bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational recognition of lncRNA signature of tumor-infiltrating activated CD4+ memory T cells with potential implications in prognosis and immunotherapy of lung adenocarcinoma.
Authors: Liu Shengbo , Li Qiaxuan , You Peimeng , Qiu Hongrui , Zhou HaiYu
Published: June 2023

e20519

Background: CD4 memory T cells are an important components of the tumour microenvironment and influence tumourigenesis and progression. However, it has not been determined whether lncRNAs in lung adenocarcinoma (LUAD) play a role in activated CD4+ memory T cells (CD4amT). Methods: The LUAD dataset acquired by The Cancer Genome Atlas was used as a training cohort (TCGA-LUAD). For the validation cohort, we used the combination of lung adenocarcinoma datasets from GENE EXPRESSION OMNIBUS database acquired 2 LUAD datasets, and set as the validation cohort (GEO-LUAD). Lung cancer immunotherapy cohorts have been published to test immune responses. The CIBERSORT algorithm was used to assess immune cell infiltration of tumours. Univariate Cox analysis was used to screen for prognostic CD4amT-related lncRNAs (CD4amTRL). LASSO analysis and multivariate Cox analysis were then performed to construct model for prognostic lncRNAs, the effects of which were assessed by Kaplan-Meier curves and subject operating characteristics (ROC). Patients were divided into high and low risk groups based on CD4amTRL signature. We have analyzed differences in enrichment pathways between the two groups and subsequently we investigated genes associated with the cancer-immune process, the immune microenvironment, immunotherapy responses and multiple anti-cancer drug sensitivity correlations. Results: In the two LUAD cohorts, compared with the high infiltration of CD4amT, those in the low infiltration group had better OS benefits (TCGA-LUAD: HR = 0.678; P = 0.028; GEO-LUAD: HR = 0.435; P < 0.0001). We identified 6 prognostic CD4amTRL and constructed prediction models. cd4 CD4amTRL signature distinguished significantly different OS between the high-risk and low-risk groups of TCGA-LUAD (HR = 4.26). The AUCs predicting 1-, 3- and 5-year survival were 0.737, 0.715 and 0.722, respectively. In the GEO-LUAD dataset, the HR was 2.03, while the AUCs predicting 1-, 3- and 5-year survival were 0.719, 0.681 and 0.630, respectively. The risk score model independently predicted OS in LUAD patients and was associated with immune checkpoints. Numerous genes related to the cancer-immune process were highly correlated. In addition, the risk model was significantly associated with multiple immune microenvironment features (p < 0.001). OS was significantly different between the two immunotherapy cohorts in the high- and low-risk groups for CD4amTRL signature (P < 0.001). Conclusions: Our novel risk model developed based on CD4amTRL signatures can aid in predicting clinical prognosis and guiding treatment in patients with LUAD.
Effects of concomitant chronic obstructive pulmonary disease on immune microenvironment in non-small cell lung cancer patients.
Authors: Lin Lin , Chen Rui , Lin Xiaoling , Zhuan Sunyongxun , Li Jianguo , Hu Xue
Published: June 2023

e20522

Background: Chronic obstructive pulmonary disease (COPD) as a progressive deterioration of lung function, has caused significant morbidity and mortality, especially in developing countries. Persistent lung inflammation and potential lung stroma remodeling in COPD may be important causes of lung cancer. Previous studies have shown that non-small cell lung cancer (NSCLC) patients with COPD have a worse prognosis than those without, but the reasons have not been determined. Due to the increasing application of ICIs in the NSCLC, the characteristics of the immune microenvironment in the NSCLC patients concomitant COPD are worth exploring. Methods: Immune microenvironment and the next generation sequencing (NGS) data of twenty NSCLC patients from Sun Yat-sen Memorial Hospital were analyzed. Formalin-fixed paraffin-embedded biopsy tissue before first-line treatment to prepare tumor tissue slides. Samples were stained using an Opal automation mIF Detection Kit (Akoya) for immune cells. The immune cell infiltration were reported as percentages and density from each individual cell subpopulation in the tumor or stromal area. The landscape of gene mutantions was obtained by NGS detection of 733-gene panel, sequencing depth was 35000x. Results: There were 8 (40%) patients concomitant COPD, and the median age was 65.5-year-old. Analysis the immune cell infiltration in all patients, including T cells, B cells, macrophages and NK cells through 13 markers, showed no difference between COPD and non-COPD groups. However, comparing the differences between tumor and stromal immune microenvironment, it was found that there was a significant difference in the percentages of M1 macrophages between tumor and stromal in COPD group (P = 0.031), but no difference in non-COPD group (P = 0.47). Further analysis of the difference in cell density between tumor and stroma showed that the stromal M1 macrophages in the COPD group was significantly higher than that in the non-COPD group (P = 0.017), as well as PD-1+CD8+ T cells (P = 0.05). Additionally, a preliminary analysis of the gene mutation characteristics had done. In COPD patients with somatic mutations, the most frequently mutated gene was EGFR (60%), followed by TP53 (50%) and GLI2 (50%), which were similar as non-COPD patients. The most common variant of COPD patients are the missense mutation of EGFR L858R, but it was EGFR 19del in non-COPD. Conclusions: The results showed that the COPD was correlated with the infiltration status of M1 macrophages and PD-1+CD8+ T cell, and poor immune cell infiltration in tumor of COPD patients may be the potential influencing factors for the worse prognosis. The characteristics of immune microenvironment suggest that promoting the entry of immune cells from stroma into tumor may be a potential mechanism for the benefit of immunotherapy in NSCLC patients with COPD.
Tumor immune infiltrates and overall survival in non-small cell lung cancer are associated with an unsupervised radiomic signature.
Authors: Oh Jung Hun , Veeraraghavan Harini , Apte Aditya , Tannenbaum Allen , Deasy Joseph O.
Published: June 2023

e20525

Background: We investigated whether radiomic features derived from computed tomography (CT) scans are predictive of survival and are correlated with immune cell types in non-small cell lung cancer (NSCLC), employing a mathematical network-based approach. Methods: DICOM data of pre-treatment CT scans and associated clinical variables for 116 NSCLC patients were downloaded from The Cancer Imaging Atlas (TCIA). RNA-Seq gene expression profiles for the matched cases were downloaded from the GEO database (GSE103584). CIBERSORT scores that consist of 22 immune cell types were generated using the R library (CIBERSORT) on the RNA-Seq gene expression profiles. From contoured tumors on CT scans, 83 radiomic features including tumor volume were extracted, utilizing the CERR radiomics toolbox. Radiomic networks were constructed with a threshold of Spearman correlation coefficient of 0.85 between each pair of radiomic features. The mathematical network-based k-means clustering method was applied to the largest connected network component that consists of 40 radiomic features, using the Wasserstein distance from optimal mass transport (OMT), to minimize the summed distance between k partitioned centroids and their respective data points. For the sub-groups identified, Kaplan-Meier survival analysis was conducted with log-rank test and CIBERSORT scores and clinical variables were then compared among the sub-groups using Kruskal-Wallis test. Results: The median age was 69 years (range: 46–85 years). Eighty-seven patients (75.0%) were males. Most patients were former (N = 75, 64.7%) or current smokers (N = 24, 20.7%). The median follow-up time (last follow-up or death) was 44 months and 75 patients were alive at last contact. The Wasserstein distance-based k-means method resulted in 3 sub-groups (high: N = 32, medium: N = 45, low-risk: N = 39). Kaplan-Meier analysis on the 3 sub-groups showed a significant difference in overall survival with log-rank p = 0.02. There were no significant differences for the variables mentioned above among the sub-groups. Two immune cell types showed statistically significant differences among the sub-groups: mast cells resting with p = 0.004 and M2 macrophages with p = 0.013 using Kruskal-Wallis test. The values for both immune cell types increased from high < medium < low-risk group. There was a significant volume difference with p < 0.001, but the difference did not fully account for the survival difference; the median volume was 30.8 cc, 2.7 cc, and 12.8 cc for high, medium, and low-risk groups, respectively. Conclusions: A radiomic network analysis, utilizing a mathematical network-based method, resulted in sub-groups with the survival difference in NSCLC patients. Furthermore, these sub-groups had significantly different immune cell types likely associated with the survival.
Perioperative IDO-1 dynamic changes in NSCLC patients.
Authors: Sun Zhijuan , Chen Weiwei , Ye Zhenghao , Wang Sichao , Pang Dazhi , Kong Feng-Ming Spring
Published: June 2023

e20532

Background: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that is involved in the metabolism of tryptophan, an essential amino acid. It is known to play a role in the regulation of the immune system, and has been linked to perioperative immune status. Specifically, IDO has been shown to be upregulated in the perioperative period, leading to an increased risk of infection and other complications. This is thought to be due to the increased production of kynurenine, a metabolite of tryptophan, which has been associated with immunosuppression. Additionally, IDO has been linked to increased levels of inflammation and oxidative stress, which can further contribute to the risk of complications during surgery. Thus, understanding the role and dynamic changes of IDO in the perioperative period is important for optimizing patient outcomes. Methods: Patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study prospectively. Peripheral blood at different time points: preoperative, post anesthesia, post-vascular incision, post-tumor resection, and 3 days after surgery. The serum tryptophan and kynurenine were measured, and the kynurenine to tryptophan (K:T) ratio was used as an indicator of IDO activity. Paired Wilcoxon test was used to identify the significant difference of IDO activity at five different time points. The Kaplan–Meier log-rank test was used to assess the correlation between overall survival (OS), progression-free survival (PFS), and IDO activity. Results: A total of 46 patients were enrolled in this study. The median follow-up time was 24.7 (range: 0.9 – 35.3) months. No patients died during the follow-up time. The PFS at 2 years was 76% (95% CI, 76%-100%). In all patients, IDO activity was not correlated significantly with better PFS. Surgical procedure does not affect levels of plasma IDO at any pathological stage in NSCLC significantly. The level of serum IDO of post-vascular incision was significantly correlated with that of 3 days after surgery (R2 = 0.7, P < 0.05). The level of preoperative level of serum kynurenine was significantly correlated with that of post-vascular incision and post-tumor resection (R2 = 0.7/0.73, P < 0.05). Conclusions: Surgical procedure does not have a significant effect on the serum IDO levels during the perioperative period. The perioperative levels of serum IDO are not correlated with the surgical prognosis of NSCLC, thus alternative markers are needed to better predict the surgical prognosis of NSCLC patients.
Tumor immune microenvironment of different lesions in patients with multiple primary lung cancer.
Authors: Li Yun , Qi Yingxue , Luo Ningning , Li Mengmeng , Sun Tingting , Qi Chuang
Published: June 2023

e20549

Background: More and more multiple primary lung cancers (MPLCs) are found clinically. The driver genes and clinical differences between different lesions in MPLCs are obvious, which may affect the choice of subsequent treatment options. As a new type of therapy, immunotherapy has improved the survival of lung cancer patients to a certain extent. However, the efficacy of immunotherapy on different lesions of the same patient with MPLCs is not yet clear. Our study explored the similarities and differences of the tumor immune microenvironment in MPLCs lesions and provided a theoretical basis for immunotherapy in MPLCs. Methods: We collected 20 surgical tumor lesion samples from 10 patients with MPLCs for 289-gene panel RNA sequencing using NanoString nCounter. All tumor tumor immune microenvironment (TIME) cell infiltration scores were calculated as arithmetic mean of the constituent genes. Immune infiltration and expression of immune-related genes in different groups were assessed. Results: All 10 patients in our study were lung adenocarcinoma. Firstly, we classified them using an unsupervised consensus clustering based on TIME-signature gene expression used nonnegative matrix factorization of R package. The results revealed the cluster number of two was optimal (TIME Cluster1: n = 6 patients / 12 lesions; TIME Cluster2: n = 4 patients / 8 lesions). It is worth noting that the two lesions of the same patient are divided into the same group, indicating that the immune microenvironment status of the two lesions of the same person is basically similar. In addition, the nertrophils, NK CD56dim cells and GEP score of Cluster1 is significantly higher than that of Cluster2. Then we grouped them according to gender, ipsilateral or heteroside primary lesions, left or right lung, and pathological infiltration or non-infiltration, and found there was no significant difference in the immune microenvironment between the all the two groups. Conclusions: Dual primary samples from the same individual have similar immune microenvironments and may respond similarly to immunotherapy. Prospective immune-related clinical trials can be designed for further verification in MPLCs patients.
Radiomics to predict checkpoint inhibitor pneumonitis based on chest CT scans in patients with advanced cancer.
Authors: Vos Wim , Cousin François , Wendling Mathieu , Freres Pierre , Guiot Julien , Occhipinti Mariaelena , Hustinx Roland
Published: June 2023

e20550

Background: Checkpoint inhibitor pneumonitis (CIP) is a concerning immune-related adverse event responsible for treatment discontinuation, hospitalization, with acknowledged possible fatal cases. The aim of our study was to assess the potential role of machine learning models, combining pre-treatment CT lung radiomic features with clinical data, to predict the risk of developing CIP. Methods: A cohort of 116 patients with different type advanced malignancies (81% lung cancer, 14% melanoma, 8% other solid tumors) treated with immune checkpoint inhibitors (ICIs) were retrospectively enrolled in this study and divided into a CIP (n = 35) and a control group (n = 81). Each patients had a chest CT scan at baseline and associated clinical covariates. Lungs and lobes were segmented semi-automatically on pre-treatment CT scans. We extracted radiomics features and selected them by the Minimum Redundancy Maximum Relevance (mRMR) method. Clinical-only, radiomics-only, and clinical-radiomics models (both lung- and lobe-based) were built using generalized linear (GLM) and random forest (RF) models to predict the occurrence of CIP. A nested 5-fold cross-validation scheme was used in the training, validation and test sets. Model performances were assessed in terms of Area under the Curve (AUC). Results: The most accurate clinical (RF) and the best radiomic (lobe-based GLM) models achieved AUCs of 0.72 (95%CI:0.51-0.92) and 0.71 (95%CI:0.58-0.84) on the test set, respectively. No statistically significant differences have been found between lung- and lobe-based radiomic models. The RF model combining lung-based radiomic and clinical features showed the best performances overall with an AUC of 0.75 (95%CI:0.62-0.88) on the test set. Conclusions: CT-based lung radiomic, and clinical models alone show moderate to good performances at identifying patients at risk of developing CIP. Nevertheless, we demonstrated the added value of machine learning models built combining clinical and radiomic features to better stratify the risk of developing CIP in patients with advanced malignancies treated with ICIs.
The association of race and curative-intent treatment with mortality outcomes among early-stage NSCLC.
Authors: Liu Qinran , Koru-Sengul Tulay , Lopes Gilberto , Pinheiro Paulo S.
Published: June 2023

e20563

Background: Racial disparities in early-stage non-small cell lung cancer (NSCLC) survival have persisted between blacks and whites in the past few decades. The role of receipt of curative-intent surgery and/or stereotactic body radiation therapy (SBRT) in this disparity is unclear. We examined the associations of race/ethnicity and curative-intent treatment (surgery and/or SRBT) with mortality outcomes among early-stage NSCLC patients, using population-based data from Florida, the third largest state in the US and the second state in the number of cancer cases diagnosed annually. Methods: Florida Cancer Data System (FCDS) data were used to estimate cancer-specific mortality for all patients diagnosed in the state between 2007 to 2018 for each racial/ethnic group: non-Hispanic black (NHB), Hispanic, and Asian/Pacific Islander (API)) and non-Hispanic whites (NHW). FCDS were further individually linked to population-based discharge data (94% match rate) containing patient-level comorbidities and treatment-specific information. Multivariable Cox proportional hazards regression models were applied to study the association of race/ethnicity and curative-intent treatment with lung cancer-specific mortality (LCSM). Competing risk analysis (deaths by other causes) for LCSM was performed. Results: We identified 63,872 early-stage NSCLC patients; 83.2% NHW, 6.6% NHB, 8.7% Hispanic, 0.77% API, and 0.79% other races; 72.2% of patients received curative-intent treatment (surgery and/or SRBT). The median lung cancer-specific survival time for all patients was 5.43 years (95% CI, 5.30-5.56). After inclusion of all clinical and sociodemographic factors including stage at diagnosis and comorbidities, race/ethnicity (NHB vs NHW: hazard ratio [HR], 1.06; 95% CI, 1.00-1.11) and curative-intent treatment (SBRT vs curative-intent surgery: HR, 1.87; 95% CI, 1.78-1.97;) were both independently associated with LCSM. Nevertheless, after combining the effect of race/ethnicity and curative-intent treatment in the same fully adjusted model, NHB patients who received curative-intent treatment experienced nearly identical survival as their NHW counterparts (HR, 0.95; 95% CI, 0.87-1.03). Similar findings were observed in competing risk analysis (subdistribution hazard ratio [sHR], 0.97; 95% CI: 0.89-1.02). Conclusions: In this racially diverse population, receipt of curative-intent treatment revealed comparable survival between NHB and NHW patients. The results underscore the importance of considering receipt of (specifically) curative-intent treatment rather than receipt of any form of surgery or radiotherapy in racial/ethnic survival disparities. The uptake of curative-intent surgery and SBRT, which currently stands at 56.5% and 9.4% respectively, should be increased to improve survival outcomes for early-stage NSCLC for all.
The role of immunotherapy in stage III large cell neuroendocrine carcinoma of the lung (LCNEC): A retrospective NCDB analysis.
Authors: Findakly Dawood , Shi Runhua , Beedupalli Kavitha
Published: June 2023

e20568

Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare lung cancer subtype. Despite advances in understanding lung cancer biology, a consensus on the use of consolidation immunotherapy (IO) in patients with LCNEC is still lacking. Methods: Using National Cancer Database (NCDB), we reviewed stage III lung LCNEC cases diagnosed from 2017 through 2019 with a follow-up through 2020. Several variables were incorporated into the multivariate logistic regression analysis, including age, gender, race, Charlson-Deyo comorbidity score (CDCS), insurance status, and IO use. Survival distribution was examined using the Kaplan-Meier analysis and compared by the log-rank test. Results: A total of 956 cases with a male:female ratio of 1.2:1, and a median age (±SD, range) of 66.4 (±9.7, 37–90) years—baseline characteristics are shown in the Table. In the univariate analysis, IO use (n = 184) resulted in a superior median overall survival (mOS; 30.6 vs. 20.3 months, HR 0.76, 95% CI 0.62-0.96, p = 0.02, compared to no IO use). Results from multivariate analysis further demonstrated survival benefit with IO use (HR 0.79, 95% CI 0.63-0.98, p = 0.03, compared to no IO use). Additionally, in the multivariate analysis, the female gender was associated with improved survival (HR 0.84, 95% CI 0.71-0.99, p = 0.04); while notable factors associated with reduced survival were age ≥75 years (HR 1.45, 95% CI 1.08-1.95, p = 0.01, compared to 18-64 years age group), CDCS of ≥1 (HR 1.19, 95% CI 1.004-1.420, p = 0.04, compared to zero), and Medicaid (HR 1.46, 95% CI 1.05-2.05, p = 0.02, compared to private insurance). There was no statistical significance for OS noted with age group 65-74 years (HR 1.09, 95% CI 0.84-1.42, p = 0.49, compared to 18-64 years age group); and race (African American, HR 1.001, 95% CI 0.77-1.29, P = 0.99, compared to White). Conclusions: This study shows that IO improves survival in stage III LCNEC. Despite the inherent limitations of the database, our findings are intriguing and warrant further evaluation through prospective clinical trials in order to assess and optimize the benefit of IO in this patient population. [Table: see text]
Correlation analysis of MRD positivity after non-small cell lung cancer surgery.
Authors: Dong Daling , Jiang Bin , Wei Wei , Wang Chao , Yang Qian , Yan Tingzhi , Zheng Liken , Shao Weikang , Xiong Gang , Zhang Shixin
Published: June 2023

e20590

Background: To explore the relationship between postoperative molecular residual disease (MRD) status in patients with non-small cell lung cancer (NSCLC) and clinicopathological features, gene mutations, the tumour immune microenvironment and treatment effects. Methods: The clinical data of 90 patients with stage I-IIIA NSCLC who underwent radical resection of lung cancer from January 2021 to March 2022 in our hospital were retrospectively collected, and demographic data, clinicopathological characteristics, genetic test results, MRD status, and treatment effects were analysed. Results: Sex, age, smoking status, pathological type, and gene mutations were not associated with postoperative MRD status. T (tumour diameter > 3 cm) and N (lymph node metastasis) were statistically correlated with MRD positivity ( p values of 0.004 and 0.003, respectively). The higher the proportion of micropapillary and solid pathological subtypes of lung adenocarcinoma, the higher was the MRD-positivity rate after surgery ( p = 0.005). MRD positivity was correlated with vascular invasion ( p = 0.0002). For the expression of programmed cell death ligand 1 (PD-L1), tumour positive score (TPS) ≥ 1% and combined positive score (CPS) ≥ 5 were correlated with postoperative MRD status ( p value distribution was 0.0391 and 0.0153). For ctDNA clearance, among postoperative MRD-positive patients, postoperative adjuvant targeted therapy was superior to chemotherapy for patients without gene mutations. Conclusions: Postoperative ctDNA-MRD status in NSCLC patients is associated with primary tumour size, lymph node metastasis, lung adenocarcinoma pathological subtype, vascular invasion, TPS and CPS for PD-L1 expression; for postoperative MRD-positive patients, clearance of ctDNA by adjuvant EGFR-TKI target treatment is superior to chemotherapy.
Treatment of newly developed metastases after definitive chemoradiotherapy +/- ICI for unresectable stage III NSCLC.
Authors: Taugner Julian , Hofstetter Kerstin , Käsmann Lukas , Kröninger Sophie , Schmidt Sofie , Tufman Amanda , Reinmuth Niels , Duell Thomas , Belka Claus , Eze Chukwuka , Manapov Farkhad
Published: June 2023

e20603

Background: Assessment of salvage treatment for newly developed metastases in patients previously treated with curative-intent concurrent chemoradiation (cCRT) +/- immune checkpoint inhibition (ICI) for unresectable stage III NSCLC. Methods: We analysed data of 136 patients treated from 2011 to 2020 in as single tertiary cancer centre. Location of first observed distant metastasis (DM) were categorized as brain/intracranial metastasis (BM), organ metastasis (OM) and skeletal metastasis (SM). Treatment with radiotherapy (RT) and systemic therapy (ST); sub-divided into chemo- (CT), immuno (IT) and tyrosine kinase inhibitor therapy (TKI) was assessed. Results: All patients received definitive cCRT ≥ 60 Gy with 2 courses of chemotherapy. Thirty-six (26%) patients received ICI. Median follow-up was 49.7 months, median PFS was 9.9 (95%CI: 7.0-12.7) months, 12- and 24-month PFS-rates were 42% and 29%, respectively. Median OS was 31.2 months (95% CI 16.9 – 45.6), 12- und 24-month-OS-rates were 74% und 53%. Sixty-one patients (45%) developed metastasis: 21 (15%) BM, 20 (15%) OM und 20 (15%) SM. Median OS of patients with BM, OM and SM was 27.4, 25.5 and 17.9 months, respectively (p = 0.821). In total 45/61 patients were initially treated with cCRT and 16 with cCRT+ICI. Median OS was 26.5 (cCRT+ICI) vs. 23.4 (cCRT) months (p = 0.121); 12- and 24- month survival rates were 94% vs. 64% and 63% vs. 47%. Patients with SM survived significantly longer, if the initial treatment included ICI (Median not reached vs. 7.5 months; p = 0.042). Fifty-three (87%) of 61 patients received the following salvage therapy: 28 (53%) RT, 10 (19%) ST and 15 (28%) combined RT + ST. Patients with SM showed a trend towards longer OS after RT-alone (p = 0.069). Thirteen patients with adenocarcinoma received ST: 7 CT and 6 TKI with a significant longer OS (40.1 months TKI vs. 12.1 months CT; p = 0.040). All 21 patients with BM were treated with RT. Patients treated with stereotactic radiosurgery (SRS) showed a significant longer OS of 40.1 months vs. 12.2 months for patients treated with whole brain radiotherapy (WBRT) (p = 0.016). Conclusions: Patients with SM had a significantly longer OS if their initial therapy consisted of cCRT+ICI vs. cCRT alone. Patients with BM as first site of metastasis had a significantly longer OS when treated with SRS vs. WBRT. Salvage treatment with TKI resulted in a significantly longer OS compared to salvage CT in patients with adenocarcinomas.
Incidence of central nervous system metastases (mCNS) and overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation followed by durvalumab (Durva).
Authors: Sharp John , Zhao Songzhu , Patel Sandip , Wei Lai , Li Mingjia , Brownstein Jeremy , WELLIVER Meng Xu , Haglund Karl , Palmer Joshua David , Beyer Sasha , Raval Raju R. , Shields Peter G. , He Kai , Kaufman Jacob , Memmott Regan Michelle , Alahmadi Asrar , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J , Owen Dwight Hall
Published: June 2023

e20605

Background: In the landmark PACIFIC trial, 6.3% of patients with unresectable stage III NSCLC receiving durva after chemoradiation developed mCNS. Data on incidence of mCNS in non-clinical trial patient populations are needed to evaluate CNS surveillance strategies. Methods: We conducted a retrospective study of patients with unresectable stage III NSCLC treated with durva following chemoradiation from 2018 to 2021 with baseline CNS imaging showing no mCNS. Patient characteristics and outcomes were assessed, including age, tumor histology, stage, mCNS incidence, and survival. OS was calculated from date of initiation of durva to death or censored at last follow-up. Results: Out of 86 patients included in our study, a total of 17 (19.8%) developed mCNS after starting durva. Development of mCNS was not associated with age, sex, histology, T or N staging or PD-L1 expression (Table 1). Three patients (3.5%) had CNS-only metastases whereas 14 (16.3%) had progression outside the CNS. The median time from baseline CNS imaging to first durva was 3.8 months (IQR 3.0 – 4.9) in the cohort. The median time from first durva to development of mCNS was 4.7 months (IQR 2.3 – 8.7). Median OS in patients with mCNS was 15.2 months (95% CI 8.6 – 25.9) compared to 36.9 months (95% CI 27.2 – NR) in patients without mCNS (p = 0.010). Conclusions: Incidence of mCNS among a cohort of patients with stage III NSCLC managed with durva after chemoradiation was 19.8% which is higher than that observed in landmark clinical trials. The OS for patients with mCNS was shorter than those without mCNS. Most mCNS occurred within 6 months of starting durva and were often accompanied by systemic progression. Further research is needed to understand optimal surveillance strategies for mCNS in this patient population. [Table: see text]
Radiation fractionation effect on IDO1 through NF-kB/COX2 axis in non-small cell lung cancer.
Authors: Lan Yanli , Pi Wenhu , Zhou Zhangjie , Mei Dan , Xu Yixiu , Xia Xinhang , Wang Wei , Yang Haihua , Kong Feng-Ming (Spring)
Published: June 2023

e20613

Background: Lung cancer is the leading cancer mortality worldwide. Radiotherapy(RT) plays an important role in lung cancer treatment. Different does fractionation of RT has different effects on the prognosis of lung cancer. For example, stereotactic body radiotherapy can significantly improve the prognosis compared with conventionally Fractionated Radiotherapy. In non-small cell lung cancer, we have previously shown that Indoleamine 2,3-dioxygenase 1 (IDO1) metabolites and radiation induced changes had significant effects on long-term survival in patients treated with either Stereotactic body Radiation Therapy of 10Gy fraction size or conventional fractionated radiotherapy of 2Gy fraction size. However, the underlining molecular mechanism is unknown. In this study, we aimed to elaborate the molecular mechanism of such clinical differential effects in the laboratory. Methods: This study applied two dose/fractionation regimens with a similar BED10: 10Gyx1 and 2Gyx8. 10Gyx1 and 2Gyx8 were tested in cell lines of A549, H1299, Calu-1, TC-1 of human and murine NSCLC as well as normal rat cardiomyocyte cell line H9c2, and in vivo (TC-1 implanted C57Bl/6 mice). The mRNA and protein levels of IDO1, p-NF-kB, COX2 from cells and tumor tissues were determined by using qPCR, western blot and immunohistochemistry. Survival outcome was tested by colony formation assay in vitro and tumor growth curve in vivo. Results: In vitro, 10Gyx1 and 2Gyx8 induced IDO1 expression in all tested cell lines and the level of IDO1 expression induced by 10Gyx1 was lower than 2Gyx8. Both 10Gyx1 and 2Gyx8 increased p-NF-kB and COX2 expression and the level induced by 10Gyx1 was lower than 2Gyx8. In tumor bearing mice, two dose/fractionation regimens also induced intratumor IDO1 expression and increased the levels of p-NF-kB and COX2. Interestingly, the increased levels of IDO1, p-NF-kB, COX2 after 10Gyx1 were also significantly lower than 2Gyx8 in vivo. IDO inhibitor synergized with RT and enhanced cell killing efficacy of RT. Conclusions: The findings of this study suggest different does fractionation of RT induced up-regulation of IDO1 through NF-kB/COX2 axis in NSCLC and non-cancerous cell lines, what’s more, hypofractionated radiotherapy 10Gyx1 had less upregulation that of conventionally fractionated radiotherapy 2Gy x8 on IDO1 immune inhibitory pathway. The finding of hypofractionated radiotherapy less immune suppression differ from the traditional belief of more immune stimulation. Our current study provides a rationale in using IDO1 as a biomarker to design RT dose fractionation and/or immunotherapy in combination and possibilities for clinical trials to design IDO1 inhibitors in combination with radiotherapy.
Early detection of lung cancer using a panel of circulating cell-free DNA methylation biomarkers.
Authors: Hu Shuo , Tao Jinsheng , Peng Minhua , Wang Bo , Ye Zhujia , Chen Zhiwei , Chen Haisheng , Yu Haifeng , Fan Jianbing , Ni Bin
Published: June 2023

e20614

Background: Lung cancer remains the leading cause of cancer mortality worldwide. Early detection of lung cancer helps improve treatment and survival. Numerous aberrant DNA methylations have been reported in early-stage lung cancer. Here, we sought to identify novel DNA methylation biomarkers that could potentially be used for noninvasive early diagnosis of lung cancers. Methods: This prospective-specimen collection and retrospective-blinded-evaluation trial enrolled a total of 317 participants (198 tissues and 119 plasmas) comprising healthy controls, patients with lung cancer and benign disease from The First Affiliated Hospital of Soochow University between January 2020 and December 2021. Tissue and plasma samples were subjected to targeted bisulfite sequencing with a lung cancer specific panel targeting 9,307 differential methylation regions (DMRs). DMRs associated with lung cancer were identified by comparing the methylation profiles of tissue samples from patients with lung cancer and benign disease. Markers were selected with minimum redundancy and maximum relevance (mRMR) algorithm. A prediction model for lung cancer diagnosis was built through logistic regression algorithm and validated independently in tissue samples. Furthermore, the performance of this developed model was evaluated in a set of plasma cell-free DNA (cfDNA) samples. Results: We identified 7 DMRs corresponding to 7 differentially methylated genes (DMRs, including HOXB4, HOXA7, HOXD8, ITGA4, ZNF808, PTGER4, and B3GNTL1), highly associated with lung cancer by comparing the methylation profiles of lung cancer and benign nodule tissues. Based on the 7-DMR biomarker panel, we developed a new diagnostic model in tissue samples, termed “7-DMR model”, to distinguish lung cancers from benign diseases, achieving AUCs of 0.966 (95%CI: 0.933-1.000)/0.961 (0.924-1.000), sensitivities of 0.887 (0.824-0.951)/0.922 (0.863-0.980), specificities of 0.938 (0.889-0.986)/1.000 (1.000-1.000), and accuracies of 0.896 (0.835-0.957)/0.938 (0.886-0.991) in the discovery cohort (n = 96) and the independent validation cohort (n = 81), respectively. Furthermore, the 7-DMR model was applied to noninvasive discrimination of lung cancers and non-lung cancers including benign lung diseases and healthy controls in an independent validation cohort of plasma samples (n = 106), yielding an AUC of 0.935 (0.862-1.000), sensitivity of 0.808 (0.733-0.883), specificity of 0.975 (0.945-1.000), and accuracy of 0.934 (0.887-0.981). Conclusions: The 7 novel DMRs could be promising methylation biomarkers that merits further development as a noninvasive test for early detection of lung cancer.
Role of adjuvant chemotherapy (CT) in node negative 4-5 cm non-small cell lung cancer in elderly population.
Authors: Gaire Suman , Budhathoki Pravash , Shah Anish Kumar , Jasaraj Ranjit , Uprety Dipesh
Published: June 2023

e20615

Background: The role of adjuvant CT for 4-5 cm primary lung tumors without any regional lymph node involvement following surgical resection is somewhat controversial. While it is favored in most cases, it should be individualized depending on other pathological risk factors and the patient's performance status. In this study, we investigated the benefit of adjuvant CT in elderly patients with 4-5 cm tumor size following complete surgical resection. Methods: We utilized Surveillance, Epidemiology, and End Results Program (SEER) database to identify elderly patients (≥65 years) with 4 to 5 cm sized non-small cell lung cancer after complete surgical resection diagnosed from 2010-2015. The baseline characteristics among the patients who received and didn’t receive adjuvant CT were compared using relevant parametric/non-parametric tests. Kaplan Meir curve was generated for the univariate survival analysis, and the log-rank test was used for comparison. Multivariate survival analysis was done using the cox proportional hazards regression model. Results: The database included 2582 patients. Among them, 492 (19.1%) cases had received adjuvant chemotherapy while 2090 (80.9%) cases had not. The population that received chemotherapy was younger than those that did not (Median:75 years vs 71 years, p < 0.001). The 5-year overall survival for patients who received chemotherapy was significantly higher than those who did not (53.9% vs 46.5%, P = 0.002). On the multivariate analysis adjusted for age, gender, race, income status, and type of surgery, cases with adjuvant chemotherapy had lower hazards as compared to those who had not received adjuvant chemo (Hazard Ratio (HR):0.86, confidence interval (CI): [0.75,0.99], P value = 0.04). Conclusions: Our study demonstrated a survival benefit with adjuvant CT for node-negative NSCLC of 4-5 cm size in the elderly population.
The combination therapy of anlotinib and penpulimab for the treatment of small cell lung cancer after platinum-based chemotherapy: Results of a phase II exploratory study.
Authors: Yang Nong , Zhang Yongchang , Zeng Liang , Yang Haiyan , Zhou Chunhua , Liu Li , Xiong Yi , Jiang Wenjuan , Wang Zhan , Zeng Fanxu , Chen Qun , Feng Yuanqing , Zhou Chengzhi , Wu Zhijun , Zhang Bing , Li Xiantao , Xiao Maoliang , Wang Cunji
Published: June 2023

e20628

Background: Anlotinib is a multi-target receptor tyrosine kinase inhibitor that has been developed in China. It works by inhibiting various kinases involved in angiogenesis and tumor cell proliferation, including VEGFR, FGFR, PDGFR, and c-Kit. The results of the Phase II ALTER1202 trial showed that patients who received anlotinib as a third-line or later treatment after failing at least two chemotherapy regimens had a better progression-free survival (PFS) and overall survival (OS) compared to those who received placebo. In light of these results, the combination of anlotinib and penpulimab (a novel PD-1 inhibitor) is being studied as a second-line treatment for small cell lung cancer patients who failed first-line chemotherapy with platinum-containing drugs. Methods: This open-label, single-arm, multi-center, Phase II exploratory study (NCT050019710) enrolled patients with small cell lung cancer who had previously received platinum-based chemotherapy. Participants were given 200mg of penpulimab every three weeks and 10mg of anlotinib daily, with a two-week on and one-week off schedule, until disease progression, unacceptable toxicity, or study discontinuation. The primary objective of the study was to evaluate the antitumor activity of the combination therapy using the objective response rate (ORR) as measured by RECIST v1.1. Secondary objectives included evaluating the disease control rate (DCR), PFS, OS, and the safety and tolerability of the combination therapy. Results: As of January 31, 2023, 21 patients (median age 58 years, with 66% having ECOG performance status of 0 or 1, 95% being male) had been enrolled and received treatment. Of these, 18 patients were evaluable for RECIST and had an ORR of 33.33% (6/18) and a DCR of 77.78% (14/18). The median PFS was 5.934 months with a 6-month PFS rate of 33.33%. The median duration of response was 8 months. Nineteen of the 21 patients (90%) experienced treatment-related adverse events, with 4 patients (21%) experiencing grade 3 or higher adverse events. The most common adverse events related to anlotinib were hepatic injury, hematotoxicity, and hypertension. Conclusions: The combination of penpulimab and anlotinib showed promising clinical benefits and a favorable safety profile in small cell lung cancer patients who failed first-line platinum-based chemotherapy. Clinical trial information: NCT05001971 .
Treatment of extensive stage small cell lung cancer (ES-SCLC) in geriatric patients before the advent of immunotherapy: Real-life experience from one centre.
Authors: Medina Soledad , Gudiel Arriaza Paola , Rodriguez Angel , Lopez Mariana , López González Ana , Nieto Mangudo Beatriz , Pedraza Manuela , Castañon Carmen , De Sande González Luis , López Fernández Juan Ignacio , Sáez Álvarez Samuel , Segovia Alonso Pablo , Fernandez Fernandez Elvira , Fernandez Fernandez Manuel , García Palomo Andrés , Diz Pilar
Published: June 2023

e20635

Background: SCLC is an aggressive and difficult-to-treat type of lung cancer that in recent years is increasing in incidence in those over 70 years of age. Moreover, in geriatric patients, treatment of ES-SCLC may be even more difficult due to the lack of prospective data in this more vulnerable population. In this study we will evaluate first-line chemotherapy-based treatment in the elderly. Methods: Retrospective observational trial. Patients over 70 years of age diagnosed with ES-SCLC who were treated at the Hospital Universitario de León between January 2017 and January 2022 were analysed. Data were collected from each patient's electronic medical record. To limit bias, those who had previously received treatment for limited stage or who had undergone combination chemotherapy with immunotherapy were excluded. SPSS Statics was used to analyse treatment response, 1- and 2-year survival rate, overall survival (OS) and progression-free survival (PFS). Results: 22 patients (pat.) met the elegibility criteria. Mean age 75.6 (±3.99 SD), 86.4% male (19 pat.). Eastern Cooperative Oncology Group (ECOG) score: ECOG-0 18% (4 pat.), ECOG-1 59% (13 pat.), ECOG-2 5% (1 pat.), ECOG-3 18% (4 pat.). At diagnosis, 36.4% (8 pat.) were current smokers and 63.6% (14 pat.) were former smokers; 68.2% (15 pat.) were taking more than 5 drugs. The mean Charlson scale score was 11 (±1.7 SD), while the mean Frail scale score was 2.23 (±0.97 SD). All patients received platinum-etoposide chemotherapy, 77.3% (17 pat.) with carboplatin-etoposide, 22.7% (5 pat.) with cisplatin-etoposide and of the total. There were only 6 patients with reduced starting doses and of the total patients, 54.5% (12 pat.) completed 6 cycles; 18.2% (4 pat.) 5 cycles and 27.3% (6 pat.) 2 cycles or less. Response was evaluable in 18 patients: 15 had partial response, 1 had stable disease and 2 had progression disease. At the time of analysis, there had been 21 deaths. Median OS was 10 months (95% CI 5,4-14,6) and median PFS was 6 months (95% CI 4,2-7,8). The 1-year survival rate was 45% and the 2-year survival rate was 9%. Conclusions: Despite the small number of patients, our data are similar to those obtained in the control arms of immunotherapy trials. A larger sample would be needed to consolidate our results and we plan to extend the study to other hospitals. Nevertheless, these results suggest elderly patients may benefit from treatment procedures applied in younger populations.
Prophylactic cranial irradiation in small cell lung cancer patients in the era of magnetic resonance imaging: A systematic review and meta-analysis.
Authors: Gaebe Karolina , Erickson Anders W. , Li Alyssa Y. , Ahluwalia Manmeet Singh , Mehta Minesh P. , Lok Benjamin H. , Leighl Natasha B. , Chan Kelvin K. , Das Sunit
Published: June 2023

e20636

Background: Patients with small cell lung cancer (SCLC) are at a particularly high risk for the development of brain metastases. Current guidelines recommend prophylactic cranial irradiation (PCI) for these patients to prevent brain metastases and prolong overall survival (OS), although the clinical evidence for recommendations stems from an era without routine use of brain imaging. We performed a systematic review and meta-analysis of all available studies reporting on PCI for SCLC patients with minimal inclusion restrictions to assesses the efficacy of PCI in patients with limited disease (LD) and extensive disease (ED) SCLC and focus on the impact of routine brain imaging. Methods: A literature search for studies reporting on PCI in SCLC patients performed in EMBASE, MEDLINE, CENTRAL, and grey literature sources identified 4,783 studies. Random-effects meta-analyses pooled hazard ratios (HR) for overall survival (OS) between PCI and no intervention groups. Results: 208 individual studies reported on outcomes related to PCI with 175 studies assessing survival differences associated with PCI, and 87 of these being amenable to meta-analysis. The majority (n = 79) were retrospective cohort studies. PCI was associated with improved OS in all SCLC patients (HR 0.60; 95% CI 0.55-0.65; n = 87 studies; n = 50,339 patients; I2= 77%), as well as in cohorts exclusively consisting of LD patients (HR 0.60; 95% CI 0.54-0.66; n = 58 studies; n = 22,417 patients; I2= 76%) or ED patients (HR 0.63; 95% CI 0.53-0.75; n = 23 studies; n = 24,997; I2= 75%). Only eight studies confirmed absence of IMD at restaging using magnetic resonance imaging in all patients and found OS no longer to be in favour of PCI (HR 0.75; 95% CI 0.50-1.12; n = 1,318 patients; I2= 77%). Pooled OS from randomized controlled trials was not associated with PCI (HR 0.88; 95% CI 0.65-1.12; n = 5 studies; n = 925 patients; I2= 62.5%). Among studies not amenable to meta-analysis for OS, 4 radiographically confirmed absence of IMD, but none found OS to be in favour of PCI. Conclusions: Administration of PCI is associated with a significant OS benefit, but not when considering studies that radiographically confirmed absence of IMD at restaging or randomized controlled trials, suggesting that patient selection may be contributing to this observation.