bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying biomarkers associated with disease-free survival in stage I non–small cell lung cancer.
Authors: Seder Christopher W. , Moudgalya Hita , Donaldson Andrew E. , Layng Kayla Viets , Mauer Elizabeth , Subramanian Janakiraman , Fhied Cristina L. , Geissen Nicole , Alex Gillian , Karush Justin , Liptay Michael J. , Borgia Jeffrey Allen 
Published: June 2022

8543 Background: Patients with early stage, non-small cell lung cancer (NSCLC) with solitary pulmonary lesions ≤4 cm typically have favorable outcomes. However, disease recurrence impacts up to 30% of patients, leading to either additional surgical or systemic interventions. New methods to risk stratify patients based on clinical and molecular parameters may improve our ability to select cases that would benefit from more frequent surveillance or enrollment in clinical trials evaluating systemic therapy. Methods: We retrospectively analyzed data from 179 patients with early stage (T1a-2aN0M0) NSCLC from a single institution. All patients had anatomic resection, negative margins, and systematic nodal sampling. Clinical and demographic data were abstracted from patient charts and tumor samples were molecularly profiled using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage, whole exome-capture RNA-seq). Pathogenic alterations (single nucleotide variants and insertion/deletions) and RNA expression were examined. Bivariate Cox-proportional Hazards models were used to assess the association of individual clinical, demographic, and molecular variables with recurrence-free survival, defined as the time from surgery until recurrence or death. Results: Our dataset included 166 stage IA1-3 patients and 13 stage IB patients, of which 36 patients experienced a recurrence or death event after surgery. Clinical and DNA-seq data was available for all patients, and RNA expression data was available for 172 patients. Across all patients, the most common somatically mutated genes were TP53 (33% of tumors) and KRAS (16% of tumors), consistent with previous studies. Increasing log10-RNA expression for NTRK1 (HR: 5.95; 95% CI, 1.16-30.4; p = 0.027) and CD274 (PD-L1) (HR: 7.88; 95% CI, 1.61-38.6; p = 0.013) and decreasing log10-RNA expression for EGFR (HR: 0.24; 95% CI, 0.05-1.21; p = 0.071) and ERBB2 (Her2) (HR: 0.20; 95% CI, 0.04-0.97; p = 0.042) were associated with increased risk of recurrence or death. Conclusions: Increased expression of NTRK1 and CD274 (PD-L1) and decreased expression of EGFR and ERBB2 (Her2) were associated with a increased risk for recurrence following surgery. This may have mechanistic implications for heightened tumor aggressiveness and/or metastatic potential. Future work will expand our cohort and validate our findings in a broader set of early-stage NSCLC patients.
Multi-omic and spatial dissection of immunotherapy response groups in non–small cell lung cancer (NSCLC).
Authors: O'Byrne Kenneth John , Monkman James , Kim Honesty , Cumberbatch Marie , Bhagat Milan , Ladwa Rahul , Adams Mark N , Kulasinghe Arutha 
Published: June 2022

8544 Background: Immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The composition of the tumour microenvironment (TME) is becomingly increasingly recognised as an important factor to predict response to therapy. Methods: Here, we applied digital spatial profiling of the tumour and stromal compartments from a 2nd line NSCLC ICI-treated cohort (n = 41 patient) and standard of care (SOC), platinum treated NSCLC cohort (n = 47), to identify tissue-based signatures of response to therapy. Results: We demonstrate by mIHC that the interaction of CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in ICI refractory tumours (p = 0.012). Patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p = 0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA (p = 0.001) within their stroma. Immuno-inhibitory markers CTLA-4 (p = 0.021) and IDO-1 (p = 0.023) were supressed in ICI-responsive patients. Tumour CD44 (p = 0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of one of its ligands, SPP1 (osteopontin, p = 0.008). Analysis of dysregulated transcripts indicated the potential inhibition of stromal interferon-gamma (IFNγ) activity, estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR = 1.61, p = 0.01), consistent with its depletion in ICI sensitive patients. Similarly, stromal CTLA-4 (HR = 1.78, p = 0.003) and MDSC/M2 macrophage marker ARG1 (HR = 2.37, p = 0.01) were associated with poorer outcome while BAD (HR = 0.5, p = 0.01) appeared protective. The SOC cohort paralleled similar roles for immune checkpoints and pro-apoptotic markers, with LAG3 (HR = 3.81, p = 0.04) indicating poorer outcome, and BIM (HR = 0.16, p = 0.014) with improved outcome. Interestingly, stromal mRNA for E-selectin (HR = 652, p = 0.001), CCL17 (HR = 70, p = 0.006) and MTOR (HR = 1065, p = 0.008) were highly associated with poorer outcome in ICI treated patients, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance. Conclusions: Through multi-modal approaches, we have dissected the characteristics of NSCLC treatment groups and provide evidence for the role of several markers including IL2, CD25, CD44 and SPP1 in the efficacy of current generations of ICI therapy.
Epidemiology and clinical impact of EGFR mutation in patients with lung cancer after radical surgical treatment.
Authors: Bryl Maciej , Sielewicz Magdalena , Budny Bartłomiej , Woźniak Aldona , Gabryel Piotr , Kasprzyk Mariusz , Barinow-Wojewodzki Aleksander , Piwkowski Cezary 
Published: June 2022

8552 Background: The epidemiology of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma and its clinical impact are well-known. However, most studies have focused on advanced-stage inoperable cancer. Data on the frequency of EGFR mutation in surgically resected lung cancer are limited. Recent studies have shown a promising effect of Osimertinib in adjuvant settings. Hence, the need to estimate the target population in the real-world data. This study aimed to assess the occurrence of EGFR mutation in patients after radical surgical treatment of lung adenocarcinoma and explore its prognostic impact compared to EGFR negative group. Methods: This single-center retrospective analysis included the group of 732 consecutive Caucasian patients with histopathologically confirmed lung adenocarcinoma, evaluated for EGFR mutations expression, who underwent anatomical resection between January 2016, and December 2020. EGFR status was assessed by cobas EGFR mutation test v2. The frequency of EGFR mutations, disease-free survival (DFS) and overall survival (OS) in EGFR positive and EGFR negative groups were analyzed. Results: EGFR mutations were found in 65 surgical patients (8.9%) and did not differ from patients with advanced stages of lung adenocarcinoma (7.9%). EGFR mutations occurred more frequently in females than males, 48 out of 344 (14%) and 17 out of 388 (4.4%), respectively. Deletions within exon 19 and the L858R mutation in exon 21 constituted 49.2% and 24.6% of all mutations, respectively, while others comprised 26.2%. One case of L858R mutation coincided with T790M in exon 20 mutation. Detailed results divided by stages are presented in the Table. The occurrence of EGFR mutation had no significant influence on DFS and OS in patients after radical resection. Conclusions: The frequency of EGFR mutation in postoperative lung cancer was comparable to the occurrence in the general lung cancer population. EGFR mutation did not affect DFS and OS in patients after radical resection. [Table: see text]
Positive impact of academic center care on overall survival in malignant pleural mesothelioma (MPM): A National Cancer Database (NCDB) socioeconomic factor analysis.
Authors: Roof Logan , Wei Wei , Stevenson James 
Published: June 2022

8558 Background: MPM is a rare cancer with a poor prognosis. Median survival for untreated patients is 4-13 months, and for treated patients is 6-18 months. Despite asbestos regulations in the United States, annual deaths from MPM rose from 2,479 in 1999 to 2,597 in 2015. Given recent treatment advances, including improvements in multimodality therapy and the introduction of immunotherapy as a treatment option in the frontline setting, the impact that patient demographics and treatment factors have on survival outcomes for MPM requires further evaluation. Methods: We identified all patients with MPM in the NCDB from 2004 to 2017. Differences in demographic, disease, and treatment characteristics were assessed by year of diagnosis using Chi-square test. The effect of age, race, insurance status, income, distance to treatment center, and education level on overall survival (OS) was assessed by log-rank test. Results: There were 15,287 MPM diagnoses in the NCDB between 2004-2010 and 17,059 diagnoses between 2011-2017. OS improved between the two time periods, with median OS of 9.46 months (95% CI: 9.23-9.63) and 5-year OS rate of 8.3% (95% CI: 7.9-8.7%) in patients from 2004-2011 and median OS of 11.33 months (95% CI: 11.01-11.7) and 5-year OS rate of 12.4% (95% CI: 11.8-13.1%) in patients after 2011, despite an increase in stage IV disease in the latter group. Older patients (≥65 years-old), males, patients with stage IV disease, patients with government primary payer insurance, and patients from urban areas all had significantly worse OS. Patients without comorbidities and those treated at an academic center had significantly better OS. OS was found to significantly increase as both income and education level increase. Patients diagnosed after 2011 were significantly older, were more frequently female, had more stage IV disease, were more frequently treated at academic centers, more commonly had government primary payer insurance, and lived significantly further away from their treatment center. Patients’ time to treatment was significantly increased after 2011 (from 28 to 31 days). Conclusions: Socioeconomic factors play an important role in survival outcomes for patients with MPM. Many of these are linked with access to healthcare resources, which may increase the likelihood of evaluation at academic centers. For a rare malignancy such as mesothelioma, subspecialty care consisting of a comprehensive thoracic surgical evaluation and appropriate multimodality treatment are of great importance. Time to treatment increased during the study period yet OS improved, which our findings suggest are a result of an increase in evaluation and treatment at academic centers by providers skilled in delivering care to MPM patients.
Phase I clinical safety and preliminary efficacy of PD-1-mesoCAR-T cells in the treatment of malignant pleural/peritoneal mesothelioma.
Authors: Xu Qing , Liu Zhuqing , Xia Yong , Song Zongchang , Zhu Zhongzheng , Lin Zhicai , Wang Sitong 
Published: June 2022

8559 Background: Malignant pleural/peritoneal mesothelioma (MPM) is an aggressive cancer characterized by poor therapeutic response and poor survival. Programmed cell death protein-1 (PD-1)-mediated immunosuppression is believed to be associated with T cell exhaustion and dysfunction in solid tumors. We generated chimeric antigen receptor (CAR-T) cells that can secret PD-1 nanobodies and target mesothelin (PD-1-mesoCAR-T). After identifying the anti-tumor activity and cytotoxicity of PD-1-mesoCAR-T cells by pharmacokinetics and pharmacodynamics, we conducted a proof-of-concept clinical trial in the Shanghai Tenth People's Hospital affiliated to Tongji University and the Mengchao Tumor Hospital affiliated to Shanghai University to evaluate the safety and efficacy of PD-1-mesoCAR-T cells in a dose-escalation study for malignant pleural/peritoneal mesothelioma. 6 patients received one or more infusions of the CAR-T cells with prior lymphodepletion and the longest survival is up to 18 months. Methods: This open-label, single-arm, multicenter, phase 1 study was enrolled patients with pathological diagnosis with malignant mesothelioma whose mesothelin expression in immunohistochemical samples was equal or greater than 50%. Immunohistochemical samples derived from surgical tissue, puncture tissue or pleural effusion. PD-1-mesoCAR-T cells were administered intravenously ranging 1×106−1.5×107/kg. Safety and efficacy were assessed in response-evaluable patients (ie, patients who received at least one dose of PD-1-mesoCAR-T and had at least one post-baseline response evaluation). Results: From July 20, 2020 to January 31, 2022, 9 patients were screened and enrolled and only 6 patients were evaluable. Mesothelin positive rate in the samples of these patients were from 50% to 100%. Three patients of them had PD-L1 positive staining in specimen. All patients underwent lymphodepletion before infusion. Two of patients (33.3%) had cytokine release syndrome, which were grade 1 and grade 3, respectively. Four patients (66.7%) developed fever. Two patients (25%) had grade 3 pulmonary infection. Stable disease was sustained for ≥3 months in 5 patients; 1 exhibited complete response and one partial response on PET or CT scan. The objective response rate (ORR) was 33.3%, but increased to 66.7% in the patients with PD-L1 positive. Only one patient of these patients appeared progression of disease after infusion. All enrolled patients are alive and observed continually. Conclusions: The clinical study of 6 patients with malignant mesothelioma shows that PD-1-mesoCAR-T cells are safe and feasible, indicating a promising curative effect. Effect of the CAR-T cells on the long term survival will be observed continually. Clinical trial information: 01722149.
Safety and efficacy of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC): The results from a phase II single-arm trial.
Authors: Chen Dawei , Zou Bing , Meng Xiangjiao , Huang Wei , Shao Qian , Tang Xiaoyong , Guo Jun , Hu Xudong , Zhang Yan , Fu Lei , Jiajia Yuan , Yu Jinming , Wang Linlin 
Published: June 2022

8563 Background: Impower133 and CASPIAN studies showed that PD-L1 antibody combined with first-line chemotherapy could prolong the overall survival. Previous studies have shown that radiotherapy could potentially promote tumor antigen presentation and reverse immunosuppressive microenvironment in tumor. The purpose of this study was to explore the efficacy and safety of SHR-1316 (PD-L1 antibody) combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Patients (pts) included in this study received 4̃6 cycles of SHR-1316 (20mg/kg, D1, q3w) combined with EP/EC (cisplatin 75mg/m² D1-3 q3w or carboplatin AUC = 5, D1 q3w; etoposide 100mg/m2, D1-5, q3w), sequentially SHR-1316 combined with chest radiotherapy (≥3Gy*10f or ≥2Gy*25f, involved- field irradiation), and then entered the maintenance treatment stage until disease progression or intolerable side effects. The main endpoints included PFS, ORR and safety. Results: From October 2020 to December 2021, 31 pts with ES-SCLC received at least one dose of SHR-1316. The median age was 64 (range: 37-75) with 25(80.6%) male, 22(71%) former smokers and 31 (100%) ECOG performance status 1. 17 (54.8%) pts were with brain metastasis, 8 (25.8%) pts with liver metastasis, 8 (25.8%) pts with kidney/adrenal metastasis, 7(22.6%) pts with bone metastasis. At the data cutoff date, 15 pts remained on treatment, the average number of treatment cycles was 5.19. 24 pts had at least one 1 post-treatment tumor assessment. The median PFS was 7.56 months, the confirmed ORR and DCR in all pts were 50% (12/24) and 87.5% (21/24), respectively. The confirmed ORR and DCR in pts with brain metastasis were 38.5% (5/13) and 76.9% (10/13), and were 63.6% (7/11) and 100% (11/11) in pts without brain metastasis. In pts received chest radiotherapy, the confirmed ORR and DCR were 80% (8/10) and 100% (10/10). During the study period, 23 (74.2%) pts had adverse drug reactions, and 16 (51.6%) pts had grade 3 or 4 adverse drug reactions, including 12 (38.7%) neutropenia 8 (25.8%) leukopenia, 2 (6.5%) thrombocytopenia, 2 (6.5%) anemia, 1(3.2%) lymphocytopenia, 1(3.2%) amylase increased. No grade 5 adverse drug reaction was observed. Conclusions: SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. It is worthy of further clinical exploration. Clinical trial information: NCT04562337.
Impact of underrepresented populations on clinical outcomes of chemo-immunotherapy for extensive-stage small cell lung cancer: Real-world prospective cohort study.
Authors: Tamiya Motohiro , Fujimoto Daichi , Akamatsu Hiroaki , Morimoto Takeshi , Hata Akito , Matsumoto Hirotaka , Nakamura Atsushi , Oya Yuko , Amimoto Hisanori , Daga Haruko , Ikeda Hideki , Sakata Shinya , Suzuki Hidekazu , Ikeda Satoshi , Harutani Yuhei , Hiraoka Ryota , Yanai Masaaki , Hamamoto Yoichiro , Yamamoto Nobuyuki 
Published: June 2022

8567 Background: Chemo-immunotherapy is the standard 1st-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). Prospective data about underrepresented populations outside the clinical trial such as elderly or poor risk has not been revealed. Methods: We conducted a 32-hospitals prospective cohort study of consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as 1st-line therapy between September 2019 and September 2020. The primary outcome was 6-months progression-free survival (PFS) probability of all patients. The secondary outcomes were overall survival (OS), PFS, time to treatment failure, objective response rate, safety, and differences in efficacy and safety depending on whether or not the key eligible study criteria of previous trials are met. Results: In total, 207 patients with ES-SCLC were analyzed. The median age was 72 years, and 64 patients (31%) were elderly (≥75 years). Most patients (89%) had a performance status (PS) of 0 or 1. As a result, 132 (64%) was categorized as eligible patients. The 6-months PFS probability of all patients was 38.8 % (95%CI:32.4-45.7%). Between eligible and ineligible patients, there was significant difference of patients who attained disease control (93% versus 77%, p = 0.002). Median PFS was significantly longer in eligible patients than ineligible patients (5.1 vs. 4.7 months; P =.03, HR 0.72 (95% CI 0.53–0.97)), and median OS was longer in eligible patients than ineligible patients, without any significant difference (15.8 vs. 13.1 months; P =.10, HR 0.73 (95% CI 0.51–1.07)). Survival analysis identified a PS score of 0-1 (HR: 0.60, 95% CI: 0.39-0.97, p = 0.03) as a significant predictor of better PFS, while PS score of 0-1 (HR: 0.51, 95% CI: 0.31-0.89, p = 0.01) and younger patients ( < 75 years) (HR: 0.66, 95% CI: 0.45-0.97, p = 0.03) as significant-good predictor of OS. The rate of severe AEs was higher in ineligible patients than in eligible (39% vs. 27%, respectively; p = 0.07), although the difference was not significant. Older age was significantly associated with severe AEs (p = 0.049). Conclusions: The real-world efficacy of chemo-immunotherapy for ES-SCLC was similar to that of pivotal clinical trials. However, trial-ineligible patients with ES-SCLC had poor treatment outcome and the higher rates of severe adverse events in this prospective cohort study. Our study suggests that positive results among the trial eligible patients may not translate to ineligible patients. Clinical trial information: UMIN000038064.
Adverse events self-reported by patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) treated with durvalumab (D) plus platinum-etoposide (EP) or EP in the CASPIAN study.
Authors: Özgüroğlu Mustafa , Goldman Jonathan W. , Chen Yuanbin , Garassino Marina Chiara , Medic Nenad , Mann Helen , Chugh Priti , Dalvi Tapashi , Paz-Ares Luis G. 
Published: June 2022

8571 Background: The CASPIAN phase 3 study established D+EP as a global standard of care in ES-SCLC. Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to complement standard adverse event (AE) reporting in oncology trials. Here we describe patient-reported symptomatic AEs using PRO-CTCAE in CASPIAN, the first time the PRO-CTCAE tool has been piloted in SCLC research. Methods: In CASPIAN, treatment-naïve pts (WHO PS 0/1) with ES-SCLC received 4 cycles of D+EP q3w followed by maintenance D q4w until progressive disease (PD), or up to 6 cycles of EP q3w. As part of exploratory analyses, where validated local language versions were available (in English, German, Japanese or Spanish), pts were asked to complete the PRO-CTCAE by e-device at baseline, q3w during EP (in both arms), then q4w until PD, followed by day 28 post-PD, 2 months post-PD, and q8w until second progression/death. Presence/absence, frequency or severity were examined during the first 24 weeks after starting treatment across 11 AEs selected as being relevant to pts with ES-SCLC (Table). Results: In total, 164 of the 537 pts randomized to D+EP and EP in CASPIAN (31%; D+EP: 83; EP: 81) were asked to complete the PRO-CTCAE. At baseline, the PRO-CTCAE was completed by 84% of these pts in the D+EP arm and 81% in the EP arm; compliance rates > 60% were achieved up to cycle 32 for D+EP and cycle 6 for EP. Examined AEs were reported by a minority of pts before starting treatment in both arms (range D+EP vs EP: 4% vs 3% for hand-foot syndrome to 34% vs 41% for dry mouth). Baseline AE rates were generally maintained in both arms up to 24 weeks after starting treatment, except for itchy skin, which showed a numerical increase from 13% at baseline to a peak of 34% at cycle 6 in the D+EP arm and 12% at baseline to a peak of 42% at cycle 8 in the EP arm; and dizziness, which showed a numerical increase from 16% at baseline to a peak of 40% at cycle 5 in the D+EP arm, while rates were maintained vs baseline in the EP arm. Most pts reporting these AEs indicated that they occurred rarely or occasionally, or were mild or moderate in severity. Conclusions: Self-reported data from pts in CASPIAN showed that the 11 AEs examined during the 24 weeks after starting treatment were reported by a minority of pts, mostly with rare or occasional occurrence, and mild to moderate severity. Rates and patterns of AEs over time were broadly similar in the D+EP and EP arms. These results complement the CASPIAN safety profile and give insight into pts’ experience of treatment. Clinical trial information: NCT03043872. [Table: see text]