Chemotherapy最新文献

{"title":"Individualized Delivery of Vancomycin by Model-Informed Bayesian Dosing Approach to Maintain an AUC24 Target in Critically Ill Patients.","authors":"Zhi Rao, Si-Ming Guo, Yan-Ming Wei","doi":"10.1159/000531638","DOIUrl":"10.1159/000531638","url":null,"abstract":"<p><strong>Introduction: </strong>Monitoring of AUC24 was updated recommendation in the guideline for the therapeutic drug monitoring (TDM) of vancomycin in Chinese pharmacological society published in 2020. Vancomycin pharmacokinetic profiles are diverse and unique in critically ill patients because of the drastic variability of the patients' physiological parameters, while the study for population pharmacokinetic (PPK) models in Chinese critically ill patients has been rarely reported. The objectives of this study were to construct a PPK model to describe the pharmacokinetic characteristics of vancomycin in critically ill patients and to individualize vancomycin dosing by model-informed Bayesian estimation for maintenance of AUC24 target at 400-650 mg h/L recommended by the 2020 guideline.</p><p><strong>Methods: </strong>Vancomycin with different dosing was administered intravenously over 1 h for critically ill patients, TDM was started at 48 h or 72 h since initiation of vancomycin therapy for patients. Blood samples were collected from patients for trough concentrations or Cmax. Vancomycin concentrations were determined by high-performance liquid chromatography method with ultraviolet detection. PPK model was performed using the nonlinear mixed-effect model (NONMEM®). Individual PK parameters for critically ill patients treated with vancomycin were estimated using a post hoc empirical Bayesian method based on the final PPK model. AUC24 was calculated as the total daily dose divided by the clearance (L/h).</p><p><strong>Results: </strong>The PPK of vancomycin was determined by a one-compartment model with creatinine clearance as fixed effects. The PK estimates in the final model generally agreed with the median estimates and were contained within the 95% CI generated from the bootstrap results, indicating good precision and stability in the final model. The visual predictive check plots showed the adequate predictive performance of the final PK model and supported a good model fit. The model-informed Bayesian estimation was used to predict the AUC24 of critically ill patient by the acquired TDM results, and the dosing adjustment by maintenance of AUC24 at 400-650 mg h/L had made a great therapeutic effect for the case.</p><p><strong>Conclusion: </strong>This study established a PPK model of vancomycin in Chinese critically ill patients, and individualized dosing of vancomycin by model-informed Bayesian estimation to maintain an AUC24 target at 400-650 mg h/L has been successfully applied in clinic. This result supports the continued use of model-informed Bayesian estimation to vancomycin treatment in critically ill patients.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"49-55"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10020753","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":"Long-Term Progression-Free Survival of a Pre-Treated Patient with Metastatic Colorectal Cancer Receiving Trifluridine/Tipiracil.","authors":"Gerlinde Maria Michl, Florian M Vogt, Andreas Nouriani, Roland Ladurner, Marcus Kremer, Timo Reisländer, Marlies Michl","doi":"10.1159/000531525","DOIUrl":"10.1159/000531525","url":null,"abstract":"<p><p>Trifluridine/tipiracil is approved for the use in later or last-line setting in previously treated metastatic colorectal cancer (mCRC) patients who progressed on standard anti-tumor drugs including 5-fluorouracil (5-FU), irinotecan, oxaliplatin, anti-VEGF and anti-EGFR antibodies, or who are not considered candidates for those standard therapies. In this report, we describe a 67-year-old male patient with KRAS-mutated mCRC and metachronous liver and lung metastasis who failed prior 5-FU- and irinotecan-containing regimens, but then showed long-term disease control for 31 months on single-agent trifluridine/tipiracil given as second-line treatment. According to our experience, trifluridine/tipiracil is a feasible and effective treatment option in earlier but not necessarily last-line therapy in mCRC patients who are not considered candidates for doublet or triplet chemotherapy. Besides its efficacy, it is associated with maintained quality of life and a manageable toxicity profile. Considering increasing age of mCRC patients and their wish for maintaining an independent lifestyle, further research on the use of trifluridine/tipiracil in earlier lines of systemic mCRC therapy is warranted.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"27-34"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10037063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Safety of Low-Dose Apatinib Combined with Chemotherapy as Second-Line Treatment for Advanced Gastric Cancer: A Meta-Analysis.","authors":"Liang Wang, Juyuan Li, Huamin Chen","doi":"10.1159/000531524","DOIUrl":"10.1159/000531524","url":null,"abstract":"<p><strong>Introduction: </strong>At present, there are several studies on low-dose apatinib combined with chemotherapy as a second-line treatment of advanced gastric cancer (AGC), but the conclusions are controversial. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of low-dose apatinib combined with chemotherapy as a second-line treatment of AGC.</p><p><strong>Methods: </strong>Nine databases were searched for records on apatinib combined with chemotherapy in treating AGC from inception to June 2022. The observation group received low-dose apatinib combined with chemotherapy, while the controls received chemotherapy alone or other non-placebo treatments. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. The relative risk (RR) and weighted mean difference (WMD) were used as effect sizes.</p><p><strong>Results: </strong>Eight studies involving 679 patients were included in this meta-analysis. The results of the meta-analysis showed that the observation group was superior to the controls in terms of ORR (RR = 1.38, 95% confidence interval [CI]: 1.05-1.81, p = 0.02), DCR (RR = 1.35, 95% CI: 1.20-1.53, p &lt; 0.001), OS (WMD = 4.72, 95% CI: 0.71-8.72, p &lt; 0.001), and PFS (WMD = 2.67, 95% CI: 1.7-3.63, p &lt; 0.001). There were no significant differences between the two groups in adverse events of any grade except hypertension (RR = 2.82, 95% CI: 2.07-3.84, p &lt; 0.001), hand-mouth syndrome (RR = 1.84, 95% CI: 1.84-2.48, p &lt; 0.001), and proteinuria (RR = 3.63, 95% CI: 2.31-5.7, p &lt; 0.001).</p><p><strong>Conclusion: </strong>Low-dose apatinib combined with chemotherapy as a second-line therapy is more effective in improving the efficacy of AGC compared to chemotherapy alone. However, this option has the potential to increase the risk of hypertension, hand-mouth syndrome, and proteinuria.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"11-22"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9660906","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":"Changing and Evolution of Influenza Virus: Is It a Trivial Flu?","authors":"Grazia Pavia, Fabio Scarpa, Alessandra Ciccozzi, Chiara Romano, Francesco Branda, Angela Quirino, Nadia Marascio, Giovanni Matera, Daria Sanna, Massimo Ciccozzi","doi":"10.1159/000538382","DOIUrl":"10.1159/000538382","url":null,"abstract":"<p><strong>Background: </strong>Influenza viruses are etiological agents which cause contagious respiratory, seasonal epidemics and, for influenza A subtypes, pandemics. The clinical picture of influenza has undergone continuous change over the years, due to intrinsic viral evolution as well as \"reassortment\" of its genomic segments. The history of influenza highlights its ability to adapt and to rapidly evolve, without specific circumstances. This reflects the complexity of this pathology and poses the fundamental question about its assumption as a \"common illness\" and its impact on public health.</p><p><strong>Summary: </strong>The global influenza epidemics and pandemics claimed millions of deaths, leaving an indelible mark on public health and showing the need for a better comprehension of the influenza virus. The clear understanding of genetic variations during the influenza seasonal epidemics is a crucial point for developing effective strategies for prevention, treatment, and vaccine design. The recent advance in next-generation sequencing approaches, model systems to virus culture, and bioinformatics pipeline played a key role in the rapid characterization of circulating influenza strains. In particular, the increase in computational power allowed the performance of complex tasks in healthcare settings through machine learning algorithms, which analyze different variables, such as medical and laboratory outputs, to optimize medical research and improve public health systems. The early detection of emerging and reemerging pathogens is a matter of importance to prevent future pandemics.</p><p><strong>Key messages: </strong>The perception of influenza as a \"trivial flu\" or a more serious public health concern is a subject of ongoing debate, reflecting the multifaceted nature of this infectious disease. The variability in the severity of influenza sheds light on the unpredictability of the viral characteristics, coupled with the challenges in accurately predicting circulating strains. This adds complexity to the public health burden of influenza and highlights the need for targeted interventions.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"185-193"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173875","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":"Simultaneous Tumor Shrinkage and Bronchial Perforation Induced by Nivolumab plus Cabozantinib Combination Therapy in a Patient with Collecting Duct Carcinoma.","authors":"Hiroki Okumura, Kyoko Murase, Suguru Oka, Rika Kizawa, Takeshi Yamaguchi, Yuko Tanabe, Koichi Suyama, Kazushige Sakaguchi, Shinji Urakami, Yuji Miura","doi":"10.1159/000534470","DOIUrl":"10.1159/000534470","url":null,"abstract":"<p><p>Vascular endothelial growth factor receptor tyrosine kinase inhibitors are known to cause perforation as one of their severe side effects, and postoperative and postradiation therapy are known risk factors. However, there are few studies on perforation following tumor shrinkage. A 78-year-old woman with postoperative recurring left collecting duct carcinoma of the right hilar lymph nodes and mediastinum underwent eight courses of nivolumab plus cabozantinib, resulting in tumor shrinkage. Three days after the last administration, she developed fever and cough and was hospitalized for right lobar pneumonia. The patient received long-term antibiotics for bronchial fistula with the destruction of the bronchial wall and secondary lung abscess. When using nivolumab plus cabozantinib combination therapy for a tumor with bronchial invasion, physicians should be aware of bronchial perforation as the tumor shrinks.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"45-48"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41193136","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":"Erratum.","authors":"","doi":"10.1159/000539084","DOIUrl":"10.1159/000539084","url":null,"abstract":"","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"194"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853693","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":"Complete Remission of a Diffuse Large B-Cell Lymphoma in a Young Patient, with Severe Tuberous Sclerosis, Treated with Metronomic Chemotherapy and Ibrutinib: A Case Report.","authors":"Marta Banchi, Tiziana Lanzolla, Arianna Di Napoli, Arianna Bandini, Guido Bocci, Maria Christina Cox","doi":"10.1159/000533236","DOIUrl":"10.1159/000533236","url":null,"abstract":"<p><p>Tuberous sclerosis (TS) is a rare autosomal dominant genetic multisystem disease caused by mutations in either the TSC1 or TSC2 gene and results in the growth of non-cancerous masses in several organs. Diffuse large B-cell lymphoma (DLBCL) is the predominant non-Hodgkin lymphoma in adolescents and young adults. Metronomic chemotherapy (mCHEMO) can be defined as the frequent, regular administration of drug doses able to maintain a low, but active, range of concentrations of chemotherapeutic drugs during prolonged periods of time. We present the case of a young woman with severe TS who developed DLBCL. She was treated consecutively with the mCHEMO schedule R-DEVEC (prednisone, vinorelbine, etoposide, cyclophosphamide, plus rituximab) and then ibrutinib, achieving an impressive long-lasting complete remission. In conclusion, alternative treatments could be necessary when comorbidities are present in patients, and mCHEMO can be a potential successful therapeutic approach in frail subjects.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"40-44"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9954081","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":"Prolonged Complete Response with Lenalidomide in a Relapsed Diffuse Large B-Cell Lymphoma, Leg-Type: A Case Report.","authors":"Sabrina Zoli, Cinzia Pellegrini, Beatrice Casadei, Alessandro Broccoli, Lisa Argnani, Laura Nanni, Vittorio Stefoni, Pier Luigi Zinzani","doi":"10.1159/000534784","DOIUrl":"10.1159/000534784","url":null,"abstract":"<p><strong>Introduction: </strong>For primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), there are no uniform recommendations for second-line treatment in case of relapse.</p><p><strong>Case presentation: </strong>Here, we present the case of an elderly relapsed/refractory PCDLBCL-LT patient who obtained a prolonged clinical complete remission with lenalidomide.</p><p><strong>Conclusion: </strong>Lenalidomide as single agent led to an unexpected long complete response with manageable toxicity.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"23-26"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71421170","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 Hammersmith Score Optimises Patient Selection and Predicts for Overall Survival in Early-Phase Cancer Trial Participants Independent of Tumour Burden.","authors":"James Alexander Korolewicz, Bernhard Scheiner, Claudia A M Fulgenzi, Antonio D'Alessio, Alessio Cortellini, Chynna Pascual, Aman Mehan, Sarah Partridge, Dorothy M Gujral, Waleed Mohammed, Oreoluwa Mohammed, Aneta Grzesiak, Lauren Booker, Susan Cleator, Tzveta Pokrovska, Waqar Saleem, James Rackie, Yasmine Needham, Jonathan Krell, Iain McNeish, Laura Tookman, Won-Ho Edward Park, Muzamil Asif, Joanne S Evans, David J Pinato","doi":"10.1159/000539109","DOIUrl":"10.1159/000539109","url":null,"abstract":"<p><strong>Introduction: </strong>As tumour response rates are increasingly demonstrated in early-phase cancer trials (EPCT), optimal patient selection and accurate prognostication are paramount. Hammersmith Score (HS), a simple prognostic index derived on routine biochemical measures (albumin <35 g/L, lactate dehydrogenase >450 IU/L, sodium <135 mmol/L), is a validated predictor of response and survival in EPCT participants. HS has not been validated in the cancer immunotherapy era.</p><p><strong>Methods: </strong>We retrospectively analysed characteristics and outcomes of unselected referrals to our early-phase unit (12/2019-12/2022). Independent predictors for overall survival (OS) were identified from univariable and multivariable models. HS was calculated for 66 eligible trial participants and compared with the Royal Marsden Score (RMS) to predict OS. Multivariable logistic regression and C-index was used to compare predictive ability of prognostic models.</p><p><strong>Results: </strong>Of 212 referrals, 147 patients were screened and 82 patients treated in EPCT. Prognostic stratification by HS identifies significant difference in median OS, and HS was confirmed as a multivariable predictor for OS (HR: HS 1 vs. 0 2.51, 95% CI: 1.01-6.24, p = 0.049; HS 2/3 vs. 0: 10.32, 95% CI: 2.15-49.62, p = 0.004; C-index 0.771) with superior multivariable predictive ability than RMS (HR: RMS 2 vs. 0/1 5.46, 95% CI: 1.12-26.57, p = 0.036; RMS 3 vs. 0/1 6.83, 95% CI: 1.15-40.53, p < 0.001; C-index 0.743).</p><p><strong>Conclusions: </strong>HS is a validated prognostic index for patients with advanced cancer treated in the context of modern EPCTs, independent of tumour burden. HS is a simple, inexpensive prognostic tool to optimise referral for EPCT.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"205-211"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11614300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment and Prognosis of Newly Diagnosed Advanced-Stage Extranodal Natural Killer/T-Cell Lymphoma: A Single-Center Real-World Study across Two Decades.","authors":"Yu-Ce Wei, Fei Qi, Bo Chen, Chang-Gong Zhang, Hui Fang, Di Zhang, Shu-Nan Qi, Yue Chai, Ye-Xiong Li, Mei Dong","doi":"10.1159/000535128","DOIUrl":"10.1159/000535128","url":null,"abstract":"<p><strong>Introduction: </strong>Although there is now a consensus on asparaginase-based chemotherapy regimens in the treatment of advanced-stage extranodal natural killer/T-cell lymphomas (ENKTCLs), patient survival in the real-world setting is still not optimistic according to previous literature reports, and the optimal chemotherapeutic regimens and integration of different therapeutic methods under the concept of combined-modality treatment still need to be further explored and verified.</p><p><strong>Methods: </strong>Newly diagnosed stage Ⅲ/Ⅳ ENKTCL patients from Chinese National Cancer Center in the last two decades were retrospectively collected and analyzed. Overall survival (OS) and progression-free survival (PFS) were determined as primary endpoints. Log-rank tests and Cox proportional hazard models were performed to test for survival differences between subgroups and examine the univariable and multivariable associations.</p><p><strong>Results: </strong>The study included 83 newly diagnosed stage Ⅲ/Ⅳ ENKTCL patients and reported a median OS of 26.07 months and an estimated 5-year OS of 41.3% with a median follow-up of 82.13 months. First-line asparaginase-based regimens compared to non-asparaginase-based regimens significantly prolonged PFS (p = 0.007; HR = 0.48, p = 0.020) and showed a tendency to improve OS (p = 0.064; HR = 0.74, p = 0.359). Gemcitabine-based regimens also exhibited a trend toward improved PFS (p = 0.048; HR = 0.59, p = 0.164) and OS (p = 0.008; HR = 0.67, p = 0.282) compared to non-gemcitabine-based ones. The asparaginase and gemcitabine combinations yielded a 5-year OS of 55.0% and led to significantly superior PFS (p = 0.020; HR = 0.40, p = 0.022) and slightly better OS (p = 0.054; HR = 0.79, p = 0.495) compared to the remaining regimens. First-line combined-modality treatment integrating chemotherapy and radiotherapy improved PFS (p = 0.051) and OS (p = 0.036) compared to chemotherapy alone. Four autologous hematopoietic stem cell transplantation recipients reached a median OS of 58.34 months.</p><p><strong>Conclusion: </strong>Asparaginase and gemcitabine alone brought a favorable impact on PFS and OS; and the asparaginase and gemcitabine combination chemotherapy yielded the optimal efficacy, response duration, and survival outcomes. Combined-modality treatment including potent chemotherapy supplemented by radiotherapy and/or consolidative transplantation could improve prognosis in newly diagnosed advanced-stage ENKTCLs.</p>","PeriodicalId":10047,"journal":{"name":"Chemotherapy","volume":" ","pages":"108-121"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138175765","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}