bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.