bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolutions in the management of non-small cell lung cancer in the 21st century: A bibliometric analysis from the 100 most impactful articles in the field.
Authors: Chen Siyuan , Hu Yi , Liu Zhefeng 
Published: June 2022

e20562 Background: The study was designed to explore the evolution of non-small cell lung cancer (NSCLC) management in the 21st century. Methods: The top 100 most-cited papers on NSCLC treatment were retrieved from the Web of Science Core Collection database. R and VOSviewer were used to extract bibliographic information, including the year of publication, countries/regions, institutions, authors, journals, keywords, impact factor, and total citations. The topic and type of papers were checked independently by authors. Bibliometric analysis was conducted and visualized with R, CiteSpace, Excel and VOSviewer to identify output dynamics, research forces, topics, hotspots, and frontiers in the field. Results: The average citation of each retrieved top 100 most-cited NSCLC management papers in 21st century was 1,725 (range: 615-7,340). Fifty-seven corresponding authors were from the United States. This country contributed the most papers (n = 76), followed by Germany (n = 34), France (n = 33), and South Korea (n = 32). The top contributors were Paz-Ares L. (n = 12) and Reck M. (n = 12). The Memorial Sloan Kettering Cancer Center published the largest number of papers (n = 20). There were two significant citation paths, indicating publications in medicine/medical/clinical journals primarily cited journals in molecular/biology/genetics fields, partly cited health/nursing/medicine fields. Top-cited papers mainly came from the New England Journal of Medicine (n = 33, citations =80427), followed closely by the Journal of Clinical Oncology (n = 28, citations = 32408). “Chemotherapy” (n = 36) was the keyword with the greatest frequency of co-occurrence. “Open-label” was the keyword with the strongest burst strength (= 4.01), followed by “nivolumab” (= 3.85), “blockade” (= 2.86), and “efficacy” (= 2.85). Conclusions: The United States as a nation and the Memorial Sloan Kettering Cancer Center as an institute contributed the most papers on this topic in 21st century. Individual authors, such as Paz-Ares L. and Reck M., have developed extensive international collaborations. The New England Journal of Medicine is the most eye-catching journal. Molecular, biological, and genetic research plays important role in this field. Hotspots of NSCLC management have almost undergone an evolution from chemotherapy and radiotherapy to targeted therapy to immunotherapy. Immunotherapy and combination therapy are research frontiers. To our knowledge, the study is the first bibliometric assessment on the evolution of NSCLC treatment from the 21st century.
Treatment patterns and prognosis in inoperable stage III NSCLC after concurrent chemoradiotherapy with or without immune checkpoint inhibition: Historical overview.
Authors: Flörsch Benedikt , Taugner Julian , Käsmann Lukas , Kenndoff Saskia , Guggenberger Julian , Tufman Amanda , Reinmuth Niels , Duell Thomas , Belka Claus , Eze Chukwuka , Manapov Farkhad 
Published: June 2022

e20578 Background: To investigate the impact of treatment patterns in inoperable stage III NSCLC following concurrent chemoradiotherapy with or without immune checkpoint inhibition (cCRT±ICI). Methods: Patients were stratified by treatment year and divided into three subgroups: A (2011–2014), B (2015–2017) and C (2018–2020). Patient- and treatment-related characteristics regarding to PFS and OS were analyzed. Survival parameters were calculated from the last day of thoracic radiotherapy (TRT). Results: 136 consecutive enrolled patients were included. Median follow-up (FU) was 35.7 months; median age was 66.9 years. All patients completed TRT to a total dose ≥60.0 Gy; Median radiotherapy planning target volume (PTV) was 700 cc (range: 172.5–2293.2). Thirty-six (26%) patients received ICI. Median PFS in subgroups A, B and C was 8.0, 8.2 and 26.3 months (p = 0.007). Median OS was 19.9 months, 23.4 months and not reached in subgroups A, B and C (p < 0.05). In subgroup C, median PFS was 14.2 vs. 26.3 months in patients treated with and without ICI. On multivariate analysis for the entire cohort, PTV > 700cc was a negative prognosticator of PFS (HR: 1.522; p = 0.042) and OS (HR: 2.671; p = 0.001); ICI was a predictor of improved PFS (HR: 0.571; p = 0.071) and longer OS (HR: 0.401; p = 0.062). In the Non-ICI cohort, multivariate analyses revealed PTV > 700cc (HR: 1.630; p = 0.047) and SUVmax > 13.75 (HR: 1.859; p = 0.012) were predictors of reduced PFS; PTV > 700cc (HR: 1.958; p = 0.017), SUVmax > 13.75 (HR: 2.405; p = 0.002) and total lung V20 > 30 (HR: 3.357; p < 0.05) were predictors of longer OS. Conclusions: Regardless of ICI, patients receiving multimodal therapy after 2018 demonstrated improved survival compared to patients treated earlier. Both PTV > 700cc and ICI were predictive for PFS and OS in the entire cohort.
Propensity-matched analysis of concurrent/sequential versus sequential immune checkpoint inhibition in inoperable stage III NSCLC patients treated with chemoradiotherapy.
Authors: Käsmann Lukas , Taugner Julian , Eze Chukwuka , Guggenberger Julian , Kenndoff Saskia , Flörsch Benedikt , Tufman Amanda , Reinmuth Niels , Belka Claus , Manapov Farkhad 
Published: June 2022

e20589 Background: Durvalumab maintenance treatment after completion of concurrent chemoradiotherapy (CRT) in patients with inoperable stage III NSCLC is the international standard. In this propensity-matched analysis, we prospectively evaluated the role of concurrent/sequential versus sequential immune checkpoint inhibition. Methods: Between 10/1/2016 and 12/31/2020, 39 NSCLC patients in stage IIIA/B/C were analyzed. 11 (28%) patients received concurrent/sequential PD-1 inhibition (nivolumab) and 28 (72%) patients received sequential PD-L1 inhibition (durvalumab) up to one year after the end of CRT. A 1:2 propensity score matching (PSM) using age, gender, T category and histology was performed to reduce selection bias and address for confounding factors (n = 33, 11 patients receiving nivolumab (SIM-cohort), 22 patients receiving durvalumab (SEQ-cohort). Treatment-related adverse events were assessed weekly during the CRT and at 6 weeks, 3,6,9, and 12 months after the end of CRT. Results: The median follow-up time of the overall cohort, SIM-I cohort, and SEQ-I cohort was 27.6, 33.3, and 26.5 months after CRT, respectively. For the entire cohort median survival (OS) was not reached; median progression-free survival (PFS) achieved 26.3 months. In the SIM-cohort, median PFS was 22.8 months and median OS was not reached. In the SEQ-cohort, neither median PFS nor OS was reached. PFS at 12/24 months was 82/44% in the SIM-cohort and 57/57% in the SEQ-cohort (p = 0.714), respectively. In the SIM-cohort, 18.2% of patients showed grade III pneumonitis; in the SEQ-cohort 13.6% (p = 0.735). Grade 4 and 5 toxicities were not observed. Conclusions: Both concurrent/sequential and sequential immune checkpoint inhibition shows a favorable side effect profile and promising survival in terated patients. Concurrent immunotherapy did not result in an improved outcome (PFS, OS) compared to sequential approach. However, our propensity-matched analysis found that concurrent immunotherapy was associated with a non-significant moderate increase in grade III pneumonitis.
Molecular parameters impacting the success rate of a lung cancer PDX model.
Authors: Li Ziyi , Hubert Shawna Marie , Zhang Ran , Song Xingzhi , Karpinets Tatiana , Weissferdt Annikka , Little Latasha , Mohammad Mohammad , Gumbs Curtis , Negrao Marcelo Vailati , Zhang Jianhua , Pataer Apar , Swisher Stephen , Vaporciyan Ara A. , Roth Jack A. , Heymach John , Sepesi Boris , Gibbons Don Lynn , Fang Bingliang , Zhang Jianjun 
Published: June 2022

e20592 Background: Patient-derived xenograft (PDX) models can provide renewable cancer tissue resources, are being increasingly utilized for the molecular characterizations of cancers and preclinical studies on drug activities, and have the potential to advance biomarker identification. Previous research has demonstrated that PDX tumors preserve the histologic and morphologic characteristics and gene expression and mutation patterns of primary tumors, and correlate to patient survival. Tumor histological subtypes and differentiation grades are known to contribute to the success of PDX intake, but little is known about how molecular features associate with the success of PDX engraftment or whether PDX preserves subclonal architecture of primary tumors. Methods: To fill this void, we analyzed 252 primary tumor samples from the SPORE/ICON project at MD Anderson Cancer Center that were used for generating PDXs and had comprehensive genomic, transcriptomic, and immune profiling data available to evaluate the parameters impacting the intake success of lung cancer PDXs. In order to establish the impact of molecular features on PDX intake success we also assessed the fidelity of PDX in representing the molecular features of this cohort of primary tumors. Results: Only 36% of the primary tumors in this study successfully generated a PDX, with Squamous Cell Carcinoma PDX demonstrating an intake rate of 67% and Adenocarcinoma PDX demonstrating an intake rate of 21%. Genomic architecture derived from whole exome sequencing showed not only 43% (38-48%) of mutations shared, but also similar clonal architecture between primary tumors and PDX. Higher copy number aberration burden, high tumor purity and low immune infiltration in primary tumors were found to be associated with successful intake of PDX. Transcriptomics revealed 6,103 genes differentially expressed between primary tumors with successful PDX intake versus those which were unsuccessful. Pathway analysis of these genes indicated that inhibition of cell proliferation, signaling, and migration as well as DNA replication, recombination and repair were associated with PDX intake failure regardless of histology. Conclusions: These findings indicate that PDX intake success is regulated by molecular features and multiomic evaluation of lung cancer primary tumors can be used as a marker for determining which samples to use for PDX model generation.
Malignant pleural mesothelioma in Brazil: An analysis of public databases between 2000 and 2017.
Authors: Costa Guilherme Jorge , Favato Barcelos Isabella , Taveira Gabriela Monte Tenorio , De Marchi Pedro , Montella Tatiane Caldas , Thuler Luiz Claudio Santos , Ferreira Carlos G. M. 
Published: June 2022

e20597 Background: malignant mesothelioma is a rare tumor with about 31,000 new cases diagnosed annually worldwide. Malignant pleural mesothelioma (MPM) is recognized as an occupational cancer, and past exposure to asbestos represents its main risk factor. Little is known about the epidemiological and clinicopathological profile in developing countries. Methods: this is a cross-sectional study that analyzed the incidence and mortality rates and the clinicopathological profile of MPM in Brazil, from Brazilian public databases: Population-Based Cancer Registries (PBCRs - for incidence), Hospital Cancer Registry (HCR - for clinicopathological profile) and National Mortality Information System (SIM - for mortality). Results: In thirty PBCRs, from 23 of 26 states (average covered of 17% of the Brazilian population), 310 new MPM cases were reported, from 2000 to 2015. The mean age at diagnosis was 62.8 years. Incidence crude rate reached its maximum of 8.96 per 1.000.000 men in the 75-79 age group, and of 3.34 per 1.000.000 women in the 80+ age group. The clinicopathological profile registered in the HCR, from 2000 to 2017, showed a majority of men (70.2%), smoker/former smoker (62.7%) and alcohol users (58.2%). Regarding histology, 59% were described as mesothelioma, NOS (not otherwise specified), 30.6% as epithelioid, 7% as fibrous mesothelioma and 3.4% as biphasic. 54.4% were stage IV at diagnosis, 27.5% stage III and 18.1% stages I or II. A quarter of the patients received neither local nor systemic treatment. From 2000 to 2017 512 deaths related to MPM were registered in SIM database, an average of 28 deaths per year (mean age of death 63.7 years). The age-adjusted mortality rate remained statistically stable over all analyzed period. Conclusions: According to our study, most MPM patients in Brazil are elderly men, stage IV at diagnosis, with mesothelioma NOS. A considerable percentage do not receive any specific treatment for the disesase. Understanding the scenario of MPM in Brazil is important to design prevention, diagnosis and treatment strategies.
Population kinetics assessment of limited small cell lung cancer (L-SCLC).
Authors: Stewart David J. 
Published: June 2022

e20602 Background: For most advanced malignancies, progression free survival (PFS) and overall survival (OS) curves approximate first order kinetics.1 PFS and OS half-lives can be calculated by curve exponential decay nonlinear regression analysis (EDNLRA). Curve characteristics vary significantly with treatment and malignancy type.1 On log-linear plots, PFS curves are significantly more likely to be convex for extensive SCLC than for other malignancies, with late acceleration of tumor growth after completion of 1st line therapy.1,2 Here we assess L-SCLC by EDNLRA. Methods: We used https://apps.automeris.io/wpd/ to digitize PFS curves from L-SCLC studies published from 1990 to 2021. We analyzed curves for study arms having > 50 patients. We used GraphPad Prism 7 for 1 and 2 phase decay EDNLRA as previously described.1 We also constructed log-linear plots. Results: We analyzed 55 L-SCLC PFS curves from 34 published trials. Median PFS half-life was 15 months for studies published 1990 to 2010 vs 19.5 months for 2011 to 2021 (P = 0.003). This improvement over time might be explained in part by stage migration (eg, with PET scanning). Of 55 log-linear plots, 53 (96%) had an inflection to the right. The curve inflection indicates there are 2 distinct subpopulations: namely progressing patients vs cured patients. Of the 55 curves, 46 fit 2 phase decay EDNLRA models. Across these 46 2-phase decay curves, EDNLRA calculations indicated that the progressing subgroup comprised 86% of the total population and had a PFS half-life of 10.5 months. The cured subgroup accounted for the other 14% of the population, with a PFS half-life greater than 15 years. The proportion cured increased from a median of 12% for 1990-2010 studies to 22% for 2011-2021 studies (p = 0.01). Stage migration might again explain this difference. For patients who are progression-free at any time point, one can also use these EDNLRA data to calculate the proportion who would eventually progress in the future. Of those still progression free at 12, 24, 36, 48, 60 and 120 months, respectively, the proportion that would eventually progress would be 73%, 56%, 36%, 20%, 10%, and 0.2%. As with extensive SCLC, all 55 L-SCLC PFS log-linear curves displayed early convexity, with a downward inflection after a period of relative stability. This downward inflection occurred at a median of 4.4 months, in keeping with acceleration of progression after completion of planned systemic therapy. Conclusions: Population kinetic assessments permit calculation of probability of eventual progression for L-SCLC patients who remain progression-free at different time points after initiation of therapy. Of L-SCLC patients who remain progression-free at 60 months, approximately 10% are nevertheless destined to eventually relapse. References: Stewart DJ et al. Crit Rev Oncol Hematol. 2020;153:103039. Stewart DJ et al. Proc American Soc Clin Oncol 2020. Abstract # e21101.
Outcomes of anti-PD-L1 blockades plus etoposide and platinum (EP) as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC) with brain metastasis (BM).
Authors: Tian Yaru , Ma Ji , Zhu Hui , Yu Jinming 
Published: June 2022

e20607 Background: Anti-PD-L1 blockades plus EP is the standard first-line therapy for ES-SCLC from IMpower133 and CASPIAN. Subgroup analyses of the two trials indicated that patients (pts) without BMs could benefit from atezolizumab and durvalumab, while those with BMs could not. The aim of the retrospective study is to further investigate the clinical efficacy of the first-line anti-PD-L1 blockades plus EP for ES-SCLC with BMs. Methods: Between 2017 and 2021, pts with newly diagnosed ES-SCLC and baseline BM confirmed by CT or MRI at Shandong Cancer Hospital and Institute were enrolled. According to whether combined with anti-PD-L1 blockades (atezolizumab or durvalumab) or not, pts were assigned to anti-PD-L1+EP group and EP group, respectively. Response was assessed by RECIST 1.1 and survival analyses were conducted using Kaplan-Meier and log-rank tests. Results: A total of 56 pts were enrolled in the current study. Eighteen pts were allocated to anti-PD-L1+EP group and 38 were allocated to EP group. The median follow-up time was 18.17 months. Overall response rate (ORR) was 72.22% vs 78.95% ( P= 0.83) and disease control rate (DCR) was 100% vs 97.37% in the two groups, respectively. And for BMs, the intracranial ORR and DCR were 50.00% vs 68.42% ( P= 0.18) and 72.22% vs 78.95% ( P= 0.83), respectively. Progression-free survival (PFS) was numerically prolonged with anti-PD-L1 blockades, but the significance was not achieved (median: 9.4m vs 7.3m, P = 0.146, HR = 0.63 (95%CI, 0.35-1.13)). The intracranial PFS was not improved, neither (median: 8.2m vs 7.9m, P= 0. 943, HR = 1.02 (0.53-2.00)). However, overall survival was significantly prolonged with anti-PD-L1 blockades (median: NR vs 15.53m, P = 0.012, HR = 0.20 (0.09-0.46)). Conclusions: Collectively, we found that the addition of the first-line anti-PD-L1 blockades to EP brought about a significant survival benefit compared with EP alone for ES-SCLC with BMs.
First-in-human study of pelcitoclax (APG-1252) in combination with paclitaxel in patients (pts) with relapsed/refractory small-cell lung cancer (R/R SCLC).
Authors: Qin Angel , Kalemkerian Gregory Peter , Mohindra Nisha Anjali , Patel Jyoti D. , Karapetis Christos Stelios , Carlisle Jennifer W , Sands Jacob , Spira Alexander I. , Gao Bo , Amin Harshad , Paudyal Bishnuhari , Frank Genevieve , Sun Xuemei , Xu Yang , Wang Cunlin , Fu Tommy , Winkler Robert , Liang Zhiyan , Yang Dajun , Zhai Yifan 
Published: June 2022

e20612 Background: Targeting BCL-2/BCL-xL proteins is considered an important approach for anticancer drug development. Investigational pelcitoclax (APG-1252) as a single agent is a novel BCL-2/BCL-xL dual inhibitor, which has demonstrated synergistic antitumor activity in combination with chemotherapy preclinically through targeting both BCL-xL and MCL-1 pathways. The phase I study of pelcitoclax suggested promising antitumor activity and a favorable safety profile. Methods: The primary aim of this study was to determine the safety and preliminary efficacy of pelcitoclax combined with paclitaxel in patients with R/R SCLC. Patients received pelcitoclax 160 mg or 240 mg IV infusion on Days 1, 8, and 15 plus paclitaxel 80 mg/m2 on Days 1 and 8 of a 21-day cycle. The primary endpoint of phase Ib was to characterize the safety and tolerability of the combination. The primary endpoint of phase 2 was the objective response rate (ORR) of pelcitoclax at the RP2D plus paclitaxel using RECIST v1.1. Results: On December 20, 2021, 28 pts (median age, 63 [range, 37-77] years) were enrolled. The median (range) duration of treatment was 84 (7-259) days. The RP2D of pelcitoclax was determined to be 240 mg. A total of 26 pts experienced any grade treatment-related adverse events (TRAEs), including anemia (32.1%); ALT or AST elevation (28.6% each); neutropenia (25%); fatigue, leukopenia, or thrombocytopenia (21.4% each); peripheral neuropathy, nausea, or alopecia (17.9% each); peripheral sensory neuropathy or decreased appetite (14.3% each); and lymphopenia, hyponatremia, or dizziness (10.7% each). A total of 15 pts had at least one ≥ grade 3-4 TRAE, and 11 (39.3%) had serious AEs. No dose-limiting toxicity was reported. A total of 5 of 20 evaluable pts (4 pts in the 240 mg cohort and 1 in the 160 mg cohort) reported PR (ORR 25%), with a median response duration of 83 days. The pharmacokinetics profile showed that pelcitoclax systemic exposure increased between 160 and 240 mg, with an average terminal half-life of 3.7 to 7.4 hours and without any drug-drug interaction. Conclusions: Pelcitoclax was well tolerated at doses of up to 240 mg/week. Treatment with pelcitoclax 240 mg and paclitaxel 80 mg/m2 demonstrated modest antitumor activity in pts with R/R SCLC. Further clinical exploration, preferably in selected patient populations with relevant biomarkers, is warranted to fully elucidate the clinical activity of pelcitoclax. Clinical trial information: NCT04210037.
Peripheral blood T-cell receptor repertoire profiling of advanced non-small cell lung cancer patients receiving PD-1/PD-L1 treatment.
Authors: Tseng Diane , Chiou Shin-Heng , Nair Viswam , Martins Renato G. , Santana-Davila Rafael , Lee Sylvia , Eaton Keith D. , Baik Christina S , Houghton A. McGarry 
Published: June 2022

e21004 Background: Whether peripheral blood T cell receptor (TCR) repertoire profiling can serve as a biomarker to predict clinical benefit from anti-PD-1/PD-L1 checkpoint immunotherapy is not well understood. Moreover, it is not known which methods for TCR repertoire analysis are most clinically meaningful. To address this, we have performed TCR repertoire analysis of patients with advanced/metastatic non-small cell lung cancer (NSCLC) receiving PD-1/PD-L1 treatment. Methods: We analyzed 29 patients receiving PD-1/PD-L1 monotherapy or combination therapy in any line of treatment, excluding patients with EGFR mutations or Alk alterations. Genomic DNA was extracted from peripheral blood examples, and CDR3 regions of the rearranged TCR beta genes were amplified and sequenced using the immunoSEQ platform (Adaptive Biotechnologies, Seattle, WA). Libraries were sequenced using Illumina HiSeq 2500. TCR clonality, diversity, evenness, and the percentage of high-frequency clones (> 0.1% of the repertoire) were calculated at pre-treatment and post-treatment (1 – 3 months) timepoints. Morisita’s overlap index was calculated for 25 paired pre- and post-treatment samples. Metrics were compared in patients with and without durable clinical response at 6 months using the Mann-Whitney test. Results: There were no statistically significant differences in TCR repertoire clonality, diversity, evenness, or high-frequency clones between patients with and without durable clinical benefit, either at pre-treatment or post-treatment time points (p > 0.05). Conclusions: TCR repertoire metrics including clonality, diversity, evenness, percentage of high-frequency clones, and Morisita’s overlap index do not predict immunotherapy responses in this cohort of advanced/metastatic NSCLC patients receiving PD-1/PD-L1 monotherapy or combination therapy. Limitations of this study include sample size and heterogeneity of the patient cohort. This highlights the need for advanced TCR repertoire metrics, for example, considering shared TCR specificities and clonal identity. In ongoing work, we are defining TCR specificity groups and TCR clones in NSCLC as biomarkers of immunotherapy responsiveness.