bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of micronuclei DNA from erythrocytes in early-stage colorectal cancer detection.
Authors: Yao Xingyun , Sun Haobo , Pan Jie , Jiao Yurong , Kong Xiangxing , Liu Chengcheng , Zhu Fangchao , Meng Fei , Liang Honghao , Cao Yanfei , Li Jun , Gao Xiaofei 
Published: January 2024

25 Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, early detection of CRC and advanced adenoma (AA) remains challenging. Micronuclei (MN) are extranuclear bodies containing chromatin segments resulting from errors in DNA repair. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We have developed a method (WO2021/228246 A1) for purifying and sequencing micronuclei DNA (mnDNA) in erythrocytes from peripheral blood. Here, we compared mnDNA between healthy donors (HDs) and CRC patients and explored its application for early cancer diagnosis. Methods: Peripheral blood (1ml) was obtained from a training cohort of 987 individuals, a validation cohort of 246, and an independent test cohort of 193. mnDNA was isolated and sequenced from erythrocytes. Genome-wide analysis identified distinctive mnDNA features between HD and CRC. Predictive models using these features were developed to differentiate CRC and AA from HDs. A clinical trial comparing mnDNA with an approved multitarget stool DNA test (sDNA-FIT) was also conducted on 60 individuals (42 HDs, 6 AAs, and 12 CRCs). Results: Genome-wide analysis of mnDNA revealed substantial differences in distribution patterns between HDs and CRC patients. The predictive model built on mnDNA features achieved an AUC of 92.98% (95%CI: 87.85-98.12%), with an 88.64% sensitivity and 92.75% specificity in the independent test cohort. The model identified early-stage (stage I-II) CRC and AA with sensitivities of 83.33% or 69.56%, respectively. Comparing mnDNA to sDNA-FIT showed superior overall sensitivity (83.33% vs. 61.11%), AA sensitivity (83.33% vs. 16.66%), with comparable specificity (85.71% vs. 88.10%). Conclusions: Our results demonstrate that mnDNA from a small amount of peripheral blood enable accurate detection of AA and early-stage CRC. As a type of cytoplasmic DNA, mnDNA can provide a valuable tool for early cancer detection, offering different underlying mechanisms compared to current methods. A larger clinical study (NCT05875584) is ongoing and will further validate the application of mnDNA in early cancer detection.
Nivolumab (NIVO) plus (+) chemotherapy (chemo) or ipilimumab (IPI) vs chemo as 1L treatment for advanced esophageal squamous cell carcinoma (ESCC): First comprehensive biomarker analyses from CheckMate 648.
Authors: Lei Ming , Doki Yuichiro , Kitagawa Yuko , Kato Ken , Chau Ian , Yao Jin , Xu Jianming , Wyrwicz Lucjan S. , Motoyama Satoru , Ogata Takashi , Kawakami Hisato , Hsu Chih-Hung , Adenis Antoine , El Hajbi Farid , Di Bartolomeo Maria , Braghiroli Maria Ignez , Holtved Eva , Blum Murphy Mariela A. , Novosiadly Ruslan , Ajani Jaffer A. 
Published: January 2024

252 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in previously untreated patients with advanced ESCC in CheckMate 648 (NCT03143153), resulting in approvals in many countries. We present first comprehensive exploratory biomarker analysis results from this trial. Methods: Whole exome sequencing (WES) of baseline tumor tissue and matching blood was performed to assess tumor mutational burden (TMB) and select gene alterations. TMB-high tumors were defined as ≥ 199 mutations/exome. RNA sequencing of baseline tumor tissue was used to assess gene expression signatures (GES). GES subgroups were defined by signature score tertiles. Results: In total, 60% (191/321) of patients receiving NIVO + chemo were both WES- and GES-evaluable; 62% (200/325) and 58% (188/325) of patients receiving NIVO + IPI and 59% (190/324) and 59% (192/324) receiving chemo were WES- and GES-evaluable, respectively. In the NIVO + chemo arm, patients with TMB-high tumors had numerically longer median OS (mOS) compared with TMB-low tumors, whereas mOS was similar between TMB subgroups treated with NIVO + IPI, although the number of patients with TMB-high tumors was small (Table). Higher inflammation and lower β-catenin GES scores were associated with improved OS benefit of NIVO + chemo or IPI vs chemo (Table). Lower fibroblast GES scores were associated with improved OS benefit of NIVO + IPI vs chemo (Table). Additional biomarker analyses, including select gene alterations and GES in tumor cell PD-L1 subgroups, will be presented. Conclusions: These results further support the clinical efficacy of NIVO + chemo and NIVO + IPI in 1L ESCC and suggest enhanced OS benefit in multiple biomarker subgroups. The clinical utility of these biomarkers should be validated in future trials. Clinical trial information: NCT03143153 . [Table: see text]
Disparities in survival in Asian American, Native Hawaiian, and Pacific Islander patients with gastric adenocarcinoma: An NCDB analysis.
Authors: Mishra Anjali , Hu Robert , Silberstein Peter T. 
Published: January 2024

253 Background: Asian American, Native Hawaiian, and Pacific Islander (AANHPI) individuals exhibit stark disparities in gastric cancer mortality rates, with AANHPI men facing a two-fold higher risk of death and AANHPI women encountering a 2.5-fold elevated risk compared to their Non-Hispanic White (NHW) counterparts. However, the AANHPI community is a diverse group, including over 21 ethnic groups. Here, we identify disparities among AANHPI subpopulations with gastric adenocarcinoma. Methods: Using the National Cancer Database, which gathers data from over 1,500 accredited hospitals and facilities across the United States, this retrospective cohort study identified 141,906 patients with gastric adenocarcinoma (ICD code “8140”). Races listed as “unknown/other” or “Other Asian” were excluded. Kaplan Meier and Cox Regression model were performed. Results: This study compared mean overall survival (OS) of NHW (n=111,137), East Asian (EA) (n=3,745), South Asian (SA) (n=760), Southeast Asian (SEA) (n=1,379), and Native Hawaiian or Pacific Islander (NHPI) (n=325) patients with gastric adenocarcinoma. When aggregated, AANHPI had statistically significant improved OS compared to NHW (21.6 months vs 14.1 months, p < 0.001). After disaggregating, the mean OS was 26.9 months for EA; 21.3 months for SA; 14.5 months for SEA; and 14.3 months for NHPI. Only SA and EA had significantly improved OS than NHW (p<0.001 for both). SEA and NHPI had significantly worse outcomes than EA (p<0.001 for both) and SA (p<0.001 for SEA, and p = 0.033 for NHPI). Multivariate analysis accounted for age at diagnosis, insurance status, median income quartile, Charlson-Deyo comorbidity score, facility type, stage at diagnosis, and time to treatment. SA (HR=0.82; 95% CI, 0.726 to 0.925; p<0.001)), EA (HR=0.644; 95% CI, 0.609 to 0.68; p<0.001), and SEA (HR=0.896; 95% CI, 0.821 to 0.978, p=0.014) had lower survival hazard ratios compared to NHW. NHPI (HR=0.931, 95% CI 0.775 to 1.119, p=0.448) did not have a statistically significant relationship compared to NHW. EA (HR = 0.637; 95% CI 0.548 to 0.741, p<0.001) and SA (HR = 0.793; 95% CI 0.667 to 0.943, p=0.007) had significantly lower survival hazard ratios compared to NHPI. Conclusions: Survival disparities exist among AANHPI subgroups with gastric adenocarcinoma. At first glance, OS appeared significantly greater for AANHPI patients compared to NHW. However, disaggregation of AANHPI subpopulations revealed that Southeast Asian and NHPI actually had comparable OS with NHW. After controlling for socioeconomic factors, NHPI had significantly worse hazard ratios compared to South Asian and East Asian. This highlights the need to disaggregate AANHPI data so that disparities among these diverse subpopulations can be identified, investigated and ultimately addressed.
Reliability of computed tomography to determine the eligibility of conversion surgery for gastric cancer with para-aortic lymph node metastasis.
Authors: Wada Takeyuki , Yoshikawa Takaki , Sakon Ryota , Hayashi Tsutomu , Yamagata Yukinori 
Published: January 2024

259 Background: Although gastric cancer (GC) with para-aortic lymph node (PAN) metastasis is diagnosed as stage IV and basically treated with chemotherapy, it can be the candidate of conversion surgery when PAN metastasis was limited in localized area as oligometastatic status. Recently, we reported that pathological complete response at PAN (pCR at PAN) after chemotherapy was a good surrogate marker in conversion surgery for GC with PAN metastasis. However, it is difficult to predict pCR at PAN before surgery. Computed tomography (CT) is a standard procedure for clinical diagnosis of lymph node metastasis in GC.This study aimed to evaluate the reliability of CT to predict pCR at PAN after chemotherapy. Methods: The study examined patients who received radical gastrectomy with D2 and PAN dissection after chemotherapy for gastric cancer with PAN metastasis (#16a2/b1) from 2004 to 2020. PAN greater than 10mm in long axis was diagnosed as clinically positive. Patients were classified into 2 groups as pPAN-CR and pPAN-nonCR according to the pathological diagnosis of PAN. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive values for PAN diagnosis were retrospectively investigated. Moreover, the relationship between shrinkage ratio at PAN and pathological diagnosis was also investigated. Results: A total of 46 patients were examined in the present study. The number of pPAN-CR and pPAN-nonCR patients were 31 and 15, respectively. 5-year overall survival rate was 76% in pPAN-CR and 0% in pPAN-nonCR patients. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of PAN were 52.2%, 60.0%, 48.4%, 36.0%, and 28.6%, respectively. Median shrinkage ratio of PAN was 38% (-20%-88%) in pPAN-CR and 40% (-20%-75%) in pPAN-nonCR patients. There was no statistically significant relationship between shrinkage ratio and pathological diagnosis of PAN ( p=0.655). Conclusions: CT diagnosis for PAN after chemotherapy was not reliable. The indication of conversion surgery for GC with PAN metastasis should not be determined based on the size and shrinkage of PAN.
Unveiling proteomic diversity: A quantitative study of antibody drug conjugate and chemotherapy targets in gastroesophageal cancer.
Authors: Thyparambil Sheeno P. , Ghafourian Negin , Heaton Robert , Strasbaugh Amanda , Melkie Marya Abebe , Chou Chung-Jen James , Ling Xuefeng 
Published: January 2024

261 Background: Gastroesophageal cancer (GEC), is a significant global health concern with a 5-year relative survival of 7% for metastatic GEC. Standard treatments often include surgery, chemotherapy, and radiation therapy, but their effectiveness can be limited. Chemotherapy is frequently utilized in the treatment of GEC, although no biomarkers for chemotherapy are used in the selection of the chemo agent. There are several well-known biomarkers of resistance and sensitivity for various chemo agents. We used targeted proteomics to quantify protein expression levels of several protein biomarkers associated with chemotherapy efficiency in 125 GEC patients. These include resistance markers for platinum agents (ERCC1), and tubulin inhibitors (TUBB3). It also includes sensitivity markers for irinotecan/topotecan (Topo1), and doxorubicin/etoposide (Topo2A). We also assessed the protein levels of several antibodies-drug conjugate markers (EGFR, Her2, Trop2, FR-alpha, Mesothelin, Axl, CLDN18.2, and Nectin-4). Methods: FFPE tumor tissues from 125 clinical GC patients were microdissected and solubilized for mass spectrometry-based targeted proteomic analysis in our CLIA-certified laboratory. 72 proteins were quantified from 2-3 sections of FFPE tissue. Results: 5-Fluorouracil (5-FU), taxanes, and platinum agents (such as carboplatin) are among the chemotherapy agents that are frequently used to treat GEC. TYMP, a sensitivity marker for 5-FU, was expressed in 32% of GEC cases. ERCC1, a resistance marker for platinum drugs, was expressed at 34%. Additionally, 48% of GEC exhibited TUBB3, a resistance marker for paclitaxel and docetaxel. Topoisomerase 1 (Topo1) is the target for irinotecan or topotecan, and is also the target for some ADCs (e.g. trastuzumab deruxtecan, sacituzumab govitecan etc.). Topo1 was expressed in 92% of GEC with a 10x range (415 - 4195 amol/μg). Another topoisomerase, Topo2A, targetable by etoposide, epirubicin, and doxorubicin, was expressed in 59% of GEC with 19x range (402-7804 amol/μg). ADC targets, such as EGFR (82% detected with 184x range of distribution), Her3 (18%, 4x), AXL (18%,7x), MET (27%, 19x), and Trop2 (50%, 57x) showed a wide range of protein expression. With a 56x range (318 - 17786 amol/μg), Her2 was found in 46% of GEC, of which 12% of GEC had overexpression of Her2 (>740 amol/μg), suggesting that the majority of GEC has low levels of Her2 (318-690 amol/μg), which is potentially targetable by newer anti-Her2 agents. Conclusions: Every cancer is different, and the ability to quantitate simultaneously 72 protein biomarkers from 2-3 FFPE sections provides a wealth of actionable information that, when combined with other multi-omics biomarker data, will help guide clinical treatment or patient stratification for clinical trials.
Development and application of an ultra-sensitive ctDNA mutation profiling assay in monitoring therapy response and drug resistance.
Authors: Zhang Tom , Singh Harshabad , Tan Lu , Wang Xiaohong , Zhao Zhixin , Zhou Kemin , Luo Shujun , Jia Shidong , Du Pan 
Published: January 2024

264 Background: Next-generation sequencing (NGS) assays offer efficient high-throughput profiling methods for analyzing circulating tumor DNA (ctDNA) in blood or other liquid biopsy specimens. The ctDNA mutant allele fractions of patients after treatment is often very low and below the detection limit of regular cfDNA assays. Here we report the development and clinical application of a CLIA-certified ultra-sensitive NGS cfDNA assay in detecting the low-frequency ctDNA mutations and monitoring therapy response and drug resistance in patients with metastatic gastroesophageal adenocarcinoma under combined blockade treatments. Methods: PredicineCARE ULTRA cfDNA assay with 100,000X sequencing depth was validated under CLIA settings. Limit of blank (LoB) and limit of detection (LoD) were established by profiling 38 healthy donor plasma samples, 23 contrived human cfDNAs samples from patients with various cancers, and 30 replicates of well-established ctDNA reference standards. In silico down-sampling of FASTQ files was carried out to test the sensitivity of this assay with a lower coverage (50,000X). This assay was then adopted for longitudinal sequencing of 57 serial plasmas from 6 patients with HER2+ gastroesophageal adenocarcinomas (GEC) who underwent combined treatments (capecitabine, oxaliplatin, bevacizumab and trastuzumab) at different time points (baseline, response, and progression). Results: PredicineCARE ULTRA cfDNA assay exhibited exceptional sensitivity in calling single-nucleotide variants and indels, with a 98.0% detection rate at a LoD of 0.075% mutant allele frequency (MAF) for 60 ng cfDNA. This is significantly lower than the LoD (0.25% MAF) of a standard PredicineCARE cfDNA assay. The ultra-sensitive assay also displayed decent analytical specificity (>99.99%) and precision (intra-assay 100%; inter-assay 99.41%). In 6 GEC patients’ longitudinal samples, PredicineCARE ULTRA cfDNA assay detected 36 additional somatic mutations with the MAFs spanning in a range from 0.024% to 0.1% beyond 124 baseline mutations identified using standard PredicineCARE. In two representative cases presented here, all baseline mutations (genes TP53 and PIK3CA etc.) were consistently reported in the follow-up time points with a noticeable MAF reduction (lowest MAFs from 0.046% to 0.024%) during response. Subsequent elevations were observed in more genes, including low-frequency mutations (KRAS and ERBB2) not detected at baseline or only detected in PredicineCARE ULTRA. Conclusions: This study demonstrated the promise and clinical utility of the ultra-sensitive cfDNA molecular profiling at 100,000X sequencing depth in treatment selection, therapy monitoring, and drug resistance studies.
Efficacy and safety of trastuzumab deruxtecan and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer: A single-institution retrospective study.
Authors: Shimozaki Keitaro , Nakayama Izuma , Takahari Daisuke , Nagashima Kengo , Yoshino Koichiro , Fukuda Koshiro , Fukuoka Shota , Osumi Hiroki , Ogura Mariko , Wakatsuki Takeru , Ooki Akira , Shinozaki Eiji , Chin Keisho , Yamaguchi Kensei 
Published: January 2024

265 Background: Despite the difficulty of directly comparing trastuzumab deruxtecan (T-DXd) and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer (AGC) in randomized trials, discussions regarding optimal treatment strategies are desired. Methods: This single-institution retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as third- or later-line treatment for patients with HER2-positive AGC treated between March 2016 and May 2022. Results: Overall, 58 patients (median age, 64 years; 69% male) were eligible (T-DXd group, n = 20; nivolumab group, n = 38). Most had HER2 3+ (72%) and presented with metastatic disease at diagnosis (66%). Response rates in the 41 patients with measurable lesions were 50% and 15% in the T-DXd and nivolumab groups, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3–7.0) and 2.3 months (95% CI, 1.5–3.5), median overall survival of 10.8 months (95% CI, 6.9–23.8) and 11.7 months (95% CI, 7.6–17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% received subsequent treatment. Among 23 patients who received both regimens, the T-DXd–nivolumab and nivolumab–T-DXd groups had a median overall survival of 14.0 months (95% CI, 5.0–not reached) and 19.3 months (95% CI, 9.5–25.1), respectively. Conclusions: T-DXd and nivolumab had distinctive efficacy and toxicity profiles as third- or later-line treatment for HER2-positive AGC. Considering the distinct features of each regimen might help clinicians personalize the optimal treatment approaches for patients with HER2-positive AGC.
A scoring system for selecting nivolumab or irinotecan in the later-line chemotherapy for advanced gastric cancer: A Japanese multicenter retrospective study.
Authors: Amanuma Yusuke , Suzuki Takeshi , Kawakami Takeshi , Aoki Masahiko , Yamamoto Yoshiyuki , Shimozaki Keitaro , Satake Hironaga , Nojima Masanori , Boku Narikazu , Takahari Daisuke 
Published: January 2024

266 Background: Although Nivolumab (NIVO) or Irinotecan (IRI) monotherapy is one of the later-line chemotherapies for the advanced gastric cancer (AGC) patients, there are no prospective data of their comparison, and no indicators for selection of them. Methods: Clinical data of AGC patients treated with NIVO or IRI as later-line were collected from 7 institutions between September 2015 and September 2018. Efficacy of the two treatment groups was compared in the entire cohort and in the propensity score matching cohort. Factors which affect the prognosis were explored by multivariate analyses and the scoring system was developed using Cox regression. Results: In the analysis of entire cohort (317 patients), the median OS was 4.8 months (95% CI: 3.6–5.8) in the NIVO group and 5.9 months (95% CI: 4.9–7.2) in the IRI group, and those were 4.8 months (95% CI: 3.6–5.7) and 6.0 months (95% CI: 4.5–7.2) in the analysis of the propensity score matching cohort (248 patients), respectively. There were no differences in OS. We developed a risk score involving 1-Neutrophil to Lymphocyte Ratio (NLR), 2-age, 3-ECOG performance status, 4-peritoneal metastasis, 5-gastrectomy, and 6-liver metastasis to assess potential effect modification. Based on the result, IRI was favored in the higher-risk group (≥4 points, with double weight to 2, 3, and 4) for both OS/PFS. In contrast, NIVO was better OS/PFS in the lower-risk group (<1 point). Conclusions: According to the real-world data from multicenter in Japan, NIVO and IRI generally showed equivalent outcomes. The scoring system we explored may be useful for selecting appropriate later-line chemotherapy, either NIVO or IRI.
Comprehensive molecular characteristics of clinical responses to PD-1 inhibitors plus anti-angiogenic agents (PA) in metastatic HER2-negative gastric adenocarcinoma.
Authors: Wang Jingyuan , Liu Yutong , Liu Tianshu 
Published: January 2024

279 Background: Anti-angiogensis agents were reported to enhance the efficacy of PD-1 inhibitor by inhibiting the infiltration of suppressive immune cell populations. Clinical studies indicated the synergistic anti-tumor effect of the combination of PD-1 inhibitors and anti-angiogenesis agents (PA). We aim to assess the efficacy of PA versus chemo-PA regiment in mGC, as well as the potential predictive biomarkers. Methods: A total of 55 GC tumors were analyzed using the next-generation sequencing (NGS), immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence (mIHC). Clinical outcomes [Disease Control Rate (DCR), Progression-free survival (PFS) and overall survival (OS)] were compared between patients receiving PA treatment (n=32) and chemo-PA (n=23) treatment. Exploratory biomarker analyses were conducted for the prediction for the efficacy of PA/chemo-PA treatment. Results: Patients receiving PA regiment had comparable DCR (69% vs 50%, P =0.25) and PFS (median PFS: 6.53 vs 4.73 months, HR=0.70, 95%CI: 0.27-1.78, P =0.52), compared with those treated with combination of chemo-PA regiment as second or later-line treatment in mGC. Patients with HMCN1 wild-type showed significant improvements in DCR (77% vs 0%, P =0.023) and PFS (median PFS: 6.53 vs 1.17 months, P =0.0017), versus those with HMCN1 mutations in PA treatment cohort. HMCN1 mutations are associated with lower infiltration of endothelial cells and lower score of VEGF ligand-receptor interaction, according to the EPIC and pathway enrichment analysis ( P < 0.05). In addition, analysis of TIME by mIHC revealed that the fraction of CD68+ tumor-associated macrophages in the tumor center was higher in responders than non-responders before treatment (median: 17.59% vs 2.45%, P=0.016). Conclusions: PA regiment and chemo-PA regiment had similar efficacy in second or later line treatment of mGC. HMCN1 mutations maybe a predictive marker for PA regiment in HER2-negative mGC, which should be further validated in a large cohort.