Journal of Chemotherapy最新文献

{"title":"Pembrolizumab associated immune thrombocytopenia.","authors":"Perihan Perkin, Serhat Sekmek, Dogan Bayram, Fahriye Tugba Kos","doi":"10.1080/1120009X.2025.2468045","DOIUrl":"https://doi.org/10.1080/1120009X.2025.2468045","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with immune-related adverse events (irAEs). Pembrolizumab, an anti-PD-1 antibody, is widely used in non-small cell lung cancer (NSCLC), yet immune thrombocytopenia remains a rare but potentially fatal complication. We report a case of a 55-year-old male with metastatic NSCLC who developed pembrolizumab-associated immune thrombocytopenia. The patient initially responded well to combination therapy with pembrolizumab, carboplatin, and pemetrexed, achieving a metabolic complete response. However, after several cycles, he experienced recurrent grade 3 thrombocytopenia. Immune thrombocytopenia was suspected and managed with corticosteroids, leading to platelet recovery. Upon pembrolizumab rechallenge, thrombocytopenia recurred, necessitating permanent discontinuation of pembrolizumab while continuing pemetrexed maintenance. This case underscores the need for early recognition and prompt management of ICI-induced thrombocytopenia to ensure patient safety while optimizing oncologic outcomes.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"1-5"},"PeriodicalIF":1.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of SARS-CoV-2 infection on clinical characteristics, antibody levels, and immune responses in patients with malignant hematological tumors.","authors":"Yan Li, Jing Zhang, Xiang Wang, Yan Wang, Ruili Wang, Yongzhen Chen, Changkai Chen, Yuyang Tian","doi":"10.1080/1120009X.2025.2458377","DOIUrl":"https://doi.org/10.1080/1120009X.2025.2458377","url":null,"abstract":"<p><p>This study evaluated SARS-CoV-2 infection impacts on clinical characteristics, antibody levels, and immune responses in 100 malignant hematological tumor patients. Laboratory assessments included hematological, biochemical, and inflammatory markers. Multivariable analysis identified age (OR = 1.56, p = 0.004), chemotherapy cycles (OR = 1.86, p < 0.001), comorbidities (OR = 3.15, p = 0.015), WBC count (OR = 1.79, p = 0.016), CRP (OR = 2.07, p = 0.007), ferritin (OR = 1.22, p = 0.035), IL-6 (OR = 1.59, p = 0.001), IgG (OR = 2.28, p = 0.037), CD8+ T cells (OR = 2.97, p = 0.005), and NK cells (OR = 0.80, p = 0.019) as COVID-19 risk factors. COVID-19 patients showed significantly higher hospitalization (30.77% vs 10.42%, p = 0.007), ICU admission (23.08% vs 6.25%, p = 0.019), and lower 1-year survival (59.62% vs 87.50%, p = 0.002) versus controls. SARS-CoV-2 infection induces hematological/immune alterations and worsens clinical outcomes in hematological malignancy patients, emphasizing their heightened vulnerability.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"1-12"},"PeriodicalIF":1.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The gene-panel obtained by anti-PD-1 monotherapy for melanoma reveals prognostic markers and therapeutic targets.","authors":"Miaomiao Wang, Zhike Zhou, Yingying Wang, Lixin Wang","doi":"10.1080/1120009X.2025.2465013","DOIUrl":"https://doi.org/10.1080/1120009X.2025.2465013","url":null,"abstract":"<p><p>To search for key drug resistance biomarkers and potential chemotherapeutic agents for combination therapy in melanoma patients. The common up-regulated differentially expressed genes were acquired from two cohort studies, GSE91061 and PRJEB23709. Univariate and multivariate Cox regression survival analyses were performed to screen for important prognostic biomarkers. A multi-gene panel including <i>APP</i>, <i>ARHGAP42</i>, <i>GSTA4</i> and <i>UCHL1</i>, not only plays an important role in prognostic indicators, but also in predicting the probability of resistance to anti-PD-1 in patients with melanoma. Chemotherapy drug response models found five potential drugs, including all-trans retinoic acid, doxorubicin, etoposide, methotrexate and MG-132, were significantly associated with target genes in gene-panel. Molecular docking confirmed that potential drugs have good binding ability to target genes <i>APP</i>, <i>GSTA4</i> and <i>UCHL1,</i> suggesting that the multi-gene panel is expected to provide assistance for drug resistance prediction and prognosis assessment and combination therapy in patients with anti-PD-1 resistant melanoma.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"1-14"},"PeriodicalIF":1.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world effectiveness and safety of meropenem-vaborbactam in the treatment of carbapenem-resistant enterobacterales (CRE) infections: a systematic review and meta-analysis.","authors":"Dongcai Jin, Danyang Hu, Yuhong Jin","doi":"10.1080/1120009X.2025.2465129","DOIUrl":"https://doi.org/10.1080/1120009X.2025.2465129","url":null,"abstract":"<p><p>This study aimed to evaluate the effectiveness and safety of Meropenem-Vaborbactam(M-V) for treating carbapenem-resistant Enterobacterales (CRE) infections based on real-world data. A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted, considering studies up to October 31, 2024. Real-world evidence from registries and nonselected case series involving 10 or more adult patients treated with Meropenem-Vaborbactam for CRE infections was included. Meta-analyses using a random-effects model were performed, with the primary outcomes being clinical efficacy and survival, including 30-day and 90-day survival rates. Out of 1862 potentially relevant publications, six studies were included in the meta-analysis. The pooled clinical success rate was 75% (95% CI, 66%-82%), and the pooled 30-day and 90-day survival rates were 75% (95% CI, 71%-78%) and 69% (95% CI, 61%-76%), respectively. Importantly, no serious adverse effects were reported. In conclusion, Meropenem-Vaborbactam demonstrated both efficacy and safety in treating CRE infections in real-world settings. This study was registered with PROSPERO (CRD42022370880).</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"1-9"},"PeriodicalIF":1.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tumor microenvironment: shaping cancer progression and treatment response.","authors":"Sharav A Desai, Vipul P Patel, Kunal P Bhosle, Sandip D Nagare, Kirti C Thombare","doi":"10.1080/1120009X.2023.2300224","DOIUrl":"10.1080/1120009X.2023.2300224","url":null,"abstract":"<p><p>The tumor microenvironment (TME) plays a crucial role in cancer progression and treatment response. It comprises a complex network of stromal cells, immune cells, extracellular matrix, and blood vessels, all of which interact with cancer cells and influence tumor behaviour. This review article provides an in-depth examination of the TME, focusing on stromal cells, blood vessels, signaling molecules, and ECM, along with commonly available therapeutic compounds that target these components. Moreover, we explore the TME as a novel strategy for discovering new anti-tumor drugs. The dynamic and adaptive nature of the TME offers opportunities for targeting specific cellular interactions and signaling pathways. We discuss emerging approaches, such as combination therapies that simultaneously target cancer cells and modulate the TME. Finally, we address the challenges and future prospects in targeting the TME. Overcoming drug resistance, improving drug delivery, and identifying new therapeutic targets within the TME are among the challenges discussed. We also highlight the potential of personalized medicine and the integration of emerging technologies, such as immunotherapy and nanotechnology, in TME-targeted therapies. This comprehensive review provides insights into the TME and its therapeutic implications. Understanding the TME's complexity and targeting its components offer promising avenues for the development of novel anti-tumor therapies and improved patient outcomes.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"15-44"},"PeriodicalIF":1.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139097891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic implications of response to neoadjuvant chemotherapy in breast cancer subtypes.","authors":"Anil Yıldiz, Ahmet Bilici, Ozgur Acikgoz, Jamshid Hamdard, Pelin Basim, Tansel Cakir, Asli Cakir, Omer Fatih Olmez, Cem Gezen, Ozcan Yildiz","doi":"10.1080/1120009X.2024.2314830","DOIUrl":"10.1080/1120009X.2024.2314830","url":null,"abstract":"<p><p>The current study was designed to assess the response to treatment, as well as clinical and survival outcomes, across different breast cancer subtypes in patients who underwent neoadjuvant chemotherapy (NAC). From 2014 to 2019, a total of 139 patients who were histologically confirmed to have breast cancer, underwent NAC, and subsequently received breast and axillary surgery, were retrospectively included in this study. The rates of pathological complete response (pCR) to NAC were significantly higher for HER2-positive and triple-negative subtypes than for luminal A and HER2-negative subtypes (<i>p</i> = 0.013). Multivariate analysis for disease-free survival (DFS) revealed that tumour grade and the presence of pCR were independent prognostic factors. The presence or absence of a pCR with NAC was an independent prognostic indicator in the multivariate analysis for overall survival (OS). Lastly, achieving a pCR was independently predicted by ¹⁸F-FDG PET/CT findings, the HER2-positive subtype, and the triple-negative subtype. Despite the inherent methodological limitations, our findings underscore the significance of identifying predictive markers to tailor NAC plans, with the aim of improving survival outcomes.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"60-68"},"PeriodicalIF":1.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comparative study of ceftazidime/avibactam-based and fosfomycin plus meropenem-based regimens for managing infections caused by carbapenem-resistant <i>Klebsiella pneumoniae</i> in critically ill patients.","authors":"Uğur Önal, Ülkü Tüzemen, Pınar Küçükdemirci Kaya, Remzi İşçimen, Nermin Kelebek Girgin, Cüneyt Özakın, Ferda Kahveci, Halis Akalın","doi":"10.1080/1120009X.2024.2349439","DOIUrl":"10.1080/1120009X.2024.2349439","url":null,"abstract":"<p><p>The main aim of this study was to compare and analyze the effectiveness of treatment regimens using ceftazidime/avibactam (CAZ/AVI) versus fosfomycin plus meropenem (FOS/MER) for managing bloodstream infections (BSI) or ventilator-associated pneumonia (VAP) caused by carbapenem-resistant <i>Klebsiella pneumoniae</i> (CRKP) in critically ill patients. Between 4 January 2019, and 16 July 2023, adult patients (≥18 years old) diagnosed with BSI or VAP due to culture confirmed CRKP in ICU of a tertiary care hospital were investigated retrospectively. A total of 71 patients were categorized into two groups: 30 patients in CAZ/AVI-based, and 41 patients in FOS/MER-based group. No substantial disparities were found in the total duration of ICU hospitalization, as well as the 14- and 30-day mortality rates, between patients treated with CAZ/AVI-based and FOS/MER-based therapeutic regimens. We consider that our study provides for the first time a comprehensive understanding of treatment outcomes and associated risk factors among patients with CRKP-related infections.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"1-9"},"PeriodicalIF":1.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140862904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of first-line CDK 4-6 inhibitors in premenopausal patients with metastatic breast cancer and the effect of dose reduction due to treatment-related neutropenia on efficacy: a Turkish Oncology Group (TOG) study.","authors":"Hasan Cagri Yildirim, Caner Kapar, Baris Koksal, Mustafa Seyyar, Pervin Can Sanci, Murad Guliyev, Perihan Perkin, Mustafa Buyukkor, Sendag Yaslikaya, Nargiz Majidova, Merve Keskinkilic, Duygu Ozaskin, Tugay Avci, Tugce Kubra Gunes, Murat Arcagok, Alper Topal, Gul Sema Yildiran Keskin, Gozde Kavgaci, Nilgun Yildirim, Ozde Melisa Celayir, Nilufer Avci, Ferit Aslan, Ali Alkan, Mert Erciyestepe, Muhammet Cengiz, Metin Pehlivan, Ahmet Gulmez, Ismail Beypinar, Tugba Basoglu Tuylu, Erkan Kayikcioglu, Elvin Chalabiyev, Serdal Turhal, Halil Goksel Guzel, Eyyup Ayas, Mustafa Sahbazlar, Ozgecan Dulgar, Hacer Demir, Tugba Yavuzsen, Vedat Bayoglu, Derya Kivrak Salim, Banu Ozturk, Feyyaz Ozdemir, Oguz Kara, Berna Oksuzoglu, Oznur Bal, Nebi Serkan Demirci, Mesut Yilmaz, Devrim Cabuk, Sercan Aksoy","doi":"10.1080/1120009X.2024.2330835","DOIUrl":"10.1080/1120009X.2024.2330835","url":null,"abstract":"<p><p>The only phase 3 study on the effectiveness of CDK 4-6 inhibitors in first-line treatment in premenopausal patients with hormone receptor (HR) positive, HER2 negative metastatic breast cancer is the MONALEESA-7 study, and data on the effectiveness of palbociclib is limited. Data are also limited regarding the effectiveness of CDK 4-6 inhibitors in patients whose dose was reduced due to neutropenia, the most common side effect of CDK 4-6 inhibitors. In our study, we aimed to evaluate the effectiveness of palbociclib and ribociclib in first-line treatment in patients with premenopausal metastatic breast cancer and the effect of dose reduction due to neutropenia on progression-free survival. Our study is a multicenter, retrospective study, and factors affecting progression-free survival (PFS) were examined in patients diagnosed with metastatic premenopausal breast cancer from 29 different centers and receiving combination therapy containing palbociclib or ribociclib in the metastatic stage. 319 patients were included in the study. The mPFS for patients treated with palbociclib was 26.83 months, and for those receiving ribociclib, the mPFS was 29.86 months (<i>p</i> = 0.924). mPFS was 32.00 months in patients who received a reduced dose, and mPFS was 25.96 months in patients who could take the initial dose, and there was no statistical difference (<i>p</i> = 0.238). Liver metastasis, using a fulvestrant together with a CDK 4-6 inhibitor, ECOG PS 1 was found to be a negative prognostic factor. No new adverse events were observed. In our study, we found PFS over 27 months in patients diagnosed with premenopausal breast cancer with CDK 4-6 inhibitors used in first-line treatment, similar to post-menopausal patients. We did not detect any difference between the effectiveness of the two CDK 4-6 inhibitors, and we showed that there was no decrease in the effectiveness of the CDK 4-6 inhibitor in patients whose dose was reduced due to neutropenia.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"69-75"},"PeriodicalIF":1.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140143590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-occurrence of triple carbapenemase genes, <i>bla</i>_VIM-2, <i>bla</i>_NDM-1, and <i>bla</i>_OXA-48 in <i>Enterobacter hormaechei</i> clinical isolates -first report from Croatia.","authors":"Zrinka Bošnjak, Henrik Hasman, Frank Hansen, Anette M Hammerum, Louise Roer, Ivana Jurić, Ana Budimir","doi":"10.1080/1120009X.2024.2354107","DOIUrl":"10.1080/1120009X.2024.2354107","url":null,"abstract":"<p><p>Two <i>Enterobacter hormaechei</i> isolates harbouring three carbapenemase genes each, were isolated from two patients from different ICUs at University Hospital Centre Zagreb, Croatia, which is to our knowledge, the first report of triple carbapenemase (<i>bla</i>_VIM-2, <i>bla</i>_NDM-1, and <i>bla</i>_OXA-48<b>)</b> co-existence in <i>E. hormachei</i> strains and also among Enterobacterales members in Croatia. Antimicrobial susceptibility testing showed susceptibility only to colistin and amikacin. The production of carbapenemases was phenotypically tested by immunochromatographic assay and confirmed by PCR. Detailed analysis by Whole Genome Sequencing (WGS) of short reads by Illumina and long reads by Oxford Nanopore Technologies (ONT) was additionally performed and showed that both isolates belonged to ST200. They were separated by 98 Single Nucleotide Polymorphisms (SNPs) having variations in the number of <i>bla</i>_VIM-2 genes on the chromosome, the number of <i>bla</i>_NDM-1 genes on the plasmid, non-identical <i>bla</i>_NDM-1 plasmids, different plasmid content in general, and only one isolate carried a 94 kb prophage.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"10-14"},"PeriodicalIF":1.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-assembled redox-responsive BRD4 siRNA nanoparticles: fomulation and its in vitro delivery in gastric cancer cells.","authors":"Mengying Zhang, Zhonghua An, Yiming Jiang, Meijiao Wei, Xiangbo Li, Yifan Wang, Hongbo Wang, Yanling Gong","doi":"10.1080/1120009X.2024.2308980","DOIUrl":"10.1080/1120009X.2024.2308980","url":null,"abstract":"<p><p>With the development of newer biomarkers in the diagnosis of gastric cancer (GC), therapeutic targets are emerging and molecular-targeted therapy is in progress RNA interference has emerged as a promising method of gene targeting therapy. However, naked small interfering RNA (siRNA) is unstable and susceptible to degradation, so employing vectors for siRNA delivery is the focus of our research. Therefore, we developed LMWP modified PEG-SS-PEI to deliver siRNA targeting BRD4 (L-NPs/siBRD4) for GC therapy. L-NPs/siBRD4 were prepared by electrostatic interaction and characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The release characteristics, cellular uptake and intracellular localization were also investigated. The <i>in vitro</i> anticancer activity of the prepared nanoparticles was analysed by MTT, Transwell invasion and wound healing assay. Quantitative real time-polymerase chain reaction (qRT-PCR) and Western blot were used to detect the effect of gene silencing. The results showed that the optimal N/P was 30 and the prepared L-NPs/siBRD4 uniformly distributed in the system with a spherical and regular shape. L-NPs/siBRD4 exhibited an accelerated release in GSH-containing media from 12h to 24h. The uptake of L-NPs/siBRD4 was enhanced and mainly co-localized in the lysosomes. After 6h incubation, LMWP modified PEG-SS-PEI helped siRNA escape from the lysosomes and diffused into the cytoplasm. L-NPs/siBRD4 significantly inhibited the proliferation, migration and invasion of cells. This might be related with the silence of BRD4, then inhibition of PI3K/Akt and c-Myc. Our results demonstrate that L-NPs/siBRD4 are a novel delivery system with anticancer, which may provide a more effective strategy for GC treatment.</p>","PeriodicalId":15338,"journal":{"name":"Journal of Chemotherapy","volume":" ","pages":"45-59"},"PeriodicalIF":1.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}