bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVID-19 restrictions limit the circulation of H3N2 canine influenza virus in China
Authors: Guo Tingting , Ai Hui , Chen Mingyue , Wang Daoqi , Zhang Qingru , Wang Rui , Wang Zhen , Tong Qi , Liu Litao , Sun Honglei , Pu Juan , Liu Jinhua , Lyu Yanli , Sun Yipeng 
Published: June 2024

AbstractCanine health is consistently affected by the circulation of the H3N2 strain of canine influenza virus (CIV). Prior research has indicated that the isolation rate of H3N2 CIVs in dogs has gradually increased in China, and these viruses have progressively adapted to humans over the course of their evolution within canine hosts, posing a significant public health threat. However, the key factors influencing the spread of CIVs remain elusive. From January 2020 to December 2022, during the COVID-19 pandemic, strict epidemic prevention policies were implemented in China. Thus, this measure provides an ideal model for studying factors influencing the prevalence of CIVs. In this study, we continuously monitored the prevalence of CIVs in China before and after the COVID-19 pandemic. We found that the pathogen detection rate and seropositivity rate of domestic CIVs significantly declined after the implementation of epidemic control measures. However, after restrictions on human movement were lifted in 2023, the circulation of CIVs gradually increased. Our results demonstrate that restricting human activity directly impacts the epidemic caused by CIVs and provide a theoretical basis for the implementation of control measures during outbreaks of zoonotic diseases in human companion animals.
Heterogeneous reservoir seepage characterized by geophysical, hydrochemical, and hydrologic methods
Authors: Mao Deqiang , Wang Yaxun , Guo Qifeng , Li Dianji , Liu Shiliang , Meng Jian , Hu Leijian 
Published: June 2024

Seepage characterization from reservoirs is challenging for various environmental and water resource applications. Nonintrusive geophysical methods can achieve excellent detection results, but they cannot provide a quantitative description of the amount of seepage. Integrating geophysical methods with traditional hydrochemical and hydrologic methods enables simultaneous localization and quantitative analysis of heterogeneous reservoir seepage. Ground and waterborne electrical resistivity tomography are used to scan a reservoir under a typical cutoff wall antiseepage system, and the measurements reveal the northern preferential infiltration area. The hydrochemical results reveal that the seepage bypass of the cutoff wall has led to evident ion concentration variations in groundwater near the dam. Based on the geologic stratum information, the typical cutoff wall antiseepage system is divided into three scenarios for numerical simulation to calculate the seepage. The total seepage of the reservoir over 15 months is approximately 7.15 × 106 m3, which is consistent with traditional water budget methods. However, in the northern part of the reservoir, only 27% of the entire dam contributes 77% of the total seepage. All methods have confirmed that the heterogeneous seepage is caused by the absence of an antiseepage seal in the northern region, which should be a primary focus for future monitoring and operational efforts. With the geophysical results undergoing extensive cross-validation, the results from the preceding methods are comprehensively leveraged, effectively lowering uncertainties and overcoming the limitations of geophysical methods in quantitatively characterizing seepage.
Results from phase 1a/1b analyses of TTX-080, a first in class HLA-G antagonist, in combination with cetuximab in patients (pts) with metastatic colorectal cancer and head and neck squamous cell carcinoma.
Authors: Ulahannan Susanna Varkey , Marron Thomas Urban , Park Haeseong , Kaczmar John M. , Stephenson Ryan D. , Lakhani Nehal J. , Durm Greg Andrew , Grewal Jaspreet Singh , El-Khoueiry Anthony B. , Luke Jason J. , Beers Courtney , Murugappan Swaminathan , LoRusso Patricia , Adkins Douglas , Hecht J. Randolph 
Published: June 2024

2524 Background: TTX-080 is an IgG1 monoclonal antibody targeting HLA-G. This Ph1a/1b study evaluated the safety and preliminary efficacy of TTX-080 alone or in combination with cetuximab (Cetx) or pembrolizumab (Pem) in multiple solid tumor cohorts (NCT04485013). Herein, we report the safety from the Ph1a and preliminary efficacy data from Ph1b cohorts evaluating TTX-080 + Cetx in pts with head and neck squamous cell carcinoma (HNSCC) and WT RAS/BRAF, HER2-Neg metastatic colorectal cancer (mCRC) tumors. Methods: In Ph1a, pts with advanced solid tumors received single agent TTX-080 at escalating doses in a 3+3 design from 0.2-20 mg/kg IV Q3W. In the mCRC and HNSCC arms of Ph1b, pts were treated with RP2D of TTX-080 + Cetx. Patients were followed for safety and anti-tumor activity. Biopsies and blood samples were collected for biomarker analyses. Results: As of 08-Dec-23, 202 pts have received TTX-080 alone or in combination (40 pts in Ph1a and 162 pts in Ph1b). In Ph1a TTX-080 monotherapy dose-escalation, MTD was not reached and no DLT was reported. TTX-080 treatment-related AE (TRAE) of arthralgia, fatigue, and decreased appetite were seen in at least 5% of pts. R2PD for TTX-080 was determined to be 20 mg/kg IV Q3W. In Ph1b of TTX-080 alone or in combination (Cetx or Pem), the most common TRAEs in at least 5% of subjects were fatigue, nausea, anemia, diarrhea, AST increase, headache, vomiting and pruritis. Preliminary efficacy data from the select Ph1b TTX-080 + Cetx subset of pts are shown in Table. Significant HLA-G related immune cell changes in the peripheral blood and in tumors will be presented. Conclusions: TTX-080 is well tolerated alone and in combination with Cetx. TTX-080 + Cetx demonstrates promising activity in pts with HPV-Neg HNSCC and WT RAS/BRAF/Her2-Neg mCRC as manifested by the responses and PFS. These early findings warrant further investigation of TTX-080 + Cetx in a randomized controlled study against standard of care in mCRC and HNSCC. Clinical trial information: NCT04485013 . [Table: see text]
Correlations between first cycle toxicity and overall survival in patients with rare cancers treated with immune checkpoint inhibitors (NCI/SWOG S1609).
Authors: Othus Megan , Patel Sandip Pravin , Chae Young Kwang , Dietrich Eliana , Streicher Howard , Sharon Elad , Kurzrock Razelle 
Published: June 2024

2655 Background: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity incidence and overall survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers to evaluate associations between irAEs and overall survival (OS) and progression-free survival (PFS) in a cohort of patients treated with combination checkpoint inhibitor therapy. Methods: We evaluated irAEs observed in the first cycle (6 weeks) of therapy that were possibly, probably, or definitely related to treatment; irAE grade was based on CTCAEv5. Patients received ipilimumab [1mg/kg intravenously (IV) every 6 weeks] plus nivolumab (240mg IV every 2 weeks). Landmarks methods were used to avoid immortal-time bias; PFS and OS were analyzed from day 43 with patients who died or progressed before that date excluded from analyses. Cox regression analyses were used to evaluate covariate associations. Results: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer OS (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p<0.001) compared to no treatment-related irAE in the first cycle, while grade 3-4 irAEs were associated with shorter OS (HR=1.41, 95% CI=1.04-1.90, p=0.025). Similar, but weaker, associations were observed with PFS, grade 1-2 treatment-related irAEs: HR=0.83, 95% CI=0.67-1.01, p=0.067 and grade 3-4: HR=1.35, 95% CI=1.02-1.78, p=0.037 compared to no treatment-related irAE in the first cycle. Grade 1-2 dermatologic toxicity were associated with improved OS compared to other grade 1-2 toxicities (HR=0.67, 95% CI=0.52-0.85, p=0.002). There were no significant differences between OS among patients with Grade 1-2 gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities and fatigue and other Grade 1-2 toxicities. Conclusions: In this large cohort of patients with rare tumors receiving ipilimumab and nivolumab grade of irAE in the first cycle of therapy was prognostic for survival.
Comprehensive analysis of TMB, TNB, and HLA via NGS sequencing in a large cohort of Chinese pan-cancer patients.
Authors: Jin Chunhui , Wang Xu , Liao Yanlin , Guan Minxiao , Wu Huijia , Zhao Jiaxing , Jiang Zeyu , Zhang Yafei , Long Ying 
Published: June 2024

2656 Background: Evidence suggests that patients with high tumor mutational burden (TMB) and tumor neoantigen burden (TNB) are more likely to benefit from Immune checkpoint inhibitors (ICIs). Furthermore, loss of heterozygosity (LOH) in human leukocyte antigen (HLA) alleles, particularly HLA class I, impairs neoantigen presentation and contributes to resistance against ICIs. This study provides real-world insights into the distribution of TMB, TNB, and HLA variations within a large cohort of Chinese patients with various cancers. Methods: From 2021 to 2023, we performed a retrospective analysis on 1603 cancer patients, examining genetic mutations and HLA traits using the Med1 CDx DNA-based NGS panel targeting 601 cancer-related genes and HLA class I. TMB was calculated as the average number of coding mutations per megabase of the genome. HLA class I alleles (HLA-A, B and C) were identified and predicted using the OptiType and pVACtools software suites. TNB was defined as the number of high-affinity (IC50 ≤ 50 nM) neoantigens per megabase of the genome. Statistical analyses were performed to explore the relationship between TMB, TNB, and LOH status in critical regions of HLA. Results: This study enrolled participants across 25 cancer types. With 32.56% having non-small cell lung cancer (NSCLC), 11.79% colorectal carcinoma (CRC), and 18.34% unidentified solid tumors. The remaining 37.31% comprised cases of cholangiocarcinoma, hepatocellular carcinoma, pancreatic cancer, etc. High-affinity neoantigen-generating genes such as TP53, EGFR, KRAS, LRP1B, DMD, and FAT1 were identified. Our findings indicate substantial variation in tumor neoantigen burden (TNB) across various cancer types and even among different samples within the same type. Neuroendocrine tumors exhibited the highest TNB at 4 neoantigens/Mb, followed by esophageal cancer (3.3), melanoma and urothelial carcinoma (2.67 each), indicating higher TNB levels in these cancers compared to others. A significant positive correlation was observed between TMB and TNB (p< 0.0001). Analysis revealed no significant TNB differences attributable to age (cutoff at 60 years) or gender. However, individuals aged over 70 years demonstrated a higher TNB of 4 compared to those under 70 with 3.33, highlighting potential age-related differences in TNB. Conclusions: Our analysis highlights significant variation in TNB across cancer types, with the highest TNB found in neuroendocrine tumors and the lowest in gastrointestinal stromal tumors, indicating TNB's value as a biomarker for optimizing ICI therapy. Furthermore, we found that people over 70 years old have higher TNB levels than younger individuals, suggesting a potential for improved ICI efficacy without chemotherapy. The evident strong correlation between Tumor Mutational Burden (TMB) and TNB underlines their crucial role in the success of cancer immunotherapy.
A phase 1/2 study of LM-302, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate in patients with advanced gastric/gastroesophageal junction cancer.
Authors: Bai Chunmei , Xue Junli , Zheng Yi , Sun Meili , Ying Jieer , Zhou Fuxiang , Yu Yiyi , Sun Yuping , Xing Ligang , Zhang Yanqiao , Wen Jinhua , Xiong Jianping , Wu Heshui , Yang Xiuli , Wan Lixin , Guo Shiwei , Zhao Rusen , Zhu Zhizhen , Gong Zhihua , Li Jin 
Published: June 2024

3028 Background: LM-302 is a novel and potent MMAE antibody-drug conjugate (ADC) targeting CLDN18.2, which is highly expressed in gastric/gastroesophageal junction (GEJ), pancreatic, and biliary tract cancers. Preclinical studies of LM-302 have demonstrated compelling anti-tumor activity in multiple CLDN18.2-positive cell-lines and xenograft models. Methods: This phase 1/2 study included dose escalation phase and dose expansion phase. In the dose escalation phase, eligible patients received LM-302 once every three weeks (0.2-2.8 mg/kg Q3W), and once every two weeks (1.8-2.0 mg/kg Q2W) to evaluate the safety, tolerability, and pharmacokinetics. In the dose expansion phase, CLDN18.2-positive patients received LM-302 at recommended phase 2 doses of 2.4 mg/kg Q3W or 1.8 mg/kg Q2W to evaluate the efficacy and safety. The primary endpoints included dose-limiting toxicity (DLT) and adverse events (AEs) in phase 1, and objective response rate (ORR) in phase 2. Here we report the results from safety analysis of LM-302 and efficacy data in gastric/GEJ cancer. Results: As of September 23, 2023, 135 patients received LM-302 treatment and the median prior lines of systemic therapy were 2 (range 1-4). In phase 1 and 2, most common TRAEs were white blood cell decreased (51.9%), neutrophil count decreased (51.1%), anaemia (38.5%), vomiting (36.3%), and nausea (34.1%). The most frequent grade ≥3 TRAEs were neutrophil count decreased (22.2%) and white blood cell decreased (17.8%). In phase 2 dose expansion, 52 CLDN18.2-positive (TC ≥ 50%, IHC ≥ 2+) gastric/GEJ cancer patients were enrolled (4 pts at 2.4mg/kg Q3W, 48 pts at 1.8mg/kg Q2W). 1.8mg/kg Q2W was selected for further evaluation based on PK, safety, and efficacy data analysis. Of 36 evaluable gastric/GEJ cancer patients who received at least two or more prior therapies, 11 partial response (PR) and 16 stable disease (SD) were observed. The ORR was 30.6% (11/36), and DCR was 75.0% (27/36). The median PFS was 7.16 months (95% CI 2.72-NA). The median overall survival (OS) was not reached, with an OS rate of 95.0% at the 6-month (as of November 15, 2023). Conclusions: LM-302 was well-tolerated with a manageable safety profile and demonstrated promising anti-tumor activity in CLDN18.2-positive patients with third-line and beyond gastric/GEJ cancer. The results support further investigation of LM-302 as a new therapeutic approach to treat CLDN18.2-positive gastric/GEJ cancer. Clinical trial information: NCT05161390 .
Artificial intelligence (AI) -powered H&E whole-slide image (WSI) analysis of tertiary lymphoid structure (TLS) to predict response to immunotherapy in non-small cell lung cancer (NSCLC).
Authors: Kim Leeseul , SHIN Sangwon , Cho Soo Ick , Jung Wonkyung , Song Sanghoon , Chung Liam IL Young , Ock Chan-Young , Chae Young Kwang 
Published: June 2024

3135 Background: Recent data indicate that immune cells present in the TLS within the tumor microenvironment (TME) could potentially serve as a favorable predictor for immune checkpoint inhibitor (ICI) therapy. To examine this further, AI model was created to provide an assessment of TLS in H&E WSI, and to determine its correlation with survival outcomes of NSCLC patients treated with ICI. Methods: We collected H&E-stained WSI of primary and metastatic tumors and clinical data in a retrospective study of advanced-stage NSCLC patients treated with ICI (with or without chemotherapy) at Northwestern University from May 2015 to November 2022. When evaluating the TLS status in the biopsy specimen collected from the lymph nodes (LNs), TLSs were only considered if they were admixed with tumor cells and located distant from the residual parenchyma, ensuring the exclusion of innate lymphoid follicles. Following the assessment of the presence of TLS by a pathologist, the identical WSIs were evaluated by the AI-powered H&E WSI analyzer. We used Lunit SCOPE IO, an AI-powered H&E WSI analyzer developed using 21,096 H&E stained WSIs, which can segment various classes of tissue area including TLS within the TME. Survival analysis was performed using Kaplan-Meier curves, and differences in survival outcomes among TLS groups were evaluated using the log-rank test. Results: In this analysis, out of a total of 73 patients, 24 (33%) cases were identified as containing TLS (TLS +) by the AI analyzer. In contrast, the pathologist classified 17 (23%) cases as TLS+. The AI model demonstrated an accuracy of 84.9% (with a sensitivity of 88.2% and specificity of 83.9%) in identifying the presence of TLS compared to the pathologist's interpretation. The median value of the proportion of TLS area within TME (TLSP) in samples containing TLS was 0.418% (Q1: 0.228%, Q3: 1.311%). TLSP was not found to be correlated with survival outcomes. The number of clusters of TLS was not found to be correlated with survival outcomes. Conclusions: AI-powered TLS analysis can be potentially utilized as a predictive biomarker of survival outcomes of NSCLC patients treated with ICI. [Table: see text]
Therapeutic implications of acquired high tumor mutational burden (TMB-H) after targeted therapy (TT) in metastatic colorectal cancer (mCRC).
Authors: Yeh Celine , Harrold Emily , Keane Fergus , Sinopoli Jenna Cohen , Foote Michael Bonner , Cercek Andrea , Yaeger Rona 
Published: June 2024

3542 Background: mCRC treated w/ TT can acquire a high number of mutations at progression. TMB is used as a proxy of neoantigen load for predicting benefit from immune checkpoint blockade (ICB). In TMB-H CRC, benefit to ICB is restricted to microsatellite unstable (MSI-H) hypermutated or POL-D/E ultramutated tumors. We asked whether TT can sensitize microsatellite stable (MSS) CRCs to ICB by inducing an acquired TMB-H state. Methods: We screened the MSK-IMPACT dataset for mCRC patients (pts) who received TT and underwent pre-treatment (pre-TT) and post-progression (post-TT) tissue or liquid biopsies (LBx). We included pts who received TT against EGFR, BRAF V600E, KRAS G12C, or HER2. DNA sequencing of tissue and LBx was performed w/ MSK-IMPACT and Guardant 360. MSI status was assessed with algorithms measuring somatic changes in length of repetitive sequences (e.g., MSIsensor). Due to known discrepancies between tissue TMB (tTMB) and blood TMB (bTMB), we defined acquired TMB-H as: 1) tTMB <10 mut/Mb or bTMB <20 mut/Mb pre-TT; 2) ≥5-fold increase in TMB post-TT; 3) tTMB ≥10 mut/Mb or bTMB ≥40 mut/Mb post-TT. Results: We identified 26 pts w/ paired samples that had been sequenced w/ determination of TMB. 4/26 (15%) met criteria for acquired TMB-H. None had detectable pathogenic mismatch repair or DNA damage repair alterations pre-TT. All 4 post-TT samples were LBx only. One pt’s tumor acquired a somatic MLH1 mutation and converted from MSS to MSI-H. In all cases, the majority of acquired mutations were subclonal w/ many at variant allele frequencies (VAF) of ≤1% (Table). After detection of acquired TMB-H, 2/4 pts received ICB. Pt 1 had RAS wild type mCRC w/ pre-TT tTMB 6.9. She received irinotecan + panitumumab for 25.8 months. Post-TT bTMB was 40.19 and met criteria for MSI-H. She received pembrolizumab and experienced clinical + radiographic progression of disease (POD) within 49 days. Pt 2 had KRASG12C-mutant mCRC w/ pre-TT bTMB 13.4 and tTMB 4.9. She received sotorasib + panitumumab for 3.2 months w/ post-TT bTMB 145.34. She received pembrolizumab + regorafenib and experienced clinical + radiographic POD within 37 days. Conclusions: In CRC, acquisition of TMB-H at progression w/ predominantly low VAF mutations suggests activation of enhanced mutagenesis due to therapeutic pressure from exposure to TT. In this context, TMB may not be an accurate reflection of tumor immunogenicity as it does not distinguish between clonal and subclonal alterations. Our data suggest that pts w/ acquired TMB-H following TT are unlikely to benefit from ICB. [Table: see text]
Efficacy of FOLFIRI plus bevacizumab versus FOLFIRI plus cetuximab in RAS-mutant metastatic colorectal cancer: Final update on patients with RAS-mutant metastatic colorectal cancer treated in FIRE-3.
Authors: Weiss Lena , Stintzing Sebastian , Modest Dominik Paul , von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Lerchenmuller Christian A. , Kahl Christoph , Seipelt Gernot , Kullmann Frank , Moehler Markus H. , Scheithauer Werner , Held Swantje , Miller-Phillips Lisa , Stahler Arndt , Jung Andreas , Heinemann Volker 
Published: June 2024

3550 Background: Doublet chemotherapy plus bevacizumab is a well-established standard of care in the first-line treatment of RAS-mutant (RASmut) metastatic colorectal cancer (mCRC). The FIRE-3 trial was the first randomized study to compare FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC. Since this trial initially included patients irrespective of RAS mutation status, the present analysis performs an updated evaluation of therapeutic efficacy of targeted therapy with bevacizumab versus cetuximab in RASmut mCRC. Methods: FIRE-3 trial included 752 patients. Initially, pyrosequencing (PSeq) was used to identify RAS mutations. In a subsequent investigation next-generation sequencing (NGS) was applied in 373 available tumors. A 5% mutant allele cutoff was used for both PSeq and NGS both of which were done centrally. Results: Of the 224 RASmut and BRAF wild-type patients, 187 were identified by polymerase chain reaction (PCR) and PSeq, 122 by NGS. 86 tumors were PCR positive and NGS positive (PCR+/NGS+), 36 tumors PCR negative and NGS positive (PCR-/NGS+). In the overall RASmut cohort of 224 patients, no overall survival (OS) benefit was observed when cetuximab was compared to bevacizumab (20.3 months vs 21.1 months; HR 1.028; 95% CI, 0.547-1.583; P=.842). This effect was observed independent of sidedness of primary tumors (PT) for left-sided (21.5 months vs 22.1 months; HR 1.054; 95% CI, 0.763-1.456) and right-sided PT (19.2 months vs 19.5 months; HR 0.931; 95% CI, 0.547-1.583). Conclusions: While cetuximab notably is not effective in RASmut mCRC, this randomized comparison does not provide an indication for superior efficacy of bevacizumab in the first-line treatment of this patient group. Trial identification number: NCT00433927 [clinicaltrials.gov]