ESMO Open最新文献

{"title":"Prognosis prediction with the IHC3 score in patients with node-negative, hormone receptor-positive, HER2-negative early breast cancer","authors":"","doi":"10.1016/j.esmoop.2024.103963","DOIUrl":"10.1016/j.esmoop.2024.103963","url":null,"abstract":"<div><h3>Background</h3><div>Prognostication has been used to identify patient populations that could potentially benefit from treatment de-escalation. In patients with hormone receptor-positive (HRpos), human epidermal growth factor receptor 2-negative (HER2neg) early breast cancer (eBC), treatment de-escalation classically involved omitting chemotherapy. With recently developed specialized therapies that require hands-on side-effect management, the therapeutic landscape is changing and therapy decisions are no longer based only on prognosis, but also consider potential side-effects. Therefore, identification of patient groups based on prognostication has gained importance.</div></div><div><h3>Materials and methods</h3><div>In this retrospective analysis, a population of 2359 node-negative HRpos/HER2neg eBC patients was selected from all patients treated at the University Breast Center of Franconia, Germany between 2002 and 2021. The prognostic value of the IHC3 score (incorporating immunohistochemical measurements of the estrogen and progesterone receptor status and Ki-67) with clinical parameters (lymph node status, tumor stage, grading) regarding invasive disease-free survival (iDFS) and overall survival (OS) was assessed.</div></div><div><h3>Results</h3><div>IHC3 positively correlated with Ki-67 expression and inversely correlated with hormone receptor expression. IHC3 categorized into quartiles identified patients with a more unfavorable prognosis: 5-year and 10-year iDFS rates for patients in the highest versus the lowest quartile were 84% versus 95% and 70% versus 88%, respectively. A sensitivity analysis of distant disease-free survival showed similar results to those of iDFS. Five-year and 10-year OS rates for patients in the highest versus the lowest quartile were, respectively, 92% versus 97% and 81% versus 92%.</div></div><div><h3>Conclusions</h3><div>IHC3 is able to define prognostic groups in patients with node-negative, HRpos/HER2neg eBC. Node-negative patients with a high IHC3 score had the worst prognosis, which was comparable to that of node-positive patients described in recent trials. This simple and cost-effective tool could thus potentially aid in identifying patient groups for innovative therapeutic approaches.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497423","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":"Encorafenib, binimetinib and cetuximab in BRAF V600E-mutated advanced pancreatic adenocarcinoma","authors":"","doi":"10.1016/j.esmoop.2024.103975","DOIUrl":"10.1016/j.esmoop.2024.103975","url":null,"abstract":"","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497421","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":"Expression of PD-L1, PD-L2, and inflammatory gene expression profile in locally advanced head and neck squamous cell carcinoma","authors":"","doi":"10.1016/j.esmoop.2024.103961","DOIUrl":"10.1016/j.esmoop.2024.103961","url":null,"abstract":"<div><h3>Background</h3><div>The tumor immune microenvironment in cancer treatment response and resistance is of increasing interest. This retrospective study characterized and investigated programmed death-ligand 1 (PD-L1), PD-L2, and the immune gene expression signature and their association with clinical outcomes in locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC).</div></div><div><h3>Patients and methods</h3><div>PD-L1 and PD-L2 expression on tumor and immune-infiltrating cells (positivity defined as combined positive score or immunohistochemistry proportion score <u>&gt;</u>1) and T-cell-inflamed gene expression profile (Tcell_infGEP) were evaluated in patients with LA HNSCC treated in South Korea from 2000 to 2015. Correlations among the three biomarkers and their associations with overall survival and recurrence-free survival were assessed.</div></div><div><h3>Results</h3><div>Among 366 patients, 38.8% had human papillomavirus-positive disease. PD-L1-positive, PD-L2-positive, and high Tcell_infGEP (≤−0.162) status were observed in 83.6%, 85.4%, and 73.2% of patients, respectively; 4.1% were posttreatment samples. Correlation between PD-L1 and PD-L2 scores was moderate (<em>r</em>_Spearman = 0.50), and each biomarker was slightly less correlated with Tcell_infGEP (0.41-0.45). PD-L1 expression and high Tcell_infGEP status were associated with human papillomavirus positivity. Higher levels of all biomarkers were observed in oral cavity and oropharyngeal cancers compared with other HNSCC sites. In a multivariable analysis that simultaneously adjusted for all three biomarkers, only high Tcell_infGEP was significantly associated with longer overall survival (adjusted hazard ratio, 0.57; 95% confidence interval 0.33-0.98) and recurrence-free survival (adjusted hazard ratio, 0.41; 95% confidence interval 0.23-0.74).</div></div><div><h3>Conclusion</h3><div>High Tcell_infGEP status, but not PD-L1 or PD-L2 expression, was independently associated with longer survival in patients with LA HNSCC. Results may have implications for evaluating therapies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) in HNSCC.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497422","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":"Carcinoid heart disease in patients with advanced small-intestinal neuroendocrine tumors and carcinoid syndrome: a retrospective experience from two European referral centers","authors":"","doi":"10.1016/j.esmoop.2024.103959","DOIUrl":"10.1016/j.esmoop.2024.103959","url":null,"abstract":"<div><h3>Background</h3><div>Up to 50% of patients with advanced small-intestinal neuroendocrine tumors (SI-NETs) and carcinoid syndrome (CS) develop carcinoid heart disease (CHD). However, the true frequency and prognostic markers for CHD in CS are lacking. We described the real-world management of patients in two NET referral centers in this clinical context and relationships between clinical features, including CHD and overall survival (OS).</div></div><div><h3>Patients and methods</h3><div>This is a retrospective analysis of patients with stage IV SI-NET and CS, treated at the European Institute of Oncology in Milan and Uppsala University in Sweden between 2015 and 2021. CHD was defined as at least one moderate right-sided heart valve defect. Median OS and cumulative incidence of CHD were estimated from the diagnosis of metastatic disease, and the association between clinical parameters with both OS and occurrence of CHD was evaluated.</div></div><div><h3>Results</h3><div>We included 165 patients, with 97% having low-intermediate-grade SI-NETs and 86% having synchronous liver metastases. Ninety-eight patients (59%) became refractory to full label dose of somatostatin analogues and 25% developed a CHD. At CHD diagnosis, baseline urine 5-hydroxyindoleacetic acid (24-h u5-HIAA) value and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) value were known in 76% of patients. Moderate-to-severe tricuspid insufficiency was the most common alteration of CHD. Prognosis was significantly impaired by CHD (multivariable hazard ratio for OS = 2.85, <em>P</em> &lt; 0.001). The median OS from the CHD diagnosis was 4.5 years [95% confidence interval (CI) 2.1-7.2 years], and the 5-year survival rate was 34% (95% CI 13% to 57%).</div></div><div><h3>Conclusions</h3><div>In our study population of SI-NET patients with CS, more than half had a refractory carcinoid syndrome (RCS) and one-quarter developed a CHD, with a negative impact on OS. Therefore, it is recommended to screen and monitor patients with CS for CHD, ideally with a combination of u5-HIAA, NT-proBNP values, and echocardiography at CS baseline, preferably in NET referral centers.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497420","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":"Global trends in adolescent and young adult female cancer burden, 1990-2021: insights from the Global Burden of Disease study","authors":"","doi":"10.1016/j.esmoop.2024.103958","DOIUrl":"10.1016/j.esmoop.2024.103958","url":null,"abstract":"<div><h3>Background</h3><div>The impact of breast carcinoma and genital tract malignancy on the physical and mental health, especially reproductive function, of women aged 15-39 years in the adolescent and young adult (AYA) group is significant. This research aims to analyze the burden of AYA female cancer in various regions and countries globally from 1990 to 2021.</div></div><div><h3>Materials and methods</h3><div>Epidemiological data were sourced from the Global Burden of Disease (GBD) study 2021. The study analyzed data on female cancers (breast, ovarian, uterine, and cervical) to assess disease burden across different ages, years, and locations, encompassing 21 GBD regions, 195 countries, and five sociodemographic index (SDI) regions.</div></div><div><h3>Results</h3><div>In 2021, AYA female cancer saw 383 241 new cases and 81 679 deaths globally, with 2 975 183 prevalent cases and 4 855 780 disability-adjusted life years. In 2021, Central Latin America recorded the highest age-standardized incidence (ASIR) and prevalence rates (ASPR), whereas South sub-Saharan Africa had the highest age-standardized mortality (ASMR) and disability rates (ASDR). Nations with high SDI typically exhibited elevated ASIR and ASPR, whereas ASMR and ASDR demonstrated inverse patterns. Over the past three decades, ASIR and ASPR of female cancers among AYA women have increased globally. In contrast, the ASMR and ASDR have demonstrated a declining trend. Notably, breast cancer emerged as the most prevalent malignancy among AYA women.</div></div><div><h3>Conclusions</h3><div>Over the past three decades, the ASIR and ASPR of AYA female cancers have consistently increased, significantly burdening this demographic. Additionally, pronounced disparities are evident across different regions and countries, with AYA women in low SDI environments experiencing poorer prognoses compared to their counterparts in high SDI environments. Consequently, it is imperative to enhance interregional collaboration and communication to optimize the overall prognosis of AYA female cancers.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460989","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":"Androgen receptor pathway inhibitors and drug–drug interactions in prostate cancer","authors":"","doi":"10.1016/j.esmoop.2024.103736","DOIUrl":"10.1016/j.esmoop.2024.103736","url":null,"abstract":"<div><div>Prostate cancer represents a major global health challenge, necessitating efficacious therapeutic strategies. Androgen receptor pathway inhibitors (ARPIs) have become central to prostate cancer treatment, demonstrating significant effectiveness in both metastatic and non-metastatic contexts. Abiraterone acetate, by inhibiting androgen synthesis, deprives cancer cells androgens necessary for growth, while second-generation androgen receptor (AR) antagonists disrupt AR signaling by blocking AR binding, thereby impeding tumor progression. Given the predominance of prostate cancer in the elderly, who often present with multiple comorbidities requiring complex pharmacological regimens, the potential for drug–drug interactions with ARPIs is a critical concern. These interactions, particularly through pathways like CYP2D6 inhibition by abiraterone and CYP3A4 induction by enzalutamide and apalutamide, necessitate a thorough understanding to optimize therapeutic outcomes and minimize adverse effects. This review aims to delineate the efficacy of ARPIs in prostate cancer management and elucidate their interaction with common medications, highlighting the importance of vigilant drug management to optimize patient care.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460988","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":"Immune checkpoint inhibitors in advanced gastroesophageal adenocarcinoma: a series of patient-level meta-analyses in different programmed death-ligand 1 subgroups","authors":"","doi":"10.1016/j.esmoop.2024.103962","DOIUrl":"10.1016/j.esmoop.2024.103962","url":null,"abstract":"<div><h3>Background</h3><div>While the benefit of immune checkpoint inhibitors (ICI) is well established in programmed death-ligand 1 high (PD-L1_high) advanced gastroesophageal adenocarcinoma (GEAC), there remains significant controversy about their benefit in PD-L1_low GEAC. To elucidate the benefit of ICI in PD-L1_low and PD-L1_negative GEAC, we conducted an analysis leveraging individual patient data (IPD) extracted from Kaplan–Meier (KM) plots of pivotal trials.</div></div><div><h3>Methods</h3><div>KM curves from randomized clinical trials investigating the efficacy of ICI for advanced GEAC were extracted from published articles. IPD were extracted from the reported curves, and, in the case of unreported KM plots, KMSubtraction was used to retrieve survival data. A patient-level meta-analysis was conducted for PD-L1_low tumors.</div></div><div><h3>Results</h3><div>In the human epidermal growth factor receptor 2 (HER2)-negative setting, pooled PD-L1 combined positive score (CPS) 1-4 subgroup KM plots from KEYNOTE-859, CHECKMATE-649, and RATIONALE-305 showed a modest overall survival (OS) benefit with the addition of an anti-programmed cell death protein 1 (anti-PD-1) agent [hazard ratio (HR) 0.868, <em>P</em> = 0.018]. Similarly, a modest OS benefit was shown by our IPD meta-analysis of PD-L1 CPS 1-9 subgroups from KEYNOTE-859, KEYNOTE-062, and RATIONALE-305 (HR 0.840, <em>P</em> = 0.002.) Conversely, when CPS 5-9 subgroup KM plots from KEYNOTE-859 and RATIONALE-305 were pooled together, no significant OS benefit was found in the ICI-chemotherapy arm (HR 0.867, <em>P</em> = 0.181), although this subgroup was relatively small.</div></div><div><h3>Conclusions</h3><div>In PD-L1_low HER-2 negative GEAC, the benefit of first-line ICI is modest, yet significant. Further translational work is warranted to better select patients who could benefit from immunotherapy in this setting. Meanwhile, alternative therapeutic options such as zolbetuximab in Claudin18.2-positive disease must be taken into account.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460990","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":"Recursive partitioning analysis model for de novo metastatic nasopharyngeal carcinoma treated with locoregional radiotherapy following chemoimmunotherapy","authors":"","doi":"10.1016/j.esmoop.2024.103960","DOIUrl":"10.1016/j.esmoop.2024.103960","url":null,"abstract":"<div><h3>Background</h3><div>Chemoimmunotherapy is the first-line treatment of <em>de novo</em> metastatic nasopharyngeal carcinoma (dmNPC), with additional locoregional radiotherapy (LRRT) significantly prolonging patient survival. <em>De novo</em> metastatic nasopharyngeal carcinoma, however, demonstrates considerable heterogeneity, resulting in significant variability in patient outcomes. We developed and validated a prognostic tool for patients undergoing first-line chemoimmunotherapy plus LRRT and to evaluate the benefit of local therapy (LT) for distant metastases across different risk levels.</div></div><div><h3>Patients and methods</h3><div>We studied 364 dmNPC patients receiving initial platinum-based chemotherapy and anti-programmed cell death protein 1 immunotherapy followed by LRRT. Patients were randomly divided into training and validation cohorts (7 : 3 ratio). The primary endpoint was progression-free survival (PFS). A prognostic model for PFS was developed using recursive partitioning analysis (RPA).</div></div><div><h3>Results</h3><div>An RPA model categorized patients into five prognostic groups based on number of metastatic lesions, liver metastasis status, and post-treatment Epstein–Barr virus DNA levels. Survival analysis identified three distinct risk groups. High-risk patients had significantly poorer PFS compared with medium- and low-risk groups (2-year PFS rate: training cohort: 13.7% versus 69.4% versus 94.4%, <em>P</em> &lt; 0.001; validation cohort: 7.8% versus 65.1% versus 87.3%, <em>P</em> &lt; 0.001). We investigated the impact of LT for distant metastases across these risk groups and found that only patients in the medium-risk group derived benefit from LT (2-year PFS rate: 77.5% versus 64.0%; hazard ratio = 0.535, 95% confidence interval 0.297-0.966, <em>P</em> = 0.035). Conversely, no survival benefit from LT for distant metastases was observed in the low-risk (<em>P</em> = 0.218) and high-risk subgroups (<em>P</em> = 0.793).</div></div><div><h3>Conclusions</h3><div>Our RPA-based prognostic model integrates number of metastatic lesions, liver metastasis status, and post-treatment Epstein–Barr virus DNA levels to predict PFS in dmNPC patients undergoing chemoimmunotherapy plus LRRT. This model offers personalized treatment guidance, suggesting that patients in the medium-risk group may benefit from LT for distant metastases, while those in high- and low-risk groups may not.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460991","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":"Response to: Cholangiocarcinoma patients with FGFR2 fusions/rearrangements but primary refractory to pemigatinib: the real challenge?","authors":"","doi":"10.1016/j.esmoop.2024.103937","DOIUrl":"10.1016/j.esmoop.2024.103937","url":null,"abstract":"","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446570","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":"Final analysis of the ALTTO trial: adjuvant trastuzumab in sequence or in combination with lapatinib in patients with HER2-positive early breast cancer [BIG 2-06/NCCTG N063D (Alliance)]","authors":"","doi":"10.1016/j.esmoop.2024.103938","DOIUrl":"10.1016/j.esmoop.2024.103938","url":null,"abstract":"<div><h3>Background</h3><div>Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial.</div></div><div><h3>Patients and methods</h3><div>The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety.</div></div><div><h3>Results</h3><div>Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups.</div></div><div><h3>Conclusions</h3><div>With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442747","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}