bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between smoking status and lymph node metastasis in Chinese patients with T1 non-small cell lung cancer: A real-world observational study.
Authors: Jiang Feng , Zhao Heng , Li Xiaofei , Liu Lunxu , Liu Yang , Hu Jian , Fu Xiangning , Li Yin , Xu Yijun , Liu Deruo , Yang Haiying , Xu Lin
Published: March 2020

e20012

Background: Smoking and lymph node metastasis (LNM) are widely known to be the important risk factor for the induction and poor prognosis of non-small cell lung cancer (NSCLC) , respectively. However, the association between smoking status and LNM in Chinese patients with NSCLC is largely unknown. Methods: The patients with pathologically diagnosed T1 NSCLC undergoing surgical resection during 2014 to 2017 were retrospectively reviewed based on LinkDoc database. Patients without smoking status in the case records were excluded. Chi-square test was used for comparison between groups. Results: Of the 10,622 patients enrolled, 1,760 patients had LNM (16.6%). For smoking status, 3,260 (30.7%) patients were recorded with smoking history, with an average smoking index (SI) of 221.2. The incidence of LNM especially N2 station LNM in patients who ever smoked was significantly higher than those of never smokers in the enrolled population (22.8% vs. 13.6%, p < 0.001; N2: 14.3% vs. 9.1%, p < 0.001). Similarly, a larger proportion of current smokers than never smokers had LNM (24.0% vs. 13.6%, p < 0.001), and also more current smokers in only N2 station LNM (14.1% vs. 9.1%, p < 0.001). However, no statistically difference was observed in the proportion of patients with LNM particularly with N2 LNM between former and current smokers (24.0% vs. 22.8%, p = 0.401; N2: 14.1% vs. 14.3%, p = 0.887). Compared with non to light smoking (SI < = 400), patients with middle to heavy smoking ( > 400) were found to be more likely to develop LNM (N1/N2: 24.8% vs. 14.6%, p < 0.001; N2: 14.3% vs. 9.8%, p < 0.001). Conclusions: These findings from the real-world study indicated a close association between smoking both former and current and LNM especially N2 station LNM in patients with T1 NSCLC. [Table: see text]
A nomogram to predict outcomes of lung cancer patients after pneumonectomy based on 47 indicators.
Authors: Cheng Bo , Wang Cong , Meng Xue
Published: March 2020

e20014

Background: Nomograms are commonly used tools to estimate prognosis in oncology and medicine.We aimed to establish a nomogram with patients’ characteristics and all available hematological biomarkers for lung cancer patients. Methods: All indexes were cataloged according to clinical significance. Principle component analysis (PCA) was used to reduce the dimensions. Each component was transformed into categorical variables based on recognized cut-off values from receiver operating characteristic (ROC) curve. Kaplan-Meier analysis with log-rank test was used to evaluate the prognostic value of each component. Multivariate analysis was used to determine the promising prognostic biomarkers. Five components were entered into a predictive nomogram. The model was subjected to bootstrap internal validation and to external validation with a separate cohort from Shandong Cancer Hospital. The predictive accuracy and discriminative ability were measured by concordance index (C index) and risk group stratification. Results: Two hundred thirty-six patients were retrospectively analyzed in this study, with 134 in the Discovery Group and 102 in the Validation Group. Forty-seven indexes were sorted into 8 subgroups, and 20 principle components were extracted for further survival analysis. Via cox regression analysis, five components were significant and entered into predictive nomograms. The calibration curves for probability of 3-, and 5-year overall survival (OS) showed optimal agreement between nomogram prediction and actual observation. The new scoring system according to nomogram allowed significant distinction between survival curves within respective tumor-node-metastasis (TNM) subgroups. Conclusions: A nomogram based on the clinical indexes was established for survival prediction of lung cancer patients, which can be used for treatment therapy selection and clinical care option. PCA makes big data analysis feasible.
Can smoking duration alone replace pack-years to predict the risk of smoking-related oncogenic mutations in non-small cell lung cancer (NSCLC)?
Authors: Ogawa Koichi , Kawaguchi Tomoya , Koh Yasuhiro , Isa Shun-Ichi , Kubo Akihito , Ando Masahiko , Saka Hideo , Yoshimoto Naoki , Matsumura Akihide , Kaneda Hiroyasu , Tamiya Akihiro , Taniguchi Yoshihiko , Sawa Kenji , Matsumoto Yoshiya , Izumi Motohiro
Published: March 2020

e20017

Background: P has widely been used for the risk assessment of lung cancer and chronic obstructive pulmonary disease (COPD). We previously reported that mutations in KRAS, TP53, and EGFR were also associated with P from a prospective multicenter molecular epidemiology study (JME study; Kawaguchi T, J Clin Oncol 2016). Recently, D alone has been reported to provide stronger risk estimates of COPD than P. Here, we show the comparison of these two indices in predicting the risk of smoking-related oncogenic mutations in NSCLC, utilizing the database from the JME study including detailed smoking information and the mutational profile by next generation sequencing. Methods: In 439 ever- and 437 never-smokers, the frequency of mutations in KRAS, TP53 and EGFR were 9.4, 26.8 and 42.5%, respectively, and smoking-related cytosine to adenine base substitution (C > A) was observed in 12.7 % of cases. AUC values (area under the ROC curves) for logistic regression determined from P and D to predict the mutations or C > A change were compared, considering gender, age, stage and histology as covariates. Results: The median of P and D were 43 (1-189) and 41 (years, 1-65) in smokers, respectively. The AUC values in EGFR and KRAS were numerically higher than others, suggesting stronger association with smoking. There was no significant difference in AUC values between P and D in TP53, EGFR and C > A, and P was a significantly better estimate of KRAS mutations (table). Conclusions: P remains the standard method to evaluate the risk of oncogenic mutations in NSCLC. D, however, warrants further investigation as a simpler alternative to P.[Table: see text]
Correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC: A retrospective analysis.
Authors: Yu Yao , Lin Rongbo , He Ning , Yang Yadong , Jin Ge , Wang Jianfei
Published: March 2020

e20019

Background: To investigate the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in tumor tissue of patients with NSCLC. Methods: 79 patients with confirmed NSCLC admitted from January 2018 to January 2019 were included. Tumor DNA was isolated from FFPE samples or fresh tissue samples. Mutation profiles were obtained by targeted deep sequencing of 620 selected genes. Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per 1Mbp and divided into tertiles. PD-L1 expression, CD8+ T cell and tumor infiltrating lymphocyte density were evaluated by immunohistochemical analysis. The correlation coefficient of TMB, tumor microenvironment and alterations of driver genes was calculated by chi-square test. Results: Median TMB of these patients is 6.915 Muts/Mbp (4.22-9.44 Muts/Mbp). Prevalence of PD-L1 expression is 28.0% (n = 7/25) at a tumor proportion score cutoff of at least 5% evaluated by Dako 28-8 PharmDx Assay kit and prevalence of CD8+ T cell density is 95.8% (n = 23/24). TP53 mutations are the most common alteration (n = 49/79, 62.0%), followed by EGFR alterations (n = 31/79, 39.2%), CDKN2A alterations (n = 11/79, 13.9%), KRAS mutations (n = 10/79, 12.7%), STK11 mutations (n = 5/79, 6.3%), ALK fusions (n = 4/79, 5.1%) and POLE mutations (n = 4/79, 5.1%). According to results of chi-square test, squamous cell carcinoma has higher TMB (p= 0.023) than adenocarcinoma. Metastatic NSCLC has higher PD-L1 expression (p= 0.049) than non-metastatic NSCLC. Furthermore, EGFR alterations are associated with lower TMB (p=0.020) and POLE mutations are associated with higher TMB (p= 0.015). There are no correlations among CD8+ T cell density, tumor infiltrating lymphocyte density and other variants. Conclusions: Our study highlights the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC. This result may be the reference of anti-PD-1 therapy.
The prognostic value of KRAS mutation subtypes and PD-L1 expression in patients with lung adenocarcinoma.
Authors: Tao Luwei , Sun Jingxin , Mekhail Tarek , Meng Lingbin , Fang Cheng , Du Yuan , Socinski Mark A. , Allen Amanda , Rzeszutko Brenda L. , Chang Chung-Che
Published: March 2020

e20022

Background: KRAS gene mutations are found in 20-30% of non-small cell lung cancer (NSCLC), especially in adenocarcinoma. Compared to EGFR and ALK mutations, KRAS mutation in NSCLC may be associated with poorer prognosis. However, prognostic value of different KRAS mutation subtypes in NSCLC remains unknown. The goal of this study is to evaluate the association of KRAS mutation subtypes, PD-L1 expression and clinical outcome in patients diagnosed with primary lung adenocarcinoma. Methods: A total of 256 patients diagnosed with KRAS mutated (determined by pyrosequencing) lung adenocarcinoma between 2011 and 2015 in AdventHealth-Orlando were evaluated for their cancer staging, Relapse-free survival (RFS) and overall survival (OS). PD-L1 staining was performed in a subgroup of 95 patients from the same cohort. PD-L1 expression was determined with immunohistochemistry staining using Ventana PD-L1 (SP263) assay. Results: In this cohort of patients, 65 had stage I disease, 29 stage II, 49 stage III, 110 stage IV and 3 with no clinical stage information; 104 male, 152 female; median age 67. All patients received standard surgical/chemo/radio therapy according to the disease stages. Only one single patient received immunotherapy. Nine subtypes of KRAS mutation were detected, predominantly in codon 12. Three major subtypes account for 83.6% KRAS mutations, namely G12C (45.7%), G12V (21.9%) and G12D (16.0%). We found that these three major subtypes had no difference in cancer stages (P = 0.58) or brain metastasis at diagnosis (P = 0.78). Kaplan Meier analysis also showed similar OS and RFS among all KRAS subtype. 34% of KRAS mutated patients were found to be PD-L1 positive with tumor proportion score of greater than or equal to 1. PD-L1 expression status was indistinct among the three major mutation subtypes (P = 0.38). Of interest, among patients with G12C mutation, positive PD-L1 expression was associated with significantly shorter OS (5.7 vs 12.8 months; P = 0.007). In contrast, for patients with other KRAS mutation subtypes, PD-L1 expression status had no impact on OS (P = 0.63). Conclusions: The clinical courses, including tumor stage at diagnosis, presence of brain metastasis, OS and RFS, are similar among lung adenocarcinoma patients with different KRAS mutation subtypes. Additionally, PD-L1 expression status appears to be independent of KRAS mutation subtypes. Of note, concurrent PD-L1 expression and G12C mutation is associated with particularly poorer prognosis. Further study is needed to see if PD1/PD-L1 block may improve outcome of this group of patients.
Outcomes among patients with a history of substance abuse in non-small cell lung cancer: A county hospital experience.
Authors: Concannon Kyle , Thayer John Henry , Hicks Roxana , Wu Vicky , Jenkins Isaac , Baik Christina S , Linden Hannah M.
Published: March 2020

e20031

Background: Insufficient outpatient care among vulnerable patients, such as those with a history of alcohol or illicit substance use disorder (SUD), may contribute to poor outcomes in non-small cell lung cancer (NSCLC). We hypothesize that patients with newly diagnosed localized NSCLC and a history of SUD have a shorter time from diagnosis to last known contact, greater rates of depression, less family support, poorer follow-up, and increased emergency room and inpatient usage compared to those without a history of SUD. Methods: To investigate this, we conducted a retrospective review of all lung cancer patients with localized non-small cell carcinoma (N = 52) with visits between 9/2012 and 9/2018 at an academic county hospital with a dedication to the underserved in a major US city. Data were collected from electronic medical records manually and analyzed using ANOVA for continuous variables or Pearson's Chi-squared for categorical data. Results: Among patients with localized NSCLC (n = 52), 44% had a history of SUD. The mean time from diagnosis to last known contact and rate of loss-to-follow-up among those with a history of SUD vs no history of SUD was: 2.9 vs 4.4 years (p = 0.14) and 26.1% vs 20.7% (p = 0.64) respectively. Patients with history of SUD were more likely to live without family members and have a history of depression, anxiety or PTSD than those without a SUD history; 78.3% vs 44.8% (p = 0.023) and 60.9% vs 20.7% (p = 0.004). In the year following diagnosis the mean percentage of missed appointments, number of ER visits, number of inpatient stays, and total length of inpatient stay for patients with history of SUD vs no history of SUD were: 19% vs 8% (p = 0.01), 3.7 vs 1.4 (p = 0.08), 2.6 vs 0.9 (p = 0.10), and 17.7 vs 5.9 days (p = 0.06) respectively. Conclusions: In this retrospective analysis of patients with localized NSCLC, those with a history of SUD had shorter time from diagnosis to last known contact without increased rates of loss-to-follow-up. They also had greater rates of depression, less family support, increased rates of missed appointments, more emergency room visits, increased hospitalizations, and increased total duration of inpatient stay in the year following their diagnosis.
Longitudinal tumor size and NLR as predictive factors of individual survival compared to their baseline values in patients with non-small cell lung cancer treated with durvalumab.
Authors: Zhudenkov Kirill , Gavrilov Sergey , Peskov Kirill , Helmlinger Gabriel , Aksenov Sergey
Published: March 2020

e20047

Background: Our ability to accurately predict survival of patients with non-small cell lung cancer (NSCLC) while on treatment is limited. Prognostic markers such as stage and tumor size are well established, while neutrophil-to-lymphocytes ratio (NLR) and other hemogram measurements have recently been studied. Gain in prognostic accuracy of these markers when measured longitudinally has not been established. Methods: There were 679 NSCLC patients (Stage 3 or 4, ECOG PS 0 or 1) from clinical studies of durvalumab 10 mg/kg every two weeks (NCT02087423 and NCT01693562). We developed three models of overall survival (OS) all with ECOG as covariate: a Cox proportional hazards model with baseline tumor sum-of-longest-diameters (SLD) and NLR as covariates (COX); a joint model of OS and longitudinal SLD and baseline NLR (JM SLD); and a joint model of OS and longitudinal SLD and NLR (JM SLD&NLR). We compared prognostic accuracy of these markers measured longitudinally vs. at baseline, using predicted probability of OS at 12 months after start of durvalumab as a prognostic score. We evaluated predictive performance of the models using area under the receiver-operating characteristic curve (ROC AUC) describing trade-off between true and false positives (i.e., survival past 12 months). The AUCs were calculated for patients in the dataset using longitudinal data up to different cut-offs. Results: The AUC for all patients starting durvalumab using baseline ECOG, SLD and NLR was 0.73, while it decreased to 0.64 for patients surviving to 6 months, compared to 0.50 for noninformative models. The AUC using longitudinal information for SLD and NLR was larger the more longitudinal data was used for prediction and was 0.81 using 6 months’ worth of data. Conclusions: Using longitudinal information for SLD and NLR increased individual predictive performance of these markers compared to only baseline information in NSCLC patients. [Table: see text]
Report of four cases of pulmonary malignant tumors treated with SBRT using BODYFIX plus 4D-CBCT image guidance technique.
Authors: Wu Lei , Li Tao , Wang Qifeng
Published: March 2020

e20050

Background: To monitor the range of motion in SBRT treatment of lung tumors by using BODYFIX combined with four-dimensional cone beam CT (4D-CBCT), and provide evidence for delineating the reasonable internal target area (ITV) of lung cancer, and observe the short-term outcom of treatment and treatment of complications. Methods: 4D-CT was used to locate CT scan, delineate the GTV of the tumor, make a simple radiation treatment planning, determine the treatment center point, and then use line accelerator 4D-CBCT to perform pre-SBRT treatment on 4 patients with lung malignant tumor. The system automatically reconstructs the image and matches the CT image of the treatment plan to obtain the placement error of the patient in the head and foot (SI), left and right (LR), and front and rear (AP) directions. The double registration technique is used to correct the correction first. Positioning error, the 4D-CBCT dynamic image is again registered with the target area, the range of motion within the tumor is observed, and the time-weighted 4D-CBCT image is transmitted back to the Monaco planning system to delineate the target area to accurately determine the range of the ITV. According to this target area, a radiation treatment planning was developed, GTV 20Gy/f, 1 to 3 fractions, and then 4D-CBCT scan was performed in each SBRT treatment to observe the range of tumor motion in real time. Results: 3 of the 4 patients the lung tumors were CR at 3 months after treatment, and 1 patient was SD. No serious complications occurred during the treatment or within 3 months after radiotherapy. Conclusions: The BODYFIX plus 4D-CBCT image can more accurately outline the ITV range of lung cancer. The patient is well tolerated and the short-term outcom is good.
The relative impact of patient and institutional rurality on lung cancer disparities.
Authors: Ray Meredith , Faris Nicholas Ryan , Derrick Anna , Smeltzer Matthew , Osarogiagbon Raymond U.
Published: March 2020

e20052

Background: We quantified variation in stage specific, guideline concordant treatment and examined the interaction with rurality and overall survival (OS). Methods: We used tumor registry data for non-small cell lung cancer (NSCLC) patients at 5 institutions in the Mississippi Delta from 2011-2017, including patient demographics, clinical stage, treatment, and OS. We defined rurality by Rural-Urban Commuting Area codes, hospital and patient zip codes; based stage-stratified treatment on National Comprehensive Cancer Network guidelines; used Chi-squared and ANOVA F-tests to assess differences across institutions and logistic regression to assess associations between appropriate care, patient- and institution-level rurality. We used Log-rank tests to examine differences in OS and Cox proportional hazard regression to calculate hazard ratios (HR). Results: 6,259 patients were identified across 2 rural (n = 1255, 20%) and 3 metropolitan (metro) institutions (n = 5004, 80%). There were significant demographic and clinical differences between institutions: proportion of African-Americans (range: 6-37%, p < 0.001), uninsured (3-18%, p < 0.001), patient rurality (17-99%, p < 0.001), ‘no treatment’ rates (17-31%, p < 0.001). Metro patients or those treated at metro institutions were more likely to receive guideline-concordant treatment (odds ratio: 1.34, 95% CI [1.20 - 1.49]; 1.45 [1.28 - 1.65], respectively) than their rural counterparts and had improved OS (HR: 0.89; 95% CI [0.84 - 0.95]; 0.68 [0.63 - 0.72], respectively). They were also less likely to receive ‘no treatment’ (0.62 [0.55 - 0.71], p < 0.001; 0.51 [0.49 - 0.66], p < 0.001, respectively). Among patients with proper care, there were no patient-level rurality based OS differences (p = 0.2203) but those treated at metro institutions had better OS (p < 0.001). When stage-stratified, only advanced-stage patients treated at metro institutions had better survival (p < 0.001), no other differences in OS were detected for early or late-stage patients. Conclusions: Institution-level rurality had greater influence than patient-level rurality on receipt of guideline concordant care and OS. Appropriate care eliminated patient-level rurality OS disparities.
Therapeutic targeting of polyamines in malignant pleural mesothelioma xenograft models.
Authors: Ho James C. M. , Yan Sheng , Lam Sze Kwan
Published: March 2020

e20060

Background: Although the use of asbestos has been restricted, the incidence of malignant pleural mesothelioma (MPM) is still rising. The US FDA approved a combination of pemetrexed with cisplatin for treatment of unresectable MPM. And development of novel adjuvant therapeutic options for resected early-stage disease is also urgently needed. From our preliminary data, ornithine decarboxylase (ODC) is highly expressed in MPM xenografts and clinical tumor samples. Upregulation of ODC increases polyamines production and enhances tumor growth. a-difluoromethylornithine (DFMO) is a specific ODC inhibitor. This study aims to disclose the adjuvant (minimal residual disease setting) and therapeutic (metastatic setting) effects of DFMO in MPM xenografts. Methods: In adjuvant therapy setting, nude mice were fed with DFMO in drinking water 7 days before subcutaneous inoculation of 200,000 tumor cells. In therapeutic setting, 107 corresponding cells were injected subcutaneously into nude mice which were randomized for treatment after established tumor growth. Mice with tumor size > 600mm3 were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentration, and apoptosis were investigated by Dot plot, Western blot, ELISA, and TUNEL assay respectively. Results: In adjuvant therapy setting, DFMO suppressed tumor growth and increased median survival in both 211H and H226 xenografts. In H226 xenografts, 43% of treated mice have not yet reached humane endpoint, mimicking long-term survival. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, and activation of apoptosis were observed in both xenografts. In addition, increase in nitrosocysteine level, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesions and inhibition of Akt/mTOR pathway were induced by DFMO in H226 xenografts, which may explain higher potency of DFMO in these xenografts. In therapeutic setting, DFMO also suppressed tumor growth in both xenografts with similar mechanisms. Conclusions: DFMO may have a potential role as adjuvant therapy in MPM especially epithelioid mesothelioma.
Survival meta-analysis from fifteen years of a standard systemic therapy in malignant pleural mesothelioma.
Authors: Friedberg Joseph S. , Culligan Melissa
Published: March 2020

e20066

Background: Malignant pleural mesothelioma is a rare malignancy with an annual incidence of 3,000 cases in the US and is still considered incurable. The standard of care for this cancer, a combination of pemetrexed and a platinum drug, was established in 2003 as the result of a landmark study that reported a median overall survival of 12.1 months for this combination in patients not eligible for surgery. The aim of the current analysis was to determine if there has been a change in the outcome for this population in the past 15 years. Methods: A PubMed search was performed and 9 prospective, randomized or single arm (minimum n = 50), trials were selected. All studies included patients treated using pemetrexed in combination with platimun as front line therapy in unresectable mesothelioma patients. Average and weighted average OS were calculated and also corrected per the reported odds ratio for survival between the epithelioid and non-epithelioid histologies. Results: The average OS was 12.9 months and the weighted average OS was 13.3 months (range: 8.5 – 16.1 months). The two studies showing the highest median OS (MAPS and LUME-meso) had a higher percentage of tumors with epithelioid histology, which could explain their favorable outcome. Adjusting the average OS using the reported odds ratios for survival between epithelioid and non-epithelioid histologies eliminated the superior outcome in these studies. Furthermore, correcting average survival per the original ratio between tumor histologies for all studies included in the meta-analysis showed an average and weighted average OS lower than 13 months. Conclusions: This analysis strongly supports the contention that survival results for nonoperative patients with mesothelioma should be stratified by histology, epithelioid versus nonepithelioid, similar to the trend in the surgical mesothelioma literature. When factoring in histology, it appears that overall advances in patient care and additional treatments have not significantly changed the overall survival for nonoperative mesothelioma patients in the last 15 years. This meta-analysis underscores the desperate need for new and innovative treatments for this cancer.
Predictors associated with development of pleural and pericardial effusions in patients with small cell lung cancer treated with third-line therapy.
Authors: Jiang Rui , Koch Martina , Gulbranson Scott , Komarnitsky Philip B. , Papademetriou Eros , Tyczynski Jerzy Edward
Published: March 2020

e20088

Background: Pleural (Pl) and pericardial (Pc) effusions are often encountered clinical problems in patients with lung cancer, contributing to a poor quality of life. Population-based data on predictors for Pl and Pc effusions in small cell lung cancer (SCLC) are scarce, particularly, in later lines. Methods: We estimated the predictors for treatment-emergent Pl and Pc effusions in SCLC patients treated with third-line of therapy (LOT) using Optum’s electronic health records (EHR) de-identified database. Of 8,291 patients with newly diagnosed SCLC between 01/01/2008 and 09/30/2016, 428 patients received 3rd LOT. Pc/Pl effusions were identified by a combination of ICD-9/ICD-10 codes, procedures, or natural language processing (NLP) SDS term and sentiment. Each patient contributed to follow-up time from start of 3rd LOT to the day prior to start of next LOT or earlier of (loss to follow-up date or 365 days from end of 3rd LOT) if there was no subsequent LOT, or first occurrence for those with an outcome event. Stepwise Cox regression with sle = 0.25 and sls = 0.10 was applied for variable selection. Results: At start of 3rd LOT, median age was 65, 46% were male, 97% had extensive disease (excluding n = 53 with missing staging). Cardiac history, pulmonary history, renal impairment (eGFR < 60 mL/min/1.73m2), prior Pl and Pc effusion, albumin levels below 3.5 g/dl, sodium levels below < 136 mmol/l, treatment regimens (others except platin-containing vs. topotecan mono) was each associated with increased risk of Pl effusions. Cardiac history, prior Pl and Pc effusion, and region (South vs. Midwest/West) was each associated with increased risk of Pc effusions. When the stepwise Cox regression was applied, cardiac history, prior Pl effusion, and treatment regimens were selected as significant predictors of Pl effusions (p < 0.05). Prior Pc effusion and cardiac history were selected as significant predictors of Pc effusion (p < 0.05). Conclusions: Awareness of the determinants associated with development of Pl and Pc effusions in SCLC patients treated in third-line therapy may aid in earlier recognition of patients at risk and lower the risk of developing Pl/Pc effusions in this group of patients.
A novel mutation panel for predicting etoposide in small cell lung cancer.
Authors: Luo Peng , Qiu Zhengang , Lin Anqi , Li Kun , Lin Weiyin , Wang Qiongyao , Wei Ting , Zhu Weiliang , Zhang Jian
Published: March 2020

e20090

Background: Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC. Methods: The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC); the data regarding of sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide. Results: Receiver Operating Characteristic(ROC) analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve (AUC) = 0.804 (95% confidence interval (CI): 0.679-0.930, p < 0.001). Conclusions: This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.
Thoracic radiotherapy in a cohort study of patients with metastatic small-cell lung neoplasms.
Authors: Mañes Anabel , Jove Josep , Antelo Gabriela , Esteve Anna , Arellano Antonio , Caro Monica , Luguera Ernest , Ballester Rosa , Tuset Victoria , Planas Isabel , Rosales Hugo , Baena Eduardo , Villà Salvador
Published: March 2020

e20093

Background: Thoracic radiotherapy (TRT) for extensive stage small-cell lung cancer (ES-SCLC) patients is controversial. Slotman et al. (2015) demonstrated a 2-year overall survival (OS) benefit for patients who received TRT after chemotherapy (CT) and prophylactic cranial irradiation (PCI), but obtaining a median OS of 8 months (m). We wanted to confirm results of Slotman’s work in a real-world setting with higher doses of TRT. Methods: We retrospectively reviewed 67 patients with ES-SCLC treated between 1995 and 2015, after completing CT administration. Patients with initial brain metastasis and those who rejected PCI were excluded. All of them received PCI. All patients were followed until death. Disease-specific survival (DSS), disease-free survival (DFS) and OS were analyzed and computed with Kaplan-Meier method, groups were compared with log-rank test. Adjusted hazard risk (HR) of death for TRT was estimated through multivariate Cox model. Results: Patients (59 male, 8 female) with median age 64 years (42-79) had a median Karnofsky performance status (KPS) of 80. Twenty-three patients received high doses TRT (mean dose: 45.4 Gy). No significant differences between groups were found in age, gender, KPS, number of metastatic sites, residual thoracic disease or smoke activity. Non-TRT patients had more metastatic lesions. Median OS for TRT-patients was 19.9 m and 11.2 m for non-TRT patients (p = 0.01). DSS was 23.4 m for TRT-patients and 13.5 m for non-TRT patients (p = 0.007). For TRT-patients and non-TRT patients, median DFS were 15.5 and 8.3 m (p = 0.001), respectively. In the multivariate analysis, TRT (p = 0.003, HR 0.35), KPS (p = 0.012, HR 0.95) and residual thoracic disease (p = 0.02, HR 3.30) were independent prognostic factors for survival. The best benefit was obtained for those patients with consolidative TRT (CTRT): OS of 24.7, DSS of 27.4 and DFS of 15.9 m, compared with 13.4 (p = 0.003), 13.9 (p = 0.003) and 8.5 m (p = 0.007), respectively, for patients not treated with CTRT. Conclusions: TRT impacts positively in OS, DSS and PFS and should be administered to ES-SCLC patients who complete CT and PCI. High TRT doses could achieve better results than those described for low TRT doses.
Defining the role of RUNX1T1 in "combined" small cell lung cancer.
Authors: He Tian , Wildey Gary , McColl Karen , Kresak Adam , Tan Aik-Choon , Dowlati Afshin
Published: March 2020

e20101

Background: The RUNX1T1 gene, also known as ETO, was first identified in the fusion transcript AML1/ETO, generated by the translocation between chromosome 8 and 21, which occurs in 12%-15% of AML. We recently discovered that RUNX1T1 was specifically amplified only in the small cell lung cancer (SCLC) but not the non-small cell lung cancer (NSCLC) component of combined SCLC tumors. Here, we investigated if RUNX1T1 expression plays a role in transforming NSCLC to SCLC in combined SCLC tumor formation. Methods: We examined tumors from 92 of our SCLC patients by targeted exome and CNV analyses. RUNX1T1 mRNA expression was determined in various cancers by analysis of the CCLE and TCGA databases. RUNX1T1 mRNA expression was detected by RNAscope analysis of another 22 patient SCLC tumors. Stable overexpression of RUNX1T1 in NSCLC and SCLC cell lines used commercial RUNX1T1 lentiviral constructs. The resulting stable cell lines were analyzed by RT-qPCR, western blotting, Affymetrix gene array, and E2F-luciferase assays. Results: We found that 2 of 2 patients with combined SCLC demonstrated RUNX1T1 amplification in the SCLC component. Notably, only 2 of the remaining 90 patients with pure SCLC demonstrated RUNX1T1 amplification. RUNX1T1 mRNA is highly expressed in SCLC compared to the majority of other cancers, including NSCLC, using either CCLE or TCGA databases. Western blots confirmed higher RUNX1T1 protein expression in SCLC vs NSCLC cell lines, and RNAscope analysis confirmed greater RUNX1T1 mRNA expression in SCLC vs NSCLC patient tumors. When we stably overexpressed RUNX1T1 in NSCLC cell lines, there was no increase in neuroendocrine protein expression, however we did find an increased sensitivity to etoposide. Bioinformatic analysis of microarray data demonstrated significantly altered E2F pathway activity, and we could show a significant increase in E2F-luciferase activity after RUNX1T1 overexpression. Interestingly, this was associated with decreased p21 expression, which is a putative suppressor of E2F activity. Conclusions: RUNX1T1 expression is specifically upregulated in SCLC compared to NSCLC. E2F pathway activity is elevated after RUNX1T1 overexpression, consistent with an increased SCLC phenotype.
Immunotherapy plus chemotherapy versus chemotherapy alone in metastatic non–small-cell lung cancer: A systematic review with meta-analysis.
Authors: Sasse Andre Deeke , Ferreira Fernanda Proa , Scherr Adolfo Jose de Oliveira , Cunha David Pinheiro , Vasconcelos Vivian Castro Antunes , Ramalho Susana Oliveira Botelho , Conceicao Vinicius Correa , do Carmo Rafael Luis Moura Lima
Published: March 2020

e20700

Background: Palliative systemic therapy is the primary approach for stage IV non-small cell lung cancer(NSCLC). For patients with NSCLC that lacks targetable mutations, immunotherapy alone or in combination with chemotherapy has become a promising alternative, focusing survival and quality of life. Our objectives were to review, summarize and compare the evidence of immunotherapy plus chemotherapy in first-line treatment in comparison with chemotherapy alone in patients with metastatic NSCLC in terms of effectiveness. Methods: A systematic review of randomized controlled trials (RCTs) was planned. PubMed, Embase and Lilacs were searched for trials evaluating metastatic NSCLC patients, comparing chemotherapy alone versus chemotherapy plus anti-PD1, anti-PDL1 or anti-CTLA-4 agents. Four investigators independently extracted characteristics and results of identified studies and performed standardized quality ratings. Meta-analyses for overall survival (OS), progression-free-survival (PFS), overall response rates (ORR) and toxicities were performed. Results: Six RCTs met the inclusion criteria. One trial with anti-PD-L1 (Atezolizumab), three trials with anti-PD-1 (Pembrolizumab) and two trials with anti-CTLA-4 (Ipilimumab) were included. Three trials included non-squamous carcinomas, two trials included squamous cell carcinoma and one trial included all NSCLC. The combination of anti-PD-1 or anti-PDL1 to chemotherapy improved OS (Hazard Ratio [HR] for death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; p < 0.0001). This combination also improved PFS (HR for progression or death, 0.57; 95% CI, 0.51 to 0.63; p < 0.00001) and ORR (Odds Ratio [OR], 2.55; 95% CI, 1.80 to 3.61; p < 0.00001). The combination of anti-CTLA-4 to chemotherapy slightly increased the PFS (HR 0.84; 95% CI, 0.73 to 0.96; p = 0.01), but not OS (HR 0.92; 95% CI, 0.80 to 1.05; p = 0.21) or ORR (OR 0.92; 95% CI, 0.71 to 1.19; p = 0.52). General and immune mediated adverse events were higher in all combination groups. Conclusions: In patients with previously untreated metastatic squamous and non-squamous NSCLC without EGFR or ALK mutations, the addition of anti-PD-1 or anti-PD-L1 to standard chemotherapy resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.
Decreasing BMI/weight immediately prior to starting anti-PD-1/PDL-1 monoclonal antibodies for treatment for stage IV non-small cell lung cancer is associated with shorter progression-free survival.
Authors: Kollipara Revathi , Fughhi Ibtihaj , Batus Marta , Basu Sanjib , Borgia Jeffrey Allen , Bonomi Philip D. , Fidler Mary J.
Published: March 2020

e20710

Background: Currently, prognostic markers associated with immunotherapy treatment outcomes in patients with metastatic NSCLC include PDL-1 expression, tumor mutational burden (TBM), and neutrophil to lymphocyte ratio (NLR). In this study we examine the influence of pretreatment changes in weight, BMI, and NLR in 237 patients treated with anti-PD-1/PDL-1 therapy (ICI) at our institution. Methods: This was a retrospective analysis of previously-treated stage IV NSCLC patients who received ICI. Pretreatment (≥ 6 weeks before starting therapy) values of weight, BMI, and NLR were compared to baseline values and NLR was analyzed as continuum and according to standard cutoffs of 3.5 and 5. The same variables were correlated with progression-free survival (PFS) and overall survival (OS) using the Log-Rank test. Results: 237 patients were analyzed: 45% were male, 73% were Caucasian, 72% were former smokers, and 25% were age ≥ 75 years. 148 patients had pretreatment NLR values. Of these, 32% had a ratio < 3.5 and 54% had ratio < 5. 34% had increased NLR at baseline, the majority of which (48/77) had a > 5% increase. 187 patients had pretreatment weight and BMI. Of these, 14% had a pretreatment BMI < 20. 71% had a negative change in BMI and 29% had a > 5% decrease in BMI. 65% had a negative change in weight and 26% had a > 5% decrease in weight. BMI decrease greater than 5% (p = 0.0039), negative weight change (p = 0.0371), and pretreatment NLR > 5 (p = 0.0136) were associated with shorter PFS. Change in NLR trended towards decreased PFS but was not statistically significant (p = 0.07) though only 77 of 237 patients had both values available. There was no statistical PFS difference between patients less than or ≥ 75 years old. Conclusions: The results suggest that decrease in pretreatment BMI and weight along with high baseline NLR are associated with significantly shorter PFS in NSCLC treated with anti-PD-1/PDL-1 therapy. If confirmed, these observations raise the possibility that specific treatment which reverses cancer associated weight loss might enhance effectiveness of immunotherapy.
Precision medicine for lung cancer decision-making: Evaluation of an -omics based FFT approach to personalized medicine.
Authors: Mambetsariev Isa , Djulbegovic Benjamin , Pharaon Rebecca , Hewelt Blake , Massarelli Erminia , Koczywas Marianna , Reckamp Karen L. , Salgia Ravi
Published: March 2020

e20713

Background: The prevalence of next-generation sequencing and the availability of a large number of targeted therapies in the clinics, has complicated treatment decision-making in lung cancer. While national guidelines and commercial pathways offer a method to improve the oncologists’ adherence to appropriate testing and treatment modalities available, more effort is required to solidify this as a standard of care model at academic and community sites. A better understanding of the improved durable survival of targeted therapy assignment compared with non-targeted therapy outside of the clinical trial setting is needed to understand the efficacy and accuracy of precision medicine. Methods: We perform an in-depth analysis of a series of lung AD patients (n = 798) with genomic and clinical data in a recently created thoracic patient registry, who were treated at COH between 2009-2018 period. Results: 798 individuals with lung AD were identified in the Thoracic Oncology Registry who were treated or were intended to be treated at COH; 662 (83%) of the patients had genomic testing performed at the request of their treating oncologist and 460 (58%) of whom received a 1st-line targeted therapy decision (including clinical trial assignment based on bio-marker). Oncogenic alterations were detected in 653 (82%) patients with the majority presenting with EGFR (47%), who were mostly treated with erlotinib (78%). 462/653 (70%) patients had an alteration detected with an available FDA approved therapy and 90% (416/462) of the patients were appropriately matched to a targeted therapy based on the oncologist’s decision. Several decision-making algorithms were tested and fast-and-frugal trees (FFTs) proved superior with a positive predictive value (PPV) of 90% and only required two important cues in informing the decision of the type of treatment to give to the patient. Furthermore, a targeted therapy treatment decision showed a significant benefit with a median OS of 38 months as compared to 22 months in the non-targeted therapy decision-making group (p < 0.00001). This was also evident in the PFS analysis where targeted therapy decision-making had a median survival of 9 months as compared with 5 months in the other groups (p < 0.00001). Conclusions: FFTs are a novel tool to test the efficacy of precision medicine in a real-world setting and can provide a more streamlined method for clinical guidance and decision-making. FFTs were able to predict with 90% PPV a precision medicine decision that was correlated with improved PFS (9 vs 5 months) and OS (38 vs 22 months).
Trends in immunotherapy use and survival impact in stage IV non-small cell lung cancer.
Authors: Otaibi Zachary , Kamran Amir , Wegner Rodney E , Colonias Athanasios , Weksler Benny , Finley Gene Grant
Published: March 2020

e20715

Background: Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. 5-year survival rate for metastatic non-small cell lung cancer (NSCLC) is estimated at 4%. For patients who lack a driver mutation, platinum based chemotherapy had been the cornerstone treatment, but the addition of immunotherapy has altered the treatment landscape for many advanced NSCLC patients. Immunotherapy, with or without chemotherapy, has been demonstrated in many clinical trials to extend survival in both the first-line setting as well as subsequent lines of therapy. While the clinical trial data over the past several years has been robust, less is known about how these agents have fared in routine clinical practice. To understand this better, we utilized the National Cancer Data Base (NCDB) to examine the survival of patients who received immunotherapy for stage IV NSCLC. Methods: We queried the NCDB from 2004-2015 for patients with stage IV NSCLC treated with chemotherapy and at least 3 months of follow-up. Multivariable logistic regression was used to determine predictors of immunotherapy use. Multivariable cox regression was used to determine predictors of overall survival. A propensity score was calculated and used to mitigate indication bias. Results: Of 203,069 eligible patients, 5,877 received immunotherapy. The median age was 65 years (40-90). The median follow up was 10.6 months (3-154). Patients were more likely to receive immunotherapy if they were younger, had a lower comorbidity score, received treatment at an academic facility, had adenocarcinoma histology, private insurance, Caucasian race, and a more recent treatment year. The use of immunotherapy rose steadily across the dataset years, rising from 1% to 12%. Predictors of survival were younger age, lower comorbidity score, lower grade tumor, treatment at an academic facility, higher education, higher income, private insurance, metropolitan location, immunotherapy use, adenocarcinoma histology, and more recent year of treatment. On propensity-matched Kaplan-Meier analysis patients treated with immunotherapy in addition to chemotherapy had improved survival, 13.7 months compared to 11.8 months, p < 0.0001. Conclusions: This analysis demonstrates improved overall survival in stage IV NSCLC patients who received immunotherapy. There are inherent limitations of retrospective analyses of data from large databases, however the survival improvement noted in this study is concordant with the more robust prospective clinical research published to date.
Mature, real world progression-free survival (PFS) and overall survival (OS) milestones in stage IV, non-squamous, non-small cell lung cancer patients (nsqNSCLC) treated with first line pemetrexed(Pem)/platinum(Plat) followed by pem+/-bevacizumab(Bev) maintenance.
Authors: Bhatt Parva Kiran , Fughhi Ibtihaj , Basu Sanjib , Fidler Mary J. , Borgia Jeffrey Allen , Bonomi Philip D. , Batus Marta
Published: March 2020

e20721

Background: Pemetrexed maintenance therapy is associated with superior survival in stage IV nsqNSCLC patients. We have observed long term disease control in some patients treated with at least one cycle of Pem/Plat with potential for maintenance pem. There are no reports of data regarding long term PFS and OS in patients treated with Pem regimens. The objectives of our retrospective analysis are to determine the frequency of long term disease control on Pem maintenance and to identify parameters associated with longer PFS/OS. Methods: We included all patients with Stage IV nsqNSCLC who received at least one cycle of pem/plat between May 2010 and Nov 2013. We identified 240 patients from our database and analyzed their demographics, lab values, dates of therapy, and dates of progression. PFS/OS was estimated by the Kaplan-Meier method and associations with patient characteristics were assessed by log-rank tests and Cox proportional hazards analysis. The shortest potential follow up was 5 years. Results: Median age was 66 years, 60% were female, and 72% were Caucasian. Baseline ECOG performance status was 0(22%), 1(50%) and ≥ 2(22%). Median PFS was 6.2 months. At 1, 2, 3, 4, and 5 years of follow up absence of disease progression was seen in 33%, 14%, 7.5%, 4%, and 3%, respectively. Additionally, in terms of OS at 1-5 years, we observed 54.5%, 35%, 21%, 14%, and 11%. Lower baseline neutrophil: lymphocyte ratio (NLR) was strongly associated with improved PFS when using NLR≤5 vs > 5 (median PFS 13.2 mo vs 5.6 mo) Additionally, baseline Hemoglobin (mean = 12.03 g/dL, HR = .904, p = .0046) and Albumin (mean 3.3 g/dL, HR = .7722, p = .024) were associated with better PFS. Conclusions: The similarity in median PFS in our patients (6.2 mo) and clinical trial data suggests that our group of real world patients did not have uniquely favorable baseline characteristics. However, the patients most likely to reach long PFS/OS milestones had favorable baseline prognostic indicators suggesting that this patient subset might also be most likely to benefit from the recently approved regimen which combined Pembrolizumab with Pemetrexed/Carboplatin.