bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intraoperative quality metrics and association with survival following lung cancer resection.
Authors: Heiden Brendan , Eaton Daniel B. , Chang Su-Hsin , Yan Yan , Schoen Martin W. , Meyers Bryan F. , Kozower Benjamin D. , Puri Varun 
Published: June 2022

8502 Background: Surgical resection remains the preferred treatment for functionally fit patients with clinical stage I non-small cell lung cancer (NSCLC). Process-based intra-operative quality metrics (QMs) are important for optimizing long-term outcomes following curative-intent resection. We sought to characterize overall survival using a novel surgical quality score. Methods: We performed a retrospective cohort study using a uniquely compiled dataset of US Veterans with clinical stage I NSCLC receiving definitive surgical treatment. Based on contemporary treatment guidelines, we defined five surgical QMs: timely surgery (within 12 weeks of diagnosis), minimally invasive approach, anatomic resection via lobectomy, adequate nodal sampling (≥10 nodes), and negative margin. Using a multivariable Cox proportional hazards model, we developed a surgical quality score reflecting the relationship between these QMs and overall survival (OS). We also examined the relationship between this score and disease-free survival (DFS). Results: The study included 9,628 Veterans undergoing surgical treatment between 2006 and 2016. QMs were met as follows: timely surgery (n=6,633, 68.9%), minimally invasive approach (n=3,986, 41.4%), lobectomy (n=6,843, 71.1%), adequate nodal sampling (n=3,278, 34.1%), and negative surgical margin (n=9,312, 96.7%). The median (IQR) follow-up was 6.2 (2.5-11.4) years. A normalized score from 0 (no QMs met) to 100 (all QMs met) was constructed, with higher scores reflecting progressively improved risk-adjusted OS (Table). The median (IQR) OS was 86.8 (37.8-149.6) months in the highest score quintile versus 25.3 (7.1-45.8) months in the lowest score quintile. Recurrence was detected in 2,268 (23.6%) patients. Higher surgical quality score was associated with improved DFS (multivariable-adjusted hazard ratio, aHR 0.494, 95% CI 0.245-0.997). Conclusions: Adherence to intra-operative QMs is associated with markedly improved overall and disease-free survival. Efforts to improve adherence to surgical QMs can dramatically improve patient outcomes following curative-intent resection of early-stage lung cancer. [Table: see text]
Targeting genomic instability in extrapulmonary small cell neuroendocrine cancers: A phase II study with ATR inhibitor berzosertib and topotecan.
Authors: Takahashi Nobuyuki , Desai Parth Anil , Sciuto Linda , Nichols Samantha , Steinberg Seth M. , Thomas Anish 
Published: June 2022

8518 Background: Extra-pulmonary small cell neuroendocrine cancers (EP-SCNC) are rare cancers with no standard treatments at relapse that share molecular similarities with small cell lung cancer (SCLC). Concurrent inhibition of ataxia telangiectasia and Rad3 related (ATR) and topoisomerase 1, key enzymes for maintaining genomic stability, exacerbated replication stress in SCLC cells and produced durable antitumor responses in patients with relapsed SCLC (Cancer Cell 2021; PMID: 33848478). Methods: Combination of berzosertib and topotecan was evaluated in patients with relapsed EP-SCNC (NCT02487095). Berzosertib was administered at 210 mg/m2 on days 2 and 5 and topotecan 1.25 mg/m2 on days 1-5 in 21-day cycles. Whole exome sequencing (WES) and transcriptome analyses were performed to assess the genomic features associated with response. Results: Fifteen patients with EP-SCNC involving various primary sites were enrolled [three each: cervix, transformed SCLC; two each: bladder, breast, prostate; one each: gallbladder, ovary, rectum]. Two patients (13.3%: breast and rectum) achieved a confirmed partial response (PR; -72.2% and -48.5% tumor reduction in size) lasting 6.9 and 5.8 months. Responses occurred irrespective of platinum-sensitivity or prior treatment with topotecan or immunotherapy. Pre-treatment tumor gene expression profiles of EP-SCNC patients who achieved clinical benefit revealed enrichment of neuroendocrine differentiation (normalized enrichment score and p-value of a gene set enrichment analysis: 2.1 and 2.1 x 10-4). Principal component analysis showed convergent gene expression profiles of both SCLC and EP-SCNC patients who achieved PR. Pre-treatment tumor of a breast small cell cancer patient who achieved durable response revealed amplifications of multiple genes driving replication stress such as KRAS and CCND1. Longitudinal tumor sampling of the patient through treatment course revealed increasing intra-tumor heterogeneity as a potential resistant mechanism. Conclusions: Combination of berzosertib and topotecan is a novel therapeutic paradigm for patients with EP-SCNCs. Both SCLCs and EP-SCNCs responding to this approach show a similar transcriptional phenotype characterized by high replication stress. Clinical trial information: NCT02487095.
Driver coexistence characteristics of ALK-fusion in Chinese patients with lung cancer.
Authors: Gao Min , Fang Yu , Zhang Xiaoyan , Wang Bin , Wang Meng , Hua Li , Ma Tonghui 
Published: June 2022

8530 Background: ALK fusions and other driver mutations are usually mutually exclusive. With the widespread application of genetic testing techniques, the coexistence of ALK fusions and other driver mutations could be detected, such as ALK fusion and EGFR driver mutations. However, there were no systematical studies about the coexistence of ALK fusions and other driver mutations. Here, we retrospectively investigated the coexistence of ALK fusions and other driver mutations. Methods: Samples with ALK fusions were extracted from a Chinese lung cancer cohort, which from OncoPanscan (Genetron Health) based sequencing of tissue. Driver mutations of EGFR, ROS1, RET, NTRK1/2/3, BRAF, MET, KRAS and ERBB2 could be detected. Results: In the cohort, 692 samples with ALK fusions contained the intact kinase domain. These samples could be classified into three forms: canonical fusions (only EML4 partner, n = 601), single non-canonical fusions (only non- EML4 partner, n = 51) and complex non-canonical fusions (two or more partners, n = 40). Among the 692 samples, only 20 samples (20/692, 2.89%) coexisted with other driver mutations, which indicated that the driver coexistence were rare. 70% (14/20) of driver coexistence were happened on canonical fusions ( EML4-ALK) samples. They were coexisting with EGFR L858R (3), EGFR L858R plus ROS1 fusion (1), EGFR L858R plus MET amplification (1), KRAS G12C/D/V (3), MET amplification (3), MET Exon14 skipping (1), ERBB2 amplification (1), and MET amplification plus ERBB2 amplification (1), respectively. 20% (4/20) of driver coexistence samples were single non-canonical ALK fusions coexisting with EGFR 19del (1) or 20ins (1) or L858R (1) or MET amplification (1). Another 10% (2/20) samples were complex non-canonical ALK fusions coexisting with EGFR G719S (1) or RET fusion (1). Most co-mutations have corresponding targeted inhibitors, maybe these patients can be treated by combined or sequential therapies. Among canonical fusions, single non-canonical fusions and complex non-canonical fusions of ALK, the frequency of the samples without coexistence of driver mutations was respectively 97.67% (587/601), 92.16% (47/51), 95.00% (38/40), without significant difference (P = 0.056). Maybe single/complex non-canonical fusions are also strong drivers as canonical fusions. Conclusions: In this cohort, very few of ALK fusion patients coexisted with other driver mutations. Among the co-existence samples, ALK fusion were mainly coexisting with the site mutations of EGFR and KRAS, amplifications of MET and ERBB2, fusions of ROS1 and RET. These samples maybe obtain more effective outcomes by combined or sequential therapies.
Prognostic role of preoperative chemosensitivity in patients with non–small cell lung cancer (NSCLC) treated with preoperative chemotherapy: A study of National Cancer Database (NCDB).
Authors: Deng Lei , Jiang Changchuan , Perimbeti Stuthi , Chen Hongbin 
Published: June 2022

8538 Background: Response to preoperative systemic therapy may provide valuable information regarding tumor biology and prognosis. This is increasingly relevant nowadays considering the promising results from preoperative chemoimmunotherapy. This study aims to examine the prognostic role of preoperative chemosensitivity defined by TNM stage change in NSCLC. Methods: Patients with histologically confirmed clinical stage II-III NSCLC who have received preoperative chemotherapy followed by R0 curative surgery were identified in the NCDB between 2006 and 2017. Patients who have developed metastasis at the time of surgery, received any perioperative radiotherapy or single agent chemotherapy, or died within 90 days of surgery, were excluded. Preoperative chemosensitivity is categorized as ypT0N0, downstaged (pTNM < cTNM, excluding ypT0N0), and not downstaged (pTNM ≥ cTNM). Logistic regression was used to evaluate associations between chemosensitivity and demographic, clinical, and pathological factors. Log-rank was used for survival analysis and adjusted by cox regression for age, gender, race, year of diagnosis, academic center, insurance, comorbidity, histology, and clinical stage. Results: A total of 1266 patients were included, of whom 104 (8.2%) had ypT0N0, 575 (45.4%) were downstaged, while 587 (46.4%) were not. Female, diagnosis in recent years, treatment at academic centers, and squamous histology were significantly associated with better chemosensitivity, while clinical TNM stage, age, race, and comorbidity were not. Five-year overall survival rate is 81.2%, 57.7%, and 46.2%, respectively (log-rank p < 0.001). After Cox regression adjustment, compared with not downstaged, ypT0N0 (HR 0.28, 95% CI 0.17 – 0.45) and downstaged (HR 0.61, 95% CI 0.51 – 0.74) were independently associated with improved postoperative survival. Conclusions: Preoperative chemosensitivity defined by TNM stage change before and after chemotherapy may prognosticate NSCLC after curative surgery. It may be a useful clinical tool to identify patients with high risk of treatment failure after neoadjuvant chemoimmunotherapy in the future.[Table: see text]
Association of the KRAS genotype and clinicopathologic findings of resected non–small cell lung cancer.
Authors: Oya Yuko , Masago Katsuhiro , Matsushita Hirokazu , Kuroda Hiroaki 
Published: June 2022

8545 Background: This study assessed the clinicopathological background of early-stage KRAS-mutated non-small-cell lung cancer and analyzed the biological process of KRAS-mutated tumor using an RNA sequencing procedure. Methods: We used a cohort of consecutive series of 179 surgically resected early-stage non-small-cell lung cancers harboring KRASmutations and analyzed the clinicopathological features, including the KRAS genotypes, affecting the recurrence-free survival and prognosis. Consequently, we performed RNA sequencing to determine the gene expression profiles of nineteen KRAS-mutated non-small-cell cancers. Results: The most common KRAS genotype was p.G12C (57; 31.8%). A high p-stage (hazard ratio [HR], 4.181; P < 0.0001) and solid predominant adenocarcinoma histology (HR, 2.343; P = 0.0076) were significant independent prognostic factors for the recurrence-free survival. A high p-stage (HR, 3.793; P < 0.0001), solid predominant adenocarcinoma histology (HR, 2.373; P = 0.0147), and KRAS p.G12V genotype (HR, 1.975; P = 0.0407) were significant independent prognostic factors for the overall survival. A gene expression analysis of the two factors revealed the p.G12V genotype to be closer to those of stem cells, and the traits of e an enhanced fatty acid and amino acid metabolism as well as a solid predominant phenotype were shown to an acquired a trait that can withstand hypoxia and the effect of prostaglandin-endoperoxide synthase Conclusions: The KRAS p.G12V genotype and solid predominant adenocarcinoma phenotype may be independent predictive factors of a poor clinical course in resected early-stage non-small-cell lung cancers, possibly due to the differentiation tendency observed in stem cells, the trait of an enhanced fatty acid and amino acid metabolism, and the effect of prostaglandin-endoperoxide synthase.
Treatment interruptions and discontinuations among patients with stage III unresectable non–small cell lung cancer treated with durvalumab at the Veterans Health Administration.
Authors: Alkadimi Munaf , Moore Amanda , Frei Christopher R , Reveles Kelly R , Brannman Lance , Cotarla Ion , Frankart Andrew , Mulrooney Tiernan , Datta Paromita , Whitehead Jennifer , Franklin Kathleen , Reichelderfer Renee , Williams Madison H. , Williams Ryan A. , Smith Sarah Allison , Jones Xavier , Nooruddin Zohra 
Published: June 2022

8554 Background: The PD-1/PD-L1 pathway is a mechanism of immune evasion and disruption of this pathway with immune checkpoint inhibitors (ICIs) has shown clinical benefit in multiple malignancies. Based on results from the PACIFIC trial, durvalumab is approved as consolidation therapy in patients (pts) with stage III unresectable non-small cell lung cancer (UR-NSCLC) without progression following concurrent chemoradiotherapy (cCRT). Durvalumab has been used extensively in Veterans Health Administration (VHA) facilities, providing an opportunity to evaluate durvalumab treatment interruptions (TI), treatment discontinuations (TD), and the reasons for these on a national scale. Methods: Patients with stage III UR-NSCLC receiving durvalumab consolidation immunotherapy at the VHA between January 1, 2017 and June 30, 2020 with a minimum follow up for 12 months were included using ICD-10, HCPCS, and J codes and followed from their durvalumab start date through the earliest of last VHA visit, loss to follow up, death, or end of study (excluded if durvalumab therapy was ongoing at the end of the study, because the full treatment course could not be determined). TI were defined as durvalumab infusions separated by >28 days. Reasons for TI and TD are presented descriptively. Durations are reported using medians and interquartile ranges (IQR). Results: 935 pts were included (median age = 69 years; 95% males; 96% current or former smokers; 70% with COPD; histologies [squamous (50%), non-squamous (43%), other/missing (7%)]; and 77% with carboplatin-paclitaxel as their platinum-based CRT). Durvalumab TI were experienced by 19% of pts (median [IQR] number of TI = 1 [1-1], median [IQR] TI duration = 53 days [39-90]). The main reasons for TI were toxicity (8%) and social reasons (3%) (Table). The median duration of treatment (DoT) with durvalumab (TI included) was 9.0 months (IQR 2.9-11.8). Durvalumab TD occurred in 59% of pts. Top reasons for discontinuation across all 935 pts included disease progression (24%) and toxicity (18%) (Table). Conclusions: In this real world analysis of national VHA data, durvalumab DoT was similar to PACIFIC despite having a patient population with worse prognostic factors (e.g. more males, squamous, COPD) with 8% of VHA pts experiencing TI and 18% TD due to toxicity. Patients could benefit from additional efforts to prevent, identify, and manage toxicities in the UR-NSCLC population [Table: see text]
Durvalumab treatment initiation delays in patients with unresectable stage III non–small cell lung cancer treated at Veterans Health Administration facilities.
Authors: Datta Paromita , Moore Amanda , Frei Christopher R , Reveles Kelly R , Brannman Lance , Cotarla Ion , Frankart Andrew , Mulrooney Tiernan , Alkadimi Munaf , Whitehead Jennifer , Franklin Kathleen , Reichelderfer Renee , Williams Madison H. , Williams Ryan A. , Smith Sarah Allison , Jones Xavier , Nooruddin Zohra 
Published: June 2022

8556 Background: Durvalumab is an FDA-approved immunotherapy for the treatment of adults with UnResectable stage III non-small cell lung cancer (UR-NSCLC) without disease progression following concurrent chemoradiotherapy (CRT). There are limited real-world data regarding Durvalumab treatment initiation delays (TIDs) and reasons for them in the UR-NSCLC population. Methods: Patients with stage III UR-NSCLC receiving consolidation Durvalumab at the Veterans Health Administration (VHA) between January 1, 2017 and June 30, 2020 were selected from the VHA database using ICD-10, HCPCS, and J codes. All had the opportunity to be treated for 12 months and were followed from Durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or the study’s end (and excluded if Durvalumab therapy was ongoing at the study’s end). Trained data abstractors determined the occurrence and reasons for TIDs (> 6 weeks from end of CRT to initiation of Durvalumab as in the PACIFIC trial) by chart review. Results: 935 patients were eligible for analysis (median age = 69 years; 95% males; 16% with ECOG performance status >1). TIDs occurred in 39% of the patients (Table). Durvalumab was initiated 61 days (median) from the end of CRT in TID patients vs. 31 days for those without TIDs. There were no significant (α<0.05) differences in age, race, smoking status, histology, or ECOG performance status and no comorbidity differences (except in patients with a history of cerebrovascular accident, for whom TIDs were more likely) between the TID/No-TID patients. Patients without timely post-CRT scans were more likely to have a TID. Of the 367 patients who experienced TIDs, 200 had documented reasons for the delay, consisting of other (not categorized) (28.5%), physician preference (20%), toxicity (11%), patient preference (10.5%), decline in performance status (10%), system issues (9.5%), social reasons (9%), and progression (0.5%). Conclusions: This is one of the largest retrospective cohort studies reporting real-world data in patients with UR-NSCLC receiving Durvalumab. TIDs were associated with increased time to post-CRT scans. This potential issue can be improved with care coordination and involvement of cancer navigators. Additional studies are needed to assess the impact of TIDs on survival outcomes.[Table: see text]
Atezolizumab and bevacizumab in patients with relapsed mesothelioma: MIST4—a phase IIa trial with cellular and molecular correlates of efficacy.
Authors: Fennell Dean Anthony , King Amy , Branson Amy , Barber Shaun , Greystoke Alastair , Dulloo Sean , Poile Charlotte , Harber James , Scotland Molly , Darlison Liz , Bajaj Amrita , Morgan Bruno , Brookes Cassandra , Wells-Jordan Peter , Richards Catherine Jane , Thomas Anne 
Published: June 2022

8560 Background: Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM) however the factors that determine sensitivity are unknown. Combined inhibition of vascular endothelial growth factor (VEGF) may potentiate efficacy through remodelling of the tumour microenvironment and inhibition of angiogenesis. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis and to uncover cellular and molecular determinants of efficacy as arm 4 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST4). Methods: Patients with any histological subtype or site of MM (pleural or peritoneal) were enrolled. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Atezolizumab 1200mg iv q3w with bevacizumab 15mg/kg iv q3w (AtzBev). Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Baseline BAP1, p16ink4a, PD-L1 (DAKO22C3), gut microbiome 16s RNA metagenomics, multiplex immunofluorescence, and whole exome and RNA transcriptome sequencing was conducted to explore cellular and molecular correlates of sensitivity. Results: Between January 2020 and February 2021, 26 patients with MM started treatment and received at least one dose of AtzBev. The median age of pts was 68 (range, 44-80) years, 69% were male, 77% epithelioid, 85% ECOG PS1, > 1 prior systemic therapy 54%. The median cycles of Atz dosing was 4.5 (IQR, 2-8) and Bev dosing was 4.5 (IQR, 2-7). DCR12w: 53.8% (95% confidence limit (CI), 33.4% – 73.4%), DCR24w: 23.1% (95%CI, 9.0% – 43.6%). Best responses (evaluable within 24w): partial – 3.8% (95%CI, 0.1- 19.6%); stable disease – 69.2% (48.2 – 85.7%); progression – 15.4% (4.4 – 34.9%). Adverse events (any cause): ≥ grade 3 toxicities affected 35% of pts. Conclusions: MiST4 met its primary endpoint however responses were heterogeneous. Analysis of cellular and molecular correlates are ongoing and will be presented. Clinical trial information: NCT03654833.
Exploratory analysis using cfDNA-based fragmentomics to predict disease recurrence in limited disease small cell lung cancer.
Authors: Park Sehhoon , Kang Jun-Kyu , Kim Hwang-Phill , Kim Su Yeon , Lee Naeun , Jung Hyun Ae , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Lee Se-Hoon 
Published: June 2022

8569 Background: The current standard of care (SOC) for limited disease (LD) small cell lung cancer (SCLC) is definitive concurrent chemoradiotherapy (CCRT). Despite the high response rate to SOC, up to 70% of the patients potentially experience disease recurrence and fail to show the prolonged clinical benefit. We investigated the feasibility of cell-free DNA (cfDNA) based genomic alteration and fragmentomic analysis using pre-and post-treatment samples to investigate the predictive value of disease recurrence in LD-SCLC. Methods: The blood sample from fifty LD-SCLC who were treated with definitive CCRT were collected before and after the treatment. Target sequencing, AlphaLiquid scan (IMBdx, Korea), composed of 106 target genes, was conducted using cfDNA and peripheral blood mononuclear cells. Based on the recurrence-free survival (RFS) interval of 12 months, patients were categorized into group with persistent response (PeR, n = 29) and non-PeR (n = 21). Fragmentomics analyses were collected using the proportion of cfDNA fragments sized in P1 (100 – 155 bp) and P2 (160 – 180 bp) ranges. Results: Initial analysis was conducted based on the gene of interest. Patients with RB1 mutation (n = 11) detected in follow-up sample demonstrated significant shorter RFS compared to the RB1 wild type (WT) patients (n = 39) (7.9 mon. vs. NR, P = 0.002). Among the patients who were available for our fragmentomics analysis in follow up samples (n = 19), non-PeR (n = 9) group were significantly high in P1 range ( P = 0.003) and low in P2 range ( P = 0.002) compared to PeR group (n = 10). AUCs using the fragment proportion in P1, proportion in P2, and the fragmentation ratio (proportion in P1 / proportion in P2), were 0.889, 0.911, and 0.889, respectively. The survival analysis using fragmentation ratio showed significantly longer RFS in fragmentation ratio low group compared to the high group (7.6 mon. vs. NR, P = 0.002). Integrating RB1 mutation status with fragmentation ratio, patients with both RB1 WT and fragmentation ratio low (n = 9) showed the most favorable outcomes ( P = 0.006). On the contrary, patients with either RB1 mutated or high in fragmentation ratio (n = 10) showed median RFS of rest than 12 months. Conclusions: In this study, we investigated the clinical feasibility of cfDNA detected mutation and size of the fragment in disease recurrence of LD-SCLC using the sample collected before and after definitive CCRT. It is observed that patients with either RB1 mutation or high fragmentation ratio detected from cfDNA after the completion of CCRT are likely to experience early disease recurrence. Our findings suggest that cfDNA could provide supplementary information in predicting early treatment failure and support the clinical decision in selecting high-risk patients who might need intense monitoring and additional consolidative treatment.