bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of DDR1 with immune exclusion and outcomes in non-small cell lung cancer.
Authors: Zhang Lei , Lou Ning , Yu Qingxiang , Ma Rui 
Published: June 2022

e20553 Background: Discoidin domain receptor 1 (DDR1) is a collagen receptor with tyrosine kinase activity. Although DDR1 has been reported to implicated in cancer progression and metastases, the underlying mechanism remains poorly characterized and its prognostic value is also contradictory in non-small cell lung cancer (NSCLC). Methods: Clinical and DDR1 mRNA expression data of 1925 patients with NSCLC were obtained from 14 publicly available datasets utilizing an online tool KM-plotter. All patients were split into 2 groups by median expression of DDR1. The Kaplan-Meier curve and log-rank test, and Cox regression analyses were used to examine the association between DDR1 expression and overall survival (OS). The table shows 48 immune-regulatory genes classified into 4 signatures associated with activated T cells, immune cytolytic activity, and antitumor immunity. Expression data of these genes for 994 patients with NSCLC were gathered from the TCGA Pan-Cancer Atlas. Abundance data of various immune cell types in tumor microenvironment for the TCGA patients were inferred using xCell, and then immune infiltration extent was calculated as immune score. Associations of DDR1 with immune genes expression and immune score were determined with Spearman rank correlation. Results: DDR1 overexpression was significantly associated with inferior OS in this large-scale cohort (median, 62 vs 78.5 months; hazard ratio [HR], 1.16; 95% CI, 1.02-1.31; P = .02). Of note, multivariable Cox model indicated DDR1 overexpression was an independent risk factor for OS (HR, 1.41; 95% CI, 1.01-1.98; P = .046), controlling for potential confounders (histology, stage, sex, and smoking history). Of the 48 immune-regulatory genes, 44 (92%) showed significant negative correlations with DDR1 expression (all P < .05), implying the role of DDR1 in decreasing immune infiltration into tumor microenvironment. Further, higher immune score was observed in tumors underexpressing DDR1 (correlation coefficient, -0.44; P < .001), more directly demonstrating the link between DDR1 and immune infiltration. Conclusions: To our knowledge, this is the largest study to evaluate the prognostic role of DDR1 expression in NSCLC. Our results suggest that DDR1 overexpression may predict poor outcomes and a possible mechanistic explanation regarding this role may be immune exclusion instigated by DDR1. Thus, targeting DDR1 expression to abrogate immune exclusion warrants further investigation.[Table: see text]
Pattern of failure in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy with/without immune checkpoint inhibition.
Authors: Taugner Julian , Käsmann Lukas , Eze Chukwuka , Nieto Alexander , Guggenberger Julian , Flörsch Benedikt , Kenndoff Saskia , Tufman Amanda , Reinmuth Niels , Belka Claus , Manapov Farkhad 
Published: June 2022

e20570 Background: We compared pattern of failure in patients treated with chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (IO, immuno-oncology therapy) and CRT alone for inoperable stage III NSCLC. Methods: Prospective data of thirty nine consecutive patients who completed CRT-IO with sequential durvalumab (72%, 28 patients) or concurrent and sequential nivolumab (28%, 11 patients) and a sensitive propensity score matched (PSM adjusted for patients age, gender, T- and N-status, PTV, histology) cohort of 39 patients treated with CRT alone were analyzed. First site of failure was compared between the CRT-IO and the CRT alone subgroup. Results: All patients were treated with conventionally fractionated thoracic irradiation to a total dose of at least 60Gy (range: 60-66Gy), all patients received either sequential or simultaneous chemotherapy while 95% (74 patients; CRT-IO: 38/39; CRT alone: 36/39) received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 33.3 (range: 1.5-102.9) months; median overall survival (OS) was 34.9 (95%CI: 10.7-59.1) months (CRT-IO: not reached; CRT alone: 24.4, p = 0.003); median progression-free survival (PFS) was 13.6 (95% CI: 10.5-6.7) months (CRT-IO: 26.3; CRT alone: 8.3; p < 0.001). At the time of evaluation 21 (53.8%) vs. 7 (17.9%) patients of the CRT-IO vs. CRT alone subgroup were progression free and alive (p = 0.003); 4 (10.3%) vs. 3 (7.7%) had brain metastases as first site of failure; 7 (17.9%) vs. 6 (15.4%) had ≤ 3 extracranial metastasis and 3 (7.7%) vs. 4 (10.3%) had multi-organ progression. Local-regional recurrence (LRR) as first site of failure was significantly less frequent in patients treated with CRT-IO vs. CRT alone, namely 3 (7.7%) vs. 12 (30.8%) patients (p = 0.001); median time to LRR was not reached vs. 15.0 (95%CI: 0.9-33.7) months. Conclusions: Pattern of failure differ significantly in patients treated with CRT-IO vs. CRT alone; CRT-IO patients are significantly less likely to develop a LRR. No differences in the prevalence of brain metastases as first site of failure could be detected.
Genetic alteration profiling of Chinese lung adenocarcinoma: A targeted and immunotherapy biomarker analysis.
Authors: Zou Zhiqiang , Nguyen Thi Phuong Anh , Xia Chaoran , Ding ShouTai , Luo Peng 
Published: June 2022

e20572 Background: Lung adenocarcinoma is the most common primary lung cancer, comprises about 30% of lung cancers. So far, little is known about an in-depth molecular characterization for lung adenocarcinoma in Chinese patients. The genomic characteristics, microsatellite instability (MSI) status, programmed cell death-1 (PD-L1) and tissue tumor mutational burden (tTMB) in Chinese lung adenocarcinoma patients will benefit to understanding drug resistance-related mechanisms. Methods: 591 Formalin-Fixed Paraffin-Embedded (FFPE) lung adenocarcinoma samples were collected and detected by Next Generation Sequencing 603-gene panel. The biomarkers of immunotherapy (TMB-High [≥10/Mb], MSI-High, and PD-L1 22C3 [TPS] were also calculated. Results: Of 591 patients, 312 patients (52.8%) were male and 279 (47.2%) patients were female. The median age of the patients was 60.7 (range 28-99). The most commonly mutated genes were EGFR (45.5%), TP53 (22.1%), KRAS (7.8%), PIK3CA (5.3%), ERBB2 (2.5%), BRAF (2.2%), CTNNB1 (1.5%), SMAD4 (1.5%),NRAS (1.0%), SMAD4 (1.5%), NRAS (1%), ATM (1%), RB1 (1%), NF1(1%), IDH2 (0.67%). Three genes mutations (EGFR, TP53, KRAS) were identified significantly different between male and female. EGFRmutations were significantly more frequent in females (54.12%) than in males (37.5%;p = 0.000051). In contrast, TP53 mutations were significantly more frequent in males (11.53%) than in females. KRASmutations were significantly more frequent in males (25.6%) than in females (17.9%;p = 0.023). (3.6%;p = 0.0003). The aging of patients was associated with a higher PTEN mutations (< 50 years-old, p = 0.039), RAF1 mutations (> 76 years-old, p = 0.038), BRCA1 mutations (< 42 years-old, p = 0.032). The average of TMB was 5.3 mut/Mb (range 0-54.8). Immunotherapy markers were presented in 36.4% of cases (TMB-High in 15.91%, PD-L1+(TPS > 1%) in 47.12%,PD-L1+(TPS > 50%) in 5.17%, MSI-High in 0.17%). PD-L1 expression and TMB score were not significantly correlated in lung adenocarcinoma. The TMB score was associated with a higher TP53 mutations(TMB > 6.6, p < 0.0001), KRAS(TMB > 6.1, p = 0.034), NF1(TMB > 9.8, p = 0.0018), IDH2(TMB > 11.3, p = 0.0028). Conclusions: These findings may be helpful for identifying therapeutic targets strategies in lung adenocarcinoma patients that were previously unavailable to clinicians in China.
Single-cell profiling of immune cells associated with response to neoadjuvant chemoimmunotherapy in IIIA non-small cell lung cancer (NSCLC).
Authors: Hui Zhenzhen , Zhang Jiali , Ren Yulin , Li Xiaoling , Yu Wenwen , Wang Tao , Zheng Liuqing , Xiao Shanshan , Chen Yu-Long , Wei Feng , You Jian , Ren Xiubao 
Published: June 2022

e20584 Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the underlying molecular mechanism has not been fully elucidated. Methods: To identify factors associated with the clinical outcome, single-cell RNA/TCR sequencing was performed using 10x Genomics on CD45+ immune cells isolated from tumor and multiple immune-relevant tissues and peripheral blood of four treatment-naïve and eight neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients (responders versus non-responders). Bioinformatics analysis was used to screen immune cell factors associated with therapy response in single-cell sequencing profiles, and results were verified at protein level by flow cytometry, multiplex fluorescent immunohistochemistry (mIHC) and ELISA. Results: A total of 186,477 immune cells from 48 samples were acquired after quality-control filtering. The synergistic increase of B cells and CD4+ T cells are associated with positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell class switching to IgG1 and IgG3 plays a critical role in anti-tumor immune response in tumor lesion, and this process is driven by increased IL-21 protein secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Several critical events lead to the positive clinical outcome during neoadjuvant chemoimmunotherapy, including the diminished activated TNFRSF4+ regulatory T cells (Tregs), increased LAMP3+ dendritic cells (DCs), high pretreatment peripheral blood T-cell diversity, and the expansion of intratumoral CD4+ T clones and peripheral CD8+ T clones. A validation cohort of 26 treatment-naïve and 30 neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients verified these findings. Conclusions: Single-cell profiling of the immune response to neoadjuvant chemoimmunotherapy uncovered several critical factors of anti-tumor immune response and provided insight of potential novel predictive factors and therapeutic targets for improving the efficacy of treatment in NSCLC.
Risk factors and clinical characteristics of pneumonitis among patients with ALK-rearranged non-small cell lung cancer who received alectinib and thoracic radiotherapy.
Authors: Xu Yiyue , Qie Wenting , Yu Jinming , Wang Linlin 
Published: June 2022

e20591 Background: Alectinib and thoracic radiotherapy (TRT) are important modalities in the management of ALK-rearranged non-small cell lung cancer. We therefore aimed to assess the incidence and risk factors of pneumonitis when these two treatments were combined. Methods: Patients with ALK-rearranged non-small cell lung cancer, receiving alectinib and TRT from January 2018 to December 2020 were reviewed, and the clinical and dosimetry data were collected. Logistic regression analyses were performed to evaluate risk factors associated with treatment-related pneumonitis (TRP). The prediction ability of dosimetry parameters for pneumonitis were examined by receiver-operating characteristic (ROC) curve analyses. Results: Of the 25 enrolled patients, 16 (64%) developed pneumonitis, and 12 (48%) developed grade 2 or higher pneumonitis. Logistics regression analyses revealed chemotherapy (OR = 8.750, 95% CI 1.207 - 63.428, p = 0.032), higher ipsilateral V5 (OR = 1.060, 95%CI 1.002 - 1.122, p = 0.043) and total lung V5 (OR = 1.083, 95%CI 1.000 - 1.174, p = 0.05) to be risk factors for TRP. Total lung V10, total lung V5, and ipsilateral V5 were strong predictors of TRP among the dosimetry parameters (AUC = 0.800, 0.786 and 0.781, respectively). After developing pneumonitis, 52% of patients recovered or improved, but one patient died due to respiratory failure. Conclusions: The combined use of alectinib and TRT significantly increased the risk of pneumonitis. Clinicians should consider the elevated risks and related dosimetric factors when deciding on combination treatment for ALK-rearranged NSCLC patients.
T-cell infiltration in matched samples from malignant pleural mesothelioma (MPM) during evolution of disease.
Authors: Cedres Perez Susana , Serna Garazi , Assaf Pastrana Juan David , Iranzo Patricia , Callejo Ana , Pardo Nuria , Navarro Alejandro , Martinez-Marti Alex , Cabrera Galvez Carlos , Gonzalez-Medina Alberto , Fasani Roberta , Guardia Xavier , Gonzalo Javier , Carbonell Caterina , Frigola Joan , Amat Ramon , Vivancos Ana , Nuciforo Paolo , Felip Enriqueta 
Published: June 2022

e20595 Background: MPM is an aggressive cancer associated with asbestos exposure. Chemotherapy has been a mainstay of therapy and recently immunotherapy has been associated with survival improvements. Chemotherapy and immunotherapy influence the tumor microenvironment and some reports have shown increased of TIL after chemotherapy in MPM. The purpose of this study was to determine dynamic changes in the tumor immune environment during mesothelioma evolution and after systemic therapies in paired samples. Methods: We examined 20 matched formalin-fixed paraffin embedded tissue samples from 10 patients (p) with MPM taken at diagnosis and at disease progression (follow-up), including untreated and treated with chemotherapy or immunotherapy. Tissue densities (number of cells/mm2) of key immune effector cells such as total lymphocytes (CD3), cytotoxic T cells (CD8), regulatory T cells (FOXP3) and monocytes/macrophages (CD163) were quantified by image analysis using multiplexed immunohistochemistry (IHC). PD-L1 expression in both tumor cells and immune cells was analysed by singleplex IHC and quantified using the CPS score. Results: Median age was 62 years (range 53-84), 7 p were male and all p presented epithelioid histology. Three matched samples belong to patients that did not receive any systemic treatment between biopsies and the other 7 pair of samples belong to patients treated with chemotherapy +/- immunotherapy. The median interval between paired biopsies was 12 m (3-33 m). Median overall survival was 27.8 months (1 m-NR). Median densities of T cells and macrophages in diagnostic and matched follow-up samples were: CD3+:982 vs 712; CD8+:422 vs 334, FOXP3+: 22 vs 25 and CD163+: 2086 vs 1706. Median PD-L1 CPS was 2.5 and 4 in diagnostic and follow-up samples, respectively. In p receiving treatment between sample pairs, the median densities in diagnostic and follow-up matched samples were: CD3+:979 vs 407; CD8+:467 vs 225, FOXP3+: 25 vs 15, CD163+: 1583 vs 1508, and PD-L1: 2 and 1. In p without any systemic treatment between sample pairs, the median densities were CD3+:1645 vs 2397; CD8+:376 vs 1605, FOXP3+: 19 vs 121, CD163+: 2102 vs 2377, and PD-L1: 3 vs 25. Conclusions: In our small series with paired samples from MPM p, we observed immune cells infiltration changes during MPM evolution with a trend towards a decrease after systemic therapy. Further investigation in tumor microenvironment in MPM to define the most appropriate time for immunotherapy is needed.
Efficacy and safety of low-dose radiotherapy (LDRT) concurrent atezolizumab plus chemotherapy as first-line therapy for ES-SCLC : Interim analysis of Phase II MATCH trial.
Authors: Zhou Lin , Sun Jianguo , Xie Conghua , Gong Youling , Huang Meijuan , Yuan Zhiyong , Wu Lin , Wang Hui , Bi Nan , Yaping Xu , Zhu Jiang , Zhang Yan , Fan Min , Zou Bingwen , Yu Min , Na Feifei , Xiu Weigang , Zhang Xuanwei , Xue Jianxin , Lu You ,   MATCH Study Group
Published: June 2022

e20611 Background: The IMpower 133 trial represents the current SoC in the 1L setting for pts with ES-SCLC but still needs further efficacy improvement such as objective response rate (ORR, ̃60% in both arms) which may lead to survival benefit. LDRT could play a key role in the priming effect of immune system by acting as an immune adjuvant and having sensitive cytotoxic activity to SCLC. We have reported that LDRT plus ICIs in pretreated ES-SCLC was well tolerated with an improved efficacy. Here we conducted MATCH study to investigate the clinical benefits of adding LDRT to Atezo plus chemotherapy in ES-SCLC pts as 1L therapy. Methods: The MATCH study was a single-arm phase II trial conducted in eight centers across China. A Simon’s minimax two-stage design was adopted. Pts with measurable disease per RECIST v1.1 at baseline with ECOG 0-1 were eligible. Atezo (1200 mg IV, D1) + Cisplatin (75 mg/m2 IV, D1)/Carboplatin (AUC = 5 IV, D1) +Etoposide (100 mg/m2 IV, D1-D3) were administrated on a 21-day cycle for four cycles. Concurrent LDRT (15 Gy/5f) were conducted from D1-D5 in the first cycle. Then pts received Atezo maintenance until loss of clinical benefit or unacceptable toxicity. The primary endpoint was ORR confirmed by investigators after two consecutive evaluations ≥ 4 weeks apart. The secondary endpoints included disease control rate (DCR) and safety. Results: This is the report on the completed 1st phase of the trial. By the cutoff date of 26th August 2021, of the first 21 evaluable pts, 20 were males; mean age was 60.2 y and 85.7% pts had ECOG PS of 1. Previous smokers were 85.7%. Most pts were staged T4 (n = 15, 71.4%), N3 (n = 18, 85,7%) and M1(n = 17, 81.0%). The most common sites of metastasis were bone (47.1%) and liver (11.8%). Median follow-up was 4.0 m (range: 2.6-8.0 m). The confirmed ORR was 95.2% (95% CI, 76.2%-99.9%), among whom all pts were PR. DCR was 100%. The safety profile was consistent with the previous reports. Neutrophil count decreased (66.7%), white blood cell count decreased (42.9%) and anaemia (38.1%) were the most common grade 3-4 adverse events. No grade 5 AE occurred. Two pts experienced AEs leading to treatment withdrawal. IrAEs by preferred term were reported in 3(14.3%) pts: 2 were immune-mediated hyperthyroidism (grade 2) and 1 was immune-mediated enterocolitis (grade 3). No radiation pneumonitis occurred. Conclusions: The study met the response criteria for 1st phase. The combination of LDRT and Atezo plus chemotherapy showed promising benefit and was tolerable in pts with ES-SCLC. The 2nd phase is ongoing. Clinical trial information: NCT04622228.
Outcomes in non-small cell lung cancer (NSCLC) patients treated with second-line therapy after progression or recurrence after initial first line immune checkpoint-based therapy.
Authors: Muhsen Ibrahim , Mylavarapu Charisma , Sarfraz Humaira , Mathur Sunil , Bernicker Eric 
Published: June 2022

e21027 Background: The use of immune checkpoint inhibitors (ICI) based therapies, including in combination with platinum-based or as monotherapy, is currently the standard of care in stage IV NSCLC patients as a first line therapy. However, there is limited data on the options and outcomes of NSCLC patients if they progress after first-line therapy. This study aims to investigate the clinical outcomes to second lines of treatment for these patients. Methods: This is a retrospective study conducted at Houston Methodist Hospital involving adult patients (> 18 years old) with metastatic stage IV NSCLC who received ICI based therapy (combination or monotherapy) for the treatment of NSCLC and subsequently progressed or recurred and received a second line of therapy between 11/1/2016 and 12/31/2019. We excluded patients with targetable driver mutations (except KRAS) and patients with a concurrent cancer diagnosis. We collected information on the second line of therapy received and evaluated outcomes including progression-free survival (PFS), overall survival (OS) and overall response rate (ORR). PFS was defined from time of second-line therapy initiation to time of documented recurrence/progression. ORR was defined as patients who achieve partial response (PR) or complete response (CR). The Kaplan Meier method was used for survival analysis. Results: Among patients who received ICI-based first line therapy, 32 patients were identified to meet the inclusion criteria. Twenty-seven (84%) patients had adenocarcinoma and 17 patients had negative PD-L1 stain. Twenty-seven (84%) patients received a combination of carboplatin, pembrolizumab, and pemetrexed, whereas five (16%) patients received ICI monotherapy (3 pembrolizumab, 1 nivolumab and 1 durvalumab). Thirteen patients had an initial response to first-line therapy (11 PR, 2 CR). After progression/recurrence, various therapies were administered as second-line with the most common being the use of ICI + chemotherapy combination (6 pts, 19%) or ramucirumab + taxotere combination (6 pts, 19%). The remaining patients received other types of chemotherapy, targeted therapy, ICI, or were enrolled in a clinical trial. Nine patients (28%) had a response after 2nd line therapy [4 CR and 5 PR], 16 (50%) had progressive disease, and 5 (16%) had mixed response/stable disease. The cohort median PFS after 2nd line of therapy was 16.9 weeks (95% CI: 14.4-19.3). Conclusions: These findings reflect the variability in practices in stage IV NSCLC patients who progress after receiving ICI-based first line therapy. Outcomes of patients who progress after their first line remain suboptimal with short-lived responses. Further studies are needed to investigate the efficacy and safety of different second line treatment options.
Preliminary clinical investigations of high-dose furmonertinib in NSCLC with EGFR Exon 20 insertions (20ins).
Authors: Lin Ying , Hu Zhihuang , Zhang Yao , Sun Si , Yu Hui , Zhao Xinmin , Wu Xianghua , Wang Huijie , Wang Jialei 
Published: June 2022

e21029 Background: Currently neither chemotherapy nor approved EGFR TKIs have satisfactory efficacy in most EGFR 20ins mutations. Activity of high-dose furmonertinib, a novel 3rd generation EGFR TKI, against EGFR 20ins was assessed in preclinical models and a phase lb study. This study aimed to retrospectively investigate the efficacy of high-dose furmonertinib against EGFR 20ins in the real world. Methods: Retrospective search identified 14 metastatic NSCLC patients (pts) with EGFR 20ins treated with high-dose furmonertinib (160mg qd) in Fudan University Shanghai Cancer Center. The clinical efficacy and safety were investigated. Results: Median age was 60 years old (range 40-75) in this cohort with 28% female. At data cutoff date of January, 2022, 9 pts had ≥1 disease assessment. 5 out of 9 pts achieved PR, and 3 patients achieved SD. No CR was observed and 1 patient PD at first assessment. The most common adverse events (AE, ≥20%) were diarrhea, paronychia, skin fissures, anorexia, pain in extremity, rash and stomatitis. No grade ≥3 AE was observed. Conclusions: High-dose furmonertinib has shown encouraging anti-tumor activity in NSCLC with EGFR 20ins.