bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of cell-free DNA (cfDNA) fragmentomes and prediction scores across distinct molecular subtypes.
Authors: Schuurbiers Milou , Leal Alessandro , Aghamirzaie Delasa , Chesnick Bryan , Peters Erica , Wu Tony , Jakubowski Debbie , Tom Jennifer , Dracopoli Nicholas C. , Bach Peter B. , Scharpf Robert B. , Velculescu Victor E. , Monkhorst Kim , van den Broek Daan , van den Heuvel Michel 
Published: June 2023

e15029 Background: Liquid biopsies have the advantage of being convenient in collecting tumor-derived DNA for clinical use. Genome-wide analysis of cell-free DNA (cfDNA) fragmentomes has emerged as a promising approach to detect lung cancer based on the examination of sequencing features other than actionable mutations. Here we report initial analyses of the DELFI (DNA evaluation of fragments for early interception) technology in patients enrolled in the Dutch Lung Cancer Early Molecular Assessment (LEMA) trial (NCT02894853), a prospective, observational, and multicenter study, to evaluate fragmentation patterns in genotyped blood samples with actionable alterations irrespective of disease stage and histology subtype. Methods: Plasma samples from 576 patients with an established diagnosis of lung cancer but awaiting the start of definitive treatment were processed and examined using low-coverage whole-genome sequencing. A lasso model that incorporated genome-wide fragmentation profiles was trained on an internal Delfi Diagnostics cohort and used to generate patient-specific DELFI scores for participants in LEMA. Results: Enrollees comprised 531 individuals with non-small cell lung cancer, 38 with small-cell lung cancer, and 7 with unknown lung cancer type. Most patients were diagnosed with late-stage disease (28% stage I, 10% stage II, 26% stage III, and 36% stage IV). Current smokers (N = 238; 41%) and former smokers (N = 295, 51%) outnumbered never smokers (N = 43; 8%). Analysis showed a stepwise increase of the DELFI scores from T1 to T4 and N0 to N1-3 disease, associating aberrant fragmentation profiles with the overall tumor burden. Small-cell carcinomas and squamous cell carcinomas presented with higher DELFI scores than adenocarcinomas ( p< 1e-7, generalized linear model). Patients without a smoking history had similar scores to those who had a previous history of smoking. When adjusted for stage, mutation status in ALK, BRAF, EGFR, ERBB2, KRAS, MET, RET, and ROS were not associated with DELFI scores ( p= 0.5, likelihood ratio test). Similarly, PD-L1 staining did not significantly affect DELFI scores when a 1% cutoff was applied to cases with PD-L1 staining data ( p= 0.07, generalized linear model). Conclusions: Our results reveal that DELFI scores increase stepwise with stage and are higher in small-cell and squamous cell carcinomas. The LEMA study reinforces the potential usefulness of genome-wide cfDNA fragmentation profiling as a liquid biopsy approach for identifying patients with lung cancer regardless of smoking status, somatic driver mutation, and PD-L1 expression scores.
Bi-directional interaction and predictive potential of inflammatory and oxidative stress-related biomarkers in patients with non-small cell lung cancer.
Authors: Nikolovski Srdjan , Jaradeh Mark , Siddiqui Fakiha , Walenga Jeanine , Jeske Walter , Fareed Jawed , Vigneswaran Wickii T. 
Published: June 2023

e15030 Background: Interplay between oxidative stress and inflammation play major role in the development and progression of various malignancies. As one of the most common and the deadliest malignancy, lung cancer has a prominent vicious cycle of oxidative stress and immune response. The aim of this study is to examine the inter-relationship between basic oxidative stress and inflammation-related plasma biomarkers in patients with non-small cell lung cancer (NSCLC) undergoing surgical resection procedure. Methods: After obtaining informed consent, pre-operative plasma levels of alpha-fetoprotein, nitrotyrosine, urokinase-type plasminogen activator, and myeloperoxidase (MPO) as oxidative stress-related biomarkers were determined in 49 patients with diagnosed NSCLC. In the same patient group, plasma levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon gamma, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and epidermal growth factor were also evaluated. Control samples were obtained from 34 healthy individuals. Plasma biomarkers were determined by enzyme-linked immunosorbent assay. Applicable statistical methods were used to analyze the data. Results: Positive correlation was observed between MPO and levels of the following inflammation-related biomarkers: IL-6 (r = 0.397, p = 0.007), VEGF (r = 0.494, p = 0.001), TNF-α (r = 0.348, p = 0.019), and MCP-1 (r = 0.377, p = 0.011). Biomarkers showing significance in correlation analysis were further analyzed by linear logistic regression in order to determine presence and strength of causality in each direction (oxidative stress to inflammation and inflammation to oxidative stress). IL-6 and VEGF were observed as a predictors of MPO levels (B = 0.334, p = 0.031, and B = 0.391, p = 0.039, respectively). Furthermore, causality was observed in the opposite direction as well. MPO levels were shown as a slightly better predictor of both IL-6 and VEGF plasma levels (B = 0.349, p = 0.007, and B = 0.433, p = 0.001, respectively), but also as a predictor of TNF-α and MCP-1 levels (B = 0.193, p = 0.019, and B = 0.217, p = 0.011, respectively). Conclusions: Conclusion: These studies showed a strong correlation between measured oxidative stress-related and inflammatory biomarkers. Furthermore, these observations underscore the importance of oxidative stress in the pathogenesis of lung cancer.
C-reactive protein in solid tumors: Clinically meaningful change and prognosis.
Authors: Lasheen Wael , Walsh Declan 
Published: June 2023

e15036 Background: C-Reactive Protein (CRP) has been associated with overall survival (OS) in both solid and hematologic malignancies. CRP is used alone or in conjunction with other variables e.g., albumin to create prognostic scores, yet use in clinical practice is limited. One barrier is the lack of guidelines quantifying clinically relevant changes. The aim of this study was to determine important changes in CRP and any association with OS. Methods: This was a retrospective cohort study of electronic medical record data. Subjects were included if they had a solid tumor, ≥2 CRP measurements post diagnosis, ≥7 days apart, age ≥18. They were divided into Baseline High CRP (HCRP≥10 mg/L), and Baseline Normal CRP (NCRP < 10 mg/L) groups and analyzed separately. Median (range) and counts (%) were reported. Variables compared with parametric or nonparametric tests. CRP change (∆ = (2nd CRP-1st CRP)/1st CRP) cut-off points were determined by Receiver Operator Curves or dividing groups into tertiles for sensitivity and specificity. We report the Kaplan-Meier survival plots and Cox Proportional Hazard Survival Models. Results: 4931 solid tumors were identified with CRP values; 1473 ≥2 CRP at least one week apart. N = 943 HCRP; N = 530 NCRP. HCRP were more likely to have gastrointestinal cancers, high white blood cell count, liver disease, metastatic disease, undergone surgery. NCRP were more likely breast or skin cancer, female, higher BMI, longer OS. 50% ↓ or 2-fold ↑ in CRP from baseline were statistically relevant cut-off points. In HCRP, estimated OS for ≥50% and < 50% ↓ in CRP was, mean (SE), 87(2) and 81(4) months respectively; a six-month difference. In NCRP, estimated OS for ≥2 and < 2-fold ↑ was 90(3) and 105(3) respectively; a fifteen-month difference. In the COX models, ≥ 50% CRP ↓ in HCRP was associated with 40% lower mortality risk; ≥ 2x CRP ↑ in NCRP was associated with 2-fold ↑ mortality risk. Conclusions: CRP level changes with cut-off points of either a 50% reduction or a 2-fold ↑ from baseline correlated with better and worse OS respectively, during follow up of solid tumors. This was both statistically and clinically important. CRP has the characteristics of an ideal tumor biomarker. This could aid in disease prognostication and impact treatment decision making in routine clinical practice. [Table: see text]
Implementing liquid biopsy in rural cancer care when tissue is insufficient for molecular testing: Retrospective review.
Authors: Singh Jaswinder , Singh Siraj , Singh Gina J. , Nagaich Amitoj 
Published: June 2023

e15039 Background: Liquid biopsy is a promising and minimally invasive genetic test examining plasma circulating tumor DNA. Coupled with the rapidly developing next-generation sequencing (NGS) technologies, it holds the potential for implementation in selecting signal-matched therapeutic options. Analysis of tumor cell free DNA, or liquid biopsy, is emerging as a useful adjunct to tissue biopsies in advanced solid tumors. These tests may reduce the need for repeating invasive biopsies, and may be performed serially with minimal risk to patients. Many a times solid tumor biopsies are not sufficient enough to run next generation sequencing and hence the need for repeat biopsies. The purpose of our study is to document how liquid biopsies are being used in a large, diverse community based practice in rural Missouri where travel to tertiary care center for repeat biopsies is not easy and how often the results were able to demonstrate yield of finding FDA approved therapeutic options or clinical trials for these patients. Methods: A retrospective chart review was conducted on adult patients with advanced solid tumors whose tumors were not sufficient enough to be tested for next generation sequencing and hence tested with Guardant360 assay, between December 2015 and December 2022. A total of 515 patients were referred for testing by 4 oncologists from within a five satellite rural community cancer centers. Results: The majority of patients were tested upfront for molecular marker evaluation, in either newly diagnosed advanced cancer patients, or in recurrent patients without enough tissue for testing. 66 out of 515 patients (12.8 %) were not found to have any tumor alterations on liquid biopsy. A total of 16 histological types were tested among 449 patients with lung ( n = 177; (39.42% ),breast cancer ( n = 58; 12.9 %) and colorectal ( n = 135; 30 % ); cancers being the most common types of the 16 histological subtypes. Of those with positive test results (n = 449 ), 56 (12.4%) patients had ≥ 1 FDA approved, target-matched therapeutic opportunity. Similarly, 329 patients (73%) had ≥ 1 target-matched therapeutic opportunity, outside current indications. Lastly, when no FDA-approved target-matched therapy was available results from liquid biopsy testing offered signal-based clinical trial opportunity in all 449 patients. Conclusions: Implementation of NGS-based liquid biopsy testing is feasible within a community rural oncology practice. In the era of precision oncology, such assays have the potential to expedite the efforts towards target-matched therapies and signal-based clinical trial opportunities especially when there is problem of lack of accessibility and affordability of repeat biopsies is a problem.
Cancer signature ensemble integrating cfDNA methylation, copy number, and fragmentomic patterns for multi-cancer early detection.
Authors: Kim Su Yeon , Jeong Seongmun , Lee Wookjae , Jeon Yujin , Kim Yong-Jin , Park Seowoo , Go Dayoung , Lee Sanghoo , Woo Hyun Goo , Yoon Jung-Ki , Park Young Sik , Kim Young Tae , Lee Se-Hoon , Kim Kwang Hyun , Lim Yoojoo , Song Sang-Hyun , Kim Jin-Soo , Kim Hwang-Phill , Bang Duhee , Kim Tae-You 
Published: June 2023

e15040 Background: The use of cfDNA sequencing has demonstrated great potential for cancer screening; particularly, methylation signatures, copy number variations, and fragmentomic profiles have proven to be effective for identifying early cancer signals. However, most large-scale studies have only focused on either targeted methylation sites or whole-genome sequencing, limiting comprehensive analysis that integrates both epigenetic and genetic signatures. In this study, we present a platform for multi-cancer early detection that enables simultaneous analysis of whole-genome methylation, copy number, and fragmentomic patterns of cfDNA in a single assay. Methods: For a total of 950 plasma samples (361 healthy controls and 107 colon, 113 liver, 238 lung, and 131 prostate cancer) and 239 tissue samples, whole-genome methylation sequencing data were generated. Machine learning was conducted for multiple feature types engineered from cfDNA samples, and independent test performance was assessed. Results: A multi-feature cancer signature ensemble (CSE) classifier, integrating all features, outperformed single-feature classifiers. At 95.2% specificity, the cancer detection sensitivity with methylation, copy number, and fragmentomic models were 77.2% [CI 72-82], 61.4% [CI 56-67], and 60.5% [CI 55-66], respectively; but it was significantly increased to 87.7% [CI 84-91] with CSE ( p-value < 0.0001). For tracing the tissue of origin, CSE enhanced the accuracy beyond the methylation classifier, from 74.7% [CI 69-80] to 77.5% [CI 72-82]. Conclusions: This work proves the utility of a signature ensemble integrating epigenetic and genetic information for accurate cancer detection.
Analysis of survival outcomes in patients with non–small-cell lung cancer with mutations in STK11/LKB1 receiving chemoimmunotherapy.
Authors: Kim Diana , Elsey Rachel , Meissner Tobias , Sun Yuliang , Xu Bing , Hattum Crystal , Solomon Benjamin Maurice , Lee John H. , Williams Casey B. 
Published: June 2023

e15043 Background: Many patients with non-small-cell lung cancer (NSCLC) do not benefit from first-line treatment with immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy due to resistance or toxicity. In NSCLC, significant research has been undertaken to provide prognostic markers for single agent immune checkpoint inhibitor therapy. Co-alterations in TP53, STK11/LKB1 and KRAS have a low reported prevalence in NSCLC, however, potentially may represent a distinct molecular subtype of NSCLC that conveys primary resistance to single-agent ICI. Data continues to accumulate regarding resistance mechanisms to ICI, but limited data exists exploring these alterations and the corresponding survival outcomes in patients that receive chemoimmunotherapy. The primary objective of this study was to assess the association between alterations and co-alterations in STK11/LKB1 and survival outcomes in patients with NSCLC receiving chemo-immunotherapy. Methods: This was a retrospective study of patients ≥18 years old who had completed NGS testing and had a diagnosis of non-small-cell lung cancer that received chemoimmunotherapy from January 2016 to November 2022. NGS reports were reviewed to assess the status of STK11/LKB1, KRAS, KEAP1, and TP53 alterations. Additional markers assessed were PD-L1 status, TPS, CPS, TMB, and MSI if available. Results: Sixty-five patients were identified who had received chemoimmunotherapy for NSCLC, had NGS testing results, and were considered to be evaluable for retrospective review. Four patients were identified with co-altered KRAS, STK11, and TP53, and this alone was not significant for PFS (p= 0.48) or OS (p = 0.52) compared to patients without the alterations, however patients with the co-alterations and a positive PD-L1 showed an improvement in PFS (p =0.053). Patients with altered STK11, including those classified as VUS, had a poorer OS (p = 0.088). Our analysis also showed that PD-L1 negative patients had poorer OS (p = 0.088). Conclusions: The addition of chemotherapy to ICI may overcome resistance previously described in NSCLC patients with co-alterations in KRAS, STK11, and TP53, who received single-agent ICI and these genomic findings should not deter from the use of chemoimmunotherapy based on our limited experience. Patients with alterations in STK11 did have poorer outcomes overall, which is in line with previously published data describing STK11 as a poor prognostic marker in NSCLC. STK11 alterations have previously been described to be associated with PD-L1 negativity which may explain, at least in part, the poorer responses in the STK11 mutated subgroup.
An electrochemical molecular assay for the detection of cancer-associated Thomsen-Friedenreich glycans.
Authors: Moraes Silva Saimon , Abeyrathne Chathurika , Li Miaosi , Cossins Luke Robert , Samudra Anushka , Greene Wren , Moulton Simon 
Published: June 2023

e15046 Background: Abnormal glycosylation is a fundamental characteristic in cancer cells, where expression of glycans such as Thomsen-Friedenreich (T), Tn, and sialyl-Tn (STn) are related to particular tumour patterns. T, Tn and STn antigens are unusually short and truncated O-glycans expressed on glycoproteins synthesized within cancer cells and not normally found in healthy tissue or circulating within the blood. The association between blood circulating T-glycans and cancer progression and poor prognosis is now well-known and highlights great potential as biomarkers for cancer screening, diagnosis, and surveillance of diseases during treatment and following remission. Despite this potential, there is currently no established molecular assay for detecting or quantifying these biomarkers in blood biopsy samples. Methods: Using a test strip format reminiscent of a blood glucose test, a new electrochemical molecular assay is introduced for the detection of short O-glycans directly in unprocessed bodily fluids. This assay is based on a self-assembling sensing interface consisting of two glycoproteins, recombinant human lubricin (LUB) and peanut agglutin (PNA). In this interface, the LUB functions as both an anti-fouling layer which mitigates electrode passivation in blood and as a crucial component in the biosensing mechanism for generating readable electrical signals in the presence of target glycans. The PNA, a plant-based lectin, presents high binding specificity towards the T glycoform and functions as the sensor recognition element which is bound to the LUB through T glycans naturally present in the highly glycosylated protein backbone. In this sensing interface, electrical signals are generated by engineering a redox reporter, methylene blue into the LUB/PNA interfacial complex, where the electrical signal is altered by the capture of target glycans by PNA and its impact on the molecular dynamics of the LUB/PNA interfacial complex. Results: Using this test strip, it is possible to detect short cancer-related glycans in concentrations as low as nanomolar directly in small volumes of unprocessed whole blood. These test strips likewise show comparable results to an ELISA test developed in parallel for the detection of short O-glycans. The tests carried out with retrospective blood plasma samples from patients presenting three different tumour types, including prostate (18 patients), colorectal (15 patients), and breast cancer (6 patients), and plasma samples from healthy donors (10 different donors) showed differentiation of response signals between healthy and diseased patients. Conclusions: These findings highlight the clinical potential of this new disposable test strip for the detection of tumour associated glycans, which can be incorporated into point-of-care devices, for cancer monitoring and perhaps one day in screening and diagnosis.
Importance of clinical decision making in precision oncology: Discordance in recommendation between next generation sequencing test vendor and molecular tumour board in India.
Authors: Sirohi Bhawna , Davis Sissmol , R I Anu , Suryavanshi Moushumi , Dawood Shaheenah S. , Panda Pankaj Kumar , Nag Shona Milon , Das Arunangshu , Rohatgi Nitesh , Popat Sanjay , Shah Riyaz N.H. , Thampy Cherian , Parikh Aparna Raj , Yadav Siddhartha , Mehta Prashant , Singh Randeep , Mukherji Deborah , Shilpakar Ramila , Mullapally Sujith Kumar , Mathew Aju 
Published: June 2023

e15050 Background: Molecular tumour boards (MTB) facilitate discussions among medical professionals, scientists, bioinformaticians and geneticists for clinical application of precision oncology, via interpretation of various genomic sequencing studies, most commonly Next Generation Sequencing (NGS). NGS test vendor recommendation may differ from the MTB recommendations. We aim to study the discordance rate between these recommendations. Methods: MTB discussions between April 1, 2021 and December 31, 2021, were retrospectively evaluated. MTBs which assessed NGS reports with or without significant genetic mutations but with drug recommendations were included. NGS testing was done with multiple vendors. Patients from all over India, Nepal, Bangladesh, Dubai and Abu Dhabi were discussed. We excluded MTBs which assessed NGS data without any drug recommendations. We compared therapeutic recommendations provided in the NGS report with the first-choice recommendation in the MTB discussion. Recommendation discordance was defined as disagreement between the NGS recommendation and the first MTB recommendation that either instructed its implementation either immediately or on disease progression. Results: 70 MTB data was studied. 49 MTBs assessing NGS reports of 49 unique patients (median age 54 years; range, 32-82) were included in the study. 13 patients had lung cancer, 10 colorectal, 6 breast, 7 hepatopancreatobiliary, 4 carcinoma of unknown primary and 9 others. 17 did not provide any treatment recommendations and hence were excluded. 4 were discussions based on NGS reports previously discussed in an MTB that was already included in the study, hence were excluded. Recommendation discordance rate was 49% (24 of 49). Conclusions: To our knowledge, this is the first study that assessed discordance rate in recommendations between NGS report and MTB from a low- and middle-income country setting. Accurate clinical translation of complex genomic data is at the forefront of personalized cancer care.