bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymph node dissections and survival in sublobar resection of non-small cell lung cancer ≤ 20 mm.
Authors: Takamori Shinkichi , Komiya Takefumi , Powell Emily 
Published: June 2022

e20583 Background: A recent Japanese phase III randomized trial of lobectomy versus segmentectomy for small-sized (≤ 20 mm) peripheral non-small cell lung cancer (NSCLC) (JCOG 0802) showed that patients who had undergone segmentectomy had a significantly longer overall survival (OS) in comparison with those who had lobectomy. More attention is needed regarding the required extent of thoracic lymphadenectomy in patients with small-sized NSCLC who undergo sublobar resection. Methods: The National Cancer Database was queried for patients with clinically node-negative NSCLC ≤ 20 mm who had undergone sublobar resection between 2004 and 2017. OS of NSCLC patients by the number of lymph node dissections (LNDs) was analyzed using Log-rank tests and Cox proportional hazards model. The cut-off value of the LNDs was set to 10 according to the Commission on Cancer’s recommendation. Results: This study included 4,379 segmentectomy and 23,138 wedge resection cases. The sequential improvement in the HRs by the number of LNDs was evident, and the HR was the lowest if the number of LNDs exceeded 10. Patients with ≤ 9 LNDs had a significantly shorter OS than those with ≥ 10 LNDs (hazard ratio [HR]: 1.50, 95% confidence interval [CI]: 1.40–1.61, P < 0.0001). Multivariable analysis revealed that performing ≤ 9 LNDs was an independent factor for predicting OS (HR for death: 1.34, 95% CI: 1.24–1.44, P < 0.0001). These results remained significant in subgroup analyses by the type of sublobar resection (segmentectomy, wedge resection). Conclusions: Performing ≥ 10 LNDs has a prognostic role in patients with small-sized NSCLC even if the resection is sublobar.
Characteristics of patients with EGFR-mutant non-small cell lung cancer (NSCLC) at a diverse metropolitan cancer center.
Authors: Chen Lanyi Nora , Schluger Benjamin , Lagos Galina , Henick Brian S. , Herzberg Benjamin , Mathew Matthen , Shu Catherine A. 
Published: June 2022

e20593 Background: Epidermal growth factor receptor-mutated [ EGFR(+)] NSCLC has historically been associated with young, non-smoking patients, especially those of Asian descent. Our medical center serves a diverse population within New York City and includes patients from neighborhoods that are predominantly Hispanic/Latino. We therefore sought to describe the population of patients with EGFR(+) NSCLC treated at our cancer center. Methods: We used our single institution lung cancer database to identify 2092 patients diagnosed with NSCLC between 2013-2019; of these, 375 had EGFR(+) disease. We collected retrospective data on patient demographics and disease outcomes. The chi-square test and t-tests were performed to compare between subgroups of patients. Results: Between 2013-2019, 17.9% of patients diagnosed with NSCLC at our center had an identified EGFR mutation. Incidence of EGFR mutations was higher in Asian NSCLC patients (46.7%) compared to Black (13.1%), white (16.8%), and Hispanic (16.0%) NSCLC patients. Within the 375 patients diagnosed with EGFR(+) NSCLC, however, the distribution was 62.1% white (233 patients), 13.6% Asian (51 patients), 11.2% Hispanic (42 patients), 8.3% Black (31 patients), and 4.8% unknown/other race (18 patients). Over half (57.7%) of patients with EGFR(+) NSCLC had a history of smoking, and most (68.9%) were female. Median age at diagnosis was 71 years. Frequency of tyrosine kinase inhibitor (TKI)-sensitive mutations (L858R and exon 19 deletion) was 85.7% in Hispanic patients, 91.7% in Asian patients, 76.4% in white patients, and 71.0% in Black patients. Significantly more Hispanic EGFR(+) patients were diagnosed at Stage IV (65.4%) compared to 40.4% of Asian patients, 36.7% of Black patients, and 25.7% of white patients (p < 0.02 for all comparisons). Among patients diagnosed with Stage IV disease, Hispanic patients had worse average survival compared to non-Hispanic patients (19.4 months vs. 27.9 months, p = 0.01). Conclusions: EGFR-mutant NSCLC is thought to be especially common among patients who are younger, Asian, and/or never smokers. Our population of EGFR(+) NSCLC, however, encompasses a racially diverse group of patients, most of whom were older at the time of diagnosis and many of whom had a history of smoking. This population of patients, most of whom harbor a TKI-sensitive mutation, supports the use of routine mutational testing that is agnostic to patient demographics. Our data also suggest that Hispanic patients in particular are diagnosed with more advanced disease and have shorter survival; the reasons for such disparities within the EGFR(+) NSCLC population warrant further study.
Phase I study of entinostat (Ent), atezolizumab (A), carboplatin (C), and etoposide (E) in previously untreated extensive-stage small cell lung cancer (ES-SCLC), ETCTN 10399.
Authors: Gentzler Ryan D. , Piekarz Richard , Villaruz Liza C , Rhee John C. , Lai Wei-Chu Victoria , Horton Bethany , Mock Joseph , Hanley Michael , Rudek Michelle A. , Phelps Mitch A. , Carducci Michael Anthony , Rudin Charles M. 
Published: June 2022

e20606 Background: A-CE has demonstrated improved overall survival in ES-SCLC, but there are currently no approved therapies targeting genomic alterations in SCLC. Mutations in acetyltransferases CREBBP and EP300 occur at a frequency of 15% and 13%, respectively, in SCLC, and PDX models with CREBBP mutations were demonstrated to be susceptible to targeting with HDAC inhibitors. Ent, a class I selective HDAC inhibitor, has also demonstrated clinical activity in a combination with pembrolizumab in patients with NSCLC and uveal melanoma with minimal hematologic toxicity at RP2D of 5 mg PO weekly. We conducted a phase I trial to evaluate the combination of Ent with A-CE for ES-SCLC, NCI ETCTN 10399. Methods: Patients (pts) with treatment-naïve ES-SCLC, stable or treated brain metastases, ECOG ≤2 were enrolled and treated on up to 4 dose levels of Ent. Allocation to cohorts was determined using Bayesian optimal interval (BOIN) design targeting a MTD with a DLT rate of 20%. Dose levels (DL) included Ent 2 mg, 3 mg, or 5 mg PO weekly on day (d) 1 in addition to 4 cycles of A-CE (A 1200 mg, C AUC 5, E 100 mg/m2 d 1-3) followed E+A for 1 year. Pre-treatment tissue and plasma collected for WES. Results: 3 pts were enrolled and treated at DL1 with Ent 2 mg. Pts were age 69-83, 2 male, 1 female, 2 were ECOG 1, 1 was ECOG 0, and 1 with prior SRS radiation for brain metastases. 2 of 3 experienced DLTs during cycle 1: (1) Grade (Gr) 4 febrile neutropenia after 2 doses of Ent and (1) Gr 5 sepsis after 1 dose of Ent. BOIN design required stopping accrual to dose level 1 and the trial was closed to further accrual. The pt without DLT experienced grade 3 thrombocytopenia after 2 doses of Ent, but recovered after holding cycle 1, day 15 Ent. This patient experienced Gr 3 neutropenia during cycle 2. The most common adverse events were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), hypocalcemia (2). Of these, most were Gr 3-4: anemia (1), neutropenia (3), thrombocytopenia (2), leukopenia (1), hypocalcemia (1). Conclusions: The combination of low dose Ent 2 mg PO weekly + AC-E is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia in the first 1-2 weeks and ≥Gr 3 neutropenia and thrombocytopenia prior to completing 2 cycles of treatment for all pts. There is no role for further exploration of entinostat with carboplatin, etoposide, and atezolizumab. Clinical trial information: NCT04631029.
Analysis of survival and prognostic factors of thymic neuroendocrine tumors.
Authors: Mao Yinggang , Ma Yihui , Li Xiangke , Yang Minjie , Song Lijie 
Published: June 2022

e20622 Background: To investigate the clinical characteristics of thymic neuroendocrine tumors and the relationship between treatment and survival prognosis. Methods: 69 patients, including 54 males and 15 females, who were diagnosed with NETT by puncture or surgical pathology in the First Affiliated Hospital of Zhengzhou University from September 2011 to October 2021 were retrospectively analyzed for initial symptoms, Pathological type, lesion size, treatment and prognosis of survival. Results: The median age of the 69 patients was 53 years old (28-83 years old), the median maximum diameter of the primary lesion was 6.85 cm (1.1-14.9 cm), and the clinical manifestations were not specific. The most common initial symptom was chest tightness and chest pain for 20 cases, 19 cases with hidden disease, found during physical examination. The manifestations of local invasion and metastasis included cough (6 cases), neck and face swelling (9 cases), retrosternal discomfort (3 cases), and low back pain (4 cases). There were 6 cases with systemic manifestations (anorexia, fatigue and fever). Only one case showed ectopic ACTH syndrome. The pathological types included 46 cases of well-differentiated neuroendocrine tumors (5 cases of typical carcinoid tumors, 41 cases of atypical carcinoid tumors), 23 cases of poorly differentiated neuroendocrine tumors (13 cases of small cell carcinomas, 3 cases of large cell neuroendocrine carcinomas, and high-grade neuroendocrine carcinomas). 7 cases of endocrine carcinoma). Masaoka-Koga staging: 2 cases of stage I, 10 cases of stage II, 20 cases of stage III, and 37 cases of stage IV. Thirty patients received surgical treatment, and 19 received postoperative adjuvant therapy. Long-term follow-up results showed a median overall survival time of 49.5 months. Univariate analysis showed that surgery could improve PFS (P = 0.009), while postoperative comprehensive treatment had no effect on PFS (P = 0.724). Pathological grade (P < 0.001), Masaoka-Koga stage (P = 0.004), and surgery (P = 0.014) were associated with OS. Multivariate analysis showed that pathological grade was an independent factor affecting OS (HR: 7.133; 95%CI: 2.183-23.306; P = 0.001). Conclusions: Thymic neuroendocrine tumor is a rare malignant tumor, and pathological grade is an independent risk factor for prognosis. Surgery can improve the patient's PFS.
Genomic characterization of immune checkpoint inhibitor resistance genes and hyperprogression related genes in advanced lung cancer.
Authors: Chen Shengjia , Zhu Kai , Zhong Qiaofeng , Jiang Kan , Wang Zhizheng , Mu Tianhao 
Published: June 2022

e21042 Background: Immune checkpoint inhibitors have been widely used in the treatment of advanced lung cancer, but immunotherapy still shows poor efficacy or leads to hyperprogression in some patients. Some studies demonstrated that EGFR mutations, ALK fusion, interferon pathway gene mutation, and Wnt signal pathway mutation might reduce the efficacy of immunotherapy and lead to tumor hyperprogression. The aim of this study was to determine the frequency of gene variations associated with immunotherapy resistance or hyperprogression in patients with advanced lung cancer. Methods: The tumor tissues or blood samples of 129 patients with advanced lung cancer were collected. The tumor tissues were sequenced by targated next-generation sequencing (55 genes, Illumina novaseq 6000), MSI (PCR), and PD-L1 detection (IHC). Blood cfdna was extracted and sequenced by targeted next-generation sequencing (55 genes, Illumina novaseq 6000). Results: A total of 129 patients with advanced lung cancer were included in the study, including 126 patients with non-small cell lung cancer and 3 patients with small cell lung cancer. Tissue was available for testing in 113 patients, blood samples were collected from 106 patients, and cerebrospinal fluid samples were collected from 1 patient. Among 85 samples tested for MSI, there were 81 cases of MSS (95.3%), 3 cases of MSI-L(3.5%), and 1 case of MSI-H (1.2%). PD-L1 expression was detected in 60 samples. 23 samples (38.3%) had PD-L1 expression < 1%, 31 samples (51.7%) had PD-L1 expression greater than 1% but less than 49%, and 6 samples (10%) had PD-L1 expression > 50%. Among the genes related to immunotherapy, the mutations of genes related to cell growth or cell cycle regulation (EGFR, ALK, CDKN2A, CCND1) accounted for 86 (66.7%), 12 (9.3%), 15 (11.6%), 8 (6.2%), respectively. The mutation of antigen presentation related gene (B2M) accounted for 2 (1.6%). The mutations of interferon signaling pathway related genes (JAK1, JAK2, JAK3, IFNGR1, PIAS4 and SOCS1) accounted for 6 (4.7%), 7 (5.4%), 3 (2.3%), 3 (2.3%), 1 (0.8%) and 1 (0.8%), respectively. Wnt signaling pathway related genes (APC, AXIN1, CTNNB1) accounted for 8 (6.2%), 2 (1.6%) and 4 (3.1%). Mutations in tumor suppressor genes (PTEN, STK11, KEAP1, PTPN2) accounted for 4 (3.1%), 8 (6.2%), 6 (4.7%) and 3 (2.3%). Mutations in other genes (APLNR, DNMT3A, MDM2, MDM4) accounted for 3 (2.3%), 1 (0.8%), 7 (5.4%) and 1 (0.8%). Conclusions: Our study shows that in patients with advanced lung cancer, there are multiple gene variants related to drug resistance or hyperprogression of immune checkpoint inhibitors, suggesting that this may be the reason for the difference in immunotherapy efficacy in patients. It is necessary to further study the efficacy of immunotherapy in patients with different gene mutations and the combination of immune checkpoint inhibitors for patients with different pathway mutations.
Correlation of clinical outcomes with programmed death ligand-1 expression on liquid biopsy.
Authors: Jayananda Sriraksha , Muzaffar Mahvish , Namireddy Praveen , Sharma Nitika , Meyer David , Walker Paul R. 
Published: June 2022

e21050 Background: Programmed death ligand-1 (PD-L1) expression is predictive of immunotherapy benefit. However, tissue PD-L1 protein immunohistochemical testing can be fraught with tissue acquisition and heterogeneity limitations. PD-L1 expression by RNA sequencing can be performed by both tissue and plasma with tissue PD-L1 protein correlations. What has not been well characterized is the correlation of plasma cell free circulating tumor RNA (cfRNA) PD-L1 and clinical outcomes with immunotherapy. Plasma cfRNA PD-L1 expression was evaluated and correlated with immunotherapy benefit in advanced non-small cell lung cancers (NSCLC). Methods: Patients with advanced NSCLC undergoing plasma next-generation sequencing including plasma cfRNA.PD-L1 testing in a Clinical Laboratory Improvement Amendments (CLIA) and College of American pathologists (CAP) accredited laboratory were retrospectively identified and evaluated at a single institution. Plasma PD-L1 positive patients underwent a de-identified chart abstraction to identify those patients with advanced NSCLC treated with front line immunotherapy regimens and those who received cytotoxic chemotherapy alone. Results: Sixteen patients with plasma PD-L1 expression treated with front-line immunotherapy regimens including single-agent immune checkpoint inhibitors, and combinatorial chemo-immune or chemo-immune-bevacizumab regimens were assessed for overall survival (OS). Eleven patients with plasma PD-L1 expression who received chemotherapy were used as a non-immunotherapy OS comparison. Median OS for the immunotherapy treated patients was thirteen months with a thirty percent three year landmark OS versus four months median OS and a ten percent three-year landmark OS for those treated with chemotherapy alone. Comparative log-rank test p-value 0.0091 and a hazard ratio of 0.36 (95%-CI 0.13-0.99). Conclusions: Plasma cfRNA PD-L1 expression is predictive of a statistically significant survival benefit from immunotherapy treatment compared to chemotherapy in the first line treatment of advanced NSCLC. The three year landmark OS of thirty percent parallels tissue PD-L1 directed immunotherapy-based treatment outcomes. The clinical utility of plasma cfRNA PD-L1 to overcome tissue acquisition and PD-L1 protein heterogeneity limitations and to study the dynamic nature of PD-L1 expression with non-immune cancer treatments and potential immunotherapy response monitoring are undergoing ongoing research.
DYNC2H1 Mutation as an indicator stratified patients benefit from Immune Checkpoint Inhibitors in NSCLC.
Authors: Li Chunxiang , Zhao Lele , Yu Yangyang , Xiao Mingzhe , Qi Chuang 
Published: June 2022

e21052 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) encodes a large cytoplasmic dynein protein that involved in intraflagellar transport. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between DYNC2H1 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between DYNC2H1 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with DYNC2H1 mutation were significantly associated with better PFS (HR = 0.3; 95% CI, 0.14-0.64; P= 0.001), objective response rate (ORR, 65.0% vs 27.6%; P = 0.003) and durable clinical benefit (DCB, 75.0% vs 43.4%; P = 0.031) after ICIs therapy, compared with those with wide-type DYNC2H1. DYNC2H1 mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between DYNC2H1 mutation and PFS remained significant (HR = 0.32; 95% CI, 0.14-0.73; P = 0.007). In contrast, no association between DYNC2H1 mutation and OS (LUAD: P = 0.97 ; LUSC: P = 0.34) or PFS (LUAD: P = 0.54; LUSC: P = 0.39) was observed in TCGA datasets, suggesting that DYNC2H1 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, DYNC2H1 mutation was significantly associated with higher CD8+ T cell. Moreover, DYNC2H1 mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. Conclusions: Our results demonstrated that DYNC2H1 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of DYNC2H1 in immunotherapy is needed to be further studied.
Real-world analysis of the EGFR mutation detection in plasma ctDNA from patients with non-small cell lung cancer.
Authors: Long Chaolian , Li Kun , Liu Zichen , Zhang Nana , Xing Xuya , Xu Liming , Gai Fei , Che Nanying 
Published: June 2022

e21069 Background: Plasma sample has emerged as a promising surrogate sample for EGFR mutation detection in advanced non-small cell lung cancer (NSCLC). In clinical practice, whether EGFR variants in pretreatment plasma ctDNA of advanced lung cancer can predict prognosis in addition to guiding targeted therapy remains to be further explored. Methods: In this study, we retrospectively enrolled 315 NSCLC patients from Beijing Chest Hospital, 94.9% of whom were in stage IIIB-IV. EGFR gene mutation data from tissue detected by ARMS-PCR (Amoy Diagnostics, Xiamen, China) and paired plasma samples within one month of admission detected by SuperARMS-PCR (Amoy Diagnostics, Xiamen, China) were collected. The patients’ clinicopathological characteristics and treatment information were also collected for further analysis. Differences in PFS of targeted therapy between patients with positive and negative pretreatment plasma ctDNA EGFR mutation were compared. Results: EGFR-positive rate of tissue and plasma ctDNA was 65.1% (205/315) and 43.8% (138/315), respectively. L858R, 19-DEL, T790M, G719X, 20-INS, and L861Q mutations were detected in both samples. The sensitivity, specificity, PPV, NPV and concordance of ctDNA detection was 65.4%,96.4%, 97.1%, 59.9%, and 76.2%, respectively. In the study, patients’ pathological subtype was the factor affected plasma ctDNA EGFR alteration detection accuracy. The concordance in adenocarcinoma patients was obviously higher than that in non-adenocarcinoma (p = 0.02). 92 treatment naïve advanced patients with tissue EGFR mutation were received first and second-generation EGFR tyrosine kinase inhibitors (TKIs) therapies. 59.8% (55/92) patients also had EGFR mutation in plasma ctDNA, 40.2% (37/92) patients had no detectable EGFR mutations in plasma ctDNA. The median PFS in plasma ctDNA EGFR positive patients was 7.0 months versus 14.0 month in plasma ctDNA EGFR negative patients, with significantly difference (p = 0.004). Conclusions: Plasma sample could be a surrogate sample for molecular test when tissue sample was unavailable. The poor prognosis was observed in treatment naïve advanced NSCLC patients with baseline plasma EGFR mutation.
Glycoproteomics as a powerful liquid biopsy-based screening tool for non-small cell lung cancer.
Authors: Mitchell Alan , Pickering Chad , Xu Gege , Rice Rachel , Castellanos Alyn , Bhadra Ranjan , Brcic Luka , Lindenmann Joerg , Smolle Freyja , Lindpaintner Klaus , Serie Danie 
Published: June 2022

e21148 Background: Protein glycosylation is the most abundant and complex form of post-translational protein modification. Glycosylation profoundly affects protein structure, conformation, and function. The elucidation of the potential role of differential protein glycosylation as biomarkers has so far been limited by the technical complexity of generating and interpreting this information. We have recently established a novel, powerful platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine that allows, for the first time, highly scalable interrogation of the glycoproteome. Methods: Using this platform, we interrogated 694 glycopeptide (GP) and non-glycosylated peptide transitions derived from 74 serum proteins in pre-treatment peripheral blood samples from a cohort of 316 individuals with non-small-cell lung cancer (NSCLC) (128 females, 187 males, 1 with unknown sex, median age 66 years, age range 31-89 years, stage 0-4 N’s: 1 / 99 / 80 / 84 / 49, 3 missing) and a comparison cohort of 194 healthy control samples (102 females, 92 males, median age 52 years, age range 30-63 years). Age- and sex-adjusted differential expression analysis for 596 normalized biomarkers were performed to evaluate statistically significant differential abundances using an FDR-adjusted q-value of 0.05 as a cutoff. Repeated five-fold cross-validated LASSO-regularized logistic regression was performed to create a multivariable classifier that predicts whether a serum sample belongs to the healthy or NSCLC cohort. Results: We identified 432 biomarkers with significant abundance differences at FDR ≤ 0.05 between samples with NSCLC and healthy controls. Using 70% of the complete cohort (balanced by case/control membership, NSCLC stage, sex, and age quartile) as a training set, we selected a total of 375 glycopeptide and non-glycosylated peptide biomarker features that remained differentially expressed at FDR-adjusted q-value ≤ 0.05 as input into a LASSO-regularized multivariable classifier. This resulting in a 19-biomarker model exhibiting an accuracy of 94.8% (96.9% sensitivity, 91.2% specificity) and AUC of 0.989. This classifier was validated in an independent test set comprising the remaining 30% of subjects, yielding an accuracy of 94.5% (95.5% sensitivity, 93.0% specificity) and AUC of 0.975. Sensitivity in the test set was 100% / 96% / 99% / 96% / 94% / 10%, in stages 0-4 and missing, respectively. Conclusions: Our results indicate that glycoproteomic biomarkers can be leveraged as a strong liquid biopsy-based screening tool for patients at high risk of NSCLC, as an alternative to imaging modalities.