bluuebunny/crossref_metadata_2025_split huggingface dataset:
ctDNA for clonal evolution surveillance and therapeutic efficacy prediction in unresectable locally advanced non-small cell lung cancer under radiotherapy.
Authors: Bi Nan , Yang Yufan , Wang Jianyang , Wang Jingbo , Zhao Xiaotian , Yang Yin , Zhu Minyi , Wang Luhua 
Published: June 2023

e20555 Background: Therapeutic efficacy differs across unresectable locally advanced non-small cell lung cancer (LA-NSCLC) patients receiving definitive radiotherapy/chemoradiotherapy (RT/CRT), but the underlying resistance mechanism, clonal evolution and molecular prognostic factors remain poorly understood. Methods: Unresectable LA-NSCLC patients treated with definitive RT/CRT were consecutively enrolled between May 2018 and November 2020. Next-generation sequencing covering 474 cancer-relevant genes was performed on plasma ctDNA collected at pre-treatment (TP0), 4-week post-RT (TP1), 1-month post-RT (TP2), 3-month post-RT (TP3), and progression (TP4). Main study endpoints included disease progression, progression-free survival (PFS), death from any cause, overall survival (OS), distant metastasis and distant metastasis free survival. Fisher’s exact test and two-sample t-tests were performed to compare the frequencies and means of independent groups, respectively. The median follow-up time was estimated using the reverse Kaplan-Meier method. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards models. Results: A total of 46 patients were included (median age: 63 [range: 40–80], males: 87%, clinical stage IIIB: 52%, squamous cell carcinoma: 54%, TP0 ctDNA shedding: 63%, consolidation immunotherapy: 33%). Twenty-nine (63%) patients developed disease progression by the end of follow-up (median follow-up: 23.7 months), with median PFS and OS being 15.5 and 25.4 months, respectively. The polymerase epsilon ( POLE) mutational signature at TP0 indicated inferior PFS (HR: 5.32, 95% CI: 1.83–15.45) and worse OS (HR: 20.68, 95% CI: 3.94–108.62). Notably, newly-discovered/lost mutations were rarely observed at TP4 when compared to TP0. Patients with a high ratio of mean over max variant allele frequency (m/mVAF) in TP0 samples, indicative of a clonal predominant tumor with a low subclone fraction ( P< 0.01), had relatively poor OS, compared to patients with low m/mVAF (HR: 2.92, 95% CI: 0.82–10.46) or undetectable ctDNA (HR: 3.39, 95% CI: 0.98–11.75). The prognostic value was validated in an independent publicly available dataset of 431 LA-NSCLC patients receiving definitive RT/CRT, showing patients with high m/mVAF demonstrated worse OS than those with low m/mVAF (HR: 1.43, 95% CI: 1.08–1.89). Additionally, increased m/mVAF between TP0 and TP1 indicated an elevated risk for disease progression ( vs. non-increase, HR: 3.49, 95% CI: 1.20–10.16), especially for distant metastasis ( vs. non-increase, HR: 2.85, 95% CI: 0.84–9.69). Conclusions: Our findings demonstrated the clinical value of plasma ctDNA and its derived molecular features in delineating clonal evolution, monitoring therapeutic resistance, and predicting prognosis of LA-NSCLC under definitive RT.
Neoadjuvant sintilimab combined with chemotherapy in resectable locally advanced non-small cell lung cancer: A retrospective study.
Authors: Yin Cunli , Liu Bin , Ge Jun , Hu Bin , Yang Xi , Kou Lingna , Tian Bo , Wang Chenghao , Li Siru 
Published: June 2023

e20556 Background: In recent years, neoadjuvant immunotherapy with chemotherapy has shown increasing promise for locally advanced non-small cell lung cancer (NSCLC). However, more real-world clinical outcomes are needed. In this study, we aimed to evaluate the safety and efficacy of sintilimab combined with chemotherapy as neoadjuvant therapy in patients with potential resectable NSCLC. Methods: We retrospectively reviewed thirteen patients with previously treated NSCLC receiving neoadjuvant chemoimmunotherapy in Sichuan Cancer Hospital between February 2021 and February 2023. Sintilimab injection (intravenously,200mg, iv, d1, q3w) and platinum-based chemotherapy were administered intravenously every 3 weeks, with surgery planned approximately 4-11 weeks after the last dose. The primary endpoint of the study was pathologic complete response (pCR). The secondary endpoints were objective response rate (ORR), and safety. Results: All patients received sintilimab combined with platinum-based chemotherapy for two to four cycles before. None of them needed a reduced initial dose or delay due to intolerable adverse events. A total of nine patients (69.2%) achieved pCR. Nine patients experienced neoadjuvant treatment-related adverse events (TRAEs). Only one patient (7.6%) experienced grade 4 neoadjuvant TRAE. Conclusions: Neoadjuvant sintilimab plus platinum-based chemotherapy was feasible and safe for patients with resectable stage IIB-IIIB non-small-cell-lung-cancer.
Clinical and molecular characteristics of multiple primaries identified by whole-exome sequencing-based genetic divergence in non-small-cell lung cancer.
Authors: Liu Ning , Wang Yongsheng , Li Xue , Jiang Lili , Wang Weiya , Ma Qizhi , Tang Jie , Zhu Daxing , Mei Jiandong , Zhang Benxia , Shu Pei , Chen Yue , Qin Diyuan , Guo Fuchun 
Published: June 2023

e20558 Background: With the recommendation of high-resolution chest computed tomography scan in lung cancer screening, multiple primary lung cancers (MPLC) is gaining more attention. Identifying MPLC from intrapulmonary metastases (IPM) is crucial to the clinical management. The current guidelines for the identification are always based on expert consensus rather than clinical evidence. We aim to develop a reliable identification method and further figure out the clinical and genetic features of MPLC. Methods: We retrospectively screened 305 lung lesions from 131 patients who underwent radical resection for multiple lung carcinomas. To minimize the effect of therapeutic intervention on prognostic outcomes, patients with each single tumor size smaller than 4cm, free of nodal or systemic metastases, and had high-quality whole-exon sequencing (WES) data were included. We selected 11 patients with confirmed intrapulmonary metastases for training. All patients’ follow-up information was collected until disease recurrence or metastases. A WES genetic divergence method for identifying MPLC from IPM was developed. The disease-free survival (DFS) was used as a validation tool for identification reliability. Results: A total of 61 eligible multi-lesion patients with 128 resected non-small cell lung cancer (NSCLC) lesions were finally analyzed. Based on WES genetic divergence identification, 51 MPLC patients were identified, whose DFS was significantly prolonged (HR, 0.27; 95% CI, 0.08 to 0.91; P = 0.02), while other recommended methods for identifying MPLC patients failed to show a DFS advantage. Among MPLC patients, 43.1% (22/51) had a first-degree relatives cancer family history, of whom 54.5% (12/22) had a lung cancer family history. EGFR was still the most common mutation gene (72.5%, 37/51); however, TP53 mutations was less frequent in MPLC (21% vs. 48%, P < 0.05), and tumor mutation burden (TMB) was lower (median, 0.73 muts/Mb vs. 1.15 muts/Mb, P < 0.01). Notably, despite the lack of shared alterations, unique germline variants in cancer-predisposing genes, particularly nonsynonymous SNV in solute carrier gene (SLC) family, were observed in most MPLC patients, rarely overlapping with IPM patients. Conclusions: WES-based genetic divergence clearly distinguishes independent primary tumors from IPM in NSCLC patients. MPLC patients represent a unique population which deserves further study.
A real-world analysis of nonmetastatic non–small-cell lung cancer in Italy.
Authors: Esposito Immacolata , Ronconi Giulia , Dondi Letizia , Calabria Silvia , Piccinni Carlo , Pedrini Antonella , Dondi Leonardo , Dell'anno Irene , Addesi Alice , Martini Nello 
Published: June 2023

e20566 Background: The majority of all lung cancer cases are represented by non-small cell lung cancer (NSCLC), for which the standard of care is surgical resection. Chemotherapy, radiotherapy and immunotherapy are the most important perioperative systemic treatments. This study aimed to identify newly NSCLC diagnosed, non-metastatic (i.e., stages I-III) and resected patients, and characterize them from the perspective of the Italian National Health Service (INHS). Methods: From the Fondazione ReS (Ricerca e Salute) database (~5 million inhabitants/year), in 2017 (accrual period), patients with a new in-hospital diagnosis of NSCLC (i.e., excluding those diagnosed back up to 2013), at stage I-III (i.e., excluding those with distant metastases at the first diagnosis and/or within 60 following days), and resected (i.e., with ≥1 in-hospital surgery within 6 months from the first diagnosis), were identified. The cohort was characterized by age, sex and comorbidities. The dispensation of neoadjuvant therapy (≥1 radio and/or chemotherapy session) between the first diagnosis and surgery was analyzed. Within 2 years after surgery, overall survival-OS and progression free survival-PFS (Kaplan Meier analyses), and healthcare integrated costs charged to the INHS (pharmaceuticals, hospitalizations, specialist/outpatient services) were described. Results: In 2017, of 2440 (incidence 52.1 x100,000) newly NSCLC diagnosed patients, 1605 were defined with stage I-III. Of these, 467 (29.1%) underwent surgery. They were mainly males (74.3%) and on average aged 69±10. Arterial hypertension (64.7%), chronic lung diseases (46.7%) and dyslipidaemia (36.0%) were the most frequent comorbidities. Lung lobectomy (highest mean length of in-hospital stay: 11 days) was the most common surgery (296/467; 63.4%). Before surgery, 48/467 patients (10.3%) received neoadjuvant therapy. During the 2nd year after surgery, 418/467 patients (89.5%) were analysable. At 2 years after surgery, OS was 81.6% and increased with age, while PFS was 59.8%. On average: within 1 year, the INHS spent € 20,942 per capita (hospitalizations – including first hospitalization - accounted for 56.3%, and pharmaceuticals for 35% of the total cost); within the 2nd year, the INHS expenditure was € 9,851 per capita (pharmaceuticals weighed 65.8% of the overall cost, and hospitalizations 19.8%). Conclusions: Italian administrative healthcare data can identify and describe newly NSCLC diagnosed patients with stage I-III and resected, quantify their burden on the INHS and show a substantial survival benefit.
Association of lymph node examination during resection with overall survival (OS) and healthcare costs in patients with early non–small-cell lung cancer (eNSCLC).
Authors: Lee Jay M. , To Tu My , Lin Chia-Wei , Wang Shu , Johnson Ann , Lee Janet 
Published: June 2023

e20567 Background: To evaluate the effect of LN examination status on OS and healthcare costs in patients (pts) with eNSCLC. Methods: Retrospective observational study of pts with resected stage IA-IIIB NSCLC (AJCC 7th ed) from SEER data linked with Medicare claims. Eligible pts were ≥65 years at diagnosis (Jan 2010-Dec 2017), had surgery ≤1 month before or 12 months after diagnosis and were continuously enrolled in Medicare Parts A and B for ≥6 months before diagnosis and in Parts A, B and D up to 6 months post-surgery or date of death. Pts were analyzed by LN examination status: no examination (pNX), examination and no LN metastasis (pN0) and examination with N1 (pN1) or N2 (pN2) metastasis. Extended Cox proportional hazards models presented OS hazard ratios (HRs) for specific time periods. Total healthcare costs per patient per month (PPPM) were analyzed using a gamma-log regression model. Results: A total of 9448 pts were included: 996 pNX (11%), 6457 pN0 (68%), 1003 pN1 (11%) and 992 pN2 (10%). pNX pts were slightly older with lower median income, more comorbidities and more baseline smoking history vs other LN examination status cohorts. Stage distribution in pNX and pN0 pts appeared similar. Grade 3/4 tumors were less prevalent in pNX (n = 301, 30%) and pN0 (n = 1934, 30%) pts relative to pN1 (n = 482, 48%) and pN2 pts (n = 424, 43%; P< 0.001). Unadjusted OS was worse for pN1 and pN2 vs pN0 pts and was similar between pNX and pN2 pts. Adjusted OS showed higher risk of death for pN1 and pN2 vs pN0 pts; this risk decreased over time. pNX pts also had higher risk of death vs pN0 pts. Adjusted marginal mean follow-up costs were lowest for pN0 and highest for pN2 pts (All P < 0.001). Costs were higher, but not statistically significant ( P= 0.591) in pNX vs pN0 pts. The majority of total healthcare costs (62-65%) were due to inpatient services. Conclusions: Stage distribution in pNX pts was more similar to that of pN0 than pN1/2 pts, likely due to understaging from lack of LN examination. However, prognosis in pNX pts was nearly identical to that of pN2 pts, suggesting missed LN metastasis diagnosis in a substantial proportion of pNX pts. Despite worse OS in pNX vs pN0 pts, healthcare costs in pNX pts were not significantly higher, which may reflect underutilization of systemic therapy in pts with resected eNSCLC. [Table: see text]
Surgical outcomes and patient-reported outcomes of unresectable stage III non-small cell lung cancer patients who underwent PD-1 inhibitor plus chemo as induction therapy.
Authors: Wang Xin , Liu Guixian , He Jintao , Zhuang Xiang 
Published: June 2023

e20570 Background: For locally advanced unresectable NSCLC, studies of PD-1 inhibitor plus chemo as induction therapy and its roles on subsequent surgical resection are still limited. In this study, a consecutive series of unresectable stage III NSCLC patients were collected to investigate the surgical outcome and postoperative symptom changes in locally advanced patients who received adjuvant chemotherapy combined with immunotherapy. Methods: 92 locally advanced NSCLC patients received 2-4 cycles of chemotherapy combined with immunotherapy. Surgical rates, major pathologic remissions(MPR), pathologic complete remissions(PCR), postoperative complications, and immune-related adverse reactions(irAEs) were assesd. The follow-up of symptoms was performed during treatment and within 3 months postoperatively, and symptom changes were described based on patient-reported outcomes. Results: 26.09% of patients developed irAEs, the most common was skin toxicity, followed by thyroid dysfunction. 71.74% of patients underwent surgical resection. 63.64% (42/66) achieved MPR and PCR, of which 37.87% (25/66) were PCR. Most of these patients have clinical symptoms at the time of presentation, mainly cough (90%), and after treatment, cough is significantly reduced compared with before treatment. After treatment, the cough was significantly reduced compared with before treatment , nausea and vomiting , loss of appetite , dry mouth , and diarrhea were increased or aggravated. The most common symptoms on the first day after operation included pain (90%), shortness of breath (62.5%), fatigue (45%), cough (42.5%), and dry mouth (37.5%). On the third day after surgery, the incidence and severity of each symptom changed significantly, pain and dry mouth decreased significantly compared with before, cough, shortness of breath, and fatigue worsened and the incidence increased. Pain remains the most severe symptom in the early postoperative period, with the most severe on the first day after operation and then reduced, returning to preoperative levels 1.5 months after surgery. Cough was the main symptom at the time of presentation, which was significantly reduced after preoperative treatment, and the incidence and severity of postoperative cough increased significantly compared with preoperative treatment and returned to the preoperative level within 1 week after surgery. Dyspnea lasts long after surgery. Two weeks after surgery, shortness of breath (dyspnea) becomes the most obvious symptom. Conclusions: Preoperative chemotherapy combined with immunotherapy provides more opportunities for radical resection in locally advanced NSCLC patients. The most common postoperative symptoms are pain, dyspnea, cough, and fatigue; dyspnea is the symptom that affects patients the most and lasts the longest after surgery.
Transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature in early-stage EGFR-mutant non-small-cell lung cancer.
Authors: Jung Hyun Ae , Lim Jinyeong , Choi Yoon-La , Park Sehhoon , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Lee Se-Hoon 
Published: June 2023

e20571 Background: In a previous pilot study, we classified early-stage EGFR-mutant NSCLC according to two transcriptomic subtypes (i.e., terminal respiratory unit [TRU], which was related with the downregulation of a proliferative-related pathway; and non-TRU, which was related with the activation of a proliferative-related pathway) and the presence of a co-existing TP53 mutation. In turn, the clinical significance of the APOBEC mutation signature has not been elucidated clearly owing to the small sample size of the previous pilot study. Thus, this study aimed to validate the predictive value of transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature, to expand our pilot study via the use of additional samples and a long-term follow-up. Methods: We performed whole-exome sequencing and whole-transcriptome sequencing using fresh tissue or FFPE from 101 patients with pathological stage II–IIIA non-squamous EGFR-mutant NSCLC who underwent complete resection between January 2014 and December 2020 at the Samsung Medical Center. This study evaluated the recurrence-free survival (RFS) and progression-free survival (PFS) afforded by EGFR-TKI therapy after recurrence according to transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature. Results: The median duration of the follow-up period was 54.2 months (range, 11.3–107.7 months). Six patients were excluded because of failure of the initial quality control; thus, 95 patients were included in the final analysis. The median age was 61.9 years (range, 44.7–91.0 years), and 75.8% of the patients were never-smokers. Moreover, 51.6% of the patients had stage III disease. Among the 95 patients, 47 (49.5%) patients were in the non-TRU group and 44 (46.3%) patients carried a TP53 mutation. The median RFS was 25.8 months (95% CI, 17.6–34.0 months). Patients with non-TRU and/or TP53 mutation had an inferior RFS compared with patients with TRU and wild-type TP53, regardless of the pathological stage (hazard ratio, 1.9; 95% CI, 1.4–2.7). The APOBEC mutation signature was not associated with RFS ( P = 0.17). Among the 65 patients who experienced radiological recurrence, 59 patients received EGFR-TKI therapy as the first-line treatment. The median PFS of EGFR-TKI therapy was 20.7 months (95% CI, 13.6–26.6 months). However, among these patients, those with the APOBEC mutation signature had a shorter PFS than those without this mutation signature (8.2 vs. 23.5 months, P < 0.05). Conclusions: This study showed consistently that the transcriptomic subtype and TP53 mutation status were predictive factors of RFS, regardless of the pathological stage, in patients with early-stage EGFR-mutant NSCLC. Additionally, the APOBEC mutation signature may be present at the initial diagnosis of early-stage EGFR-mutant NSCLC and was associated with a poor PFS after EGFR-TKI therapy.
Comparison of clinical outcomes in patients with advanced pulmonary sarcomatoid carcinoma treated with immunotherapy-based regimen or chemotherapy: A study based on the SEER database and multicentric real-world settings.
Authors: Peng Duanyang , Xiong Le , Luo Yuxi , Liu Anwen , Wang Xia , Zeng Zhimin 
Published: June 2023

e20573 Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare pulmonary cancer characterised by early metastasis and invasion, predominantly diagnosed with locally advanced or metastasis, hindering the possibility of surgical intervention. However, a standardised treatment strategy for advanced PSC is yet to be established. Herein, we aimed to evaluate the effects of immunotherapy-based strategies or chemotherapy on patients with advanced PSC. Methods: We conducted a retrospective study to compare the clinical outcomes of immunotherapy-based regimens and chemotherapy in patients with advanced PSC using the Surveillance, Epidemiology, and End Results (SEER) database and data from three cancer centres. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Univariate and multivariate analyses were performed to identify prognostic factors. Results: In total, 202 patients with stage IV PSC were identified from the SEER database. The median OS was 5 months. The median follow-up time of PSC patients from three cancer centres was 27.5 months Considering all three cancer centres, first-line treatment with a first-line immunotherapy-based regimen and chemotherapy were administered to 12 and 16 patients, respectively. The median PFS was 2.1 (95% confidence interval [CI] [2.1, 4.1]) and 7.2 (95% CI [6.8, 7.6]) months for the chemotherapy- and immune-based groups, respectively (p < 0.001). The median OS was 3.6 (95% CI [1.6, 5.6]) and 13.7 (95% CI [5.1, 22.3]) months for the chemotherapy and immune-based groups, respectively (p = 0.003). Multivariate analysis revealed that the immunotherapy-based regimen was an independent prognostic factor for PFS and OS (p < 0.01, hazard ratio [HR] = 0.22, 95% CI [0.07,0.67] and p < 0.01 HR = 0.27 95% CI [0.11,0.68], respectively). Conclusions: Conventional chemotherapy has limited benefits in patients with stage IV PSC. However, patients with advanced PSC who received first-line immunotherapy-based regimens exhibited a remarkable response. The immunotherapy-based regimen was an independent prognostic factor for PFS and OS.