bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carcinoid tumor of the bronchus and lung: A nationwide cross-sectional study.
Authors: Perez Esmirna , Guevara Nehemias , Portillo Shellsea , Francis-Morel Garry 
Published: June 2023

e20645 Background: Carcinoid tumor of the lung is a rare neuroendocrine tumor (NET), little is known of the in-hospital characteristics of this tumor. This study aims to describe the characteristics of patients hospitalized with NET of the bronchus and lung. Methods: This is a retrospective descriptive study of patients with lung carcinoid tumors admitted to acute care from 2016 to 2020. Data is derived from the National Inpatient Sample (NIS). The patients were divided into two groups: malignant and benign carcinoid tumors of the bronchus and lung. Patients' characteristics were described, including demographics, hospital length of stay (Los), and total cost. Mortality and common comorbidities were included. Hypothesis testing for categorical variables were tested with Chi-Square. Continuous variables were tested with a Student t-test. Statistical significance was defined as a two-tailed P value of < 0.05. Results: A total of 13,335 admissions were identified over a period of 5 years, but only 1,810 of them met inclusion criteria. The elderly population was the most affected group, with a mean age of 60 years (Malignant 61 versus Benign 52; p 0.001). There was a trend of female predominance, representing 57% vs 42% of males ( p 0.727). White patients constituted the majority of the population (72%), followed by Black (13%) and Hispanics (10%), with a minority of Native Americans and Asian/ Pacific Islanders ( p 0.016). Medicare was the most frequent primary payer (50%, p 0.015). No difference in household distribution ( p 0.138), hospital teaching status ( p 0.743) hospital region ( p 357) or hospital bed size (0.273) were noted. However, the majority of the admissions were to private-non-profit facilities, accounting for 78% ( p 0.003). Mean LoS was 7.4 days ( p 0.021). On subgroup analysis, the malignant carcinoid tumor of the lung was predominant, with 1,490 malignant carcinoid tumors of the lung and bronchus compared to 329 benign carcinoid tumors of the bronchus and lung. Affection by comorbidities like CAD and COPD was significantly associated with a carcinoid tumor of the lung (17% malignant carcinoid tumor of the lung and bronchus and 5% benign carcinoid tumor of the lung and bronchus p 0.003 and 24% malignant carcinoid tumor of the lung and bronchus and 11% benign carcinoid tumor of the lung and bronchus, p 0.008 respectively). All deaths (n = 90) were observed in the malignant carcinoid lung tumor group. Conclusions: In this cross-sectional study of patients with NET of the bronchus and lung admitted to acute care, we found that patients over the age of 50 and Whites were the most affected, with patients with malignant tumors being older. As expected, Medicare was the most frequent primary payer. In addition, COPD and CAD were not uncommon among both groups.
Effect of SARS-CoV-2 mRNA vaccine booster in serologically negative patients with thymic epithelial tumors.
Authors: Pietroluongo Erica , De Placido Pietro , Morra Rocco , Buonaiuto Roberto , Tafuro Margherita , Longobardi Alessandra , Caltavituro Aldo , Tortora Marianna , Marretta Antonella Lucia , Del Deo Vitoantonio , Malfitano Anna Maria , Gelzo Monica , Daniele Bruno , Ottaviano Margaret , Formisano Pietro , Castaldo Giuseppe , Veneziani Bianca Maria , Palmieri Giovannella , De Placido Sabino , Giuliano Mario 
Published: June 2023

e20651 Background: Thymic epithelial tumors (TETs) are rare malignancies associated with humoral and cell-mediated immunity dysregulations. Anti-syndrome coronavirus type 2 (SARS-CoV-2) vaccine is effective at preventing COVID-19 morbidity and mortality. We have previously shown an impaired seroconversion after 1st and 2nd anti-SARS-CoV-2 vaccine doses in TETs patients. The aim of this study was to evaluate the seroconversion rate after the third vaccine dose (booster) in TET patients who remained serologically negative after full vaccination. Methods: Starting from November 2021 to March 2022, consecutive TET patients found to be serologically negative after two SARS-Cov-2 mRNA vaccine (BNT162b2 by Pfizer-BioNTech) doses were enrolled. SARS-CoV-2 spike-binding IgG antibody serological levels were centrally analyzed by chemiluminescent immunoassay (CLIA) at two different time-points: T0 and T1 (before and one month after booster, respectively). Cut-off for Ab titers positivity was > 25 AU/mL. Results: Among the 23 enrolled patients, 10 (43.5%) were female and 13 (56.5%) males; 6 (26%) pts had thymic carcinoma and 17 (74%) had thymoma. Autoimmune disorders were detected in 20 patients (86.9%), of whom 3 (15%) suffered from Myasthenia Gravis, 8 (40%) from Good’s Syndrome, 7 (35%) from both diseases, and 2 (10%) from other autoimmune disorders. By the time of booster administration 2 pts were lost to follow up, 2 pts died, 5 pts suffered from SARS-CoV-2 infection and seroconverted. Of the remaining 14 pts, only 7 (50%) achieved seroconversion. Among these patients, 2 had active cancer disease, whereas the remaining were disease-free. On the other hand, among the 7 patients who did not achieve seroconversion after booster, 6 had active cancer disease. Moreover, 6 of these patients suffered from Good’s Syndrome. Conclusions: Our results suggest that the anti-SARS-CoV-2 third dose could contribute to improved seroconversion of TET patients who did respond to the first two doses. It remains to be investigated why half of the patients are still not achieving seroconversion after the booster and whether this is determined by the presence of active disease or by alterations in humoral and/or cell-mediated immune response. These data may have important clinical implications because they could help to better identify fragile patients who could benefit from improved vaccine protocols or from alternative prophylaxis strategies, such as the use of monoclonal antibodies.
Characterization of URST1 as a prognostic marker and therapeutic target for lung cancer.
Authors: Takano Atsushi , Miyagi Yohei , Daigo Yataro 
Published: June 2023

e21000 Background: The improved understanding of cancer-specific oncoproteins could lead to the development of novel biomarkers or therapeutic targets for lung cancers. Methods: We screened oncoproteins as follows: i) Identification of up-regulated genes in lung cancers by cDNA microarray, ii) Validation of clinicopathologic importance of their gene product by tissue microarray, iii) Examination of the growth of cancer cells after transfection of their siRNA or expression vector, iv) Screening of their signal pathways. Results: We identified up-regulated in solid tumor 1 (URST1) as a candidate. Immunohistochemical staining of URST1 showed that URST1 expression was observed in 231 (64.5%) of 358 non-small cell lung cancers (NSCLC) and 11 (84.6%) of 13 small cell lung cancers. High level of URST1 expression was associated with poor prognosis for NSCLC patients ( P = 0.0003). Multivariate analysis confirmed that strong URST1 expression was an independent prognostic factor for NSCLC patients that had undergone radical surgery. Knockdown of URST1expression by siRNAs against URST1 significantly suppressed the growth of lung cancer cells, and also inhibited the cell invasive ability. Treatment of lung cancer cells with small molecule inhibitor against URST1 suppressed the cell growth partly through G2/M arrest and cell death. In contrast, enforced expression of URST1 significantly promoted lung cancer cell growth. Microarray analysis coupled with siRNAs for URST1 suggested various URST1 related oncogenic pathways in lung cancer cells. Conclusions: URST1 could play an essential role in malignant potential of lung cancer and it might be useful as a prognostic biomarker and therapeutic target molecule for lung cancer.
Clinical analysis of the presence of comutations in patients with EGFR-mutated NSCLC.
Authors: Rubio Jaime , Santolaya Carlota , Fernandez Marina , Villalba Paula Lucia , Avedillo Mercedes , Garcia-Foncillas Jesus , Domine Manuel 
Published: June 2023

e21001 Background: EGFR mutation is the most common treatable molecular alteration in non-small cell lung cancer (NSCLC), in particular in adenocarcinoma it can be found in 10-15% of our patients (spanish population). But the presence of other commutations in EGFR mutated tumors and its implications has not been well characterized. Methods: We selected patients diagnosed with EGFR mutation non-small cell lung carcinoma (NSCLC) from February 2021 to March 2022 from 4 hospitals in Madrid (most of them from Fundación Jimenez Diaz University Hospital). EGFR status and the presence of commutations was determined by using the AVENIO Tumor Tissue Targeted Kit (a Next Generation Sequencing test). PD-L1 status was determined by immunohistochemistry assay (22C3 pharmDx). Molecular and clinicopathological characteristics were collected and we performed a descriptive analysis of our population. Results: Of the 48 patients evaluated, 68.8% were women and 31.3% were men. 73% were ECOG 0 and 23% ECOG 1 and only 44% were non-smokers, being 18.8% smokers and 37% ex-smokers, most of them with low consumption. The 91.7% were adenocarcinomas and 8.3% were squamous carcinomas. 43.7% were PD-L1 negative and 10.4% were high expressors (PD-L1 > 50%). Of the stage at diagnosis, 60.4% were stage IV and 16.7% were stage III, with 22.9% being stage I and II. Of the Stage IV patients, 87.7% debuted as patients with high disease burden, with only 13.3% being oligometastatic (oligometastatic being understood as those with less than 5 metastases in 3 different organs, including the primary tumor). 40% of them had brain metastasis at the diagnosis. Of the mutational profile, 50% had an exon 19 deletion, 25% had an L858R mutation and the rest had infrequent mutations (12.5% amplification, 10.4% exon 20 insertion and 6.3% exon 18 mutations). In our cases, we evidence that 56.25% of the patients, analyzed by NGS, had another mutation. Of all of them the most frequent was p53 (seen in 55% of the commutated cases), being less frequent others, such as MET and APC amplification (4.2%) and others with a 2.1% (PI3K, BAP1, KRAS, ALKt or HER2 amplification). Finally, we analyzed the progression-free survival (PFS) and overall survival (OS) of commutated patients vs. non-commutated treated with Osimertinib as a first line treatment and, although it was statistically non-significant due to the small sample size (11 vs 9) and the short follow-up, a very positive trend was seen (log-rank test p = 0.055 and p = 0.136 respectively). Conclusions: With the development of NGS, the presence of other commutations besides EGFR have implications that are still unknown, but it appears that it may cause worse OS and PFS. This should be studied in larger cohorts with longer follow-up.
Role of HLA-DRB4 as a biomarker for endocrine toxicity and survival outcomes after immunotherapy in metastatic non-small cell lung cancer.
Authors: Jiang Cindy , Ravishankar Shashidhar , Zhao Lili , Green Michael , Towlerton Andrea , Scott Anthony , Raghavan Malini , Cusick Matthew , Warren Edus H. , Ramnath Nithya 
Published: June 2023

e21005 Background: Immune checkpoint inhibitors (ICI) have significantly improved outcomes in non-small cell lung cancer (NSCLC) but are associated with development of immune related adverse events (irAEs). Currently, the role of germline determinants on immunotherapy efficacy and toxicity is unclear. Human leukocyte antigen (HLA) is emerging as a possible predictive biomarker. Our study aimed to assess HLA class II genotypes and their correlation to irAEs and survival. Methods: We conducted a single institution, prospective study with collection of baseline blood samples in patients with metastatic NSCLC treated with ICIs. Clinical characteristics and HLA genotypes (ScisGo HLA typing kits) were obtained. Kaplan-Meier method was used to calculate progression free survival (PFS) and overall survival (OS). Cox regression model was used for multivariate analysis (MVA) and we adjusted for age, gender, race, stage, and histology. Cumulative incidence function was used for association between HLA-DRB4 and endocrine irAEs. Results: Among 98 eligible patients, 85 had complete HLA genotyping. Most patients were men (96.5%), Caucasian (75.3%), and former/active smokers (98.8%) with a median age of 72 years. Median follow up time was 42.8 months. Majority of patients received pembrolizumab (83.5%). Other ICIs included durvalumab (10.6%) and nivolumab (4.7%). Twenty patients (23.5%) experienced irAEs – 11 patients had endocrine irAEs and 9 with other irAEs. 3 patients (27.3%) with endocrine irAEs had toxicity grade 3. Presence of irAE did not improve PFS (p = 0.226, HR 0.61, 95% CI [0.268,1.365]) or OS (p = 0.219, HR 0.63, 95% CI [0.301,1.316]). HLA-DRB4 was present in 39/85 patients (45.9%) and was the predominant genotype in patients with endocrine irAE (9/11, 81.8%) (Table 1). The cumulative incidence of endocrine irAEs was higher in patients expressing HLA-DRB4 (p = 0.0139 ). HLA-DRB4 improved survival in both univariate (PFS 9.9 months, p = 0.040; OS 26.3 months, p = 0.0085) and MVA (PFS p = 0.0310, HR 0.55, 95% CI [0.31, 0.95]); OS p = 0.003, HR 0.40, 95% CI [0.21, 0.73]). Conclusions: Expression of HLA-DRB4 was associated with the development of endocrine irAEs and correlated with improved survival outcomes in metastatic NSCLC patients being treated with ICIs. Further studies are necessary to validate our findings of HLA-DRB4 as a possible predictive marker for endocrine irAEs and therapy efficacy.[Table: see text]
A differential analysis of TCR repertoire between patients with EGFR-mutant and KRAS-mutant non–small-cell lung cancer.
Authors: Xie Yuancai , Li Yingmei , Dong Linfeng , Chen Shifu , Liu Jixian 
Published: June 2023

e21012 Background: T-cell receptor (TCR) repertoire could partially represent tumor micro-environment. EGFR and KRAS are common driver genes mutated and often mutually exclusive in non-small cell lung cancer (NSCLC). There’s a hypothesis that the immune system responds differently according to different mutations. Here we investigated the TCR features, including diversity, clonality, evenness and sequence similarity in EGFR and KRAS mutated NSCLC patients, to better understand the immune response in carcinogenesis. Methods: A total of 71 EGFR-mutant and 31 KRAS-mutant NSCLC tissue samples underwent multiplex PCR based TCR-β sequencing. TCR-β cdr3 amino acid sequences were obtained from the sequencing data using MiXCR and VDJtools. To compare TCR repertoires in EGFR-mutant and KRAS-mutant groups, each assemble CDR3 amino acid sequence was taken as a word, and each repertoire was taken as a document. Each repertoire was compared with every other one as a sample pair. TF-IDF (term frequency-inverse document frequency) document vectors was built for each sample and cosine similarity scores were computed for sample pairs. Results: The total cosine similarity score within EGFR-mutant group is 11.07 and average cosine similarity score is 0.0044±0.01, while in the KRAS-group, the total cosine similarity score is 13.41 and average cosine similarity score is 0.029±0.04. Between these two groups, the total cosine similarity score is 8.76 and average cosine similarity score is 0.0019±0.0009. See table for summary. The intergroup similarity score is significantly less than that within each group respectively (p < 1E10). Conclusions: Our results demonstrated that the TCR repertoire was clearly associated with cancer mutational profile. The mechanism of how mutations affect the immune system and shape the TCR repertoire is yet to be investigated. [Table: see text]
Frequency and patterns of TP53 mutations in lung cancer.
Authors: Yang Yaxian , Wang Heran , Wang Lucas , Fan WenTao , Lian Bin , Jin Ying , Luo Weiquan , Mao Jiewei , Feng Yilin , Xie Hongtao , Huang Mingjian , Zheng Liyu , Pan Zhaodong , Huang Mingming , Wang Yongsi , Wen Yunjie , Huang Jian 
Published: June 2023

e21013 Background: Lung cancer (LC) is the second leading causes of cancer-related mortality and composed of diverse molecular types. Tumor suppressor gene TP53 is one of the most frequency mutation genes in cancer, however, whether there are the hot sports of TP53 mutations has always been a challenging issue. The aim of this study was to explore the spectrums and hot spots of TP53 mutation in LC. Methods: The total 1932 LC tissue samples (from same number of patients，all cases had patients' informed consent) in formalin fixed and paraffin embedded were collected from Guangzhou Huayin Health Medical Group Co.,Ltd. By targeting next generation sequencing (NGS) of 600 genes, the mutation information of TP53 and other genes was obtained. Results: Among 1932 samples, 1025(53%) were male, 1685(87.2%) were lung adenocarcinoma (LUAD), 232(12.0%) were lung squamous cell carcinoma (LSCC), 7(0.4%) were large-cell carcinoma and 8(0.4%) were small-cell carcinoma, median age was 62.82(range: 27-92). The mutated TP53 was detected in 890 (46%) samples. Other most frequently altered genes were EGFR (1114/1932, 57%), KRAS (213/1932, 11%), PIK3CA (116/1932, 6%), APC (107/1932, 6%) and ERBB2 (97/1932, 5%) . Additionally, 412 (21.3%) patients with TP53 and EGFR co-mutation, TP53 and KRAS co-mutation occurred in 81 (4.2%) patients, PIK3CA mutation co-occurred with TP53 in 53 (2.7%) patients. The total of 920 TP53 mutant sites were detected, and these sites scattered throughout the 11 exons, especially exon 5-8. 13 of these mutation sites which accounted as high frequency ( > 10), including R273C (18/920), R248W (16/920), Y220C (15/920), Y163C (14/920), R249S (13/920), R282W (13/920), H179R (12/920), R158L (12/920), R175H (11/920), G245D (11/920), R273H (10/920), Y234C (10/920), and R273L (10/902). In addition, missense mutations were the main type, and the proportion of SNP with C > T was the highest in mutation sites. Conclusions: This study characterized the mutational signatures that TP53 mutations are interspersed, and hot spots are just in small proportions in LC. This study may provide a basis for drug development for targeting TP53 mutations in the future.
Mechanism-based peripheral blood biomarkers to evaluate anticancer effects of the plinabulin/docetaxel combination (plin/doc) vs. doc alone in second/third line EGFR wild-type (WT) NSCLC.
Authors: Feinstein Trevor , Lu Y. June , Duprez Stephen , Bai Lore , Huang Lan , Mohanlal Ramon W. 
Published: June 2023

e21017 Background: Pretreatment neutrophil to lymphocyte (L) (NLR), platelet to L (PLR), and L to monocyte (LMR) levels are established prognostic biomarkers for advanced NSCLC. Plinabulin (Plin) is a well-tolerated, differentiated tubulin-binding agent being developed for neutropenia prevention as a monotherapy and in combination, and for improving the efficacy of anticancer agents. DUBLIN-3 (NCT02504489) was a randomized, single-blinded (pts only), active-controlled Ph3 study in 2nd/3rd line stage IIIB/IV, EGFR WT NSCLC with a measurable lung lesion (RECIST 1.1). Pts (N = 559) were randomized 1:1 to Plin/Doc or Doc (21-day (D) cycle (C)). Doc (75 mg/m2) on D1 and Plin (30 mg/m2) on D1/D8 were given by IV infusion with steroid premedication (8 mg PO BID x 3D). Differential WBCs and platelet counts were collected at baseline (pre-steroid), D1, and D8. We analyzed the posttreatment effects of Plin on NLR, PLR, and LMR. Methods: All evaluable Plin/Doc vs Doc pts were included. NLR/PLR/LMR ratios and their respective change from baseline (cNLR/cPLR/cLMR) were obtained from blood draws taken at predose, C1D8, and/or C2D8. For intra/inter-arm overall survival (OS) stratification, baseline median NLR (3.2), PLR (177), and LMR (3.5) values were selected as thresholds. By examining responders & long-term survivors in both arms, posttreatment NLR/LMR and cNLR/cLMR thresholds were established for C1D8 and C2D8. Finally, PFS/OS benefits were stratified to determine the statistical significances of Plin/Doc vs Doc. Results: In agreement with literature, baseline threshold levels for NLR = 3.2, PLR = 177, LMR = 3.5 were statistically significantly predictive of OS in both the Plin/Doc and Doc arms (p values ranging from 0.05 to 0.0001). Plin prevents Doc-induced neutropenia, and post-Doc neutrophil counts were higher on D8 with Plin/Doc vs Plin (p < 0.001). Despite Doc-induced myelosuppression, Plin/Doc responding pts maintained similar NLR/LMR values as baseline at C1D8 and C2D8. After a single Plin dose at C1D8, lower NLR (cutoff = 3.0; 1.2x median value of all pts) and higher LMR (cutoff = 4.5; median value of all pts) thresholds independently predicted PFS/OS benefits of Plin/Doc vs Doc. Further, a higher cNLR threshold (cutoff = 0.25) at C2D8, best predicted Plin/Doc vs Doc in PFS and OS (p < 0.0001 and p = 0.0035 respectively). Conclusions: Bone marrow suppression remains a common serious risk of classical/non-classical cancer drugs. Under these conditions, the addition of Plin offers rapid protection of GMP lineage cells which can be captured by simple blood cell counts. Incorporation of blood-based biomarkers may help enrich NSCLC pts with better sensitivity to Plin/Doc combination than Doc alone. Clinical trial information: NCT02504489 .
Prognostic value of baseline immune suppressive biomarkers to select non-small cell lung cancer (NSCLC) patients (pts) likely to benefit from the plinabulin/docetaxel (Plin/Doc) combination.
Authors: Feinstein Trevor , Legaspi Gabrielle , Duprez Stephen , Huang Lan , Mohanlal Ramon W. 
Published: June 2023

e21018 Background: Baseline Neutrophil-to-Lymphocyte (L) ratio (NLR), Platelet-to-L ratio (PLR), and L-to-Monocyte ratio (LMR) are biomarkers that can predict anticancer outcomes. Plin, a novel small molecule immune-enhancing agent, exerts anticancer activity by GEF-H1-dependent activation of dendritic cells, and hence T-cells. We evaluated the correlation of Plin’s anticancer effects with NLR, PLR, LMR immune suppressive (IS) signature. We correlated baseline NLR, PLR, and LMR (broken down in quartiles [Q]) with overall survival (OS) in NSCLC pts from the DUBLIN-3 trial, which had met the primary OS endpoint in favor of Plin/Doc vs Doc alone (Han ESMO 2021). Methods: DUBLIN-3 (NCT02504489) was a global Phase 3 study in 2nd/3rd line EGFR-wild type, stage IIIB/IV NSCLC pts (N = 559) randomized 1:1 to Plin/Doc or Doc alone. Doc (75 mg/m2 on D1) and Plin (30 mg/m2 on D1/D8) were given by IV infusions. Baseline (i.e., prior to dexamethasone premedication, Doc and Plin) blood draws were taken from each pt within 28 days prior to any study medication given to obtain baseline NLR, PLR, and LMR. The survival duration of each pt was obtained. NLR, PLR, and LMR values for Plin/Doc and Doc were divided into Qs, and the corresponding median OS for each Q was calculated. Only 2nd line pts were included in this analysis to avoid confounding with multiple lines. Results: Increasing Qs of baseline NLR and PLR (thus with increasing IS signature) were associated with decreasing median OS for both Plin/Doc and Doc. Increasing Qs for LMR (thus with decreasing IS signature) were associated with increasing median OS in both Plin/Doc and Doc. Median OS in each Q was consistently higher with Plin/Doc vs Doc alone, except for Qs with an IS signature. With baseline NLR ≤3.6, PLR≤194, or LMR≥5.9, thus avoiding an IS signature, median OS was on average 2.5 Mo (range 0.6-4.5 Mo) longer with Plin/Doc vs Doc alone. For each of the Qs in the table, the n = 52 ± 2 pts. Conclusions: Baseline IS biomarkers were predictive of median OS with both Plin/Doc and Doc alone. Baseline NLR, PLR, and LMR, at cut-off levels to avoid IS levels, could serve as prognostic markers to identify likely responders to the immune-enhancing agent Plin in combination with Doc in NSCLC. Clinical trial information: NCT02504489 . [Table: see text]