JCO precision oncology最新文献

{"title":"POLARIS and Emerging Translational Efforts to Interrogate the Genomic Landscape of CDK4/6 Inhibitor Resistance.","authors":"Elena Michaels, Seth A Wander","doi":"10.1200/PO-25-00539","DOIUrl":"10.1200/PO-25-00539","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500539"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Cyclin-Dependent Kinase 4 Amplifications: A Pioneering Case of Metastatic Leydig Cell Tumor Responding to Abemaciclib.","authors":"Amedeo Nuzzo, Marco Barella, Melanie Claps, Matteo Zimatore, Alessandro Rametta, Marco Stellato, Francesca Ligorio, Eleonora Gusmaroli, Simone Rota, Federica Manoni, Maurizio Colecchia, Sebastiano Nazzani, Davide Biasoni, Tommaso Cascella, Mario Catanzaro, Daniele Rusconi, Chiara Vela, Carlo Silvani, Giuseppe Procopio, Andrea Necchi, Nicola Nicolai, Patrizia Giannatempo","doi":"10.1200/PO-25-00290","DOIUrl":"10.1200/PO-25-00290","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500290"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal Hematopoiesis Prevalence Years Before a Thyroid Cancer Diagnosis: A Case-Control Study.","authors":"Paloma L Cabral, Nikhila Aimalla, Kyle Shoger, John R Caskey, Luke Zurbriggen, Neepa Shah, Ahmad Basharat, Luke F Moat, Erica Reinig, Kristin Long, Paola Pozzo, Terrie Kitchner, Jens Eickhoff, Tonia C Carter, Jane E Churpek","doi":"10.1200/PO-24-00760","DOIUrl":"https://doi.org/10.1200/PO-24-00760","url":null,"abstract":"<p><strong>Purpose: </strong>Individuals with thyroid cancer have the highest prevalence of clonal hematopoiesis (CH) among patients with cancer. We sought to determine whether individuals who later develop thyroid cancer more frequently have CH before diagnosis or germline cancer susceptibility than healthy controls.</p><p><strong>Methods: </strong>We conducted a retrospective case-control study using subjects enrolled between 2002 and 2015 in a population-based biobank. Cases were healthy at enrollment but subsequently developed an incident thyroid cancer. Controls were healthy age- and race-matched subjects who were never diagnosed with a cancer. To assess baseline CH, whole-exome sequencing (WES) was performed on peripheral blood (PB) DNAs collected at enrollment. To assess CH acquisition over time, we recontacted a subset of cases and controls approximately 20 years after initial sampling for repeat PB WES.</p><p><strong>Results: </strong>At enrollment, on average 9 years before a thyroid cancer diagnosis for cases, we identified CH in three of 63 (5%) cases and four of 125 (3%) controls. Adjusting for age, sex, and race, those with CH had a 1.51 odds (0.31-7.33; <i>P</i> = .61) of a thyroid cancer diagnosis versus those without CH at baseline. We detected pathogenic germline cancer susceptibility variants in 11% of cases and 7% of controls (<i>P</i> = .44). Among seven cases and seven controls recontacted, we found incident CH development in three (43%) and two (29%), respectively.</p><p><strong>Conclusion: </strong>We found that individuals who later develop early-stage thyroid cancers do not have a significantly higher prevalence of CH years before their diagnosis nor carry germline cancer susceptibility variants more often than those who do not develop thyroid cancer. Larger longitudinal studies are needed to fully elucidate the impact of germline and exposures in CH etiology.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400760"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sociodemographic Features, Health Care Costs, and Treatment Implications of Genomic Classifier Testing for Localized Prostate Cancer in the United States.","authors":"James R Janopaul-Naylor, Dattatraya Patil, Shreyas Joshi, Martin G Sanda, Nikhil Sebastian, Kamran Salari, Jade Dodge, Vishal R Dhere, Bruce W Hershatter, Pretesh R Patel, Ashesh B Jani, Christopher Filson, Sagar A Patel","doi":"10.1200/PO-25-00406","DOIUrl":"10.1200/PO-25-00406","url":null,"abstract":"<p><strong>Purpose: </strong>Biopsy tissue-based genomic classifiers (GCs) for prostate cancer are commercially available tools to enhance prognostication. They may corroborate candidacy for active surveillance/watchful waiting (AS/WW) or identify men who are more likely to benefit from radiotherapy (RT) with androgen deprivation therapy (ADT). We analyze real-world use of GC and associations with clinical decision making.</p><p><strong>Patients and methods: </strong>We examined US commercial (n = 134,561) and Medicare (n = 68,431) insurance claims of men with newly diagnosed, localized prostate cancer between 2013 and 2022. We evaluated utilization of GCs over time and compared use of AS/WW, RT with or without ADT, radical prostatectomy (RP), or focal ablative therapy (FT) based on the receipt and type of GC.</p><p><strong>Results: </strong>GC utilization increased from <1% to 17% in 8 years with a median payment of $3,001 (IQR, $0-3,873). Younger age, higher median household income, and high-deductible health insurance were associated with higher odds of receiving a GC (all <i>P</i> < .001). Patients with GC were more likely to pursue AS/WW than treatment (odds ratio, 2.00 [95% CI, 1.85 to 2.1]; <i>P</i> < .001). Patients receiving OncotypeDX, Prolaris, and Decipher were most likely to pursue AS/WW, RP, and RT with ADT, respectively (all <i>P</i> < .001). Prolaris was ordered more than three times as often in Detroit as in any other city, whereas OncotypeDx was ordered more than twice as often in New York City as in any other city.</p><p><strong>Conclusion: </strong>We show contemporary, real-world GC utilization trends, costs, and associations with treatment patterns. Prospective trials are ongoing to validate GC-informed treatment, but US uptake has expanded and management is associated with the use and type of GC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500406"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Outcomes and Biomarker Potential of <i>CDKL3</i> of Neoadjuvant Chemotherapy in Patients With Stage IIIC Versus Stage IV Epithelial Ovarian Cancer.","authors":"Ying Jin, Ying Shan, Wen Guo, Yu Dong, Yan Li, Wei Wang, Jie Yin, Yiming Liang, Yu Gu, Lingya Pan, Han Liang","doi":"10.1200/PO-24-00505","DOIUrl":"https://doi.org/10.1200/PO-24-00505","url":null,"abstract":"<p><strong>Purpose: </strong>Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological malignancies. Although treatment options for newly diagnosed advanced EOC include primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), the comparative effectiveness of these strategies remains uncertain across different disease stages.</p><p><strong>Materials and methods: </strong>We conducted a retrospective analysis of 297 patients with EOC whose initial treatment strategy was guided by predicted primary resectability using the Suidan model. We assessed their progression-free survival (PFS) and overall survival outcomes stratified by FIGO stage and treatment approach (PDS <i>v</i> NACT-IDS). We also explored molecular markers associated with prognosis and chemotherapy response.</p><p><strong>Results: </strong>Our analysis revealed that patients with stage IIIC EOC had improved survival outcomes with PDS, whereas those with stage IV disease benefited more from NACT-IDS. Furthermore, CDKL3 was identified as a gene associated with poor prognosis and platinum resistance, potentially contributing to the observed differential survival patterns across stages.</p><p><strong>Conclusion: </strong>These findings suggest that FIGO stage provides additional value in guiding the selection of patients with EOC who may benefit from neoadjuvant chemotherapy. CDKL3 may serve as a promising biomarker for treatment stratification and a therapeutic target to overcome chemoresistance.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400505"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of <i>RPS20</i> Loss-of-Function Variants With Colorectal Cancer Risk in a Cohort of Over 950,000 Individuals.","authors":"Jennifer Herrera-Mullar, Cassidy Carraway, Ashley P L Marsh, Felicia Hernandez, Emily Kudalkar, Marcy E Richardson","doi":"10.1200/PO-25-00214","DOIUrl":"10.1200/PO-25-00214","url":null,"abstract":"<p><strong>Purpose: </strong><i>RPS20</i> is a proposed colorectal cancer (CRC) predisposition gene, with only four families with putative loss-of-function (pLoF) variants published. The prevalence, phenotypic spectrum, and clinical management recommendations for <i>RPS20</i> heterozygotes remain unknown.</p><p><strong>Methods: </strong>Retrospective review of approximately 950,000 individuals undergoing multigene panel testing (MGPT) for cancer predisposition identified 36 individuals with pLoF variants in <i>RPS20</i>. Clinical features, tumor prevalence, and age at onset were compared with Lynch syndrome (LS) and wild-type (WT) cohorts.</p><p><strong>Results: </strong>Thirty-six individuals (0.004%) had 28 unique pLoF variants in <i>RPS20</i> and a total of 42 primary tumors, 78.6% of which were CRC with a median age of diagnosis of 50 years. A total of 16.7% of individuals had multiple CRC primaries, and a majority (71.4%) were mismatch repair-proficient (pMMR). Signet ring cell (SRC) pathology was significantly enriched compared with WT (<i>P</i> = <.0001). The odds ratio for CRC was significantly higher than that for the <i>MLH1</i>-related LS cohort (odds ratio [OR], 45.3 [95% CI, 21.3 to 101] and OR, 16.9 [95% CI, 14.9 to 19.2], respectively).</p><p><strong>Conclusion: </strong><i>RPS20</i> is associated with early-onset, pMMR CRC enriched for SRC pathology. Comparison of prevalence showed a statistically significant two-fold increase in the odds of developing CRC compared with an <i>MLH1</i> LS cohort. These data confirm the gene-disease relationship between <i>RPS20</i> and CRC and support clinical management guidelines similar to <i>MLH1</i>-related LS.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500214"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIK3CB Inhibitor GSK2636771 in Cancers With <i>PTEN</i> Mutation/Deletion or Loss of PTEN Protein Expression: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols N and P.","authors":"Filip Janku, Opeyemi A Jegede, Shannon L Puhalla, Panagiotis A Konstantinopoulos, Funda Meric-Bernstam, James A Zwiebel, Robert J Gray, Xin Victoria Wang, Lisa M McShane, Larry V Rubinstein, David R Patton, P Mickey Williams, Stanley R Hamilton, Naoko Takebe, Sofia Ghani, James V Tricoli, Barbara A Conley, Carlos L Arteaga, Lyndsay N Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty","doi":"10.1200/PO-25-00265","DOIUrl":"https://doi.org/10.1200/PO-25-00265","url":null,"abstract":"<p><strong>Purpose: </strong>PTEN loss contributes to aberrant signaling of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway and may confer sensitivity to therapies targeting the PI3K pathway. The PIK3CB inhibitor GSK2636771 demonstrated efficacy in tumors with <i>PIK3CB</i> mutations and may similarly show efficacy in patients with PTEN loss.</p><p><strong>Methods: </strong>Two nonrandomized, open-label phase II subprotocols within the context of the NCI-MATCH trial targeted PTEN tumor alterations in patients with advanced relapsed/refractory solid tumors, lymphoma, or myeloma: <i>PTEN</i> mutation/deletion (arm N) or loss of PTEN protein expression (arm P). Patients were treated with oral GSK2636771 at 400 mg once per day on 28-day cycles. The primary outcome was objective response (OR); secondary outcomes included progression-free survival (PFS) ≥ 6 months, PFS, and overall survival.</p><p><strong>Results: </strong>Of the 59 patients enrolled across both subprotocols (arm N = 24, arm P = 35), 54 were eligible and treated with GSK2636771. Among 24 patients whose tumors had <i>PTEN</i> mutation/deletion but retained PTEN expression (arm N), seven patients (32%) achieved stable disease (SD), with two (9%) experiencing SD ≥ 6 months (uterine leiomyosarcoma and uterine endometrial carcinoma); the median PFS was 1.8 months. Of the 32 patients whose tumors had loss of PTEN protein expression (arm P), seven patients (22%) achieved SD, with two (6%) experiencing SD ≥ 6 months (prostate cancer; squamous bladder cancer); the median PFS was 1.8 months. Most frequent ≥grade 3 treatment-related adverse events included fatigue (n = 4) and anemia (n = 2) in arm N and hypocalcemia (n = 3), anemia, fatigue, diarrhea, and hypokalemia (each n = 2) in arm P.</p><p><strong>Conclusion: </strong>Although the primary end point of OR was not met, GSK2636771 demonstrated modest single-agent activity among patients with relapsed/refractory cancer having <i>PTEN</i> mutation/deletion with PTEN expression or PTEN protein loss.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500265"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced Detection of Druggable Mutations in Non-Small Cell Lung Cancer Using Targeted Collection of Bronchial Washing Fluid Compared With Plasma and Tumor Tissue.","authors":"Mi-Hyun Kim, Soo Han Kim, Hayoung Seong, Jung Seop Eom","doi":"10.1200/PO-25-00299","DOIUrl":"10.1200/PO-25-00299","url":null,"abstract":"<p><strong>Purpose: </strong>Next-generation sequencing (NGS) has become the gold standard for the molecular testing of patients with non-small cell lung cancer (NSCLC). This prospective study evaluated the performance of NGS using cell-free tumor DNA (ctDNA) extracted from bronchial washing fluid (BWF) collected via a targeted washing technique to detect druggable mutations.</p><p><strong>Materials and methods: </strong>All study participants simultaneously underwent NGS using three sample types: (1) BWF, (2) plasma, and (3) tumor tissue collected during bronchoscopy. The full patient set (FPS) included all enrolled patients, whereas the analysis intent group (AIG) included patients who underwent successful NGS across all specimen types (BWF, plasma, and tissue).</p><p><strong>Results: </strong>Sixty and 50 patients were included in the FPS and AIG groups, respectively. In FPS, the detection rate of druggable mutations in BWF using NGS was 65%, which was significantly higher than that of plasma (47%) and tissue samples (48%; <i>P</i> = .003 and <i>P</i> = .002, respectively). In the AIG, the concordance rate for detecting druggable mutations between BWF and tissue samples was 94%. In addition, the detection rate of co-occurring genetic alterations in BWF using NGS was significantly higher than that in plasma samples (92% <i>v</i> 64%, <i>P</i> = .001), whereas it was comparable with that in tissue samples (92% <i>v</i> 94%, <i>P</i> = 1.000). No significant adverse events occurred during the BWF collection.</p><p><strong>Conclusion: </strong>NGS using ctDNA from BWF obtained through a targeted washing technique is a feasible and reliable method for genomic profiling of NSCLC, providing a promising approach for identifying druggable mutations.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500299"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using Dose-Escalation and -Expansion Cohort Study as Pivotal Trial for Targeted Anticancer Drug Approval.","authors":"Yafang Huang, Ting Zhu, Jinjia Zhong, Jinqiu Yuan","doi":"10.1200/PO-25-00253","DOIUrl":"10.1200/PO-25-00253","url":null,"abstract":"<p><p>Early-phase clinical trials (EPCTs) have been increasingly adopted as the pivotal trial to support US Food and Drug Administration (FDA) approval of novel anticancer drugs. Among EPCT designs, dose-escalation and -expansion cohort (DEEC) substantially reduces the time and resources that are required in the traditional three-phase paradigm. DEEC facilitates expedited approvals of investigational drugs, particularly those targeting novel mechanisms, helping to address the pressing needs of patients with cancer. From 2012 to 2023, DEECs provided pivotal trial evidence that supported the FDA approval for 46 indications across 36 targeted anticancer drugs. Dose escalation uses 3 + 3, Bayesian optimal interval design, or continual reassessment method to explore the optimal dose level, whereas expansion cohorts directly incorporate dose-escalation cohort at the recommended phase II dose level. Expansion cohorts adopt flexible designs such as basket, umbrella, and platform trials. In addition, each expansion cohort in DEEC often uses adaptive approaches, such as Simon's two-stage design. To avoid the bias of end point assessment, conducting DEEC trials requires end point adjudication, often by an independent review committee. The design, conduct, and analysis of DEEC trials each have distinct characteristics. However, these characteristics were often overlooked in DEEC reporting. We reviewed the structural domains and items in trial design and conduct and discussed the strengths and limitations of DEEC studies, aiming to enhance the utilization of this trial design to generate higher-quality clinical evidence and ultimately contribute to better outcomes for patients with cancer.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500253"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aqueous Humor Liquid Biopsy Identifies Murine Double Minute 4 Segmental Gain in Retinoblastoma: Implications for Chemotherapy Response and Precision Oncology.","authors":"Elaine Huang, Shreya Sirivolu, Venkata Yellapantula, Prachi Kale, Peter Kuhn, James Hicks, Brianne Brown, Heidy Paniagua, Drishti Pandya, Rachana Shah, Jesse L Berry, Liya Xu","doi":"10.1200/PO-25-00250","DOIUrl":"https://doi.org/10.1200/PO-25-00250","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500250"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}