bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial meta-transcriptomics reveal intratumor bacterial association with lung cancer cells showing a distinct oncogenic signature.
Authors: Zhao Chen , Wong-Rolle Abigail , Dong Qiang , Zhu Yunhua , Divakar Prajan , Hor Jyh Liang , Kedei Noemi , Wong Madeline , Tillo Desiree , Conner Elizabeth A. , Rajan Arun , Schrump David S. , Jin Chengcheng , Germain Ronald N. 
Published: June 2022

8531 Background: The lung intratumor microbiome influences lung cancer tumorigenesis and treatment responses, but detailed data on the extent, location, and effects of microbes within lung tumors is missing, information needed to improve treatment outcomes and prognosis. Methods: To address this gap, we developed a novel spatial meta-transcriptomic method simultaneously detecting the expression level of 1,811 host genes and three microbe targets (16S rRNA, 28S rRNA and CMV). After rigorous validation, we analyzed the spatial meta-transcriptomic profiles of tumor cells, T cells, macrophages, other immune cells, and stroma in tumor samples from 12 patients with early-stage lung cancer. Results: Bacterial burden was significantly higher in tumor cells compared to T cells, macrophages, other immune cells, and stroma. This burden increased from tumor-adjacent normal lung and tertiary lymphoid structures to tumor cells to the airways, suggesting that lung intratumor bacteria derive from the latter route of entry. Expression of oncogenic β-catenin and epithelial-mesenchymal transition pathway genes was strongly correlated with bacterial burden, as were tumor subtypes, mutation profile, histology and smoking history. Conclusions: Intratumor bacteria were enriched with tumor cells and associated with multiple oncogenic pathways, supporting a rationale for reducing the local intratumor microbiome in lung cancer to optimize clinical outcomes. This research was supported in part by the Intramural Research Programs of the NCI and NIAID. Other funding sources included ASCO Young Investigator Award, SITC-AstraZeneca Immunotherapy in Lung Cancer (Early Stage NSCLC) Clinical Fellowship Award, NIH Bench-to-Bedside and Back Program (BtB), NCI R00 award (CA226400), Emerson Collective Cancer Research fund, Lung Cancer Research Foundation (LCRF) pilot grant and W.W. Smith Trust Foundation award. This study was approved by NCI institutional review board (NCT00242723 and NCT02146170) and Animal Use and Care Committee at the University of Pennsylvania (#806875).
Analysis of circulating tumor DNA in the phase 2 BTCRC LUN 16-081 trial of consolidation nivolumab with or without ipilimumab after chemoradiation in stage III non–small cell lung cancer.
Authors: Jun Soyeong , Shukla Nikhil , Durm Greg Andrew , Hui Angela B. , Cao Sha , Kunder Christian , Alizadeh Ash A. , Hanna Nasser H. , Diehn Maximilian 
Published: June 2022

8534 Background: The current standard of care for patients with inoperable stage III non-small cell lung cancer (NSCLC) includes chemoradiation (CRT) followed by up to 1 year of checkpoint inhibitor (CPI) therapy. However, many patients are not able to complete 1 year of treatment and the optimal duration of consolidation therapy remains unknown. Identifying minimal residual disease (MRD) via detection of circulating tumor DNA (ctDNA) may help inform the optimal duration of treatment. Here we report the results of a preplanned correlative study evaluating the association between detectable ctDNA and survival outcomes from the BTCRC LUN 16-081 phase 2 trial of consolidation nivolumab or nivolumab plus ipilimumab following CRT in patients with unresectable Stage III NSCLC (NCT03285321). Methods: Following CRT, patients with unresectable stage IIIA/B NSCLC were randomized 1:1 to receive nivolumab 480 mg IV Q4weeks for up to 6 cycles or nivolumab 240 mg IV Q2weeks plus ipilimumab 1 mg/kg IV Q6weeks for up to 4 cycles. Plasma samples for ctDNA analysis were collected after completion of CRT, prior to C2D1 of CPI, and at the end of treatment or withdrawal from the study. Tumor genotyping and ctDNA analysis were performed using CAPP-Seq with a panel targeting 260 genes recurrently mutated in NSCLC. Patient-specific tumor variants were identified using tumor tissue or baseline plasma and matched leukocyte DNA samples. Tumor variants were then monitored in plasma samples using a tumor mutation-informed bioinformatic strategy. Results: Thirty-nine patients received either nivolumab (n = 25; cycles: median = 6, range 1-6), or nivolumab plus ipilimumab (n = 14; cycles; median = 2, range = 1-6). Patients with detectable ctDNA MRD after completion of CRT demonstrated significantly inferior progression free survival (PFS) than patients who were MRD-negative (12-month 29% vs 76%, 24-month 29% vs 68%, P = 0.003), prior to C2D1 of CPI (12-month 0% vs 85%, 24-month 0% vs 72%, P < 0.0001) and at the end of CPI (12-month 14% vs 90%, 24-month 14% vs 79%, P < 0.0001). Patients with undetectable ctDNA MRD at the end of CPI (median cycles = 5.5; range 1-6) demonstrated 24-month overall survival of 91%. Additionally, patients with decreasing or undetectable ctDNA levels after one cycle of CPI had improved outcomes compared to patients with increasing ctDNA levels (24-month PFS 73% vs 0%, P < 0.0001). Progression of disease occurred within 10.8 months of starting CPI in all patients with increasing ctDNA levels at C2D1. Conclusions: Detectable ctDNA before, during, and after consolidation CPI is strongly associated with inferior survival outcomes. Furthermore, less than 12 months of CPI consolidation can result in MRD negativity and high rates of long term PFS. Clinical trial information: NCT03285321.
Molecular characteristics of ERBB2-activating mutations in Chinese patients with NSCLC.
Authors: Xu Fan , Li Qingshan , LI Wenxin , Zhang Shenglin , Zhao Yaping , Guo Didi , Lu Zhongyu , Chen Siqi , Lu Guanghua , Bu Fanfeng , Ding Ran , Deng Wanglong 
Published: June 2022

8546 Background: Activating mutations in the ERBB2 gene were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations have emerged as therapeutic targets in non-small cell lung cancers (NSCLC). However, Activating ERBB2 mutations have not been described in detail like other driver gene mutations, such as epidermal growth factor receptor (EGFR)-activating mutations. Methods: In this study, we retrospectively analyzed activating ERBB2 mutations using next-generation sequencing(NGS). From May 2019 to January 2022, 21745 patients who were diagnosed with NSCLC were detected. Results: A total of 686 activating ERBB2 mutations were found, and 12 patients carried double ERBB2-activating mutations. In this cohort, the average age of patients was 58 years (range, 13-90 years). 59.6% of the patients were female and 88.2% were diagnosed with lung adenocarcinoma.A total of 47 ERBB2-activating mutation subtypes were defined in 674 patients. The most common activating mutations were Y772_A775dup (55.0%, 371/674), followed by G776delinsVC (8.3%, 56/674), S310F (7.7%, 52/674), G778_P780dup (5.6%, 38/674) and V659E (4.1%, 28/674). All other mutations occurred in 14 or fewer patients. ERBB2-activating mutations occurred most frequently in the tyrosine kinase domain（TKD） (80.1%), which included mutations in exon 20 (76.2%), exon 19 (3.0%), and exon 21 (1.2%),In addition, 13.2% of activating ERBB2 mutations occur in the extracellular domain, and 5.5% in the Transmembrane domain. 23.1%(156/674) patients with ERBB2 activating mutations could be evaluated for concurrent mutations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Among these patients, ERBB2-activating mutations were most frequently co-mutated with TP53(54/156) and EGFR(21/156). The frequency of EGFR mutations was much higher in non-TKD mutation patients than in TKD mutation patients (56.7% vs. 3.2%, P < 0.001), but no difference was observed for TP53. All these patients were microsatellite stable (MSS) and low TMB ( < 10 mutations/megabase). Conclusions: We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.
Optimization of treatment options for EGFR-mutant, stage III, unresectable NSCLC: A systematic review and meta-analysis.
Authors: Liu Lian , Dai Xin , Li Song , Sheng Lei , Huang Kai , Chu Jiahui , Wang Jian , LI Jisheng , Liu Yanguo 
Published: June 2022

8548 Background: The PACIFIC study established a new treatment standard for Stage III unresectable NSCLC, but CRT followed by durvalumab failed to bring survival benefit to patients with EGFR mutations. EGFR-TKIs have been successful in the setting of first-line treatment of advanced NSCLC and postoperative adjuvant treatment of NSCLC. We explored whether locally advanced inoperable patients with EGFR mutations can benefit from EGFR-TKIs and the possibly best treatment regimen through meta-analysis. Methods: Studies involving unresectable stage III NSCLC with EGFR mutations published in PubMed, Embase, Cochrane, ClinicalTrials.gov, and abstracts of important international conferences (ASCO, ESMO, WCLC) from January 1, 2000 to September 30, 2021 were screened. An integrative analysis was performed using STATA (version 16.0), and a network meta-analysis based on a Bayesian framework was performed using R (version 3.6.1) for the studies with a control group. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 3291 patients were identified in 17 studies, including 5 treatment measures including concurrent chemoradiotherapy (CRT), CRT followed by durvalumab (CRT+Durva), TKI monotherapy, radiotherapy combined with TKI (RT+TKI), and CRT combined with TKI (CRT+TKI). PFS with TKI-free treatments (CRT, CRT+Durva) was significantly shorter than TKI-containing ones (TKI, RT+TKI, CRT+TKI) (HR 2.17, 95%CI 1.47-3.19), but its advantage only translated into borderline OS benefit (1.27, 0.99-1.63). In detail, the PFS with TKI-containing measures, including TKI monotherapy (0.66, 0.50-0.87), RT+TKI (0.37, 0.28-0.50), or CRT+TKI (0.14, 0.03-0.75) were all significantly longer than CRT. Furthermore, the PFS with both RT+TKI (0.40, 0.21-0.76) and CRT+TKI (0.15, 0.03-0.74) were significantly longer than CRT+Durva, while no statistical difference existed in PFS between RT+TKI and CRT+TKI. However, TKI alone had significantly shorter PFS than RT+TKI (1.78, 1.17-2.67). There was no statistical difference in OS among all the treatments, with RT+TKI ranking first in the Bayesian ranking. The integrated analysis found that RT+TKI had the longest OS (65.7 months, 55.5-76.0 months) and PFS (21.8 months, 18.0-25.7 months) and the highest response rate (77.7%, 68.8%-86.6%). Severe neutropenia was the most common with CRT+TKI, while RT+TKI brought the highest incidences of radiation pneumonitis and esophagitis. Conclusions: For EGFR mutant Stage III unresectable NSCLC, RT and TKI are both essential. RT+TKI and CRT+TKI have significantly longer PFS than CRT±immunotherapy, and RT+TKI has OS benefit trends. Due to the lack of sufficient studies on CRT+TKI, it is urgent to conduct large randomized clinical trials to explore the optimal treatment for these patients.
Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM).
Authors: Ponce Santiago , Cedres Perez Susana , Ricordel Charles , Isambert Nicolas , Levitsky Victor , Hansen Thomas Birkballe , Jaderberg Magnus Erik , Paz-Ares Luis G. 
Published: June 2022

8561 Background: MPM is an aggressive malignancy without curative treatment. ONCOS-102 is an oncolytic adenovirus expressing GM-CSF (Ad5/3-D24-GMCSF) with a clinically documented ability to stimulate local and systemic immune responses and re-modulate the tumor microenvironment, both as a monotherapy and in combination with anti-PD1 blockade. The study objectives included determining safety and tolerability, efficacy and immunological activation in repeat tumor biopsies, and correlations with clinical outcomes. Methods: Following a safety run-in of n = 6 pts, 25 patients were randomized to receive ONCOS-102 intratumorally under CT or US guidance at a dose of 3 x 1011 Virus Particles on Day 1, 4, 8, 36, 78 and 120, plus six cycles of P/C starting on Day 22, or control comprising six cycles of P/C only. Both treatment-naïve (1L) and previously treated patients (2L) were enrolled. Imaging was done at baseline, Day 43-64 and 127-148 and tumor biopsy were collected at baseline and at Day 36. Final survival analysis (n = 25) was performed after 30 mo follow up. Multiplex immunofluorescence for immune cell subsets, RNASeq and qPCR was performed on repeat tumor samples. Results: The most frequent adverse events were anaemia, neutropenia and asthenia reported by > 50% in both groups with more frequent reports of pyrexia and nausea in the experimental (exp) group. No difference in the rate of severe events (Gr 3/4 acc to NCI CTCAE vs 4.0) were observed. 30-month survival rate (n = 25) was 34.3 % vs 18.2 % (NS) with mOS of 19.3 mo (95% CI: 4.6, NA) vs 18.3 mo (95% CI: 3.1, 28.9) in the exp group vs control. For patients treated in the 1L setting, 30 mo survival was 33.3 % in the exp group (n = 8) and 0% in the control group (n = 6) with mOS of 25.0 months and 13.5 months, respectively (NS). mPFS was unchanged from prior cut-offs; 9.8 months in the exp group and 7.6 in the control (NS). ONCOS-102 + P/C induced a pronounced increase in tumor infiltration by CD4+, CD8+ and granzyme B expressing CD8+ T-cells as well as M1:M2 macrophage polarization in patients with disease control (n = 13) vs progressing patients (n = 3). The data from RNAseq and qPCR analysis will be presented. Conclusions: The addition of ONCOS-102 to P/C was well tolerated by MPM patients and resulted in numerically improved 30-month survival rate in the overall population, and improved mOS in chemotherapy-naïve patients, albeit not statistically significant. Substantial immunological activation in tumor associated with ONCOS-102 was demonstrated, correlating with clinical benefit. Further exploration of ONCOS-102 as a treatment option in MPM is warranted Clinical trial information: NCT02879669.
Preliminary safety and efficacy of camrelizumab plus nab-paclitaxel and carboplatin as frontline setting in extensive-stage small cell lung cancer (ES-SCLC) from a phase II trial.
Authors: Ren Shengxiang , Yu Jia , Xiong Anwen , Wang Qi , Wang Lei , Chen Bin , Yang Menghang , Li Wei , Yuan Jiajia , Zhao Changhong , Zhou Caicun 
Published: June 2022

8564 Background: Impower133 and CASPIAN studies showed that PD-L1 antibody combined with first-line chemotherapy could prolong the overall survival. Our previous study showed that nab-paclitaxel had a promising efficacy as later line setting in ES-SCLC. This phase II trial aimed to evaluate the efficacy and safety of camrelizumab plus nab-paclitaxel and carboplatin as front-line setting in ES-SCLC. Methods: Key inclusion factors were18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Patients (pts) received 4 ̃ 6 cycles of camrelizumab (200mg, D1, q3w) combined with nab-paclitaxel (230mg/kg, D1, q3w) plus carboplatin (AUC = 5, D1, q3w), then camrelizumab maintenance until disease progression or intolerable side effects. The primary endpoint was 6 months progression free survival rate. Secondary endpoints included PFS, ORR and safety. Results: From April 2021 to December 2021, 36 pts who received at least one dose of camrelizumab were included into this report. The median age was 60.5 (range: 32-73) with 30 (83.3%) males, 19 (52.8%) former smokers, and 36 (100%) ECOG performance status 1. The median drug exposure was 5 cycles, and 18 (50%) pts entered the maintenance stage. 33 pts had at least one 1 post-treatment tumor assessment. Among them, 32 partial responses (5 unconfirmed), 1 progressive disease (new lesion). The confirmed ORR was 81.8% (27/33), the unconfirmed ORR was 97% (32/33), DCR was 97% (32/33). The median PFS was 7.27 months (95% CI: 4.7 – 9.8 months). 24 (66.7%) pts had at least one adverse event, and 10 (27.8%) pts experienced grade 3 or 4 adverse events, including 10 (27.8%) neutropenia, 4 (11.1%) leukopenia, 2 (5.6%) thrombocytopenia, 2 (5.6%) anemia, 2 (5.6%) hepatic function abnormal,1(2.8%) alanine aminotransferase increased, 1(2.8%) hyperglycaemia, 1(2.8%) diabetes mellitus, and no grade 5 adverse event happened. Conclusions: Camrelizumab plus nab-paclitaxel and carboplatin had promising efficacy and safety profile as first-line setting in ES-SCLC, further validation is warranted. Clinical trial information: NCT04790539.
Efficacy and safety of camrelizumab combined with chemotherapy (irinotecan combined with platinum) followed by camrelizumab combined with apatinib in the first-line treatment of advanced small cell lung cancer: A phase II study.
Authors: Ni Jun , Zhang Xiaotong , Pan Ruili , Wang Hanping , Si Xiaoyan , Cui Xiaoxia , Zhang Li 
Published: June 2022

8573 Background: The treatment mode of small cell lung cancer (SCLC) is mainly based on the comprehensive treatment of chemotherapy and radiotherapy. IMpower133 study, suggesting that immune checkpoint inhibitors combined with chemotherapy first-line treatment for advanced SCLC may bring new research directions of clinical benefit. Previous study suggested that the combination of anti-PD-1 antibody camrelizumab and VEGFR-2 inhibitor apatinib significantly improved antitumor effects. The aim of this study was to evaluate the efficacy and safety of camrelizumab combined with chemotherapy (irinotecan combined with platinum) followed by camrelizumab combined with apatinib in the first-line treatment of SCLC. Methods: Extensive-stage small cell lung cancer patients were enrolled in this single-center, single-arm study. During the induction treatment phase, Patients received camrelizumab (200mg q3w), irinotecan (65 mg/m2, q3w) and platinum (cisplatin: 30 mg/m2, carboplatin: AUC=4̃5), after 4-6 cycles, the patient entered the maintenance phase, and then patients received camrelizumab combined with apatinib until disease progression or unacceptable toxicity. Treatment efficacy was assessed every 3 cycles (6 weeks). The primary endpoint is progression-free survival (PFS). Secondary endpoints are objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and overall survival (OS), which are based on RECIST 1.1. Results: At data cut-off (Jan 10, 2022), 20 extensive-stage SCLC patients were enrolled in the study, of which 18 patients were evaluable. Median age was 64 years, male accounts for 85.0% (17/20). Median follow-up was 5.0 months (range 0.4̃17.6 months). Of 18 evaluable patients, no one achieved complete response Partial response was achieved by 17 (94.4%) patients and stable disease exhibited by 1 (5.6%) patient. The ORR and DCR were 94.4% and 100%, respectively. mPFS and mDoR have not been reached. In terms of adverse events (AEs), reactive cutaneous capillary hyperplasia (RCCEP) was observed in 10 (47.6%) patients 10 patients. Grade III-IV AEs were observed in 7 (35.0%) patients with neutropenia, thrombocytopenia, hemoglobin reduction, leukopenia, rash. The rest were grade I-II AEs. Conclusions: The treatment in this study showed impressive ORR and DCR, and acceptable toxicity, and may be a promising method as a first line treatment. Clinical trial information: NCT04453930.
Immunological signature of patients with thymic epithelial tumors.
Authors: Morra Rocco , De Placido Pietro , Pietroluongo Erica , Ottaviano Margaret , Tortora Marianna , Mucci Brigitta , Montella Liliana , Del Deo Vitantonio , Malfitano Anna Maria , Pirolo Miriam , Mirra Federico , Vaia Angelo , D'Esposito Vittoria , Terracciano Daniela , De Placido Sabino , Formisano Pietro , Palmieri Giovannella , Giuliano Mario 
Published: June 2022

8589 Background: Thymic epithelial tumors (TETs) are complex diseases frequently associated with immune disorders, including Good Syndrome (GS). Etiopathogenesis of immune dysregulations in TETs patients is still not totally explained. The aim of this study was to evaluate differences in immune cell phenotype, as well as in the serum expression levels of a panel of cytokines, chemokines, and growth factors in patients with TETs and GS with or without autoimmune disorders (AD). Methods: From May 2019 to June 2020, consecutive patients with TETs and GS were recruited at Rare Tumors Coordinating Center of Campania Region (CRCTR – Naples, Italy). We analyzed the immunophenotype from peripheral blood focusing on selected immune cell subsets (monocytes, neutrophils, eosinophils, CD4+T cells, CD8+T cells, B-cells, NK cells and NKT- cells, T regulatory cells) processed for blood cell count and immunophenotyping, according to the 8-color immunophenotyping kit and Treg detection kit (CD4/CD25/CD127), and a panel of cytokines, chemokines, and growth factors from peripheral blood serum screened with pre-formed kits by Bioplex multiplex. D’Agostino-Pearson normality test was used to evaluate whether the continuous data were normally distributed, and a two-tailed t-test for independent samples was used. p-values < 0.05 were considered statistically significant. Results: Overall, 29 patients were enrolled [17 (58.6%) with and 12 (41.4%) without AD]. Sixteen patients (55.2%) were female and 13 patients (44.8%) were male. Tumor histology included thymoma in all the patients with AD, whereas there were 10 cases of thymoma and 2 of thymic carcinoma in the group of patients without AD. The analysis of leucocytes by blood cell count showed a statistically significant higher number of leucocytes, ascribable to T lymphocytes (p = 0.023), B lymphopenia (p = 0.003) and decrease of T regulatory cells (p = 0.009) in TET patients with AD, as compared with TET patients without AD. Moreover, TET patients with AD showed significantly higher circulating levels of IL-15 (p = 0.032), VEGF (p = 0.007), IP-10 (p = 0.013), GM-CSF (p = 0.042), IL-6 (p = 0.031), and MIP-1α (p = 0.017) with respect to TET patients without AD. Conclusions: To our knowledge, this is the first report describing a profound alteration in B and T lymphocytes in TET patients associated with AD. The observed differences may be potentially important in the clinical management of this complex disease. Additional studies are needed to better understand the immunophenotypic alterations in TETs patients.