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{"title":"Belzutifan for renal cell carcinoma: Balancing regulatory approval with societal and patient impact.","authors":"Jad Chahoud, Pavlos Msaouel","doi":"10.1016/j.medj.2024.11.016","DOIUrl":"10.1016/j.medj.2024.11.016","url":null,"abstract":"<p><p>LITESPARK-005 evaluated belzutifan against everolimus in advanced renal cell carcinoma (RCC),¹ demonstrating significant progression-free survival improvement but failing to meet the overall survival (OS) co-primary endpoint. Despite FDA approval, the trial highlights key obstacles in drug development in RCC, given the absence of OS improvement, lack of biomarker studies, high financial toxicity, and limited accessibility outside the United States.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 1","pages":"100563"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALIGNing the treatment of IgA nephropathy: Reducing proteinuria with endothelin A receptor inhibition.","authors":"Lisa Willcocks","doi":"10.1016/j.medj.2024.11.017","DOIUrl":"10.1016/j.medj.2024.11.017","url":null,"abstract":"<p><p>The ALIGN trial¹ demonstrates that atrasentan, an endothelin A (ETA) receptor antagonist, reduces proteinuria in patients with IgA nephropathy (IgAN), a key goal to slow progressive renal disease. These results are consistent with those from sparsentan,²^,³ a combined ETA and angiotensin inhibitor, in IgAN, suggesting two-year data will show atrasentan improves renal outcomes.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 1","pages":"100564"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The climb toward intracranial efficacy: Zorifertinib in EGFR-mutant NSCLC with CNS metastases in the EVEREST trial.","authors":"Meaghan Roy-O'Reilly, David Rogawski","doi":"10.1016/j.medj.2024.10.002","DOIUrl":"10.1016/j.medj.2024.10.002","url":null,"abstract":"<p><p>The phase III EVEREST trial evaluating zorifertinib in the treatment of metastatic EGFR-mutant NSCLC was groundbreaking in its specific inclusion of patients with brain metastases.¹ Zorifertinib prolonged systemic and intracranial progression-free survival compared with first-generation EGFR inhibitors, yet questions remain about its efficacy and toxicity compared with osimertinib.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 1","pages":"100525"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial.","authors":"Qing Zhou, Yan Yu, Ligang Xing, Ying Cheng, Ying Wang, Yueyin Pan, Yun Fan, Jianhua Shi, Guojun Zhang, Jiuwei Cui, Jianying Zhou, Yong Song, Wu Zhuang, Zhiyong Ma, Yanping Hu, Gaofeng Li, Xiaorong Dong, Jifeng Feng, Shun Lu, Jingxun Wu, Juan Li, Longzhen Zhang, Dong Wang, Xinhua Xu, Tsung-Ying Yang, Nong Yang, Yubiao Guo, Jun Zhao, Yu Yao, Diansheng Zhong, Bing Xia, Cheng-Ta Yang, Bo Zhu, Ping Sun, Byoung Yong Shim, Yuan Chen, Zhen Wang, Myung-Ju Ahn, Jie Wang, Yi-Long Wu","doi":"10.1016/j.medj.2024.09.002","DOIUrl":"10.1016/j.medj.2024.09.002","url":null,"abstract":"<p><strong>Background: </strong>Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients.</p><p><strong>Methods: </strong>In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1.</p><p><strong>Findings: </strong>Overall, 439 patients were randomized (zorifertinib n = 220; control n = 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9 months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p = 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3 months with zorifertinib and 31.8 months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib.</p><p><strong>Conclusions: </strong>Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC.</p><p><strong>Funding: </strong>This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100513"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case.","authors":"Yonika A Larasati, Moritz Thiel, Alexey Koval, Denis N Silachev, Anne Koy, Vladimir L Katanaev","doi":"10.1016/j.medj.2024.07.023","DOIUrl":"10.1016/j.medj.2024.07.023","url":null,"abstract":"<p><strong>Background: </strong>De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn²⁺ emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model.</p><p><strong>Methods: </strong>Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.</p><p><strong>Findings: </strong>We show that 16 different pathogenic missense variants cluster in three distinct groups in their responsiveness to Zn²⁺, and we provide the safety study in a mouse disease model. We further describe treatment of a 3-year-old patient with the common pathogenic GNAO1 variant c607G>A, p.Gly203Arg with oral 50 mg zinc (in the form of zinc acetate) daily, as applied in Wilson's disease. During 11 months of treatment, the patient shows cessation of daily dyskinetic crises, improved Burke-Fahn Marsden Dystonia Rating Scale movement score, reduction in epileptic seizures, and an excellent safety profile.</p><p><strong>Conclusions: </strong>Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.</p><p><strong>Funding: </strong>This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100495"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Q&A with Lin Shen.","authors":"Lin Shen","doi":"10.1016/j.medj.2024.12.001","DOIUrl":"10.1016/j.medj.2024.12.001","url":null,"abstract":"<p><p>Professor Lin Shen, MD, graduated from Xuzhou Medical College in 1984 and Beijing Medical University in 1995. She trained at the US National Institutes of Health in 2000, focusing on therapies for gastrointestinal tumors. Currently, she is director of the Department of Gastrointestinal Oncology and Department of Early Drug Development Center, Peking University Cancer Hospital. Specializing in gastrointestinal oncology, she focuses on gastric, esophageal, colorectal, pancreatic, and gastrointestinal neuroendocrine cancers. She has led and participated in various national and international drug trials and steering committees.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 1","pages":"100567"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.","authors":"Jeffrey A How, Minghao Dang, Sanghoon Lee, Bryan Fellman, Shannon N Westin, Anil K Sood, Nicole D Fleming, Aaron Shafer, Ying Yuan, Jinsong Liu, Li Zhao, Joseph Celestino, Richard Hajek, Margaret B Morgan, Edwin R Parra, Caddie D Laberiano Fernandez, Claudio A Arrechedera, Luisa Maren Solis Soto, Kathleen M Schmeler, Alpa Nick, Karen H Lu, Robert Coleman, Linghua Wang, Amir A Jazaeri","doi":"10.1016/j.medj.2024.07.022","DOIUrl":"10.1016/j.medj.2024.07.022","url":null,"abstract":"<p><strong>Background: </strong>The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.</p><p><strong>Methods: </strong>In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples.</p><p><strong>Findings: </strong>Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling.</p><p><strong>Conclusions: </strong>Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker.</p><p><strong>Funding: </strong>This investigator-initiated trial was funded by Merck.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100494"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiome pattern impacts treatment response in primary biliary cholangitis.","authors":"Qiaoyan Liu, Bingyuan Huang, Yijun Zhou, Yiran Wei, Yikang Li, Bo Li, You Li, Jun Zhang, Qiwei Qian, Ruiling Chen, Zhuwan Lyu, Rui Wang, Qin Cao, Qun Xu, Qixia Wang, Qi Miao, Zhengrui You, Min Lian, Merrill Eric Gershwin, Qiaofei Jin, Xiao Xiao, Xiong Ma, Ruqi Tang","doi":"10.1016/j.medj.2024.08.003","DOIUrl":"10.1016/j.medj.2024.08.003","url":null,"abstract":"<p><strong>Background: </strong>Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC. Here, we aimed to investigate microbial signatures that permit risk stratification and provide mechanistic insights into novel therapies for PBC.</p><p><strong>Methods: </strong>We prospectively recruited UDCA treatment-naive patients with PBC and performed metagenomic sequencing and metabolomic profiling using stool and serum samples obtained before (n = 132) and after (n = 59) treatment. PBC microbiome subtypes were identified using unsupervised machine learning methods and validated in two independent cohorts.</p><p><strong>Findings: </strong>PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridia^low microbiomes, Clostridia^high microbiomes were more similar to healthy controls. Notably, patients in the Clostridia^low subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridia^high subtype (41% vs. 20%, p = 0.015). Integrative analysis of metagenomic and metabolomic data revealed divergent functional modules and metabolic activities between the two metacommunities. In particular, anaerobic fermentation and the production of bioactive metabolites, including tryptophan derivatives and secondary bile acids, crucial for immune regulation and gut barrier maintenance, were markedly diminished in the Clostridia^low subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridia^high group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts.</p><p><strong>Conclusions: </strong>Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies.</p><p><strong>Funding: </strong>This research was mainly supported by the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100504"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"If it is a solid tumor target, then it may be a hematologic cancer target: Bridging the great divide.","authors":"Jacob J Adashek, Javier L Munoz, Razelle Kurzrock","doi":"10.1016/j.medj.2024.11.003","DOIUrl":"10.1016/j.medj.2024.11.003","url":null,"abstract":"<p><p>Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAF^V600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms. The genomically driven tissue-agnostic approach has a strong biological rationale (cancer is a disease of the genome), yields remarkably high response rates, and provides drug access to patients with an unmet need (rare/ultra-rare malignancies). Despite the solid tumor focus, both solid and hematologic cancers can harbor identical driver molecular abnormalities and respond to cognate therapies. For example, BRAF^V600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100550"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.","authors":"Marta Vaz Batista, José Manuel Pérez-García, Laia Garrigós, José Ángel García-Sáenz, Patricia Cortez, Fabricio Racca, Salvador Blanch, Manuel Ruiz-Borrego, Adela Fernández-Ortega, María Fernández-Abad, Vega Iranzo, María Gion, Griselda Martrat, Daniel Alcalá-López, Jhudit Pérez-Escuredo, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, Sofia Braga, Javier Cortés","doi":"10.1016/j.medj.2024.08.001","DOIUrl":"10.1016/j.medj.2024.08.001","url":null,"abstract":"<p><strong>Background: </strong>Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD.</p><p><strong>Methods: </strong>This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4 mg/kg T-DXd intravenously every 21 days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile.</p><p><strong>Findings: </strong>At data cutoff (April 4, 2023), the median duration of follow-up was 12.0 months (range, 2.5-18.6). The median OS was 13.3 months (95% confidence interval [CI], 5.7-NA, p < 0.001), meeting the primary endpoint. The median PFS was 8.9 months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9 months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24 weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed.</p><p><strong>Conclusions: </strong>T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition.</p><p><strong>Funding: </strong>This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100502"},"PeriodicalIF":12.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}