRT cohort was 2.43 years (95% CI 2.15-2.72). HR of death for surgery-inclusive treatment when compared to CRT was 0.65 (95% CI 0.54-0.79; p < 0.001). Subset analysis based on the location of the tumor in upper lobe and lower lobe showed improved survival with surgery as compared to CRT regardless of the location. HR for upper lobe was 0.61 (95% CI 0.48-0.78; p < 0.001) and lower lobe 0.60 (95% CI 0.41-0.87; p = 0.007). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.42-0.85; p = 0.004) favoring surgery. Conclusions: Surgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study supports a more expansive role for surgery in stage I SCLC.
PIOS ratio: predicting the best response of non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors.
Authors: Dimitrakopoulos Foteinos-Ioannis D. , Nikolakopoulos Achilleas , Kottorou Anastasia E , Liolis Elias , Frantzi Theodora , Pyrousis Ioannis , Kalofonou Foteini , Koutras Angelos , Makatsoris Thomas , Kalofonos Haralabos 
Published: May 2020

e21507 Background: With the exception of programmed death ligand 1 (PD-L1) expression and Tumour Mutational Burden (TMB), which have entered clinical practice, no other clinically useful predictive biomarker for immune checkpoint inhibitors (ICIs) has been established in the daily practice. The purpose of this study was to develop a novel, non-interventional and clinically useful predictive score for NSCLC patients with advanced disease treated with ICIs. Methods: Eighty-nine patients with advanced and histologically confirmed NSCLC (stages III and IV), treated with immunotherapy (nivolumab, pembrolizumab, atezolizumab), were enrolled in the current study. Clinicopathological data as well response rates and clinical outcome data were collected. Based on this data and using a regression model, we developed a predictive score (Patras Immunotherapy Score-PIOS) with regard to the best response to ICIs. Best overall responses (BOR) were based on the immune-based therapeutics (iRECIST) criteria. Results: Four of the studied parameters -Performance Status (PS), Body Mass Index (BMI), age and lines of treatment (LOT)- were incorporated in our formula (PS *BMI/ LOT*age) giving rise to PIOS. This score was strongly associated with BOR, with patients of a good response (SD, PR or CR) having higher PIOS compared to patients with progression disease (PD) (p<0.001). The association remained significant when we used a four-tier model (PD, SD, PR and CR) for BOR (p<0.001). PIOS predictive significance also persisted using a binary logistic regression analysis (p=0.001). Conclusions: This study suggests that PIOS, which combines 4 baseline clinical parameters, may help to identify NSCLC patients with increased probability to be benefitted from ICIs treatment. Further evaluation and possibly combination with other factors may multiply its clinical significance.
Survival differences between smokers and nonsmokers with EGFR mutated non-small cell lung cancer.
Authors: Macari David , Ibironke Oluwatoyin , Jinna Sruthi , Stender Michael J. , Jaiyesimi Ishmael A. 
Published: May 2020

e21509 Background: Patients with epidermal growth factor receptor (EGFR) mutated lung cancer have an excellent prognosis compared to other non-small cell lung cancer (NSCLC) with no driver mutation, however, there is a wide range of survival between even a cohort with an EGFR driver mutation. Given that many patients with EGFR mutations are never smokers, it is possible that those with a smoking history have tumors with other oncogenic mutations and therefore as their tumors are less dependent on the EGFR driver, they may derive less benefit from targeted therapy. Methods: Pathology specimens of NSCLC sent for EGFR testing between January 1 2012 and December 31 2016 at Beaumont Hospital, Michigan were reviewed. If a tumor harbored a targetable EGFR mutation, the chart was queried. Inclusion criteria were EGFR exon 19 or 21 mutations, stage IV disease, at least 2 time points of follow up. Exclusion criteria included small cell histology, negative EGFR test, or inadequate information in the chart. The primary endpoint of the study was median survival. Results: Out of 329 cases identified, 40 were positive for EGFR exon 19 or 21 mutations. Of the 40 positive cases, 26 fit all inclusion criteria. Median duration of follow up was 14 months (range 0-80). Smokers represented 13/26 (50%) of cases. Death occurred in 9/13 (69%) of smokers vs 7/13 (54%) in non-smokers. Median survival was 8 mo (0-26) vs 20 mo (1-80) respectively for smokers vs non-smokers. Conclusions: This data suggests there may be a clinically relevant difference in the survival between smokers and nonsmokers who have NSCLC with an EGFR driver mutation. This may be due to the relatively low burden of alternative driver oncogene mutations in the nonsmoker’s tumors resulting in a lower likelihood of an escape mechanism for the tumor to survive. Further analysis of larger datasets with complete molecular analysis of the tumors would be informative in exploring this hypothesis. This would aid in risk stratifying patients more effectively for future clinical trials targeting the EGFR mutation and refining the prognosis in this otherwise good prognosis group.