bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathological response and tumor immune microenvironment remodeling of neoadjuvant ALK-TKIs in NSCLC with ALK.
Authors: Li Li , Zheng Nan , Zhang Yi Min , Zhang Ruiguang , He Yong , Wu Fang 
Published: June 2023

e20574 Background: Anaplastic lymphoma kinase–tyrosine kinase inhibitor (ALK-TKI; ALKi) has shown potent antitumor activity in metastatic non–small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+). However, its efficacy in neoadjuvant settings for patients with ALK+ resectable NSCLC has been poorly explored. Given this, the present study aimed to examine the clinical activity and tumor immune microenvironment (TIME) remodeling of neoadjuvant ALKi therapy. Methods: In this retrospective study, ALK+ NSCLC patients treated with neoadjuvant ALKi therapy at three hospitals in China were enrolled between February 2018 and April 2022.Data on clinical features, radiographic responses, and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. Two panels (Panel 1: CD8, PD1, GB, CK, 4′,6-diamidino-2-phenylindole [DAPI]; Panel 2: CD4, FOXP3, CD68, CD163, CK, DAPI) were used to identify multiple immune cell types. Results: A total of 12 patients with stage IIA to IIIB NSCLC who received neoadjuvant ALKi therapy and R0 resection were enrolled; the median age was 54.0 years, and 66.7% (8/12) were female. The median duration of neoadjuvant ALKi was 5.5 months. The objective response rate was 91.7% (11/12). All patients successfully underwent R0 resection. The major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed asignificant increase in immune infiltration of total CD8+ (histochemistry score: median, 10.51 vs 24.01, P= 0.028; density: median, 128.38 vs 694.09 cells/mm2, P= 0.028; percentage: median, 3.53% vs 15.92%, P= 0.028) and total CD4+ (density: median, 275.56 vs 651.82 cells/mm2, P= 0.028; percentage: median, 5.98% vs 10.46%, P= 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB-. However,macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. When comparing TIME between neoadjuvant ALKi and PD1 inhibitors in resected specimens from patients with pCR, neoadjuvant ALKi therapy presented higher levels of CD8+PD1+ but lower levels of CD8+GB+. Conclusions: Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME remodeling by neoadjuvant ALKi therapy and merits further investigation in the neoadjuvant setting for patients with ALK+ resectable NSCLC.
A robust and accurate method to detect MET Exon 14–skipping mutation in pan-cancer samples using an NGS-based RNAseq approach.
Authors: Wang Yongjie , HengDa Ren , Zhang Yiqun , Pei Zhihua , Wang Dongliang , Zhou Qiming , Wang Jing 
Published: June 2023

e20575 Background: Met exon 14 skipping mutation(METex14) occurs in multiple cancer species, mainly in non-small cell lung cancer (NSCLC, 3~4%) and pulmonary sarcomatoid carcinoma (PSC, 22%). Several drugs expressed curative effect in previously treated patients who harboring METex14, such as savolitinib approved by NMPA, capmatinib and tepotinib licenced by FDA. Developing a quick and precise method which detect METex14 and help patients benefit from clinical drug treatment is a desiderative issue currently. Previous researches suggest that transcriptome-based RNA-seq method was superior to DNA-based NGS (exome, panel) and PCR method. Here We introduce a fast and accurate method to detect METex14 alternation in RNAseq data. Methods: We sequenced NGS-based Ribo-zero RNAseq (pair-end, 150bp×2) and METex14 ddPCR on 99 pan-cancer samples, of which 38 lung carcinoma (38%), 8 renal carcinoma (8%), 7 pancreatic carcinoma (7%). In 38 lung carcinoma, 35 NSCLC samples were consist by 29 lung adenocarcinoma (LUAD, 76%), 4 lung squamous carcinoma (LUSC, 10%) and 2 PSC (5%). Begin of the study, data quality control applied by Fastp and aligned to human hg19 genome by STAR subsequently. Next, MET exon14 related candidate soft-clipping reads were extracted from BAM files and translated to fastq file. Then we remapped the translated fastq file to hg19 genome with Blat using parameters ‘stepSize = 5, -repMatch = 2253, -minScore = 20, -minIdentity = 90’. Next, supporting reads were sequentially retained by: single end length longer than 18bp; block mapped reads of MET gene; the pair end reads mapped to genome if one end fall in the last 3bp of MET intron 13 and another end fall in at least initial 3bp of MET exon 15. Pair or single end support junction read, distance of junction site to reads end and site coverage were enrolled in a bayesian model to calculate METex14 confidence score (BMMETs). Threshold of our model was defined by the cut-point of max youden-index and 16 samples were validated METex14 by ddPCR. Finally, we would predict a sample with METex14 when score > = 0.752. Results: Our method reported 15 TP samples, 1 FP sample and 1 FN samples (AUC 0.97, sensitivity 0.88, specificity 0.98) while STAR-fusion detected 14 TR samples and 6 FP sample and 2 FN samples (AUC 0.715, sensitivity 0.64, specificity 0.73). BMMETs FP sample scored approximately 0.739 that close to the threshold. Conclusions: Strategy of screen reliable METex14 supporting reads and using bayesian model to calculate a METex14 confidence score could robustly and efficiently predict METex14 event in NGS-based RNAseq data.
Concurrent durvalumab plus chemoradiation therapy followed by durvalumab in Chinese patients with unresectable stage III non-small cell lung cancer: CRUISER study.
Authors: Teng Feifei , Ge Hong , Wang Buhai , Xu Yaping , Meng Xue , Wang Suzhen , Xing Ligang , Yu Jinming 
Published: June 2023

e20576 Background: Concurrent chemoradiation therapy (CRT) followed by durvalumab consolidation therapy has demonstrated significant survival benefit for unresectable stage III non-small cell lung cancer (NSCLC) in PACIFIC trial. However, there are still 20%-30% patients who have disease progression (PD) or intolerable toxicity. This prospective study aimed to evaluate safety and clinical activity of concurrent durvalumab plus CRT followed by durvalumab in unresectable stage III NSCLC (NCT04982549). Methods: This is a single-arm, open-label, multicenter phase II clinical trial and planned to enroll 35 patients with unresectable stage III NSCLC of any PD-L1 expression level and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All of patients will receive concurrent durvalumab 1500mg every 4 weeks plus SoC CRT followed by durvalumab monotherapy 1500mg every 4 weeks until PD or unacceptable toxicity. One cycle of induction durvalumab plus chemotherapy is allowed before radiotherapy upon investigator discretion. The primary endpoint is the incidence of grade ≥3 immune-mediated adverse event (AE). Here we report the preliminary clinical activity and safety of a preplanned interim analysis of this study. Results: By September 2022, 28 patients finished concurrent durvalumab plus CRT treatment and were included for analysis. 21 (75%) of 28 patients had radiographic tumor evaluation and entered the consolidation treatment stage, 7 (25%) patients discontinued treatment without radiographic tumor evaluation because of intolerable AE (5 patients) or withdrawing from the study (2 patients). 20 (71.4%) of 28 patients received one cycle induction therapy of durvalumab plus chemotherapy. The median age of these 28 patients was 64 years old, 26 (92.9%) of 28 patients with ECOG performance status of 1, and 14 (50%) of 28 patients were squamous carcinoma. Disease stage was IIIA (42.9%, 12/28), IIIB (39.3%, 11/28) and IIIC (17.9%, 5/28), with most of them (89.3%, 25/28) had N2/N3 lymphatic metastasis. 19 (90.5%) of 21 patients achieved objective response. Median interval from enrollment to the first radiological evaluation was 112 days. Grade ≥3 treatment-related adverse event (TRAEs) occurred in 13(46.4%) of 28 patients, including six (21.4%) possibly related to durvalumab. Conclusions: The interim results from CRUISER study showed promising clinical activity and manageable toxicity of durvalumab plus concurrent CRT followed by durvalumab for unresectable stage III NSCLC. The survival outcome and biomarker exploration will be analyzed upon data maturity. Phase 3 PACIFIC-2 study investigating clinical outcome of concurrent durvalumab plus CRT in unresectable NSCLC is ongoing. Clinical trial information: NCT04982549 .
Detection effectiveness of immune-related gene mutations in lung adenocarcinoma by circulating tumor DNA.
Authors: Qin Jing , Yin Fengxiang , Guo Weifeng , Zhang Guoying , Du Shasha , Liu Danni , Jing Zhang , Cheng Shaochen 
Published: June 2023

e20580 Background: Lung adenocarcinomas (LUAD) is the major pathological subtype of lung cancer with a poor prognosis. Tumor development and progression are significantly influenced by immune microenvironment. However, immune-related gene alterations have not been utilized in prognostic evaluation frequently. Circulating tumor DNA (ctDNA) provides a non-invasive approach to cancer diagnosis and prognosis. It is possible to find immune-related biomarkers that may be used to predict clinical outcomes and evaluate the effectiveness of ctDNA for the detection of immune-related gene mutations in LUAD. Methods: Immunologically relevant genes were downloaded from ImmPort, including chemokines (n = 102), cytokine receptors (n = 307), cytokines (n = 456), interferons (n = 17), interleukins receptors (n = 42), interleukins (n = 47), TGF-β family (n = 33) and TNF family (n = 12). Clinical and genetic mutation data of 604 LUAD samples were obtained from cBioPortal. The Kaplan-Meier method of survival analysis was used to estimate the overall survival (OS) of the published LUAD data set. 1837 LUAD patients collected both tumor tissue and blood samples were screened from the HapLab database (HaploX, Shenzhen, China). Results: OS analysis had been processed in each immune-related gene set and gene receptively. Only patients with cytokine receptor mutations showed a poor prognosis compared with the wild-type (log-rank test, p-value = 0.027). OS did not differ statistically significantly in patients with or without alterations in any other immune-related gene sets or individual genes. Protein-coding mutations of 32 cytokine receptor genes were found in 1290 LUAD tumor tissue samples from HapLab database. 93.75% (30/32) genes were observed mutations in paired plasma ctDNA results, and the minimum variant allele frequency (VAF) was 0.04%. 243 alterations in cytokine receptor genes were only detected in 54 peripheral blood samples. The overall sensitivity and specificity were 91.09% and 40.05% in blood ctDNA assay. Conclusions: The mutational status of cytokine receptor genes in LUAD is significantly associated with long-term OS. The presence of tumor DNA in the blood showed high diagnostic accuracy for detecting cytokine receptor mutations in LUAD patients. Circulating tumor DNA-based liquid biopsy offers LUAD patients a non-invasive prognostic assessment method based on immune-related gene mutation screening. [Table: see text]
Patients’ epidemiology in stage III, unresectable non-small-cell lung carcinoma: A real-world analysis in Brazil.
Authors: Amaral Duarte Flavia , Marques dos Santos André , Santana Pamela , Dias Caique , Lopes Danilo , Denapoli Priscila 
Published: June 2023

e20589 Background: Although breakthrough therapy options for NSCLC have emerged in the last few years, lung cancer is still the principal cause of cancer-related deaths in both men and women worldwide. In Brazil, lung cancer is the major cause of cancer mortality – the second most common cause of cancer-related death in females and the first cause among males. The main factors contributing to the high burden of the disease remain the late-stage diagnosis and unequal healthcare access, which are most prevalent in low- and middle-income countries. This study aimed to describe lung cancer epidemiology – patients in stage III, unresectable NSCLC that could benefit from consolidation therapy after chemoradiation (CRT) treatment - in the Brazilian public health system for evaluating the future impact of new therapies. Methods: We gathered information on lung cancer procedures performed between January 2018 and October 2022 using the Brazilian public health system database (DATASUS). Since this is a claim medical database without clinical data, assumptions were specified based on procedures performed to determine the potential number of patients in Brazil who would benefit from these new treatment strategies in stage III NSCLC. The assumptions were the following: 1. Having received systemic therapy for a malignant tumor of the bronchi and lung (ICD-10 - C34); 2. Having received a pre-defined list of chemotherapy regimens (to define which patients were NSCLC); 3. Having started systemic therapy with a Stage III tumor; 4. Having not undergone surgery between three months before and two months following the start of systemic treatment 5. Treated with chemotherapy and radiotherapy (concomitantly or sequentially - until two months later); 6. Patients who died or progressed during treatment were classified as incomplete treatment. Results: Between 2018 and 2022, we identified an average of 9,340 patients each year who started therapies for lung cancer; 75% (7,023) of them performed specific procedures for NSCLC and were classified as such. 21% (1,472) of patients started treatment for stage III NSCLC, and 98% (1,438) of these cases were unresectable. Of these, 26% (377) received chemotherapy and radiation, 92% of whom finished the course of treatment. In Brazil, 346 patients per year with stage III unresectable NSCLC could be treated with consolidation therapy after CRT in the public health system. Conclusions: The number of NSCLC patients who can benefit from consolidation therapy after CRT (346) represents 3.7% of all lung cancer patients starting systemic treatment annually. It allows a better management of the possible economic impact of the addition of this new therapy in the Brazilian health public system. Increased screening for early diagnosis and improving access to CRT would expand the patient population eligible for this therapeutic approach.
Efficacy and safety of pembrolizumab plus chemotherapy and sequential surgical resection in initial unresectable stage IIIB NSCLC.
Authors: Zhou Jianya , Li Yuekang , Zheng Jing , Ruan Kexin , Zhou Jianying 
Published: June 2023

e20595 Background: Neoadjuvant immunochemotherapy has been proved effective in resectable NSCLC, while its role in unresectable stage IIIB NSCLC remains controversial. This study aims to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy sequential surgical resection in initial unresectable stage IIIB NSCLC patients. Methods: This multicenter study retrospectively analyzed 59 patients with initial unresectable stage IIIB NSCLC who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. The clinical characteristics, radiological and pathological response and survival outcomes were collected and evaluated. Results: A total of 59 initial unresectable stage IIIB NSCLC patients were identified and divided into the surgery group (n = 23) and non-surgery group (n = 36) with a median follow-up time of 15.0 months. The median PFS/DFS of surgery group was significantly longer than that of non-surgery group (not reached versus 15.5 months, p = 0.0031). The median OS was not reached in both groups, overall survival rate was 100% (23/23) in surgery group and 83.3% (30/36) in non-surgery group. Pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in MPR group compared to non-MPR group ( p = 0.034). Of 23 patients in surgery group, all patients had a R0 resection, no surgical-related mortality was recorded, only 3 patients (13.0%) experienced any postoperative complications. Conclusions: Surgical resection after neoadjuvant immunochemotherapy is beneficial in the survival outcome of initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety.
Importance of DICER1 pathogenic variants in non-small cell lung cancer.
Authors: Wu Samuel , Evans Mark Gordon , Chong Anne-Laure , Thorner Paul , Fiset Pierre-Olivier , Butt Yasmeen M. , Oberley Matthew James , Gatalica Zoran , Foulkes William D. 
Published: June 2023

e20602 Background: DICER1 encodes a miRNA processing enzyme involved in regulation of cell proliferation and differentiation. The role of DICER1 pathogenic variants (PVs) in non-small cell lung cancer (NSCLC) is relatively unknown. Germline and/or somatic PVs have been reported in pleuropulmonary blastoma, pulmonary blastoma (PB), and low-grade/well-differentiated fetal adenocarcinoma (WDFLAC), with clustering of somatic PVs at specific metal ion binding residues referred to as hotspot alterations. PVs in CTNNB1, resulting in constitutive activation of the WNT signaling pathway, have also been implicated in PB and WDFLAC. This study seeks to establish the frequency of somatic DICER1 hotspot PVs that occur in all NSCLCs, their co-occurrence with other PVs in DICER1 and with alterations of CTNNB1/WNT signaling, and their histologic correlates. Methods: Molecular sequencing data collected from 12,146 NSCLCs at Caris Life Sciences were queried for cases featuring somatic DICER1 variants. For those tumors harboring hotspot PVs, sequencing for CTNNB1 and APC mutations was performed, as well as histological review, including examination of beta-catenin immunohistochemical (IHC) staining. Results: Of the 12,146 NSCLCs analyzed, 235 (1.9%) were found to have one or more DICER1 PVs. Of these 235, 225 cases demonstrated one variant, while 10 tumors featured two. Gene analysis revealed that 8 of the observed PVs cases contained hotspot alterations: 2 in the single variant cases and 6 in the double variant cases. The remaining 4 double variant cases harbored a combination of truncating, non-hotspot missense, or splice variants. No significant differences were observed for age or smoking status between DICER1 hotspot-positive and hotspot-negative groups. All but one tumor were considered to be in histologic spectrum of PB/WDFLAC. Of the 8 DICER1 hotspot-positive cases, 1 had a PV in APC, 4 had a CTNNB1 PV, 1 had a PV in both APC and CTNNB1, and 2 had neither. Beta-catenin IHC showed nuclear positivity in 5 tumors that had a PV in either CTNNB1 and/or APC.. Conclusions: This study demonstrates that DICER1 somatic hotspots select for morphologic features of tumor types such as PB and WDFLAC, but are not implicated in the most common forms of NSCLC. Furthermore, DICER1 hotspot-positive NSCLCs frequently harbor CTNNB1 and/or APC alterations, with many cases exhibiting nuclear staining by beta-catenin IHC, suggesting a possible synergistic relationship between DICER1 hotspot PVs and activation of the WNT signaling pathway in the formation of pulmonary tumors. These findings emphasize the importance of molecular testing in clinical practice such that detecting somatic DICER1 hotspot alterations aids in the diagnosis of rare lung cancers, which ultimately require special consideration with respect to disease severity and treatment.
Demographics of the tumor formerly known as bronchiolo-alveolar carcinoma.
Authors: Luker Andrew , Hsia Beau , Wu Xinxin , Silberstein Peter T. , Keirns Darby 
Published: June 2023

e20604 Background: Bronchiolo-alveolar carcinoma (BAC) is a rare subtype of non-small cell lung cancer of the lung periphery, often characterized by lepidic growth. Although BAC has undergone various reclassifications in recent years, International Classification of Disease codes still classifies these subtypes using the same codes that previously belonged to BAC. Changing diagnostic criteria and other factors cause BAC to be among the most overdiagnosed forms of lung cancer and thus a demographic study could provide insight into trends. Methods: A retrospective cohort analysis utilizing the National Cancer Database (NCDB) from 2004 – 2020 included patients with malignant forms of BAC (Invasive mucinous adenocarcinoma, mixed invasive mucinous, and nonmucinous adenocarcinoma) confirmed through histology. Demographic factors such as sex, age, race, Hispanic status, median household income, insurance status, facility type, county population, distance from facility, and Charlson Deyo score were analyzed by descriptive statistics and incidence trends. Results: In total, 12,607 patients were identified in the database with a confirmed diagnosis of BAC between 2004 – 2020. The number of cases per year remained steady (mean = 565.4) until 2018. From 2018 to 2020, the average number of diagnoses per year was 1575.0. The average age of diagnosis was 69.3 years (SD = 10.7, range = 10 to > 90 years). 58.1% of the cases were female patients. The top primary sites were the lower and upper lobes (46.2% and 39.9% respectively). The majority (59.2%) had Charlson-Deyo comorbidity scores of 0. Most cases occurred in Non-Hispanic White persons (86.8%). More patients were in the top quartile of income earners (34.0%) compared to those in lower quartiles. Medicare was the insurance provider for most patients (65.0%). More patients were diagnosed in counties with a population over 1 million (52.4%). More patients were treated in comprehensive community cancer programs (38.1%) followed closely by academic cancer programs (35.2%). Patients lived an average of 31.6 miles (SD = 113.0, range = 0.1 – 2390.7) from the treatment facility. Conclusions: This is the first NCDB analysis on the demographics of BAC. The sudden rise in cases per year in 2018 aligns with the changing pathologic and histologic definitions for BAC. A 2006 review of BAC found that 50-70% of cases occur in female patients, similar to our results. The majority of BAC patients tend to be non-Hispanic and White with a primary site diagnosis in the lower lobe, followed by the upper lobe. BAC patients are more likely to be in the top income quartile, live in densely-populated metropolitan areas, and receive treatment in a non-academic program. Further research is needed to better understand the impact of demographic, socioeconomic, and environmental factors on the diagnosis and prognosis of BAC, especially because its diagnostic criteria have changed recently.