HER2-positive breast cancer is an aggressive subtype that benefits from targeted therapies. According to the Chinese Society of Clinical Oncology (CSCO) guidelines and the National Comprehensive Cancer Network (NCCN), the combination of trastuzumab (H) with pertuzumab (P) and neoadjuvant chemotherapy has become the standard treatment for patients with HER2-positive breast cancer in the neoadjuvant setting. Nevertheless, the long-term survival benefits of neoadjuvant dual HER2 blockade (P + H) remain unaddressed by comprehensive meta-analyses to date. This study is the first systematic review and meta-analysis to directly compare the long-term efficacy of P + H vs. H (excluding trastuzumab-derived or similar drugs, such as T-DM1, T-DXd, and so on) in the neoadjuvant treatment of HER2-positive breast cancer. We conducted a systematic literature search in PubMed, Embase, the Cochrane Library, CNKI, Wan Fang, and VIP databases for relevant studies published up to June 1, 2025. RCTs with HER2-positive breast cancer patients who had not received breast cancer-related treatments previously were included. Treatment of P + H or H arms with chemotherapy combined with pertuzumab plus trastuzumab or trastuzumab as neoadjuvant treatment. The primary outcome was the event-free survival (EFS), disease-free survival (DFS), and overall survival (OS), and secondary outcomes included total pathological complete response (tpCR), objective response rate (ORR), and grade ≥ 3 adverse effects (AEs). The quality of evidence was assessed using the GRADE. A total of six RCTs involving 803 patients were included. In long-term efficacy, the P + H arm showed significant improvements in 3-year EFS rate (RR 1.08, 95

Carbapenem-producing Enterobacterales (CPE) pose a serious global health threat. This study aimed to develop a rapid and cost-effective ultraviolet (UV) spectrophotometry-based assay for detecting carbapenem resistance and identifying the carbapenemase enzyme category in Enterobacterales, thereby substantially reducing diagnostic turnaround times. The assay quantified Meropenem hydrolysis using ΔA = A300-A340 and was evaluated using 137 Enterobacterales strains. The hydrolysis level, measured by residual Meropenem after 3 h at 37 °C, was used to assess resistance. The A300-A340 method showed strong agreement with standard disk diffusion and VITEK-2 Compact results. Furthermore, the inhibitory effect of EDTA on Meropenem hydrolysis was tested on 79 CPE strains (35 MBL-producing and 44 non-MBL-producing) to differentiate carbapenemase categories, with PCR serving as the reference. A strong linear correlation (R2 = 0.9934) was observed between Meropenem concentration and ΔA. The assay demonstrated 98.54% accuracy in detecting Meropenem resistance using an 85% Meropenem retention threshold, and both the hydrolysis and inhibitor enhancement assays showed 97.47% specificity for distinguishing MBL from non-MBL producers. In conclusion, this UV spectrophotometry-based assay provides a rapid, accurate, and economical approach for detecting carbapenem resistance and classifying carbapenemase type, offering great potential for improving CPE infection management and guiding antibiotic therapy.

Gene fusions are an important driver of cancer and require rapid and accurate detection to guide clinical decisions. However, the performance characteristics of whole transcriptome sequencing (WTS) for the detection of gene fusions have not been thoroughly investigated. We developed a novel WTS-based assay for the detection of gene fusions, MET exon 14 skipping and EGFR VIII alterations in clinical samples. We defined a DV200 value ≥ 30

PurposeThis study investigated the clinical features, risk factors, and recurrence of immune-mediated liver injury (IMLI) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs).MethodsA retrospective cohort of 274 NSCLC patients receiving ICIs was analyzed. Baseline inflammatory markers, including white blood cell count (WBC), albumin levels, and prognostic nutritional index (PNI), were assessed for their association with IMLI. Risk factors were identified using logistic regression, and recurrence outcomes were analyzed.ResultsIMLI incidence was 35.4%, with 15.5% of cases classified as grade 3-4. WBC ≤11.0×109/L (P<0.001) and albumin ≥35 g/L (P<0.001) were independent predictors of IMLI. Among patients with IMLI, 28.9% experienced recurrence, with 17.9% classified as grade 3-4. Recurrence risk was not significantly higher than the initial onset (P=0.21).ConclusionLow baseline inflammatory status predicts IMLI in NSCLC patients undergoing ICI therapy. Monitoring baseline inflammatory markers can guide risk stratification, and re-challenging ICIs in selected patients appears feasible without significantly increasing recurrence risk.

Background: Multidrug-resistant (MDR) Pseudomonas aeruginosa, especially carbapenemase-producing strains, poses major clinical challenges due to their widespread dissemination and limited treatment options. Case and Methods: A 65-y-old patient with intracranial infection was hospitalized. An MDR P. aeruginosa strain isolated from her cerebrospinal fluid was analysed using MALDI-TOF mass spectrometry, antimicrobial susceptibility testing, and whole genome sequencing. Results: P. aeruginosa strain YB1 was resistant to carbapenems, cephalosporins, quinolones, and aminoglycosides, except colistin. Its genome comprised a 6.41-Mb chromosome and a 448-kb IncP-like plasmid. Six β-lactamase genes were identified on the chromosome: blaPER-1, blaOXA-1, blaIMP-45, and blaAFM-3 in the MDR region, with blaOXA-488 and blaPAO-201 located outside it. The chromosomal MDR region shared high homology with plasmid-borne Tn6485e, which originated from multiple plasmids. Specifically, the novel carbapenemase gene blaAFM-3 resided in a conserved transposon (ISCR27n3-groL-△floR-blaAFM-3-bleMBL-trpF-ISCR27n2), identical to that originally characterized in the Alcaligenes faecalis plasmid. Additionally, blaIMP-45 was located in a conserved type I integron (IntI-aac(6′)-Ib-blaIMP-45-blaOXY-1-catB3-△qacE-sul1). Notably, the 3′-terminal sequence of Tn6485e (IS26-aph(3′)-Ia-IS26-tet(C)-tetR(C)-IS26-IS6100), absent from the chromosomal MDR region, was found on YB1’s plasmid. Moreover, IS26 flanked the 71 600-bp chromosomal fragment covering the MRD region, with a 14-bp inverted repeat (5′-GGCACTGTTGCAAA-3′) on their outer sides in the same orientation, implying potential IS26-facilitated plasmid-chromosome recombination. Conclusions: This study first identified the coexistence of the blaAFM-3 and blaIMP-45 genes on the chromosome of P. aeruginosa. Monitoring gene transfer from plasmids to chromosomes is crucial, as it boosts bacterial survival against antibiotics and enables heritable resistance, threatening human health.

Fibrosis, characterized by excessive extracellular matrix (ECM) accumulation and fibroblast proliferation, significantly contributes to global morbidity and mortality, affecting millions worldwide. Despite its prevalence, the mechanisms underlying fibrotic skin diseases remain poorly understood, and effective treatments are scarce. This study leverages single-cell RNA sequencing (scRNA-seq) to unravel the heterogeneity of fibroblasts in fibrotic skin diseases, including normal skin, scar, keloid, and scleroderma. Through comprehensive analysis of scRNA-seq data from public repositories, we identified distinct fibroblast subpopulations specific to each fibrotic condition. Notably, pivotal regulators for each sub-fibroblast cluster were discovered: IRF4 for scar, CLOCK for keloid, RUNX3 for scleroderma, and HOXC4 for normal skin. Further, CLOCK was found to be predominantly expressed in keloid tissues, with its upregulation enhancing fibroblast proliferation and migration in vitro. Analysis of The Cancer Genome Atlas (TCGA) data revealed that CLOCK and its regulon genes were upregulated in skin cutaneous melanoma and even more so in metastatic tumors. Our findings underscore the utility of scRNA-seq in dissecting the cellular complexity of fibrotic skin diseases and highlight potential therapeutic targets. This study not only advances our understanding of fibroblast heterogeneity in fibrosis but also opens avenues for targeted therapeutic strategies, moving closer to personalized medicine for fibrotic diseases.

BACKGROUND:Klebsiella michiganensis, an emerging opportunistic pathogen, poses public health risks due to its increasing multidrug resistance (MDR), especially to carbapenems. CASE AND METHOD:A 46-year-old man with pulmonary fibrosis was hospitalized in Guangzhou, China, for worsening pneumonia. A multidrug-resistant K. michiganensis strain (YK6) was isolated from his sputum before treatment. The strain was characterized using MALDI-TOF mass spectrometry, antimicrobial susceptibility testing (AST), and whole genome sequencing (WGS). Targeted therapy guided by AST successfully resolved the infection. RESULTS:The YK6 strain exhibited resistance to carbapenems, β-lactam/β-lactamase inhibitors, cephalosporins, aminoglycosides, and quinolones, except colistin and tigecycline. Genomic analysis revealed a 41.9-kb MDR island and an intact I-E CRISPR-Cas system on the chromosome, along with two plasmids: IncFIA/IncFII plasmid pYK6-1 carrying blaKPC-2 and IncC plasmid pYK6-2 harboring blaVEB-3. A novel blaKPC-2-transposon in pYK6-1 was identified, consisting of a non-Tn4401 element (NTE)-like structure (Tn3-ISKpn27-blaKPC-2-ΔISKpn6-korC) flanked by inversely oriented ISKpn19-tnpM-tnpR elements and 31-bp inverted repeats never reported, a configuration did not reported previously. Furthermore, the blaVEB-3 genetic environment in pYK6-2 featured a unique cassette: IS26-IS6100-blaVEB-3-tnp-ISAs1-qacEΔ1-sul1-ISCR1. An additional ISAs1 insertion between the tnpF-like integrase and qacEΔ1 distinguishes it from similar blaVEB-3-harboring cassettes. The blaVEB-3 resistance region in pYK6-2 likely originated from homologous recombination mediated by IS26 and Tn5403, which flank the gene cassette. CONCLUSIONS:To our knowledge, this is the first report of concurrent blaVEB-3 and blaKPC-2 in K. michiganensis, along with a novel blaKPC-2 transposon structure. These findings highlight the urgent need for enhanced surveillance of MDR K. michiganensis to prevent treatment failures.

Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-β-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-β-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.

Central nervous system (CNS) aspergillosis is uncommon in immunocompetent patients. We present a 64-year-old man with chronic otitis media and uncontrolled diabetes. Aspergillus flavus was identified in cerebrospinal fluid via metagenomics next-generation sequencing technology. Initial voriconazole treatment offered limited relief, but personalized dosage adjustments, guided by drug concentration, led to remission. This case underscores the importance of diverse diagnostic approaches and tailored therapy for CNS Aspergillus infections.

Objective: To describe the distribution of lipoprotein (a) [Lp(a)] levels in non-arteriosclerotic cardiovascular disease (ASCVD) population in China and explore its influencing factors. Methods: This study was based on a nested case-control study in the CKB study measured plasma biomarkers. Lp(a) levels was measured using a polyclonal antibody-based turbidimetric assay certified by the reference laboratory and ≥75.0 nmol/L defined as high Lp(a). Multiple logistic regression model was used to examine the factors related to Lp(a) levels. Results: Among the 5 870 non-ASCVD population included in the analysis, Lp(a) levels showed a right-skewed distribution, with a M (Q1, Q3) of 17.5 (8.8, 43.5) nmol/L. The multiple logistic regression analysis found that female was associated with high Lp(a) (OR=1.23, 95%CI: 1.05-1.43). The risk of increased Lp(a) levels in subjects with abdominal obesity was significantly reduced (OR=0.68, 95%CI: 0.52-0.89). As TC, LDL-C, apolipoprotein A1(Apo A1), and apolipoprotein B(Apo B) levels increased, the risk of high Lp(a) increased, with OR (95%CI) for each elevated group was 2.40 (1.76-3.24), 2.68 (1.36-4.93), 1.29 (1.03-1.61), and 1.65 (1.27-2.13), respectively. The risk of high Lp(a) was reduced in the HDL-C lowering group with an OR (95%CI) of 0.76 (0.61-0.94). In contrast, an increase in TG levels and the ratio of Apo A1/Apo B(Apo A1/B) was negatively correlated with the risk of high Lp(a), with OR (95%CI) of 0.73 (0.60-0.89) for elevated triglyceride group, and OR (95%CI) of 0.60 (0.50-0.72) for the Apo A1/B ratio increase group (linear trend test P≤0.001 except for Apo A1). However, no correlation was found between Lp(a) levels and lifestyle factors such as diet, smoking, and physical activity. Conclusions: Lp(a) levels were associated with sex and abdominal obesity, but less with lifestyle behaviors.

Massive Open Online Courses (MOOCs) are a new phenomenon in education worldwide. In China, MOOCs have been widely used in medical courses. However, the effects of MOOCs on improving clinical skills are controversial. Therefore, we conducted the study to verify whether the application of MOOCs in medical courses can improve participants' clinical skills in China. A systematic literature search was carried out using the PubMed, Embase, Web of Science, CNKI and Wanfang databases according to the predetermined criteria. The Hedges' g and its corresponding 95% confidence interval were selected to assess the effects of MOOCs on participants' clinical skills. Subgroup analyses, sensitivity analysis and publication bias test were performed in the study. A total of thirty-two records (thirty-two studies) with 3422 participants were identified in our study. There was a significant improvement in clinical skill scores of participants in the MOOC group compared with the control group. Subgroup analyses showed similar results in different student groups. Our study supported the notion that the MOOC-based teaching method appeared to be a more effective method than the conventional teaching technique for the improvement of participants' clinical skills in China.

Objective: To describe the prevalence of daytime nap habit in participants of the China Kadoorie Biobank (CKB) study, across 10 study regions and explore its correlation with prevalence of major chronic diseases. Methods: Participants with a self-reported pre-diagnosis of any cancer at baseline survey were excluded. Logistic regression models were used to analyze the differences in study regions and age distribution of the prevalence daytime nap habit, and its correlation with the prevalence of diabetes, hypertension, coronary heart disease (CHD), stroke, chronic obstructive pulmonary disease (COPD), and chronic liver diseases. Results: Among 510 145 participants, 39.9% had daytime nap habit in summer and 20.8% had daytime nap habit all the year round. Urban-rural differences were observed in the prevalence of summer nap habit and perennial nap habit. Daytime nap in summer was common in rural areas and Suzhou, with prevalence ranged from 32.9% to 73.3%. Haikou and Liuzhou had higher prevalence of perennial nap (60.4% and 63.3%). The proportion of people with daytime nap habit all the year round increased with age (P for trend <0.001), the proportion was highest in those aged 70- years (31.9%). Daytime nap habit in summer was positively correlated with the prevalence of diabetes, hypertension, CHD and chronic liver disease with OR of 1.10 (95%CI: 1.07-1.14), 1.03 (95%CI:1.02-1.05), 1.07 (95%CI: 1.02-1.12) and 1.07 (95%CI:1.00-1.14), respectively. Daytime nap habit all the year round was positively correlated with the prevalence of diabetes, hypertension, CHD, stroke, COPD and chronic liver disease with OR of 1.33 (95%CI: 1.29-1.37), 1.11 (95%CI: 1.09-1.13), 1.39 (95%CI: 1.33-1.45), 1.33 (95%CI: 1.26-1.41), 1.12 (95%CI: 1.08-1.16) and 1.27 (95%CI:1.18-1.37) respectively. Conclusion: There were regional and age differences in prevalence of daytime nap habit among CKB participants. Daytime nap habit, especially daytime nap habit all the year round, was positively correlated with the prevalence of major chronic diseases.

AbstractBackgroundNeuroendocrine carcinomas of the gastrointestinal tract (GI‐NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI‐NECs.MethodsComprehensive genomic analysis using whole‐exome sequencing was performed on 143 formalin‐fixed, paraffin‐embedded samples of surgically resected GI‐NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors.ResultsIn total, 143 GI‐NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty‐three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI‐NECs showed distinct genetic alterations from their lung counterparts and non‐neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low‐density lipoprotein receptor‐related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT‐β‐catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI‐NECs harbored putative clinically relevant alterations, and non‐gastric location andRB1bi‐allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI‐NECs first gain clonal mutations inTP53,RB1,NOTCH1andAPC, followed by subsequent whole‐genome doubling (WGD) and post‐WGD clonal mutations inLRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb‐b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations.ConclusionsGI‐NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI‐NECs.

e12089 Background: The efficacy evaluation of neoadjuvant chemotherapy (NCT) for locally advanced breast cancer (LABC) is still a questionable issue. The clinical imaging is always discrepant from pathological assessment postoperatively, and conventional tumor markers, such as CEA and CA15-3, did not show significantly correlation with the response to NCT in breast cancer patients. Analysis of circulating tumor DNA (ctDNA) from blood may provide a promising alternative. Methods: Collectively, 63 tissue and 204 blood samples from 32 patients with LABC were collected. There were four sampling nodes for blood collection: at baseline, during chemotherapy, after chemotherapy and after operation. Hybrid capture-based genomic profiling with a 1021-gene panel was carried out for both tissue and blood samples. Results: Totally, 151 somatic mutations were detected in tissue samples from 32 patients. TP53 (n = 14, 43.75%) and PIK3CA (n = 13, 40.63%) were the most recurrent mutant genes. Among 11 patients with HER2 overexpression, 10 (90.91%) carried ERBB2 amplification. All of 21 patients with normal HER2 present diploid ERBB2. The overall concordance between HER2 overexpression and ERBB2 amplification was 96.88%. At least one tissue mutation could be detected in blood collected at baseline for 21 patients, during chemotherapy for three patients, after chemotherapy for nine patients, and after operation for four patients. There was no tissue mutation in blood collected during and after chemotherapy for four patients reached pathologic complete response (pCR). The median of pathological tumor decrease in situ was 54.63% (17.07% to 98.04%) for patients with tissue mutations in blood collected either during or after chemotherapy, and 86.53% (7.69% to 98.04%) for patients without tissue mutation in both blood samples. Furthermore, the median number of pathologically involved lymph nodes was 3.5 (0 to 16) and 1 (0 to 9) for two patients cohort, respectively. All of four patients with tissue mutations in postoperative blood experienced distant metastasis during follow-up, while only 7.14% (2/28) of those without tissue mutation relapsed. The median DFS was 9.8 and 22.7 months, respectively (HR 26.14, 95% CI 1.161 to 588.5, p < 0.0001). Conclusions: Sequential genomic profiling of blood ctDNA can be used to evaluate the therapeutic efficacy of NCT, as well as the postoperative survival. This study highlights the feasibility of integrating ctDNA profiling into the clinical management for LABC undergoing NCT. Clinical trial information: NCT02797652.

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor (p = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p < 0.001) but the worse outcomes in non-EGFR-treated (HR 2.623, p = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p = 0.001) and non-EGFR-treated patients (HR 0.308, p = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.

Abstract Background: Immunotherapy can induce a long response in part patients of lung squamous cell carcinoma (LUSC). And accurate biomarkers are needed for suitable populations. As important tumor suppressor, tumor protein p53 (TP53) and low density lipoprotein receptor-related protein 1B (LRP1B) genes may be associated with immunogenicity. However, the interaction of TP53 and LRP1B and its potential association with response to immunotherapy are not fully understood in LUSC. Methods: Three cohorts were divided into four groups, respectively (A: TP53mut and LRP1Bmut, B: TP53mut and LRP1Bwild, C: TP53wild and LRP1Bmut, D: TP53wild and LRP1Bwild). 525 LUSCs form Geneplus database which performed next-generation sequencing were assessed the differences of genomic landscape, tumor mutation burden (TMB), and PD-L1 expression in four groups (cohort 1). TCGA-LUSC RNA data (n=466) from cBioPortal were used to evaluate immune cell infiltration thought single sample gene set enrichment analysis (cohort 2). The LUSCs (n=125) which received immunotherapy of POPLAR and OAK cohort were used to evaluate the efficacy of immunotherapy in four groups (cohort 3). Results: The proportion of patients in A, B, C and D groups of cohort 1 was 26%, 59%, 2%, 13%, respectively, suggesting that most patients with LRP1B mutation also carry TP53 mutation (98.6%) in LUSC. This similar ratio is 88.2% in cohort 2 and 74.3% in cohort 3. For group A, the most common mutated gene except TP53 and LRP1B was CDKN2A (31%). Group B was MLL2(28%). Group C was CDKN2A (33%). Group D was FAT1 (13%). The median TMB was 14.4 mutations/Mb (2.9-80.0) in group A, 9.8 (0.96-95.0) in group B, 11.5 (2-25) in group C, 3.8 (0.96-18.2) in group D. TP53 and LRP1B co-mutation had a highest TMB compared with the other three groups in all cohorts, while TP53wild and LRP1Bwild completely opposite. In cohort 1, PD-L1 expression had no significant difference in four groups. In cohort 3, progression-free survival (PFS) was longer in group D compared with the other three groups (p = 0.047, A: 1.5m, B: 1.6m, C: 2.1m, D: 4.2m). The same trend on overall survival (OS) were found but it was not significant. Group D also had a higher disease control rate (A: 50%, B: 46%, C: 44%, D: 69%). We than divide into two groups (D vs Other) to compare PFS and OS. It showed that group D had a prolonged PFS (p = 0.02) and OS (p = 0.03). Multivariate cox regression analysis showed that the results were independent of TMB, gender and age. Analysis of immune cell infiltration in cohort 2 showed that the better outcomes of group D might associated with elevated infiltrations of activated dendritic cell and activated CD8 T cell. Conclusion: TP53mut and LRP1Bmut, which accounted for a high proportion of LUSC, was associated with high TMB. And TP53wild and LRP1Bwild has better anti-PD-L1 outcome in LUSC. This might be related with a stronger activated dendritic cell and activated CD8 T cell infiltration despite lower TMB. Citation Format: Jiangyong Yu, Zhipeng Zhou, Ping Zhang, Pansong Li, Xu Li, Min Tang, Nannan Fan, Xiaonan Wu, Xin Nie, Xiaoyan Chen, Di Ma, Xi Chen, Yanfang Guan, Xuefeng Xia, Ling Yang, Xin Yi, Lin Li. Association of TP53 and LRP1B co-mutation status with response to immunotherapy in lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2492.

Next‐generation sequencing (NGS)‐based circulating tumor DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. Studies for T cell lymphoma are limited.

PURPOSE:We investigated the value of circulating tumor DNA (ctDNA) in predicting tumor response to neoadjuvant chemoradiotherapy (nCRT), monitoring tumor burden, and prognosing survival in patients with locally advanced rectal cancer (LARC).EXPERIMENTAL DESIGN:This prospective multicenter trial recruited 106 patients with LARC for treatment with nCRT followed by surgery. Serial ctDNAs were analyzed by next-generation sequencing at four timepoints: at baseline, during nCRT, presurgery, and postsurgery.RESULTS:In total, 1,098 mutations were identified in tumor tissues of the 104 patients being analyzed (median, seven mutations/patient). ctDNA was detected in 75%, 15.6%, 10.5%, and 6.7% of cases at the four timepoints, respectively. None of the 29 patients with pathologic complete response (ypCR) had preoperative ctDNA detected. The preoperative ctDNA-positive rate was significantly lower in the well-responded patients with pathologic tumor regression grade of ypCAP 0-1 than ypCAP 2-3 group (P < 0.001), lower in ypCR than non-ypCR group (P = 0.02), and lower in pathologic T stage (ypT) 0-2 than ypT 3-4 group (P = 0.002). With a median follow-up of 18.8 months, 13 patients (12.5%) experienced distant metastasis. ctDNA positivity at all four timepoints was associated with a shorter metastasis-free survival (MFS; P < 0.05). Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in baseline ctDNA was a strong independent predictor of MFS (HR, 1.27; P < 0.001).CONCLUSIONS:We show that ctDNA is a real-time monitoring indicator that can accurately reflect the tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of MFS.

Objective This study aimed to quantitatively summarize the evidence for VDR BsmI gene polymorphism and osteoporosis risk in postmenopausal women. Materials and methods The PubMed, EMBASE, Weipu, CNKI, and Wanfang databases were searched for eligible studies. Case-control studies containing available genotype frequencies of B/b were chosen, and odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association. Results 4485 osteoporosis and 5490 controls were identified in our meta-analysis. In the stratified analysis, a significant association was observed between VDR BsmI gene polymorphism and osteoporosis susceptibility in Caucasians (additive model: OR = 0.809, 95% CI 0.678~0.965, p = 0.019; recessive model: OR = 0.736, 95% CI 0.568~0.955, p = 0.021; and co-dominant model: bb vs. BB OR = 0.701, 95% CI 0.511~0.962 p = 0.028), and we failed to find any significant relationship in Asians. Conclusion The present meta-analysis suggests that VDR BsmI genotype is associated with increased risk of postmenopausal osteoporosis in Caucasians but not in Asians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between VDR BsmI polymorphism and osteoporosis in postmenopausal women.

Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. This prospective cohort study enrolled 46 patients with stage I–III gastric cancer that underwent resection with curative intent. Sixty resected tumor samples and 296 plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. ctDNA detection was correlated with clinicopathologic features and post-operative disease-free (DFS) and overall survival (OS). ctDNA was detected in 45% of treatment-naïve plasma samples. Primary tumor extent (T stage) was independently associated with pre-operative ctDNA positivity ( p = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 95%CI, 7.991–61.29, p < 0.0001 and HR = 7.664, 95% CI, 2.916–21.06, p = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.