bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of DLL3-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) and evaluation of their clinical relevance during front-line treatment.
Authors: Messaritakis Ippokratis , Nikolaou Michail , Koinis Filippos , Politaki Eleni , Koutsopoulos Anastasios , Lagoudaki Eleni , Georgoulias Vassilis , Kotsakis Athanasios 
Published: March 2020

e20086 Background: The aim of the study was to characterize and evaluate the presence of DLL3-positive Circulating Tumor Cells (CTCs) in SCLC patients receiving front-line chemotherapy and assess their clinical relevance. Methods: Peripheral blood was obtained from treatment-naïve patients with SCLC (n = 108 patients), after one-etoposide/platinum cycle (n = 68 patients) and on disease progression (n = 48 patients). CTCs were detected after immunofluorescence staining using antibodies against the DLL3, cytokeratins (CK), CD45 and vimentin (Vim). Results: Before treatment, 74.1% of patients had detectable CTCs (DLL3+/CD45-). One-treatment cycle significantly decreased both the detection rate of DLL3+/CD45- CTCs ( p< 0.001) and their absolute number ( p< 0.001). Triple immunofluorescence staining using anti-CK, anti-Vim and anti-DLL3 antibodies revealed an important CTC heterogeneity since DLL3 could be detected in Vim+, Vim-, CK+ and CK- CTCs. On disease progression, both the detection rate of DLL3+/CD45- CTCs as well as their number were significantly increased compared to post-1st cycle values ( p< 0.001 and p= 0.002, respectively). In addition, 22.7% of patients had detectable DLL3+/CD45- cells which could not be captured by the CellSearch assay. In multivariate analysis, the detection of DLL3+/CD45- CTCs at baseline was significantly associated with decreased progression-free survival (HR = 10.8; p= 0.005) whereas their detection on disease progression was associated with decreased overall survival (HR: 28.2; p= 0.016). Conclusions: These findings demonstrate an important heterogeneity of CTCs, based on the expression of CK, Vim and DLL3, in patients with SCLC and the changes of DLL3+/CD45- CTCs during treatment seem to be a dynamic biomarker associated with treatment efficacy and patients’ clinical outcome.
Proteomics analysis discovers biomarkers in serum months to years before small cell lung cancer: The HUNT study.
Authors: Nguyen Olav Toai Duc , Markaki Maria , Chatzipantsiou Christina , Sharma Animesh , Lagani Vincenzo , Tsamardinos Ioannis , Røe Oluf D. 
Published: March 2020

e20095 Background: The high incidence and high mortality rate of small-cell lung cancer (SCLC) calls for identification of methods for early diagnosis. Searching of cancer-related proteins and proteins signature in biofluids is an emerging approach in early diagnostic of malignancies. In the present study we have used proteomics-based profiling of serum collected 2 months to 5 years before SCLC diagnosis to search for early diagnostic biomarkers. Methods: All serum samples in this study were obtained from the Nord-Trøndelag Health Study (HUNT) Research Centre’s Biobank. Discovery sample set (Cohort I): Serum samples from 12 individuals that subsequently developed SCLC and 12 matched controls were obtained. Validation sample set (Cohort II): Serum samples from 5 future SCLC patients and 5 matched controls were obtained. The serum samples in both cohorts were collected in a time frame of 2 months to 5 years before diagnosis. All controls included in the study were matched to the cases for smoking status (pack years and quit time), gender and age, and were cancer-free at least 5 years before blood sampling. All subjects were smokers or ex-smokers. Twenty (20) µl of serum was depleted of its high-abundant proteins and the cleaned-up peptides were analysed by LC- MS with an Orbitrap Elite mass spectrometer. Data were processed/analysed using MaxQuant software. Using Cohort I as training set, proteins most related to diagnosis were identified at first with limma univariate analysis. Reference and equivalent signatures were identified using JADbio with SES as feature selection algorithm. The JADbio matched pipeline with 50 repetitions for performance assessment (AUC with 95% CI) was used. Results: In each serum sample the analysis detected 435 proteins in Cohort I and 609 proteins in Cohort II. Reference signature for 12 SCLC future cases vs 12 matched controls had a conservative AUC of 0.686 (95% CI: 0.557, 0.765) in the discovery cohort. Three proteins in the reference and equivalent signatures were also found to be differentially expressed in validation Cohort II; all three proteins discriminated small-cell lung cancer patients from their respective controls (AUC 0.757-0.826 in the discovery Cohort I and AUC 0.68-0.84 in the validation Cohort II). Conclusions: The results indicate that differential levels of a few proteins in serum may help detecting SCLC 2 months to 5 years prior to clinical diagnosis. This is one of the first large-scale proteomics screening studies of pre-diagnostic serum of future SCLC patients. Further validation studies are in progress.
KMT2C mutation associated with tumor mutational burden in small cell lung cancer.
Authors: Gu Weiguang , Wang Hongbiao , Li Kunsong , Wei Ge , Zhang Junkai , Zhang Shiyue , Zhang Lin , Shi Xiaoliang , Liu Angen 
Published: March 2020

e20098 Background: Immune checkpoint inhibitors are used to treat small cell lung cancer (SCLC). Tumor mutational burden (TMB) emerges as a promising predictor of immunotherapy efficacy, but the relationship between TMB and genetic features of SCLC remains unclear. In this study, we explored the correlation between genetic profiles and TMB in SCLC. Methods: FFPE tumor and matched blood samples were collected from 119 SCLC patients for panel targeted based next-generation sequencing. Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. Results: This study enrolled 114 SCLC and 5 mixed SCLC patients (91 males and 28 females) with a median age of 59 years. Median TMB was 9.3 muts/Mb (25% quantile: 6.3 muts/Mb, 75% quantile: 13.2 muts/Mb). For all patients, 31 (26%) had low TMB (≤6.3 muts/Mb), 55 (46%) had intermediate TMB (6.4-13.1 muts/Mb), and 33 (28%) had high TMB (≥13.2 muts/Mb). KMT2D mutations (mut), included substitution/indel (6/25) and truncation (19/25). KMT2D exhibited substitution/indel (6/25) and truncation (19/25) mutations in 19% of SCLC tumors while KMT2C exhibited substitution/indel (11/17), gene homozygous deletion (1/17) and truncation (5/17) mutations in 12% of SCLC tumors. Tumors with KMT family gene mut (KMT2C and KMT2D) (n = 33) had higher TMB (11.7 vs. 8.5 muts/Mb, p = 0.009). KMT2C mut tumors had higher TMB than KMT2C wildtype (wt) tumors (15.2 vs. 9.2 muts/Mb, p = 0.0036). TP53 mut occurred in 86% of KMT2C mut tumors and KMT2C/TP53 co-mutated tumors had higher TMB than KMT2C wt/TP53 mut tumors (17.8 vs. 9.3 muts/Mb, p = 0.0035) or KMT2C wt/TP53 wt tumors (17.8 vs. 5.4 muts/Mb, p = 0.027). Conclusions: Our data indicates that KMT family genes were frequently mutated in SCLC. KMT2C mut positively correlated with higher TMB and KMT2C co-mutated with TP53 or FAT1 may have a synergic effect on TMB. Our study explored a novel relationship between GAs and TMB that may greatly improve immunotherapeutic strategies for SCLC.
Early assessment of therapy response in non-small cell lung cancer (NSCLC) via longitudinal ctDNA analysis.
Authors: Ma Xiaoju Max , Ju Christine , Woestmann Corinna , Xi Liu , Yaung Stephanie J. , Hinzmann Bernd , Thomas Michael , Heussel Claus Peter , Lasitschka Felix , Meister Michael , Schneider Marc , Herth Felix , Muley Thomas , Wehnl Birgit , Palma John F. 
Published: March 2020

e20701 Background: Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. Despite disease heterogeneity in NSCLC, we set out to identify a broadly applicable ctDNA-based method for disease monitoring. By employing plasma taken during early treatment cycles, we tested whether early response assessed by ctDNA level could predict treatment effect. Methods: Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), we measured ctDNA levels in post-treatment plasma samples based on variants identified at baseline. We used samples from an observational German Lung Cancer Multi-Marker Study. In a cohort of 83 stage IV lung adenocarcinoma treated with first-line chemo or chemoradiation therapies, we evaluated the association between survival and ctDNA levels in the first available post-treatment plasma sample (median number of days after start of treatment = 23). We used a ctDNA-based monitoring algorithm, and applied it to an independent set of 22 late stage lung squamous cell carcinoma (SCC) that also underwent chemo or chemoradiation therapies to further evaluate the algorithm in different histology subtypes. Results: We divided the 83 adenocarcinoma cohort into training (n = 53) and test (n = 30) sets. We found that subjects with longer progression free survival (PFS) had mean allele fraction (AF) < 1% in the training set. We applied the classifier to our validation set and found that subjects with mean AF < 1% had longer PFS (HR 0.35; 95% CI 0.12 - 0.93; log-rank P = 0.028) and overall survival (OS) (HR 0.29; 95% CI 0.09 - 0.89; log-rank P = 0.021). Using cutoffs identified in adenocarcinoma, we applied the same algorithms to the SCC cohort. Subjects with mean AF < 1% had longer PFS (HR 0.26; 95% CI 0.10 - 0.71; log-rank P = 0.005) and OS (HR 0.12; 95% CI 0.05 - 0.51; log-rank P = 0.001). Conclusions: Even in heterogeneous diseases such as NSCLC, changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects who may not benefit, which is earlier than current standard of care methods like computed tomography (CT) scan. Future prospective studies to confirm these results are warranted.
Totality of evidence in development of the bevacizumab biosimilar ABP 215: Central and investigator evaluation of efficacy from the MAPLE study.
Authors: Thomas Michael , Thatcher Nick , Goldschmidt Jerome H , Ohe Yuichiro , McBride Helen , Hanes Vladimir 
Published: March 2020

e20708 Background: ABP 215 (MVASI™ [bevacizumab]) is the first biosimilar to Avastin (bevacizumab) approved in the US and EU. This phase 3, double-blind study compared efficacy of ABP 215 with bevacizumab reference product (RP) in patients with advanced non-squamous NSCLC. Here we report the totality of evidence supporting similarity between ABP 215 and RP, including preclinical VEGF-A isoform binding relevant to the mechanism of action across indications, and clinical results of central and investigator evaluation of tumor response. Methods: VEGF-A kinetic parameters were compared for common isoforms 121, 165 and 189. Patients were randomized 1:1 to ABP 215 or RP 15 mg/kg Q3Wx6 cycles. All patients received carboplatin and paclitaxel Q3W for up to 6 cycles. Disease assessments (CT/MRI) were performed at screening, weeks 7, 13, 19, and Q9W thereafter by the investigator and, independently, by central, blinded radiologists. Efficacy was based on objective tumor assessments according to RECIST 1.1. Copies of all radiographs were submitted for central analysis. The primary efficacy endpoint was risk ratio of objective response rate (ORR); clinical equivalence was confirmed if the 2-sided 90% CI of the risk ratio was within the margin of 0.67-1.5. Additional efficacy analyses included duration of response (DOR) and progression-free survival (PFS). Results: Binding to all 3 isoforms was similar for ABP 215 and RP. In the MAPLE study, 642 patients (ABP 215, 328; RP, 314) were randomized. Based on central analysis, ORR was achieved in 128 (39.0%) patients in the ABP 215 and 131 (41.7%) in the RP groups, (ORR risk ratio: 0.93 [90% CI: 0.80, 1.09]). Based on investigator analysis, ORR was achieved in 157 (47.9%) patients in the ABP 215 and 151 (48.1%) in the RP groups (ORR risk ratio: 1.01 [90% CI: 0.88, 1.16]). Hazard ratio (HR, ABP 215 vs RP) for DOR was 1.08 (95% CI, 0.76, 1.54) and 0.76 (95% CI, 0.48, 1.23) per investigator and central assessment. PFS HR was 1.10 (90% CI, 0.92, 1.33) and 1.03 (90% CI, 0.83, 1.29) per investigator and central assessment. Conclusions: These results further confirm the similarity of ABP 215 and RP and support extrapolation to all available bevacizumab indications. Clinical trial information: NCT01966003.
Economic evaluation crizotinib, alectinib and brigatinib in anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Choi Briana , Alkhatib Nimer S , Pae Elizabeth , Babiker Hani M. , Garland Linda L. , Henglefelt Alyssa , McBride Ali , Abraham Ivo 
Published: March 2020

e20714 Background: Crizotinib and alectinib are approved as 1st and brigatinib as 2nd line (post crizotinib) therapy for ALK+ NSCLC. Alectinib and brigatinib are more expensive but potentially clinically more beneficial in terms of progression free survival (PFS). We performed cost-effectiveness/utility analyses based on published PFS data. Methods: The Bücher method was used to indirectly estimate comparative PFS hazard ratios (HR) for PFS between the 3 agents. A 2-state Markov model (progression, death) was specified, PFS survival curves were digitized, and Weibull distributions fitted with life time horizon. Drug costs were per RedBook (US$ 2018). Cost of adverse event management, disease progression and follow up were per published data. Outcomes included PFS life years (PFSLY) and quality adjusted life years (PFSQALY). Incremental cost effectiveness/utility ratios (ICER/ICUR) of PFSLY and PFSQALY gained were estimated. Deterministic results were verified by probabilistic sensitivity analyses (PSA). Analyses were from the US payer perspective. Results: In indirect comparisons, alectinib (HR 0.47, 95%CI 0.34-0.65) and brigatinib (HR 0.49, 95%CI 0.33-0.74) were superior, but equivalent to each other (HR 1.04, 95%CI 0.62-1.75), in PFS over crizotinib in their respective lines. Deterministic (probabilistic) PFSLY, PFSQALY and cost estimates were 0.86 (0.91), 0.54 (0.57) and $193,544 ($203,881) for crizotinib; 1.27 (1.36), 0.80 (0.85) and $236,279 ($251,183) for alectinib; 1.25 (1.33), 0.79 (0.83) and $492,681 ($522,533) for brigatinib. See Table for deterministic (probabilistic) ICER/ICUR results ($ in parentheses denote savings). Conclusions: In this independent economic evaluation not considering intracranial metastasis, brigatinib had the highest life time cost compared to alectinib and crizotinib (all drugs as approved). Comparable gains in PFSLY and PFSQALY for brigatinib can be achieved with alectinib at lower cost, making alectinib the most cost-effective treatment option for ALK+ NSCLC. [Table: see text]
Real-world economic burden of rapid disease progression (RDP) in patients (pts) with advanced/metastatic non-small cell lung cancer (aNSCLC).
Authors: Byfield Stacey DaCosta , Molife Cliff , Batus Marta , Winfree Katherine B. , White John C , Cui Zhanglin Lin , Lal Lincy S. , Stefaniak Victoria Jennifer , Bonomi Philip D. 
Published: March 2020

e20716 Background: RDP on initial therapy imposes significant clinical burden among pts with aNSCLC. This retrospective claims study provides estimates of the economic burden associated with RDP during subsequent therapy following RDP v non-RDP on platinum-based (Pt) therapy. Methods: Adult Medicare Advantage or commercially insured aNSCLC pts receiving a subsequent line of therapy (LOT) from 03/2015 to 08/2017 after initial Pt therapy were identified in the Optum Research Database and assigned to unmatched RDP & non-RDP cohorts based on Pt treatment duration (≤ 12 and > 12 weeks, respectively) as a surrogate. All-cause healthcare costs were inflation adjusted to 2017 US$ and computed as per patient per month (PPPM) during the subsequent LOT. Total costs were the sum of medical (inpatient, ambulatory, ER, and other costs) and outpatient pharmacy costs. Results: Patient characteristics were similar between RDP (n = 751) and non-RDP (n = 1,304) cohorts, with mean age of 68 years for the total study sample (n = 2,055). Overall, nivolumab was the most common subsequent regimen post Pt; 40% of the total study sample. While duration of subsequent LOTs was shorter for RDP pts (Kaplan-Meier median, 167 v 192 days and log rank test P = 0.03), mean systemic therapy drug costs were similar ($10,516 v $9,642, P = 0.14) during the LOT and PPPM total costs for RDP pts were $4,103 higher than those for non-RDP pts, driven by higher PPPM costs for inpatient stays and ambulatory visits (Table). Conclusions: This study sheds light on the significant economic burden of aNSCLC that rapidly progresses, and may inform management strategies to improve outcomes and lower downstream costs for RDP pts. Future research should continue to explore unmet needs for RDP pts, including underlying cost drivers, to provide context for the rapidly changing aNSCLC treatment landscape.[Table: see text]
Sedation practices in pediatric ALL patients.
Authors: Nugent Bethany D. , Davis Peter J. , Noll Robert , Tersak Jean M. 
Published: March 2020

e21500 Background: The 5-year survival rate for pediatric acute lymphoblastic leukemia (ALL) is greater than 90%. A common late effect of pediatric ALL is neurocognitive deficits, such as lower IQ. In recent years, the use of sedation during lumbar punctures (LPs) for treatment of pediatric ALL is becoming increasingly widespread. These patients are exposed to repeated doses of sedatives. Among the most common Children’s Oncology Group (COG) ALL protocols, approximately 30 LPs are performed over a period of 2-3 years. Studies in animals (both rodents and primates) have revealed that common sedation drugs cause harm to the developing brain and can negatively affect behavior, learning, and memory. Gaps in knowledge exist regarding their use in children, particularly with repeated exposures. For children with ALL, little is known about sedation practices such as how commonly sedation is used; what medications are most common; and who administers the medications. The purpose of this study is to summarize sedation practices at COG institutions for LPs related to treatment of pediatric ALL. Methods: All Responsible Investigators (RIs) of the Cancer Control Committee (a subcommittee of COG) were invited to complete an internet-based survey about sedation practices for ALL patients at their institution. Results: Surveys were sent out to 103 RIs with a 62.1% response rate ( N = 64). A combined 2018 new patients with ALL were seen each year ( M = 31.5, range = 3-110); of these patients, 95.7% received sedation for LPs. While there was considerable variability across institutions in medications used (general anesthesia, Propofol with opioid and/or Versed, Versed and opioid, other), the most common was Propofol alone ( n = 36, 56.3%). Anesthesiologists administered sedation at the majority of institutions ( n = 36, 56.3%) while trained sedationists, oncologists, and nurses administered sedation at other institutions. Conclusions: A substantial number of pediatric patients with ALL receive sedation for LPs. However, there is much variation in the types of medications administered and who is administering these medications. Better understanding of sedation practices in children with ALL may inform future research to investigate which methods of sedation are safest, with a particular emphasis on its long-term effects.
High concentration of plasma cell free DNA alerted progressive and recurrent disease in children with high risk neuroblastoma.
Authors: Su Yan , Wang Lijun , Jiang Chiyi , Yue Zhixia , Hongjun Fan , Hong Huimin , Duan Chao , Jin Mei , Zhang Dawei , Qiu Lihua , Cheng Xianfeng , Xu Zhong , Ma Xiaoli 
Published: March 2020

e21506 Background: Neuroblastoma (NB) happens most frequently among babies and it is also the third-most common cancer in children after leukemia and brain tumor. The unexpected occurrence of NB progression and relapse accounts for the low survival free event rates, therefore finding an effective biomarker to predict the progressive and recurrent events is urgent. Methods: A total of 116 NB patients with high risk (HR-NB) from Beijing Children’s Hospital between February 1, 2015 and December 31, 2017 were recruited. All patients received the regular multiple-disciplinary treatments and then followed the evaluation for therapeutic response according to the standards of Response Evaluation Criteria in Solid Tumors (RECIST). Blood samples were collected to quantify cell-free DNA levels at important time points including one week before or the beginning of maintenance stage, every or every three month after the beginning of maintenance stage, diagnosis of progression and recurrence. Results: Results showed that 36 HR-NB patients developed progressive disease (PD) and recurrent disease. More intriguingly, cfDNA concentration was extremely higher in NB patients with progression and recurrence than those with events free (29.34 ng/ml VS 10.32 ng/ml), and increasing cfDNA levels happened at least 0.55 months before the progression and recurrence was confirmed. By analyzing the area under the receiver operator characteristic (ROC) curve (AUC), it showed that the area of cfDNA level was 0.67 at 12.93 ng/ml with 62.5% sensitivity and 71.3% specificity. Conclusions: Taken together, it was suggested increasing cfDNA concentration in plasma may benefit to warn the incurrence of progression and recurrence in NB patients in clinic, which will help clinicians win much more valuable time to save patients’ lives.