bluuebunny/crossref_metadata_2025 huggingface dataset:
Interferon gamma resistance in setting of LKB1 loss: Phenotypic characterization and investigation of mechanism.
Authors: Kaufman Jacob
Published: May 2020

e21015

Background: NSCLC Patients with LKB1 loss respond poorly to immune checkpoint inhibitors (ICI). Determining mechanisms of the underlying immune resistance and strategies to overcome it are urgent and unmet clinical needs. Methods: We re-expressed WT LKB1 into LKB1 mutant NSCLC cell lines and measured effects on immune associated phenotypes in vitro. Specifically, we evaluated response to exogenous interferon gamma (IFNG), as well T-cell mediated cytotoxicity using a T-cell co-culture assay. To identify IFNG signaling changes influenced by LKB1, we evaluated the differential effects of LKB1 on IFNG induced gene expression using RNAseq. Finally, we performed a whole genome loss of function screen using CRISPR-Cas9 library (TKOv3) to identify genes and pathways that modify susceptibility to IFNG in the LKB1 mutant and LKB1 WT state in the A549 cell line. Results: Across multiple LKB1 mutant cell lines, restoration of WT LKB1 enhanced anti-proliferative effects of IFNG in vitro. Furthermore, WT LKB1 enhanced T-cell mediated cytotoxicity in T-cell co-culture assays using anti-NY-ESO TCR and expression of NY-ESO antigen into an HLA matched NSCLC cell line, H2023 (17% vs 40% cell death; P < 0.01). IFNG treatment induced expression of a core set of interferon-driven genes in both the mutant and LKB1 WT state. However, differentially expressed gene classes included downregulation of proliferation-associated genes in the LKB1 WT state, as well as upregulation of ferroptosis genes, and enhanced IFNG-driven expression of immune evasion genes including PDL1, PDL2, TRAF1, and IDO1 in the LKB1 WT state. PDL1 expression was assessed by flow cytometry and found to be upregulated upon expression of LKB1. Our functional genomics screen identified genes whose inhibition enhanced IFNG susceptibility in the A549 mutant state, and genes whose inhibition restored IFNG resistance in the A549 LKB1 WT state. Preliminary analysis identifies candidate signaling and metabolic pathways that appear to confer IFNG sensitivity in the mutant state without significant effect on IFNG sensitivity after LKB1 add-back. These include modifiers of the Hippo/YAP pathway as well as modifiers of ferroptosis, which will form the basis for further mechanistic experiments. Conclusions: ICI resistance caused by LKB1 loss is associated with insensitivity to IFNG, and can be modified in vitro by re-expression of WT LKB1. An integrated approach to evaluate modifiers of IFNG effects identifies resistance mechanisms that may be potential therapeutic targets.
Causal inferencing of -omics data from The Cancer Genome Atlas: Lung adenocarcinoma tumors for mechanistic disease characterization and feature engineering.
Authors: Schneider Nimisha , Korkhov Sergey , Foroozan Alexis , Marshall Scott , Deehan Renee
Published: May 2020

e21016

Background: Advances in high throughput measurement technologies (-omics data) have made it possible to generate high complexity, high volume data for oncology research. Researchers are often confronted many more measurements than samples (p > > > n), which poses challenges for both modeling the complexity of disease at the molecular mechanism level, and overfitting when generating predictive models with complex data. Here, we applied a prior knowledge-driven approach to characterize and classify heavy versus light smokers with lung cancer from The Cancer Genome Atlas, an open source repository that catalogs, harmonizes and hosts -omics data collected from samples generously donated from cancer patients. Methods: We applied a reverse inferencing approach to systematically interrogate RNAseq measurements from tumor and control biopsies against a knowledgebase of directed gene networks curated from published experiments. If patterns observed in the data are significantly similar to those in a network, an inference about the directional activity of that network can be made; e.g., the increased transcriptional activity of NFKB. Our library was nucleated through an open sourced knowledge graph and enhanced with updated and relevant knowledge using the open sourced Biological Expression Language framework. Directed networks were either qualitatively scored and used to build disease models, or semi-quantitatively scored and used as classification features. Results: In LUAD tumors, we detected a pattern of gene signatures which indicated a tumor stem cell-like phenotype characterized by predicted decreases in the activity of pro-differentiation factors and an increased response to hypoxia. Analysis of patients with heavy ( > 40) versus light ( < 10) pack-year burden suggested an augmented dedifferentiation profile in heavy smokers. In this example, improved classification was observed through features compression through directed network scoring compared to using individual RNA measurements selected by filtration methods. Conclusions: In-silico analysis of lung cancer patient biopsies generated hypotheses implicating stem cell signaling in tumors, and a further stratification of this signal based on patient pack year burden. Mechanistic modeling may be a useful application to the overfitting problem often encountered with -omics data in translational studies. Data from other TCGA indications can be used to evaluate the consistency of this type of approach
Low TWEAK expression indicates poor survival and is correlated with sparse TIICs in lung adenocarcinoma (LUAD).
Authors: Wu Jinchun , Liu Xianyu , Mou Yanhua , Zeng Shan , Zhang Jin , Zhou RongRong , Lu Jingchen , Yang Gao , Zhang Chunfang , Duan Chaojun , Li Bin
Published: May 2020

e21017

Background: Lung adenocarcinoma (LUAD) occupies the most of non-small cell lung cancer (NSCLC) and shows promising response to PD-1 immunotherapy, but immune escape will cause treatment failure indicating poor prognosis. TWEAK (Tumor necrosis factor-related weak inducer of apoptosis, also known as TNFSF12) combining with its receptor FN14 (fibroblast growth factor–inducible 14) mediates crucial innate and adaptive immune pathways to promote the progression of multiple autoimmune diseases. So we assumed that TWEAK is a prognostic predictor and related with tumor-infiltrating immune cells (TIICs) in LUAD. Methods: TWEAK expression of LUAD was primarily investigated in The Cancer Immunome Atlas (TCIA) and then validated in Tumor Immune Estimation Resource (TIMER) databases. We assessed the effect of TWEAK on the survival via the Kaplan-Meier plotter, GEPIA2 (gene expression profiling interactive analysis) and PrognoScan databases. The relation between TWEAK and TIICs was explored in TIMER and TCIA, as well as the correlation of TWEAK and FN14 was analyzed in TIMER and GEPIA2. Results: Low TWEAK expression was significantly associated with poor relapse-free survival (RFS) (HR = 0.62, 95% CI = 0.4~0.97, logrank P = 0.035) and overall survival (OS) (HR = 0.61, 95% CI = 0.46~0.83, logrank P = 0.0012) in LUAD from Kaplan-Meier plotter. Similar impacts of TWEAK on the survival were validated in GEPIA2 and four independent cohorts from PrognoScan (jacob-00182-CANDF, GSE13213, jacob-00182-MSK and GSE31210). Moreover, reduced TWEAK expression was closely related with the paucity of TIICs which contributed to poor OS, including central memory CD8 T cells, plasmacytoid dendritic cells, activated CD8 T cells, monocytes, T follicular helper cells, immature B cells and eosinophils. In addition, TWEAK expression was positively related with the expression level of FN14 in both GEPIA2(R = 0.13, P= 0.0031) and TIMER (partial.cor = 0.212, P= 2.04e-06). Conclusions: Low TWEAK expression maybe indicate poor prognosis in LUAD, and correlated with the impaired infiltration of immune cells in the tumor region. The defective TWEAK/FN14 pathway possibly accounts for these observations, but the underlying mechanism needs to be further explored.
Non-small cell lung cancer: Analysis using mass cytometry and next generation sequencing reveals new opportunities for the development of personalized therapies.
Authors: Raju Paul Susan , Bagaev Alexander , Valiev Ivan , Zyrin Vladimir , Zaitsev Aleksandr , Dyykanov Daniyar , Nuzhdina Katerina , Kotlov Nikita , Frenkel Felix , Korek Skylar , Reeves Patrick , Davies Diane L. , Wright Cameron D , Ott Harald , Muniappan Ashok , Tsiper Maria , Fowler Nathan , Lanuti Michael , Ataullakhanov Ravshan , Poznansky Mark C
Published: May 2020

e21026

Background: Comprehensive molecular profiling and the use of biomarkers as companion diagnostics have transformed precision medicine for cancer patients. To identify patient-specific tumor microenvironment and biomarker profiles, we assessed the accuracy of our deconvolution algorithm in identifying cellular compositions from whole exome (WES) and whole transcriptome (RNA-seq) sequencing of solid tumors compared with cell populations identified by Mass Cytometry by Time of Flight (CyTOF) in surgically resected tissue from non-small cell lung cancer (NSCLC) patients. Methods: Resected NSCLC tissue was divided for RNA-seq and WES of whole tissue (n = 9) and for generating tissue single cell suspensions through mechanical dissociation and enzymatic digestion (n = 11). Bulk RNA-seq and CyTOF were performed on all cell suspensions. Cellular phenotypes were identified using clustering algorithms in CyTOF and predicted from bulk RNA-seq using our proprietary computational method. Results: Cellular composition reconstructed from RNA-seq correlated with the composition detected by CyTOF (R2= 0.922, n = 7) from cell suspensions. To recover the cell percentage from bulk RNA-seq, a machine learning framework was trained on the cell compendia comprising 7,117 unique cell type RNA-seq profiles. A two-stage hierarchical learning procedure generated a gradient boosting Light GBM model that included training on artificial RNA-seq mixtures of different cell types. With this method, we found that stromal and malignant cells were depleted during single cell suspension preparation, resulting in statistically significant differences in the tumor cell composition reconstructed from solid tissue and single cell suspensions. Immune cell types namely T cells and macrophages were similarly represented in both the bulk tumor tissue and matched single cell suspensions. Transcriptomics revealed a subgroup of patients whose tumors were B-cell-enriched, which was validated in other NSCLC cohorts and was associated with greater CD4+ and CD8+ T cell infiltration and improved clinical outcomes. Conclusions: Since preparation of single cell suspensions leads to the loss of several cellular components, RNA-seq of tumor bulk tissue better describes the molecular and cellular properties of the tumor microenvironment. The combination of RNA-seq and WES of tumor tissue provides a comprehensive profile of cellular composition, suggesting that this combination is ideal for precision medicine applications.
PD-1 or PD-L1 co-localizes with immune cells for prediction of prognosis in non-small cell lung cancer.
Authors: Zhou Chengzhi , Lai Jinhuo , Chen Yanhui , Wang Yating , Zhang Henghui
Published: May 2020

e21029

Background: A number of studies have shown that tumor cells expressing PD-L1 correlate with a better prognosis of immunotherapy in patients with non-small cell lung cancer(NSCLC). However, there were few studies on the immune cells that expressing PD-1 or PD-L1 affect the clinical outcome of patients with NSCLC. Therefore, further research is needed Methods: A total of 336 tumor tissues from patient with non-small cell lung cancer were collected and divided into two cohorts, discovery cohort (174 patients) and validation cohort (162 patients). We used multiplex IHC to identify and quantify CD8, CD57, CD68, CD163, PD-1 and PD-L1 positive rate in tumor tissues, and analyzed its relationship with clinical prognosis. Results: Both PD-1 and PD-L1 were detected on CD8+, CD57+, CD68+, and CD163+ immune cells, but the positive rate were different. PD-1 was higher on cytotoxic T cells (CD8+PD-1+) and PD-L1 was higher on macrophages and cytotoxic T cells (CD68+PD-L1+ and CD8+PD-L1+). By undifferentiated clustering analysis in discovery cohort, the survival rate of tumors with more immune cells expressing PD-1 or PD-L1 was worse. Univariate analysis using X-tile plots to generate the optimum cut off score for all features revealed that immune cells expressing PD-1 or PD-L1 were adverse factors of clinical prognosis of patients with NSCLC, and this result was also confirmed in the validation cohort. Conclusions: In 336 non-small cell lung cancer cases, the expression characteristics of PD-1 and PD-L1 on tumor-infiltrating immune cells were related to survival of patient. In this study, high level of PD-1 and PD-L1 expression on immune cells were associated with lower survival rate, and biomarker characteristics based on this analysis probably enables us to better guide clinical treatment
Genetic profiling and TCR repertoire feature of synchronous multiple primary lung carcinomas.
Authors: Yang Huaxia , Bing Zhongxing , Cao Lei , Wang Yadong , Jia Ziqi , Wang Yanyu , Yang Xiaoying , Wu Pancheng , Song Yang , Xu Huihui , Gu Dejian , Chen Rongrong , Xia Xuefeng , Gao Chao , Cao Zhili , Li Shanqing , Liang Naixin
Published: May 2020

e21031

Background: The incidence and detection rates of multiple primary lung cancer are increasing, as a result of the advances in lung cancer screening techniques. However, the molecular and immune mechanisms of their carcinogenesis were little known, which may have important diagnostic, prognostic and therapeutic implications. Methods: We retrospective analyzed 10 patients (pts) with clinically designated synchronous multiple primary lung cancers (sMPLC). 28 different tumor lesions were included and mutation profiles were analyzed using 1021 genes panel based next-generation sequencing (NGS). Meanwhile, the T-cell receptor (TCR) β repertoire of 28 tumor lesions and peripheral blood were analyzed by amplifying and sequencing the CDR3 region. T-cell clonality was defined as 1-normalized Shannon entropy, which was normalized by dividing Shannon entropy by the natural logarithm of the number of unique productive TCR sequences. Results: 8 of 10 pts were female and only one pts was smoker. The genetic profiles of 28 tissues were analyzed and almost no common mutations were detected between different tumors of one patient. The most common mutation was EGFR and it was detected in 11 tissues belonging to 7 pts. KRAS mutations were detected in 6 tissues belonging to 4 pts and only one patient detected both EGFR and KRAS mutation in different lesions. TP53 mutations were found in 6 tissues, which 5 co-existed with EGFR. Unlike the mutually exclusive between KRAS and EGFR, 4 pts were detected BRAF mutation whose other tissue aslo carried EGFR mutation. Next, we studied T-cell clonality, which ranges from 0 to 1 and describes the shape of T-cell frequency distribution. Analysis of TCR clonality revealed that this metric ranged from 0.092 in Pts T8 to 0.192 in Pts T5. Furthermore, heterogeneity of different lesions of pts was observed, with differences as large as 78% in T-cell clonality across different tumor lesions in Pts T2, which is bigger than difference of between patients. Beside, EGFR mutation lesions showed lower clonality but no significant differences (0.105 vs 0.130,p = 0.245). There no difference of number of non-synonymous mutation (NNSM) between EGFR-mutant and EGFR-wt group (3 vs 2, p = 0.748), and same in KRAS (3.5 vs 2, p = 0.410). However, frequency of share TCR of tissue and blood was positive correlated with NNSM (spearman r = 0.384,p = 0.048), which might means local immune microenvironment was related with regions mutation. Conclusions: Our results reveals independent molecular and immune feature of sMPLC pts, which may have contradictory therapeutic implications.
Analysis of exhaled breath of lung cancer patients using infrared spectroscopy.
Authors: Reiman Tony J. , Thompson Robert , Naz Farah , Michael James Charles Roger , Scheme Erik , Phinyomark Angkoon , Galvis Luisa , Daigle-Maloney Trisha , Caissie Amanda , Ojah Joseph , Salem Maged , Campbell Holly Anne , Brooks Erin , Graham Stephen , Purves Chris , Beydaghyan Gisia , Abdelsalam Mahmoud
Published: May 2020

e21037

Background: Currently low-dose computed tomography is used for lung cancer (LC) screening, but is limited by radiation exposure, cost, and a high false detection rate (1,2). An accurate, accessible and affordable screening technology is needed to improve detection of LC in high risk individuals. Methods: We conducted an unblinded, prospective cohort study on the effectiveness of a novel technology utilizing infrared absorption measurements via cavity ringdown spectroscopy (IR-CRDS) to differentiate the expired breath of treatment-naïve LC patients from controls without known cancer. Breath samples were taken from 100 LC patients and 98 control subjects but, only 62 non-small cell lung cancer (NSCLC) and 96 control samples were analyzed. Patients on treatment were eligible but, the protocol was amended to exclude these due to signal ambiguities. Samples were also excluded due to missing data, unclear histologic subtypes, or if they were classified as small cell LC samples to prevent obscuring the NSCLC signal. A piecewise cubic spline interpolation was used for the spectra with missing values (3). After first- and second-derivative spectra were computed to increase the information density, a one-dimensional local binary pattern extracted features from the spectra (4). Meaningful spectra-based features were selected using a minimum redundancy maximum relevance algorithm (5). Finally, a classification model was built using a support vector machine classifier (3). Results: The table below characterizes each cohort. The discriminant analysis differentiated between NSCLC and control cases with a cross validation accuracy of 86.1% (89.6% sensitivity and 80.7% specificity) using 20 selected spectra-based features. Conclusions: IR absorption measurements can be used to accurately discriminate between NSCLC and control participants. We continue to build our database to support more robust machine learning models. To our knowledge, this is the first time IR-CRDS has been used to differentiate between NSCLC and control cases. [Table: see text]
Patho-genomic feature of PI3K / AKT / mTOR pathway mutations in Chinese patients with non-small cell lung cancer.
Authors: Li Weiwei , Qiu Yuan , Chen Hanzhang , Yang Haihong , Deng Qiuhua , Liu Liping , Xiao Dakai , Zhu Changbin , Jiang Wenxi , Shao Di , Lin Yongping , He Jianxing
Published: May 2020

e21049

Background: Inhibition of PI3K/AKT/mTOR pathway has emerged as a promising anticancer strategy. Measuring genetic alterations in PI3K/AKT/mTOR pathway are critical for clinical decision making for patients with lung cancer. This study aims to analyze PI3K/AKT/mTOR pathway-related gene mutations in non-small cell lung cancer (NSCLC) in a consecutive cohort. Methods: 536 surgically resected tumor tissues were collected. Target region capture sequencing for 508 cancer-related genes was conducted on MGI-seq 2000 platform. Results: PI3K/AKT/mTOR pathway genes were mutated in 120 samples (22.4%). Female or older patients displayed higher mutation incidence of PI3K/AKT/mTOR pathway (P = 0.06 for female, P = 0.05 for patients ≥60 y). In NSCLC samples, mutations mainly occurred in NF1/2(18/499), PTEN (7/499), MTOR (4/499), TSC1/2(18/499), PIK3CA (26/499), PDK1 (2/499), AKT1/2/3 (5/499) and KRAS (49/499) genes. Genetic alterations of AKT2 (p = 0.003), mTOR (P = 0.03), PTEN (P = 0.005) and PIK3CA (P < 0.001) are preferred to occur in squamous NSCLC. PIK3CA variants (p.E542K, p.E545K, p.Q546K) were more enriched in non-squamous NSCLC, while amplification of PIK3CA was more prevalent in squamous NSCLC (P = 0.038). Histologically, TSC1/2 mutations were more correlate with micro-invasion subtype in non-squamous NSCLC (P = 0.002). Meanwhile, PIK3CA alterations, especially, amplification occurred more often in keratinizing squamous NSCLC (P < 0.001). In addition, four patients with biallelic NF1 loss of function mutations were exclusively found in non-squamous NSCLC without co-occurrence of mutation in known driver genes like EGFR or TP53, which indicated biallelic loss of function of NF1 might be sufficient to drive oncogenesis of non-squamous NSCLC. Conclusions: PI3K/AKT/mTOR pathway alterations present a heterogenous distribution across various types of lung malignancies especially in NSCLC. As more small molecule inhibitors developed to target PI3K/AKT/mTOR pathway, this study might shed light on further clinical investigation of these lately developed therapeutic approaches. [Table: see text]
Early-stage KRAS G12C-mutated non-small cell lung cancer (NSCLC) in Australia.
Authors: Mitchell Paul , Dharmaraj Devisri , Knight Simon
Published: May 2020

e21053

Background: KRAS is frequently mutated in NSCLC, especially in Caucasian populations. Until recently there have not been effective targeted therapies against KRAS but the recent advent of active agents has thrown a spotlight on this disease. Methods: A database of NSCLC cases undergoing lobectomy or pneumonectomy with curative intent at Austin Health, Victoria, Australia was examined. Analysis for KRAS mutations was carried out using the LungCarta panel. Results: Four hundred and fifty nine cases underwent mutation analysis and 203/459 (44%) were wild type. KRAS mutations were identified in 100/459 cases (21.8%), including 3 cases where the specific mutation was not specified. KRAS G12C cases comprised 40/97 (8.5% of all cases, 41% of specified mutation KRAS cases) and other KRAS mutations comprised 57/97 (59%) - most commonly G12V (25 cases) and G12D (13 cases). Additional mutations were identified in 14/40 (36%) G12C mutation cases (10 dual and 4 triple – most commonly TP53 9, STK11 3 and PIC3CA 2). In non-G12C cases, multiple mutations were identified in 24% of cases. Considering the 40 G12C cases, histology was squamous cell in 21 cases, adenocarcinoma 13 and other 5. Males comprised 21/40 cases, median age at diagnosis was 61 year (range 34 – 78), with stage I 22 cases, stage II 12; stage IIIA 5 and one stage 4 (solitary brain metastasis). Thirty six patients (90%) had smoked tobacco with median exposure of 44 pack years (range 13-100) including 18 ex-smokers who had ceased a median 9 years (range 1 - 28) prior to the diagnosis of lung cancer. PD-L1 expression was analysed using the 28-8 antibody. For the 38 cases analysed, PD-L1 expression was ≥ 50% in 6 (16%), ≥ 5% in 12 (32%) and < 1% in 24 (63%). The estimated median overall survival was 4.9 years with 27% 10 year survival. Twenty three patients (58%) died from the index lung cancer, 8 (20%) remain alive and 9 (23%) died of other causes: 4 from a 2nd lung cancer, 4 from a non-lung cancer and one from liver failure. Data on sites of recurrence were available for 16 of the 23 cases who died from the index lung cancer, with initial recurrence sites being lung/local 7 patients, brain 6, bone 2, liver 1. A total of 9 patients (56%) developed brain metastases at some time. Conclusions: KRAS G12C is a common subgroup of NSCLC in the Australian population and almost all of cases were tobacco smokers. Additional mutations were identified in over a third of cases. Locally recurrent disease or brain metastases are the most frequent sites of relapse and over half of patients with recurrent disease develop brain metastases.
The association between IDO activity and clinical prognosis in patients with early stage non-small cell lung cancer after stereotactic body radiotherapy.
Authors: Zhu Yaoyao , Hu Min , Xu Qinghua , Xu Yaping
Published: May 2020

e21054

Background: Immunity affects the efficacy of radiotherapy of lung cancer patients. Indoleamine 2,3-dioxygenase (IDO) is a key enzyme that converts tryptophan (T) into heparin (K), which can promote immune suppression and assist tumor cells in immune evasion. The purpose of this study was to quantitatively analyze the immune activity of IDO in serum before and after SBRT, and to explore the changes in immune activity of IDO mediated by SBRT and its relationship with patient's survival. Methods: High-performance liquid chromatography and mass spectrometry were used to determine serum K and T in 30 patients with early non-small cell lung cancer before and after SBRT treatment. K: T stands for IDO activity. The Kaplan-Meier method and log-rank test were used to evaluate the correlation between overall survival (OS), progression-free survival (PFS), and IDO activity. Cox proportional hazards model was used for univariate and multivariate analyses. Results: The median follow-up time was 37.4 months. The median PFS was 37.5 (95% CI, 31.0-44.0) months. The median survival was not reached. In all patients, lower post/pre kynurenine ratio correlated significantly with better PFS (HR = 0.31, 95% CI = 0.11-0.90, P = 0.032). The lower K: T ratio at post-RT received longer OS (HR = 0.27, 95% CI = 0.079-0.95, P = 0.042). In multivariate analysis, smoking < 30 packs / year (P = 0.030), higher BED (P < 0.001), and lower post/pre kynurenine (P = 0.043) were associated with better PFS. Lower K: T ratio post-RT (P = 0.040) and higher BED (P < 0.001) were significantly associated with better OS. Conclusions: SBRT could alter IDO-mediated antitumor immune activity. The lower level of post/pre kynurenine ratio was significantly related with better PFS. The lower K: T ratio at post-RT was related with better OS. This study shows that IDO is a potentially valuable biomarker for monitoring the immune status and predicting survival in early NSCLC patients after SBRT.
Locoregional control, failure patterns and clinical outcomes in patients with stage III non-small cell lung cancers treated with chemoradiation and durvalumab.
Authors: Offin Michael , Shaverdian Narek , Rimner Andreas , Lobaugh Stephanie , Shepherd Annemarie , Simone Charles B. , Gelblum Daphna Y. , Wu Abraham Jing-Ching , Lee Nancy Y. , Kris Mark G. , Rudin Charles M. , Zhang Zhigang , Hellmann Matthew David , Chaft Jamie E. , Gomez Daniel Richard
Published: May 2020

e21058

Background: Definitive concurrent chemoradiation (cCRT) and durvalumab is a standard therapy for patients with unresectable stage III non-small cell lung cancers (NSCLC). Data is limited on outcomes with this regimen outside of clinical trials. Local-regional control rates to date remain undefined. Methods: We reviewed patients with stage III unresectable NSCLC treated between November 2017 and February 2019 with cCRT. Patients that received at least one cycle of durvalumab were further assessed for 12-month progression free survival (PFS), overall survival (OS), and the incidence and pattern of local-regional and metastatic failures. Disease-relapse was characterized to determine patients potentially eligible for metastasis-directed ablative therapies. Toxicities leading to durvalumab discontinuation were evaluated using CTCAE v.5.0. Results: Of the 83 patients with stage III NSCLC treated with cCRT (median 60Gy), 62 received durvalumab and were evaluable (median follow-up: 12 months). Patients (n = 21, 25%) did not receive durvalumab largely related to metastatic progression (n = 9) or persistent cCRT toxicity (n = 10). In the 62 durvalumab treated patients the median age was 66 (range: 49 - 86), 73% had stage IIIB (n = 33) or IIIC (n = 12) disease, and 58% (n = 36) had adenocarcinoma. The median time from cCRT end to durvalumab start was 1.5 months. Patients received a median of 8 months of durvalumab; 35% (n = 22) of patients completed 12 months of therapy. Common reasons for discontinuing durvalumab included disease progression (32%, 20/62) and toxicity (24%, 15/62). The estimated 12-month PFS and OS were 65% (95% CI: 51 - 79%) and 85% (95% CI: 75 - 95%), respectively. High TMB (≥ 8.8 mt/Mb) or PD-L1 (≥ 1% or PD-L1 ≥ 50%) did not predict improved PFS. Patients who discontinued durvalumab due to toxicity did not have inferior PFS. The cumulative 12-month incidence of local-regional and distant metastatic failures were 18% (95% CI: 5.9 - 30%) and 30% (95% CI: 16.3 - 44.5%), respectively. Of the 17 patients with distant metastases, 9 had oligometastases and would have been potential candidates for comprehensive ablative therapies. Conclusions: Outcomes and toxicities outcomes with cCRT and durvalumab in clinical practice align with the PACIFIC trial. Analysis of disease-relapse suggests a substantial minority of patients with disease progression may be potential candidates for metastasis-directed therapies. Local regional outcomes appear improved to historical data of cCRT alone.
The variance of lymphatic vascular invasion (LVI) diagnosis and its impact on overall survival(OS) independent of node stage in patients undergoing surgical resection on NSCLC.
Authors: Hebert Christine , Emmerick Isabel M , Voland Rick , Varlotto John M. , Maddox Debra , DeCamp Malcolm , Flickinger John Charles , Maxfield Mark , Lou Ferian , Rassaei Negar , Zander Dani , McIntosh Lacey , Fitzgerald Thomas J. , Griffin Molly , Rava Paul , Walsh William Vincent , Baima Jennifer , Uy Karl
Published: May 2020

e21060

Background: The criteria for diagnosis of lymphatic vascular invasion(LVI) have not been standardized. Our investigation uses the National Cancer Database(NCDB) to assess the impact of this factor on survival(OS) and whether there are differences in the diagnosis of LVI based upon institution type and regional location in patients undergoing definitive resection. Methods: The NCDB was queried from the years 2010-2014 to find a patient population who underwent (bi)lobectomy with at least ten lymph nodes examined. Multivariable analysis was used to find factors associated with diagnosis of LVI, and the impact of LVI on OS. Propensity score matching(PSM) was used to adjust for bias in diagnosing LVI while testing the impact of LVI on OS. Results: 18,057 patients were eligible for our study with a median follow-up of (36.1 months). LVI status was determined in 91.8%. 19.1% of surgical specimens were found to be LVI positive. 2,323 patients had positive nodes with 50.8% of specimens having LVI, while 14.0% of specimens with negative nodes had LVI. Academic medical centers(AC); Medical centers associated with populations > 1,000,000(1M); and Mid-Atlantic(MA) region had higher rates of LVI(all p values < 0.0001, AC 22.7% vs 16.5%, OR = 1.49; 1M 21.1% vs 16.8%, OR = 1.32; MA 27.6% vs 17.1%, OR = 1.85), and higher rates of LVI associated with positive nodes (all p values < 0.0001, AC 34.6% vs 7.9%, OR = 6.14; 1M 36.4% vs 7.7%, OR = 6.82; MA 31.0% vs 6.2%, OR = 6.76). LVI was most frequently diagnosed in the MA region and least frequently found in the Mountain location( 27.6% vs 12.2%, OR = 2.73). LVI was associated with a significant decrement in OS that was independent of institution type, regional population, and institution location. PSM demonstrated that LVI was associated with a decrement in OS to the same degree per each nodal stage(N0,N1,N2) (p < 0.0001, HRs = 1.21 N0, 1.26 N1, 1.18 N2). Conclusions: LVI diagnosis and its association with positive nodes varies based upon hospital location/type and population. LVI was associated with a decrement in OS that was independent of N-Stage. LVI must be standardized and considered as a prognostic factor for staging cancer patients.
Sublobar resection versus lobectomy for early-stage pulmonary carcinoid tumors with three centimeters or less in size: A population-based study.
Authors: Li Xiongfei , Ren Fan , Zhao Shikang , Wang Yanye , Ren Dian , Liu Renwang , Chen Gang , Chen Jun , Xu Song
Published: May 2020

e21062

Background: Pulmonary carcinoids (PCs), comprising of typical carcinoids (TCs) and atypical carcinoids (ACs), are rare low-grade malignant tumors and surgical resection is considered as the standard treatment for early stage PCs. However, it is not clear whether sublobar (Sub-L) resection of PCs would compromise the long-term oncologic outcomes. Here we investigate the equivalency of Sub-L resection versus lobectomy (Lobe) for patients with early stage PCs using the population-based Surveillance, Epidemiology, and End Results (SEER) registry. Methods: The clinical and survival data of early stage PC patients with less or equal 3cm diameter were retrieved. Kaplan-Meier method and log-rank tests were used to assess differences in overall survival (OS). We further performed the subgroup analysis by tumor size (T≤1cm, 1cm < T≤2cm, 2cm < T≤3cm) and patient age ( < 70y and ≥70y). To reduce the bias of inherent retrospective study, we also performed propensity score matching (PSM) analysis by 1:1 fixed ratio nearest neighbor matching using Matchit package in R. Results: In total of 2934 PC patients, including 2741 TCs and 193 ACs, were recruited. 1011(34.46%) and 1923(65.54%) patients received Sub-L resection and lobectomy, respectively. After PSM, there was no significant difference between Sub-L and Lobe group in terms of OS in PC patients (P = 0.33). From the cox regression analysis, it indicated that older age, male gender, larger tumor size, AC histology type and Sub-L surgery were associated with a worse OS. We further performed PSM analysis on TCs and ACs, respectively. For TC patients, it indicated that patients in Lobe group had a much better OS compared to those in Sub-L group (p = 0.0067). In the subgroup analysis, the log-rank tests showed that there was a significant survival advantage for lobectomy in comparison with Sub-L resection for the TC patients with diameter 2cm < T≤3cm (p = 0.0345), but not for those with diameter lower than 2cm. In the subgroup analysis of age, the log-rank test indicated that Lobe group in age < 70 had a better prognosis with statistical difference compared to Sub-L group (p = 0.0032). For ACs, there was no statistic difference between Sub-L and Lobe group after PSM analysis in all the subgroup investigations. Conclusions: Sublobar resection may not significantly compromise the long-term oncologic outcomes in early stage PC patients. However, there is a survival benefit of lobectomy in certain pathological type and population, such as TCs patients with tumor size more than 2cm and age lower than 70-year-old.
Recurrence patterns following curative therapy for stage I NSCLC.
Authors: Butts Emily , Gococo-Benore Denise , Pai Tanmayi , Chen Ruqin , Manochakian Rami , Lou Yanyan
Published: May 2020

e21069

Background: Lobectomy remains the standard of care for definitive management of stage I non-small cell lung cancer (NSCLC). Stereotactic body radiation therapy (SBRT) is considered primarily for patients who were either unwilling to have surgery or deemed to be medically unfit for surgery. Current NCCN guidelines indicate the use of CT for surveillance following curative-intent therapies and recommend CT every 6 months for 2-3 years followed by CT annually without clear guidance on how long to keep doing annual CT scans. This study aims to evaluate the patterns of lung cancer recurrence within and beyond five years post curative therapy. Methods: Patients diagnosed with stage I NSCLC and treated with either curative surgery or SBRT from 1998-2016 at Mayo Clinic Florida were identified. Through retrospective chart review, data was collected on clinical and demographic features, surveillance imaging, pathology, time to recurrence or new primary lung cancer, and location of recurrence (loco-regional vs. distant). Statistical analysis with chi-square test was performed to identify risk factors associated with recurrence. Results: In total, 203 patients with stage I NSCLC were identified with most patients treated with surgery (n = 181) compared with SBRT (n = 22). Median time of follow up is 85 months. Overall, 48 patients (23.6%) developed a recurrence, with the median time to recurrence of 22.3 (3.9-69.8) months. Most recurrences were identified within 5 years from curative therapy (42/48) with 6 patients having a recurrence between 5 and 10 years post curative therapy. Of the 37 patients followed for more than 10 years, there were no recurrences. Twenty seven patients had new primary lung cancers identified and among them, 15 were found within 5 years, 10 found between 5-10 years and 2 found beyond 10 years. Median time to new primary lung cancer was 58.1 months. A positive smoking history and stage IB were found significantly associated with lung cancer recurrence (chi-square test P = 0.007 and P = 0.04 respectively), while age, gender, histology, grade, and treatment type had no association. Conclusions: In this study of 203 patients with stage I NSCLC treated with curative intention, there was no evidence of recurrent disease after 10 years following curative therapy, questioning the utility of continued annual CT surveillance once patients hit this milestone.
Impact of clinical and pathological variables on stage I non-small cell lung cancer outcomes.
Authors: Lee Matthew C , Stefanov Dimitre C , Angert Mallorie B , Cohn Erica C , Kohn Nina , Esposito Michael J , Seetharamu Nagashree
Published: May 2020

e21071

Background: Stage I patients (pts) have 5-year survival ranging 50-75% suggesting heterogeneity within. While American Joint Committee on Cancer 8th edition upstages tumors with visceral pleural invasion (VPI) to IB, other histological features namely lymphovascular invasion (LVI), micropapillary pattern (MIP), spread through airspace (STAS) & neuroendocrine differentiation (NE) may also affect prognosis. This retrospective single institution study evaluated influence of these factors along with pt variables age, gender, smoking, Charleston comorbidity index (CCI) & chemotherapy (CT) on recurrence & mortality. Methods: 351 resected stage I cases from 2015-2019 were included. Data was summarized as means (standard deviation/SD) or percentages. Association between variables & outcomes (measured from diagnosis till event or last visit if no event) were investigated using Univariate & Multiple Cox proportional hazards models. Survival curves were compared using the Log-Rank test when the assumption for the proportional hazards was not satisfied. All predictors were included in the multiple Cox regression models based on their clinical importance. P < 0.05 was considered statistically significant. SAS 9.4 (SAS Institute, Cary, NC) was used for the analysis. Results: Mean age was 69.62 years (9.83). Majority were female (57.3%), smokers (76.9%), & had adenocarcinoma (AC) (78.6%). 39% had COPD & mean CCI was 6.3 (1.74). 193 (55%) pts had lobectomy or larger procedure while 158 (45%) had sub-lobar resection. 45 (12.8%) pts received CT. Recurrence & death occurred in 33 (9.4%) & 15 (4.3%) pts respectively. Univariate models indicated higher recurrence risk with NE (HR = 4.18 95% CI 1.47-11.9, p = 0.0075), LVI (HR = 2.68, 95% CI 1.03-6.94, p = 0.0423), COPD (HR = 3.28 95% CI 1.56-6.9, p = 0.0017), age (HR = 1.05 95% CI 1.01-1.09, p = 0.0212), & CCI (HR = 1.57 95% CI 1.35-1.83, p < .0001). CT was also associated with increased recurrence risk (HR = 8.61, 95% CI 4.28-17.33, p < .0001). Multivariable model for recurrence retained significance for CT & CCI. Age (HR = 1.07 95% CI 1.01-1.14, p = 0.0312), CCI (HR = 1.27 95 % CI 1.02-1.59, p = 0.0347) were associated with mortality in univariate models. Multivariate analysis for mortality wasn’t feasible due to few events. Conclusions: Histological features other than VPI may be associated with recurrence. Pts who received CT had increased recurrence but they possibly had multiple risk factors or other adverse features not assessed here. Limitations included retrospective nature, limited sample size & small number of events.
Phase II trial of biweekly carboplatin and nab-paclitaxel with concurrent radiotherapy for patients with locally advanced unresectable stage III non-small cell lung cancer.
Authors: Tanaka Hisashi , Okumura Fumihiko , Tabe Chiori , Ishioka Yoshiko , Itoga Masamichi , Taima Kageaki , Hasegawa Yukihiro , Yokouchi Junichi , Takanashi Shingo , Aoki Masahiko , Tasaka Sadatomo
Published: May 2020

e21078

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced non-small cell lung cell cancer (LA-NSCLC). We previously reported the phase I study of biweekly carboplatin and nab-paclitaxel (nab-PTX) with RT. Recommended dose for phase II study was carboplatin (AUC 4) and nab-PTX (100 mg/m2) (J Clin Oncol 2015 suppl; abstr 7529). Here we report the phase II part designed to assess the efficacy of biweekly carboplatin and nab-PTX with concurrent RT (UMIN000023802). Methods: Patients with inoperable stage Ⅲ NSCLC were treated with carboplatin (AUC 4) and nab-PTX 100 mg/m2 on days 1, 15, and 29. Thoracic radiotherapy was administered from day 1 to a total dose of 60 Gy in 30 fractions. Consolidation chemotherapy after CCRT was 2 cycles of carboplatin (AUC 6) on day 1 and nab-PTX 100 mg/m2 on days 1, 8, and 15. The primary endpoint for the phase II part is 2-year overall survival (OS) rate. Assuming an expected survival rate was 60% and a lower limit was 35% (alfa 0.05, beta 0.2). Secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), OS, and safety profile. Results: A total of 28 patients (median age 66 years, male 94%) were enrolled. Of the evaluable patients (n = 28), the rate of 2-year OS was 67.8% (95% CI: 49.3–82.1). The ORR was 96%, a median follow-up time was 33.2 months. Median PFS was 18.2 months (95% CI 13.1–not reached), and median OS was not reached (95% CI, 25.6–not reached). The most common toxicities of grade 3 or higher were neutropenia (60.5%), anemia (14.2%), thrombocytopenia (7.6%) and pneumonitis (3.6%). Conclusions: This study achieved the primary endpoint. Biweekly carboplatin and nab-PTX with concurrent RT therapy was well tolerated and promising systemic antitumor activity for patients with LA-NSCLC. Clinical trial information: 000023802 .
Clinical characteristics and outcomes of simultaneous multiple primary lung cancer.
Authors: Liu Ying
Published: May 2020

e21088

Background: Simultaneous multiple primary lung cancer (sMPLC) is detected increasingly nowadays with the development of image technology. But it has not been well characterized. Methods: All consecutive patients diagnosed as sMPLC according to Martini-Melamed and American College of Chest Physicians criteria from June 2010 to June 2019 were enrolled in our center. The clinical characteristics and outcomes were compared between patients with same histology and different histology. Results: A total of 336 patients were enrolled, consist of 297 (88.4%) patients with same histology and 39(11.6%) patients with different histology. Compared to patients with same histology, patients with different histology were more common male (87.2% vs. 34%, p < 0.001) and diagnosed at an older age (54 [62-69] vs. 59 [52-65], p < 0.001). Also, more than half of them (56.4%) had respiratory symptom or pain before diagnosis and most of them had smoking history (79.5% vs. 19.2%, p < 0.001). During follow-up, 5 patients were lost and 16 patients were died, contributing the 1-, 2-, and 3-year survival of overall patients was 97.7%, 96.1%, and 92.2%, respectively. Importantly, the survival rate was lower in patients with different histology (1-, 2-, and 3-year 88.5%, 75.4, and 64.3%) than same histology (1-, 2-, and 3-year 99.2%, 99.2, and 96.8%) (p < 0.001). Conclusions: Although relative less common in sMPLC, patients with different histology showed different clinical features and worse prognosis. [Table: see text]
Comprehensive investigation of mutational features of various lung adenocarcinoma histological subtypes among Chinese patients.
Authors: Han Yuchen , Xiang Chan , Teng Haohua , Zhu Lei , Shao Jinchen , Zhao Jikai , Ma Shengji , Lin Jing , Zheng Jingjing , Lizaso Analyn
Published: May 2020

e21090

Background: Lung adenocarcinoma (LUAD) is further classified into several histological subtypes according to the World Health Organization classification; however, data on the molecular profile of these histological subtypes are limited. In this study, we aimed to investigate the mutational features of various LUAD histological subtypes among Chinese patients. Methods: We retrospectively analyzed clinical, histopathologic, and sequencing data from 3,425 consecutive patients diagnosed with stage IA-IVB LUAD between January 2017 to December 2019 at the Department of Pathology. Results: Based on histologic subtype, the cohort comprised of 0.2% atypical adenomatous hyperplasia (AAH, n = 6), 7.2% adenocarcinoma in situ (AIS, n = 246), 14.0% minimally invasive adenocarcinoma (MIA, n = 479), and 78.6% invasive adenocarcinoma (INV, n = 2,694), including 42.0% acinar (n = 1,438), 12.7% papillary (n = 435), 8.8% lepidic (n = 302), 8.5% solid (n = 290), 3.2% micropapillary (n = 109), 2.8% invasive mucinous (n = 95), 0.6% enteric (n = 21), 0.1% fetal (n = 3), and 0.1% colloid (n = 1). Analysis of mutation profiles revealed significantly higher mutation detection rates of ERBB2 ( P< 0.01), BRAF ( P< 0.01), and MAP2K1 ( P= < 0.01) among patients with AIS, AAH and MIA as compared to patients with INV. Meanwhile, TP53 ( P< 0.01) and EGFR ( P< 0.01) mutations were significantly higher among patients with INV as compared to patients with AIS and MIA. Among the invasive subtypes, patients with invasive mucinous adenocarcinoma had significantly higher KRAS mutation rate (75%, P< 0.01). Lepidic (81%), acinar (80%), papillary (77%), and micropapillary (66%) were the subtypes with the highest EGFR mutation rates. Conclusions: By analyzing the genomic data of a large cohort of patients, our study provides a more comprehensive outlook of gene mutations according to LUAD histological subtypes. Enrichement of actionable mutation in particular histological subtype contributes to more treatment option and better clinical outcomes as compared to other histological subtype, indicating the clinical relevance of performing comprehensive mutation profiling in addition to histopathologic analysis in all LUAD patients.
Real-world outcomes of pembrolizumab in peritoneal mesothelioma.
Authors: Marmarelis Melina Elpi , Wang Xiao , Roshkovan Leonid , Walker Suzanne , McNulty Sally , Ciunci Christine Agnes , Muira John , Katz Sharyn I. , Cengel Keith A. , Karakousis Giorgos , Langer Corey J.
Published: May 2020

e21094

Background: Clinical trials evaluating pembrolizumab (P) in malignant mesothelioma (MM) have included small numbers of peritoneal MM (MPM) patients (pts), but the efficacy of P in the MPM subpopulation remains unclear. We evaluated the efficacy of P in a cohort of MPM pts treated at our institution. Methods: This retrospective cohort study identified MPM pts via ICD9/10 codes seen at our institution between 1/1/2009 and 9/1/2019. Pts were included if they received P as treatment for MPM. Median progression free survival (PFS) and median overall survival (mOS) were estimated from Kaplan-Meier curves. PFS was defined as the start of P until radiologic or clinical progression. Best overall response rate (BOR) and disease control rate (DCR) were determined retrospectively using RECIST 1.1 criteria. Results: We identified 13 non-papillary MPM pts who received P. All pts had received prior chemotherapy (12 platinum/pemetrexed, 1 pemetrexed). Median age at diagnosis was 65.6 years; 77% were white; 46% never smokers; 62% with known asbestos exposure; 70% epithelioid/15% biphasic/ 7.7% sarcomatoid/ 7.7% desmoplastic. BOR to P was 18% (Partial response (PR): 2, Progressive disease (PD): 2, Stable disease (SD): 7, Lost to follow up: 2). DCR was 81% and mPFS 5.7mo. From the start of P mOS was 20.9 mo. Only 3 pts had known PDL1 positivity (1%, 2%, 80%), 4 were negative, 6 untested. Median PFS was not statistically different between PDL1 positive and negative pts (mPFS 5.1mo vs. 5.7 mo, log rank p = 0.73, respectively). Three pts experienced a PFS of > 2 years (PDL1/BOR/% tumor change: Unknown/SD/19%, Negative/SD/-21%, 80%/PR/-70%). The patient with PDL1 80%, biphasic histology and a PR experienced skin toxicity requiring a treatment break. Outcomes for epithelioid histology vs non-epithelioid after P did not differ statistically (mPFS 5 mo vs 39 mo, log rank p = 0.14; mOS 17.5 mo vs NA, log rank p = 0.31). Conclusions: In a real world setting, P has clinically meaningful activity in a PDL1 unselected cohort of MPM pts and should be considered a treatment option for this subpopulation of MM. We did not detect a difference in outcomes based on PDL1 level or histology.