Seminars in oncology最新文献

{"title":"Bone-modifying agents for non–small-cell lung cancer patients with bone metastases during the era of immune checkpoint inhibitors: A narrative review","authors":"Jinyoung Kim ,&nbsp;Chaiho Jeong ,&nbsp;Jeongmin Lee ,&nbsp;Jeonghoon Ha ,&nbsp;Ki-Hyun Baek ,&nbsp;Seohyun Kim ,&nbsp;Tai Joon An ,&nbsp;Chan Kwon Park ,&nbsp;Hyoung Kyu Yoon ,&nbsp;Jeong Uk Lim","doi":"10.1053/j.seminoncol.2023.09.002","DOIUrl":"10.1053/j.seminoncol.2023.09.002","url":null,"abstract":"<div><p><span>During the course of lung cancer progression, bone metastases occur in about 40% of patients. Common complications associated with bone metastases in lung cancer patients include </span>musculoskeletal pain<span><span><span>, pathologic fractures<span>, spinal cord compression, and </span></span>hypercalcemia. We discuss the efficacy of bone-modifying agents (BMAs) in reducing skeletal-related events (SREs) and improving cancer-related outcomes, particularly </span>in patients<span> with stage IV non–small-cell lung cancer with bone metastases. In addition, the combined effects of BMAs with radiotherapy or immunotherapy in reducing SREs in patients with lung cancer and bone metastases are explored.</span></span></p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 3","pages":"Pages 105-112"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10301511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successful restoration of checkpoint inhibitors efficacy after allogeneic hematopoietic cell transplant for classic Hodgkin lymphoma patients","authors":"Riad El Fakih,&nbsp;Abdulwahab A. Albabtain,&nbsp;Saud Alhayli,&nbsp;Khawlah Farhan,&nbsp;Walid Rasheed,&nbsp;Alfadel Alshaibani,&nbsp;Naeem Chaudhri,&nbsp;Mahmoud Aljurf","doi":"10.1053/j.seminoncol.2023.05.001","DOIUrl":"10.1053/j.seminoncol.2023.05.001","url":null,"abstract":"<div><h3>Background</h3><p>Classic Hodgkin lymphoma<span> (cHL) is a highly-curable disease. However, relapses after bone marrow transplant are challenging especially relapses after allogeneic transplant.</span></p></div><div><h3>Methods</h3><p>A retrospective chart review of the institution transplant database to summarize the safety and efficacy of checkpoint inhibitors (CPIs) use for cHL relapses postallo-HCT in patients who already failed to derive sustained benefit from CPIs received prior to allo-HCT.</p></div><div><h3>Results</h3><p>Six cases were identified and reviewed. All patients received and failed to derive sustained benefit from CPIs and brentuximab vedotin<span> preallo-HCT. The median age at the time of allo-HCT was 28.6 years (IQR 23.6–34.2), the median number of lines received prior to allo-HCT was 6.5 (range 5–9). The median duration of CPI therapy prior to allo-HCT was 8.1 months (IQR 6.7–12.9). The median time between the discontinuation of CPI and allo-HCT was 5.78 months (IQR 3.15–15.8). The median time to progression postallo-HCT was 5.75 months (IQR 2.6–11.7). The median time between allo-HCT and re-challenge with a CPI was 7.6 months (IQR 3.2–28.6). The median time of follow up after starting postallo-HCT CPIs was 16 months (IQR 7.25–25.75). Five out six patients responded and two patients developed GvHD.</span></p></div><div><h3>Conclusion</h3><p>Our report shows preserved efficacy without any new safety signals by using CPIs postallo-HCT despite using and having failed to derive sustained benefit from CPIs preallo-HCT.</p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 3","pages":"Pages 76-85"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10084798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NTRK fusion-positive cancer in nonagenarian patient. The importance of comprehensive geriatric assessment in older people for the inclusion in clinical trials","authors":"Patricia López Pardo ,&nbsp;Miguel Soria Tristán ,&nbsp;Mercedes Margarita Cavanagh Podesta ,&nbsp;Santos Enrech Francés","doi":"10.1053/j.seminoncol.2023.06.001","DOIUrl":"10.1053/j.seminoncol.2023.06.001","url":null,"abstract":"","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 3","pages":"Pages 86-89"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10131366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bleeding risk with concomitant administration of VEGF-TKIs and anticoagulant agents","authors":"Melina Verso ,&nbsp;Andres Munoz ,&nbsp;Giancarlo Agnelli","doi":"10.1053/j.seminoncol.2023.05.002","DOIUrl":"10.1053/j.seminoncol.2023.05.002","url":null,"abstract":"<div><p><span><span><span>Anti-cancer treatment is considered an independent risk factor for emergent bleeding during </span>anticoagulant treatment </span>in patients<span> with cancer-associated thrombosis. This increased bleeding risk is perceived as major concern particularly when tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial derived </span></span>growth factor receptor<span> (VEGFR-TKIs) are co-administered with anticoagulants<span><span><span>. We evaluated the effects of the combined administration of a VEGF-TKI and the oral direct anticoagulant (apixaban) or the low-molecular weight-heparin </span>dalteparin<span> in a sub-analysis of the Caravaggio study in patients with a diagnosis of cancer patients with venous thromboembolism<span>. The rate of major bleeding was 4.2% in the 668 patients who received any type of anti-cancer treatment and 3.5% in the 487 patients who did not receive any anti-cancer treatment. The relative risk for patients treated with a VEGF-TKI was 1.58 (95% CI: 0.69–3.68), compared to patients treated with anticancer agents other than a VEGF-TKI and 1.73 (95% CI: 0.73–4.07) compared to patients who did not receive any anticancer treatment. The administration of a VGEF-TKI did not have any impact on the recurrence rate of venous thromboembolism. We observed a numerically not statistically significant increase in major bleeding events in patients on concurrent VEGF-TKI and therapeutic </span></span></span>anticoagulation<span> with no excess in those who received apixaban. Further prospective well-designed studies are needed to evaluate whether the concomitant administration of VGEF-TKI and anticoagulant agents may result in an increase of bleeding in patients with a diagnosis of cancer treated for venous thromboembolism.</span></span></span></p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 3","pages":"Pages 67-70"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10084797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute liver failure secondary to malignant infiltration: A single center experience","authors":"Rocío González Grande,&nbsp;Ana Bravo Aranda,&nbsp;Inmaculada Santaella Leiva,&nbsp;Susana López Ortega,&nbsp;Miguel Jiménez Pérez","doi":"10.1053/j.seminoncol.2023.05.003","DOIUrl":"10.1053/j.seminoncol.2023.05.003","url":null,"abstract":"<div><p><span><span>Acute liver failure (ALF) requires early and very precise </span>treatment decisions for a diagnosis that is not often easy and may lead to erroneous decisions. Accordingly, we undertook a review of ALF secondary to malignant infiltration given the rarity of the condition, plus its singularity and therapeutic implications. This review should aid in establishing future frameworks for action. Analyze cases of ALF secondary to malignant infiltration in our center during the last 5 years and review the literature. We undertook a retrospective review of all cases of ALF due to malignant infiltration in our center between January 2015 and December 2019. Data were recorded on demographic characteristics, clinical presentation, type of tumor, diagnostic techniques used, treatment and evolution. We also undertook a literature review on the subject and compared the results. AFL secondary to malignant infiltration was diagnosed in five patients, four women and one man with a median age 58 years. The most common clinical presentation was jaundice. Three cases were due to infiltration by hematological tumors (non-Hodgkin lymphoma and histiocytosis), one a </span>cholangiocarcinoma<span> and one lung cancer. In all cases a liver biopsy<span> was required for diagnosis, this being conclusive in four cases; diagnosis in the non-conclusive case was by analysis of the hepatectomy sample after transplantation. Three patients died due to AFL in a mean of 13.8 days, another died 5 months after diagnosis as a consequence of the tumor while the patient with a diagnosis of non-Hodgkin lymphoma and transplant recipient remains alive after a follow-up of 6 years and after receiving chemotherapy. AFL due to malignant infiltration is a very unusual condition but with a high rate of mortality. It requires a rapid and precise diagnosis given the relevant treatment options.</span></span></p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 3","pages":"Pages 71-75"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9683953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TOC","authors":"","doi":"10.1053/S0093-7754(23)00071-4","DOIUrl":"https://doi.org/10.1053/S0093-7754(23)00071-4","url":null,"abstract":"","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 3","pages":"Page A3"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50185687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral selective estrogen receptor degraders (SERDs): The new emperors in breast cancer clinical practice?","authors":"Antonella Ferro ,&nbsp;Daniele Generali ,&nbsp;Orazio Caffo ,&nbsp;Alessia Caldara ,&nbsp;Delia De Lisi ,&nbsp;Mariachiara Dipasquale ,&nbsp;Martina Lorenzi ,&nbsp;Sara Monteverdi ,&nbsp;Palma Fedele ,&nbsp;Yari Ciribilli","doi":"10.1053/j.seminoncol.2023.08.002","DOIUrl":"10.1053/j.seminoncol.2023.08.002","url":null,"abstract":"<div><p><span>Endocrine therapy (ET) targeting estrogen receptor<span><span><span> (ER) signaling is still the mainstay treatment option for early or advanced ER-positive breast cancer (BC) and may involve suppressing </span>estrogen production<span> by means of aromatase inhibitors or directly blocking the ER pathway through selective estrogen receptor modulators such as </span></span>tamoxifen<span> or selective estrogen receptor degraders such as fulvestrant. However, despite the availability of this armamentarium in clinical practice, </span></span></span><em>de novo</em><span> or acquired resistance to ET is the main cause of endocrine-based treatment failure leading to the progression of the BC. Recent advances in targeting, modulating, and degrading ERs have led to the development of new drugs capable of overcoming intrinsic or acquired ET resistance related to alterations in the </span><em>ESR1</em><span> gene. The new oral selective estrogen receptor degraders, which are capable of reducing ER protein expression and blocking estrogen-dependent and -independent ER signaling, have a broader spectrum of activity against </span><em>ESR1</em> mutations and seem to be a promising means of overcoming the failure of standard ET. The aim of this review is to summarize the development of oral selective estrogen receptor degraders, their current status, and their future perspectives.</p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 3","pages":"Pages 90-101"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer stage and time from cancer diagnosis to first treatment during the COVID-19 pandemic","authors":"Diego Rodrigues Mendonça e Silva ,&nbsp;Gisele Aparecida Fernandes ,&nbsp;Ivan Leonardo Avelino França e Silva ,&nbsp;Maria Paula Curado","doi":"10.1053/j.seminoncol.2023.03.005","DOIUrl":"10.1053/j.seminoncol.2023.03.005","url":null,"abstract":"<div><p>The 2019 coronavirus disease (COVID-19) pandemic has impacted cancer care and the diagnosis of new cases of cancer. We analyzed the impact of the COVID-19 pandemic on patients with cancer by comparing the number of newly diagnosed cases, cancer stage, and time to treatment in 2020 with those in 2018, 2019, and 2021. A retrospective cohort of all cancer cases treated at A.C. Camargo Cancer Center in 2018–2021, identified from the Hospital Cancer Registry, was studied. We analyzed single and multiple primary cancer case and patient characteristics—by year and by clinical stage (early <em>v</em> advanced). Times from diagnosis to treatment were compared according to the most frequent tumor sites between 2020 and the other study years. Between 2018 and 2021, a total of 29,796 new cases were treated at the center including 24,891 with a single tumor and 4,905 with multiple tumors, including nonmelanoma skin cancer. The number of new cases decreased by 25% between 2018 and 2020 and 22% between 2019 and 2020, followed by an increase of about 22% in 2021. Clinical stages differed across years, with the number of new advanced cases decreasing from 17.8% in 2018 to 15.2% in 2020. Diagnoses of advanced-stage for lung and kidney cancer decreased between 2018 and 2020, while the number of thyroid and prostate cancer cases diagnosed in advanced-stages increased from 2019 to 2020. The time from diagnosis to treatment decreased between 2018 and 2020 for breast (55.5 <em>v</em> 48 days), prostate (87 <em>v</em> 64 days), cervical/uterine (78 <em>v</em> 55 days) and oropharyngeal (50 <em>v</em> 28 days) cancers. The COVID-19 pandemic affected the numbers of single and multiple cancers diagnosed in 2020. An increase in the number of advanced-stage cases diagnosed was observed only for thyroid and prostate cancer. This pattern may change in coming years due to the possibility that a significant number of cases went undiagnosed in 2020.</p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 1","pages":"Pages 60-65"},"PeriodicalIF":4.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10030331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10033236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor testing and treatment patterns in veterans with metastatic castration-resistant prostate cancer","authors":"Anna Hung ,&nbsp;Danielle Candelieri ,&nbsp;Yanhong Li ,&nbsp;Patrick Alba ,&nbsp;Brian Robison ,&nbsp;Fatai Agiri ,&nbsp;Cristina Perez ,&nbsp;Kyung-Min Lee ,&nbsp;Kara N. Maxwell ,&nbsp;Weiyan Li ,&nbsp;Himani Aggarwal ,&nbsp;Kathryn Pridgen ,&nbsp;Shelby D. Reed ,&nbsp;Scott DuVall ,&nbsp;Yu-Ning Wong ,&nbsp;Julie A. Lynch","doi":"10.1053/j.seminoncol.2023.03.001","DOIUrl":"10.1053/j.seminoncol.2023.03.001","url":null,"abstract":"<div><h3>Introduction</h3><p>In 2016, the Department of Veterans Affairs (VA) and Prostate Cancer Foundation (PCF) began a partnership to improve access to testing. The primary objective of this analysis was to describe the use of tumor testing and treatment patterns in Veterans who progressed to metastatic castration-resistant prostate cancer (mCRPC) from 2016 to 2021. Secondary objectives including identifying factors associated with receipt of tumor testing, and reporting HRR mutation results among a subset who were tested.</p></div><div><h3>Methods and Materials</h3><p>Natural language processing algorithms were applied to VA electronic health record data to identify a nationwide cohort of veterans with mCRPC. Tumor testing over time and by region were reported, alongside first-, second-, and third-line treatment patterns. Factors associated with receipt of tumor testing were identified using generalized linear mixed models with binomial distributions and logit links to account for clustering by VA facility.</p></div><div><h3>Results</h3><p>Of the 9,852 veterans analyzed, 1,972 (20%) received tumor testing, with 73% of testing occurring in 2020–2021. Factors associated with tumor testing included younger age, later diagnosis year, being treated in the Midwest, or Puerto Rico or other compared to the South, and being treated at a PCF-VA Center of Excellence. Fifteen percent of tests were positive for a pathogenic HRR mutation. Seventy-six percent of the study cohort received first-line treatment, and among those, a subsequent 52% received second-line treatment. A subsequent 46% received third-line treatment.</p></div><div><h3>Conclusion</h3><p>After the VA-PCF partnership, one-fifth of veterans with mCRPC received tumor testing, with most tests occurring in 2020–2021.</p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 1","pages":"Pages 11-24"},"PeriodicalIF":4.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9659283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved outcomes in women with BRAF-mutant melanoma treated with BRAF/MEK-targeted therapy across randomized clinical trials. A systematic review and meta-analysis","authors":"Laura Pala ,&nbsp;Tommaso De Pas ,&nbsp;Eleonora Pagan ,&nbsp;Saverio Minucci ,&nbsp;Chiara Catania ,&nbsp;Nunzio Digiacomo ,&nbsp;Emilia Cocorocchio ,&nbsp;Daniele Laszlo ,&nbsp;Antonio Di Muzio ,&nbsp;Chiara Barigazzi ,&nbsp;Erika Stucchi ,&nbsp;Laura De Grandi ,&nbsp;Sara Stucchi ,&nbsp;Giuseppe Viale ,&nbsp;Richard D. Gelber ,&nbsp;Vincenzo Bagnardi ,&nbsp;Fabio Conforti","doi":"10.1053/j.seminoncol.2023.03.003","DOIUrl":"10.1053/j.seminoncol.2023.03.003","url":null,"abstract":"<div><p>Available evidence suggests that in patients with advanced BRAF V600-mutant melanoma treated with the combination of BRAF and MEK inhibitors, gender could be associated with survival outcome. We performed a systematic review and meta-analysis of all randomized clinical trials (RCTs) testing the combination of BRAF and MEK inhibitors, to assess the interaction between treatment effect and patients’ gender. We searched PubMed, MEDLINE, Embase, and Scopus, for phase II and III RCTs up to January 30, 2022. We included all RCTs that enrolled patients with BRAF V600-mutant advanced cutaneous melanoma and assessed combinations of BRAF and MEK inhibitors versus BRAF inhibitor monotherapy. Our aim was to assess differences if any in treatment efficacy between men and women, measured in terms of the differences in progression-free survival (PFS) and overall survival (OS) log-hazard ratios (log-HRs). We calculated the pooled PFS- and OS-HRs with 95% confidence intervals (CIs) in men and women using a random-effects model and assessed the heterogeneity between the estimates using an interaction test. Five RCTs that enrolled a total of 2,113 patients were included in the analysis. In women, the combination of BRAF and MEK inhibitors halved the risk of progression or death as compared with BRAF inhibitor monotherapy with a pooled PFS-HR of 0.50 (95%CI 0.41–0.61). In men, the benefit obtained with BRAF and MEK inhibitors was smaller with a pooled PFS-HR of 0.63 (95%CI 0.54–0.74), <em>P</em>-heterogeneity = .05. A similar trend was observed for OS where the pooled OS-HR was 0.62 (95%CI 0.48–0.80) in women and only 0.78, (95%CI 0.67–0.92) in men, <em>P</em>-heterogeneity = 0.11. These results support meaningful gender-based heterogeneity of response to combination of BRAF and MEK inhibitors targeted therapy in patients with advanced BRAF-mutant melanoma, that should be considered in future research to improve treatment effectiveness.</p></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"50 1","pages":"Pages 34-39"},"PeriodicalIF":4.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9659260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}