Nicolas Vinit , Thomas Blanc , Isabelle Bloch , Luca Pio , Rani Kassir , Giammarco La Barbera , Enzo Bonnot , Pietro Gori , Jeanne Goulin , Aurore Pire , Nathalie Boddaert , Cécile Lozach , Sabine Sarnacki
{"title":"Robotics and 3D modeling for precision surgery in pediatric oncology","authors":"Nicolas Vinit , Thomas Blanc , Isabelle Bloch , Luca Pio , Rani Kassir , Giammarco La Barbera , Enzo Bonnot , Pietro Gori , Jeanne Goulin , Aurore Pire , Nathalie Boddaert , Cécile Lozach , Sabine Sarnacki","doi":"10.1016/j.ejcped.2024.100181","DOIUrl":"10.1016/j.ejcped.2024.100181","url":null,"abstract":"<div><p>In an attempt to minimize surgical trauma in already vulnerable patients, pediatric surgeons are increasingly using minimally invasive surgery in surgical oncology, with similar outcomes as open surgery. In addition to its technical benefits, robotic surgery allows integration of technological enhancements, such as artificial-intelligence-based software or tri-dimensional (3D) modeling, into the operating room. In this article, we report our experience in robotic-assisted surgery for the resection of pediatric tumors and present current developments in 3D modeling applied to pelvic tumors. Since 2016, 149 oncology cases have been undertaken using the robotic approach. Neuroblastic tumors account for the most part, with a median hospital stay of two days [1–7 days] and very few intraoperative events. The use of robotics was mainly extended to renal tumors (predominantly Wilms tumors) and endocrine tumors, but was found of particular interest for pelvic tumors. Our experience led us to publish a first set of guidelines on robotic surgical oncology, focusing on its apparent contraindications. 3D models derived from preoperative magnetic resonance imaging have been developed for more than 150 patients with solid tumors, but the pelvic area was made a key focus because of its anatomical complexity. In addition to their educational benefits, some of these 3D models were integrated into the robotic console as a surgical aid and proved invaluable for difficult dissections or nerve plexus preservation. As evidenced by the development of robotics and 3D modeling, pediatric oncology is leaning toward ultra-precise surgical resection tailored to the patient and the tumor.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000412/pdfft?md5=2c14fac63f4ef10577bd0b7fa73a3acf&pid=1-s2.0-S2772610X24000412-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141840541","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}
John Anderson , Giuseppe Barone , Alexandra Zehner
{"title":"GD2 targeting CAR T cells for neuroblastoma","authors":"John Anderson , Giuseppe Barone , Alexandra Zehner","doi":"10.1016/j.ejcped.2024.100179","DOIUrl":"10.1016/j.ejcped.2024.100179","url":null,"abstract":"<div><p>Treatment of neuroblastoma is a significant clinical unmet need in paediatric oncology epitomised by high-risk disease in which relapse is common and outcomes for children with relapse or primary refractory disease are typically poor, with 4-year progression-free survival for relapse/refractory disease of 6 %. Immunotherapy targeting disialoganglioside GD2 using monoclonal antibodies (mAb) has become a component of standard of care treatment in neuroblastoma following published studies that have demonstrated clinical activity and survival benefit associated with this treatment. Hence a number of research groups have developed and clinically evaluated chimeric antigen receptor gene modified T cells (CAR-T cells) targeting GD2 in patients with relapsed and refractory neuroblastoma. Preclinical and clinical results using a range of receptor technologies and immune effectors have demonstrated the basic safety and feasibility of this approach, progressing into clinical data exhibiting promise for sustained patient benefit.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000382/pdfft?md5=5d10795fb06447198c2e5666f25cfbc2&pid=1-s2.0-S2772610X24000382-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141699985","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}
Jette J. Bakhuizen , Franck Bourdeaut , Karin A.W. Wadt , Christian P. Kratz , Marjolijn C.J. Jongmans , Nicolas Waespe , SIOPE Host Genome Working Group
{"title":"Genetic testing for childhood cancer predisposition syndromes: Controversies and recommendations from the SIOPE Host Genome Working Group meeting 2022","authors":"Jette J. Bakhuizen , Franck Bourdeaut , Karin A.W. Wadt , Christian P. Kratz , Marjolijn C.J. Jongmans , Nicolas Waespe , SIOPE Host Genome Working Group","doi":"10.1016/j.ejcped.2024.100176","DOIUrl":"10.1016/j.ejcped.2024.100176","url":null,"abstract":"<div><h3>Background</h3><p>Cancer Predisposition Syndromes (CPSs) have been identified in 7–15 % of children with cancer. The possibilities for germline genetic testing have increased in recent years, presenting new opportunities but also challenges. There is currently no consensus on germline genetic testing in children with cancer in diagnostic settings.</p></div><div><h3>Methods</h3><p>The International Society of Pediatric Oncology Europe (SIOPE) Host Genome Working Group used a consensus development conference method to reach agreement on four key topics: Who do we test? Which genes do we test? What do we disclose? How do we evaluate the benefits of testing?</p></div><div><h3>Results</h3><p>The Working Group members agreed that: (1) All children with cancer should undergo clinical screening for their risk of harboring a CPS. (2) Targeted genetic testing based on clinical indication is recommended. Comprehensive CPS gene panels with more than 100–150 genes for all children with cancer should preferably be evaluated within research settings. (3) Smaller actionable gene panels can be considered including genes supporting diagnosis or influencing treatment decisions. (4) Clear pre-test information and consenting processes that highlight potential outcomes and implications of germline genetic testing are imperative. (5) Consequences of genetic testing, treatment adaption, and tumor surveillance in children with CPSs, including economic impact and psychosocial factors, should be further explored.</p></div><div><h3>Conclusions</h3><p>These consensus-based recommendations provide guidance on germline genetic testing in children with cancer. Regular review of these recommendations is essential. Collaboration and the use of data sharing platforms can further improve screening procedures and its impact on care.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000357/pdfft?md5=cdba34fb344e6fd6f94b5d8d42d104d0&pid=1-s2.0-S2772610X24000357-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141707708","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":"DNA repair and replicative stress addiction in neuroblastoma","authors":"Kaat Durinck , Meredith S. Irwin","doi":"10.1016/j.ejcped.2024.100177","DOIUrl":"10.1016/j.ejcped.2024.100177","url":null,"abstract":"<div><p>Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system. Survival remains poor for the almost 40 % of patients with high-risk NB. Targeted therapy options for high-risk NB are limited and single compound strategies often fail due to escape mechanisms, driven either by tumor heterogeneity or adaptive (epigenetic) responses or mutations. Novel NB therapeutic approaches rely increasingly on biomarker selected cohorts for phase I/II clinical trials. Parallel intensive research programs are needed to identify novel therapeutic vulnerabilities or drug targeting strategies and to further inform clinical trials and prioritize potent, less toxic combinations. While several effective chemotherapies work by increasing replication stress in cancer cells, recently, newer putatively less toxic small molecule-based approaches that directly target DNA damage response (DDR) pathway components such as ATR, CHK1 and PARP inhibitors are being evaluated in early phase trials for many cancers. NB sequencing studies have identified recurrent alterations (copy number and mutations) in many of these genes encoding critical DDR pathway proteins suggesting susceptibility to specific classes of DDR-targeting therapies. In this review, we summarize current data supporting the roles of DDR and replicative stress addiction in NB, including genetic alterations which impact DDR signaling pathways. Finally, we review the mechanisms, pre-clinical evidence and ongoing trials for drugs that target DDR-deficient and/or replication addicted NB.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000369/pdfft?md5=65420e1bade528c17bfd1edcf5c4f497&pid=1-s2.0-S2772610X24000369-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141714107","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}
Felix M. Onyije, Roya Dolatkhah, Ann Olsson, Liacine Bouaoun, Joachim Schüz
{"title":"Environmental risk factors of Wilms tumour: A systematic review and meta-analysis","authors":"Felix M. Onyije, Roya Dolatkhah, Ann Olsson, Liacine Bouaoun, Joachim Schüz","doi":"10.1016/j.ejcped.2024.100178","DOIUrl":"https://doi.org/10.1016/j.ejcped.2024.100178","url":null,"abstract":"<div><p>Wilms tumour (WT) is the fourth leading cause of cancer death in children. Elucidating modifiable risk factors is crucial in identifying venues for primary prevention of the disease. This study aimed to review literature and synthesize environmental risk factors for WT. We conducted a systematic review and meta-analysis of epidemiological studies using PubMed, Web of Science, and Embase databases. Studies were included if they were case-control or cohort studies of children under the age of 20 years at diagnosis and reported Relative Risks (RRs) with 95 % confidence intervals (CIs). Pooled effect sizes (ES) and 95 % CIs for risk factors associated with WT were estimated using random-effects models. We included 58 eligible studies from Asia, Europe, Latin and North America, and Oceania totalling approximately10000 cases of WT diagnosed between 1953 and 2019. We confirmed an association between high birthweight ((>4000 g) ES 1.54, CI 1.20–1.97) and WT. Similarly, consistent associations were suggested for Caesarean section (ES 1.23, CI 1.07–1.42), gestational age <37 weeks (ES 1.45, CI 1.21–1.74), and large-for-gestational age (ES 1.52, CI 1.09–2.12). Parental occupational exposure to pesticides during preconception / pregnancy also showed increased risks of WT (maternal ES 1.28, CI 1.02–1.60, paternal ES 1.48, CI 0.98–2.24). There were inverse associations for breastfeeding (ever breastfed = ES 0.71, CI 0.56–0.89; < 6 months ES 0.67, CI 0.49–0.91; and ≥6 months ES 0.75, CI 0.59–0.97), and maternal intake of vitamins (unspecified) and folic acid during pregnancy (ES 0.78, CI 0.69–0.89). Among factors showing no associations were low birthweight (<2500 g), small-for-gestational age, assisted reproductive technology, parental age, and smoking or alcohol consumption during preconception / pregnancy, paternal occupational extremely low frequency magnetic fields (ELF-MF) exposures, and maternal X-ray exposure during pregnancy. Our findings suggest that modifiable risk factors of WT are parental occupational exposure to pesticides, breastfeeding (beneficial), and intake of folic acid during preconception / pregnancy (beneficial), but all associations were rather modest in strength.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000370/pdfft?md5=4227eb0bc82535b5aab3d1efc1ae64b1&pid=1-s2.0-S2772610X24000370-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141594921","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}
Julia Beckhaus , Jale Özyurt , Aylin Mehren , Carsten Friedrich , Hermann L. Müller
{"title":"Fatigue in patients with hypothalamic syndrome – A cross-sectional analysis of the German childhood-onset craniopharyngioma cohort","authors":"Julia Beckhaus , Jale Özyurt , Aylin Mehren , Carsten Friedrich , Hermann L. Müller","doi":"10.1016/j.ejcped.2024.100174","DOIUrl":"https://doi.org/10.1016/j.ejcped.2024.100174","url":null,"abstract":"<div><h3>Objective</h3><p>Patients with suprasellar tumors are at risk for hypothalamic syndrome (HS), including fatigue and excessive daytime sleepiness. The aim of this cross-sectional study was to determine the severity of fatigue in patients with and without HS.</p></div><div><h3>Methods</h3><p>Patients diagnosed with CP or pilocytic astrocytoma were recruited from the KRANIOPHARYNGEOM studies. Eligibility criteria were availability of one completed Multidimensional Fatigue Inventory-20 (MFI-20) questionnaire and complete medical records on criteria for HS. The associations between HS and levels of fatigue symptoms (MFI-20 sum score) were assessed. MFI-20 scores were compared to sex- and age-matched reference values from a German normative population.</p></div><div><h3>Results</h3><p>Data on 41 patients, with a median age of 22 years, were available for analyses of which 25 (61 %) patients presented with HS. After adjustment for age and sex, patients with HS reported higher scores in the physical (<span><math><mi>β</mi></math></span>= 3.39 [95 %-CI:1.18–5.60]) and sum MFI-20 (<span><math><mi>β</mi></math></span>=11.42 [95 %-CI:2.06–20.79]) domain than patients without HS. Compared to reference values, all patients reported higher mean scores in each fatigue domain. Abnormal self-reported daytime sleepiness was reported in 6 of 25 (24 %) patients with HS. Regardless of the level of daytime sleepiness in patients with HS, the reported fatigue scores were high. Daytime sleepiness did not correlate with fatigue.</p></div><div><h3>Conclusions</h3><p>Fatigue symptoms are present in patients with CP. However, patients with HS are more affected with physical and overall fatigue. It is crucial in clinical practice, to distinguish between daytime sleepiness and fatigue and to target patients with HS.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000333/pdfft?md5=e9260be7848859e02090b30f0acd0a8f&pid=1-s2.0-S2772610X24000333-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141594920","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}
Laura G.Y. Rotte , Coco C.H. de Koning , Yvette G.T. Loeffen , Marc B. Bierings , Jaap Jan Boelens , Caroline A. Lindemans , Tom F.W. Wolfs
{"title":"Prophylactic use of liposomal amphotericin B in children and adolescents undergoing allogeneic hematopoietic cell transplantation: A 10-years single center experience","authors":"Laura G.Y. Rotte , Coco C.H. de Koning , Yvette G.T. Loeffen , Marc B. Bierings , Jaap Jan Boelens , Caroline A. Lindemans , Tom F.W. Wolfs","doi":"10.1016/j.ejcped.2024.100175","DOIUrl":"https://doi.org/10.1016/j.ejcped.2024.100175","url":null,"abstract":"<div><h3>Background</h3><p>Azoles are recommended as antifungal prophylaxis in decreasing the incidence of invasive fungal disease (IFD) in high-risk patients in pediatric oncology, including patients receiving allogeneic hematopoietic cell transplantation (HCT). However, azole related toxicity, pharmacological interactions with immunosuppressive medication and conditioning regimen and growing incidence of azole resistance makes this antifungal agent not ideal in the transplant setting. This study reports on the contemporary incidence and outcome of IFD after allogeneic HCT in children with prophylactic liposomal amphotericin B (L-AMB).</p></div><div><h3>Methods</h3><p>This single-center retrospective study included all patients transplanted between 2012 and 2022. Primary endpoint was the incidence of IFD until hospital discharge post-transplant. Secondary aims were the incidence of IFD and survival 180 days after allogeneic HCT, the evaluation of toxicity of L-AMB and further risk factors for development of IFD during antifungal prophylaxis. Descriptive statistics were performed.</p></div><div><h3>Results</h3><p>161 pediatric patients received L-AMB. Incidence of breakthrough IFD post-transplant was 7.5 % (12/161). The 12 cases comprised of three invasive yeast infections (1.9 %), three probable (1.9 %) and six possible (3.7 %) mold infections. Adverse events were in 22.4 % of the patients, most of them mild and reversible. Discontinuation of L-AMB occurred in 2.5 % (4/161) of the patients due to severe hypersensitivity reactions.</p></div><div><h3>Conclusions</h3><p>The risk of breakthrough IFD in pediatric patients undergoing allogeneic HCT under L-AMB prophylaxis is comparable with the reported risk under first line recommendation drugs for antifungal prophylaxis. If no hypersensitivity reaction occurs, L-AMB is tolerated with manageable side effects. This antifungal agent should therefore be considered as an alternative option to azoles in pediatric allogeneic HCT recipients.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000345/pdfft?md5=8f3b20ab25e8b4a0f652436bc6bf2f1a&pid=1-s2.0-S2772610X24000345-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141594919","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}
K.L. Juliëtte Schmidt , Noortje R. Severeijns , Noël M.M. Dautzenberg , Peter M. Hoogerbrugge , Caroline A. Lindemans , Stefan Nierkens , Gaby Smits , Rob S. van Binnendijk , Marta Fiocco , Louis J. Bont , Wim J.E. Tissing
{"title":"Long-term immunity after BNT162b2 mRNA COVID-19 vaccination in pediatric patients with cancer","authors":"K.L. Juliëtte Schmidt , Noortje R. Severeijns , Noël M.M. Dautzenberg , Peter M. Hoogerbrugge , Caroline A. Lindemans , Stefan Nierkens , Gaby Smits , Rob S. van Binnendijk , Marta Fiocco , Louis J. Bont , Wim J.E. Tissing","doi":"10.1016/j.ejcped.2024.100172","DOIUrl":"https://doi.org/10.1016/j.ejcped.2024.100172","url":null,"abstract":"","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X2400031X/pdfft?md5=07a204fa58544d703abcaf4923ef8f1f&pid=1-s2.0-S2772610X2400031X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141485655","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}
Jean Hunleth , Sarah Burack , Lindsey Kaufman , Caroline Mohrmann , Thembekile Shato , Eric Wiedenman , Janet Njelesani
{"title":"Inequities in childhood cancer research: A scoping review","authors":"Jean Hunleth , Sarah Burack , Lindsey Kaufman , Caroline Mohrmann , Thembekile Shato , Eric Wiedenman , Janet Njelesani","doi":"10.1016/j.ejcped.2024.100171","DOIUrl":"https://doi.org/10.1016/j.ejcped.2024.100171","url":null,"abstract":"<div><p>An integral part of understanding and then designing programs to reduce childhood cancer inequities includes adequate representation of people with cancer in research, including children. A scoping review was carried out to understand how cancer research is oriented toward inequities and to identify who has participated in childhood qualitative cancer research. A systematic search identified 119 qualitative studies that met inclusion criteria, with most studies taking place in high-income countries (n=84). Overall, data were lacking on social determinants of health at multiple levels—structural, household, child, and guardian. Only 29 studies reported on race and/or ethnicity, with the majority of those including predominantly or all white children. Six articles included socioeconomic information, and across most articles, attention was absent to the financial ramifications of cancer care. Limited reporting of sociodemographics highlights a broader issue of neglecting key demographics and social factors that contribute to inequities.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000308/pdfft?md5=d1dbc3ad73b75049f0309e8e65b7d4c3&pid=1-s2.0-S2772610X24000308-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141438760","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}