Karl Björkström,Cissi Liu,Anna Fager,Lisa L Liu,Lars Ny,Hildur Helgadottir
Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) was approved for advanced melanoma in 2016. The CheckMate 511 trial demonstrated improved tolerability with the flipped dose, NIVO3+IPI1, but this regimen has not been approved in melanoma by regulatory authorities. In this study, patients with advanced unresectable melanoma treated with NIVO3+IPI1 or NIVO1+IPI3 were included. The objective response rate was 48.8% with NIVO3+IPI1 (n = 209) and 36.9% with NIVO1+IPI3 (n = 190) (P = .016). Adjusted hazard ratio (aHR) was 0.67 (95% CI = 0.53 to 0.87, P = .002) for progression-free survival and 0.59 (95% CI = 0.44 to 0.78, P < .001) for overall survival (OS). In most studied subgroups aHR was <1, in favor of NIVO3+IPI1. The incidence of grade 3-5 immune-related adverse events was 30.6% with NIVO3+IPI1 vs. 51.1% with NIVO1+IPI3 (P < .001). This study shows that in a real-world setting, NIVO3+IPI1 demonstrated superior efficacy compared with NIVO1+IPI3, possibly related to a beneficial safety and tolerability profile allowing for more received doses.
Nivolumab 1mg /kg + ipilimumab 3mg /kg （NIVO1+IPI3）于2016年被批准用于晚期黑色素瘤。CheckMate 511试验表明，翻转剂量NIVO3+IPI1可改善耐受性，但该方案尚未获得监管机构批准用于黑色素瘤。本研究纳入了NIVO3+IPI1或NIVO1+IPI3治疗的晚期不可切除黑色素瘤患者。NIVO3+IPI1组客观有效率为48.8% (n = 209)， NIVO1+IPI3组客观有效率为36.9% (n = 190) （P = 0.016）。校正风险比（aHR）为0.67 (95% CI = 0.53 ~ 0.87, P =。002)，无进展生存期为0.59 (95% CI = 0.44 ~ 0.78, P <。001)总生存期（OS）。在大多数亚组中，aHR <1，有利于NIVO3+IPI1。NIVO3+IPI1组3-5级免疫相关不良事件发生率为30.6%，NIVO1+IPI3组为51.1% （P < 0.001）。这项研究表明，在现实环境中，NIVO3+IPI1比NIVO1+IPI3表现出更好的疗效，可能与更大剂量的安全性和耐受性有关。
{"title":"Evaluation of the flipped dose NIVO3+IPI1 in patients with advanced unresectable melanoma.","authors":"Karl Björkström,Cissi Liu,Anna Fager,Lisa L Liu,Lars Ny,Hildur Helgadottir","doi":"10.1093/jnci/djaf327","DOIUrl":"https://doi.org/10.1093/jnci/djaf327","url":null,"abstract":"Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) was approved for advanced melanoma in 2016. The CheckMate 511 trial demonstrated improved tolerability with the flipped dose, NIVO3+IPI1, but this regimen has not been approved in melanoma by regulatory authorities. In this study, patients with advanced unresectable melanoma treated with NIVO3+IPI1 or NIVO1+IPI3 were included. The objective response rate was 48.8% with NIVO3+IPI1 (n = 209) and 36.9% with NIVO1+IPI3 (n = 190) (P = .016). Adjusted hazard ratio (aHR) was 0.67 (95% CI = 0.53 to 0.87, P = .002) for progression-free survival and 0.59 (95% CI = 0.44 to 0.78, P < .001) for overall survival (OS). In most studied subgroups aHR was <1, in favor of NIVO3+IPI1. The incidence of grade 3-5 immune-related adverse events was 30.6% with NIVO3+IPI1 vs. 51.1% with NIVO1+IPI3 (P < .001). This study shows that in a real-world setting, NIVO3+IPI1 demonstrated superior efficacy compared with NIVO1+IPI3, possibly related to a beneficial safety and tolerability profile allowing for more received doses.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696619","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}
Dean A Shumway,Kimberly S Corbin,Satomi Shiraishi,Magdoleen H Farah,Farah Fleti,Bashar Hasan,Mohammed M Firwana,Samer Saadi,Tarek Nayfeh,Moustafa Hegazi,Mark R Waddle,Adam C Amundson,Carlos E Vargas,Laura A Vallow,Oluwadamilola T Oladeru,Tina J Hieken,Sean S Park,Robert W Mutter,M Hassan Murad,Zhen Wang
BACKGROUNDPartial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited.METHODSThis trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR).RESULTSBetween 2013-2023, 1,041 women with early-stage breast cancer were treated with PBI. 1,026 patients were included in the analyses. The median age was 66 years; 22.51% had DCIS, and 97.56% were estrogen receptor positive. With median followup of 38.2 months, the rate of IBR in the overall group was 3.05% (95% CI 1.99-4.65%) at 3 years. After IPW, Compared to photon PBI, the hazard ratio (HR) for IBR for proton PBI was 2.11 (95% confidence interval [CI] 0.70-6.33), and for brachytherapy, 3.86 (95% CI 1.39-10.69). Compared to proton PBI, the HR for IBR for brachytherapy was 1.83 (95% CI 0.88-3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size >10 mm, the HR for IBR for brachytherapy was 7.64 (95% CI 1.64-35.58) and 3.59 (95% CI 1.22-10.56) relative to photons and protons, respectively.CONCLUSIONPartial breast irradiation with applicator-based brachytherapy was associated with higher ipsilateral breast recurrence than photon or proton PBI in patients with tumor size > 10 mm, suggesting the need for more careful PBI patient selection for this modality.
背景：乳房部分照射（PBI）是治疗早期乳腺癌的有效方法。然而，比较不同PBI模式的证据是有限的。方法本试验采用多州大型三级卫生系统的电子病历。比较了质子放射治疗、光子放射治疗和基于应用器的近距离放射治疗的三种PBI方式。采用逆概率加权（IPW）来平衡混杂因素。主要结果为同侧乳房复发（IBR）。结果2013-2023年间，1041名早期乳腺癌患者接受了PBI治疗。1026名患者被纳入分析。年龄中位数为66岁；22.51%为DCIS， 97.56%为雌激素受体阳性。中位随访38.2个月，3年时整体组IBR率为3.05% （95% CI 1.99-4.65%）。与光子PBI相比，质子PBI的IBR风险比（HR）为2.11(95%可信区间[CI] 0.70-6.33)，近距离治疗的IBR风险比（HR）为3.86 （95% CI 1.39-10.69）。与质子PBI相比，近距离IBR治疗的HR为1.83 （95% CI 0.88-3.81）。对于肿瘤大小≤10 mm的患者和接受DCIS治疗的患者，不同PBI方式的IBR风险相似。在肿瘤大小为bbb10 mm的患者中，相对于光子和质子，近距离放疗IBR的HR分别为7.64 （95% CI 1.64-35.58）和3.59 （95% CI 1.22-10.56）。结论在肿瘤大小为bbb10 mm的患者中，基于涂抹器的部分乳房近距离照射比光子或质子PBI有更高的同侧乳房复发率，提示在选择这种方式的PBI患者时需要更加谨慎。
{"title":"Comparison of partial breast radiation modalities in women with early-stage breast cancer: a target trial emulation.","authors":"Dean A Shumway,Kimberly S Corbin,Satomi Shiraishi,Magdoleen H Farah,Farah Fleti,Bashar Hasan,Mohammed M Firwana,Samer Saadi,Tarek Nayfeh,Moustafa Hegazi,Mark R Waddle,Adam C Amundson,Carlos E Vargas,Laura A Vallow,Oluwadamilola T Oladeru,Tina J Hieken,Sean S Park,Robert W Mutter,M Hassan Murad,Zhen Wang","doi":"10.1093/jnci/djaf346","DOIUrl":"https://doi.org/10.1093/jnci/djaf346","url":null,"abstract":"BACKGROUNDPartial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited.METHODSThis trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR).RESULTSBetween 2013-2023, 1,041 women with early-stage breast cancer were treated with PBI. 1,026 patients were included in the analyses. The median age was 66 years; 22.51% had DCIS, and 97.56% were estrogen receptor positive. With median followup of 38.2 months, the rate of IBR in the overall group was 3.05% (95% CI 1.99-4.65%) at 3 years. After IPW, Compared to photon PBI, the hazard ratio (HR) for IBR for proton PBI was 2.11 (95% confidence interval [CI] 0.70-6.33), and for brachytherapy, 3.86 (95% CI 1.39-10.69). Compared to proton PBI, the HR for IBR for brachytherapy was 1.83 (95% CI 0.88-3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size >10 mm, the HR for IBR for brachytherapy was 7.64 (95% CI 1.64-35.58) and 3.59 (95% CI 1.22-10.56) relative to photons and protons, respectively.CONCLUSIONPartial breast irradiation with applicator-based brachytherapy was associated with higher ipsilateral breast recurrence than photon or proton PBI in patients with tumor size > 10 mm, suggesting the need for more careful PBI patient selection for this modality.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"128 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688962","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}
Luana G Sousa,James Edward Bates,Payal Anand,Jimmy J Caudell,A Dimitrios Colevas,Christina L Runge,Jeffrey D Sharon,Musaddiq Awan,Beth M Beadle,Jennifer H Choe,Paul W Gidley,Paul M Harari,Christina Henson,Jed A Katzel,Nancy Y Lee,Lachlan Mcdowell,Loren K Mell,Marc-Elie Nader,Soumon Rudra,Kaiwen Wang,George Yang,Sue S Yom,Trisha M Wise-Draper
BACKGROUNDCisplatin remains the cornerstone radiosensitizer for definitive and adjuvant chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). However, despite decades of clinical use, many practical aspects of cisplatin administration remain unstandardized in clinical practice and trials.METHODS AND FINDINGSDrawing on the collective experience of the NRG Oncology Head and Neck Working Group, this consensus manuscript provides practical guidance on the administration of cisplatin during radiation therapy. We review and propose recommendations regarding the timing of chemotherapy and radiation initiation, premedication and hydration regimens by dose, monitoring and grading of cisplatin-induced ototoxicity, and management strategies during cisplatin shortages. Our guidance is informed by clinical trial protocols, retrospective and prospective data, and multidisciplinary expert consensus. We emphasize the importance of protocol flexibility to support equitable trial accrual, minimize treatment delays, and improve patient-centered outcomes.CONCLUSIONThis manuscript offers a unified framework to optimize the use of cisplatin in chemoradiation protocols, improve adherence, reduce toxicity, and preserve oncologic efficacy. Our recommendations are particularly timely in the context of evolving clinical practices and recent cisplatin shortages. Insights from the NRG Oncology collaborative group aim to inform future trial designs and clinical practice guidelines, ensuring consistent and equitable care for patients with head and neck cancer.
{"title":"Cisplatin during radiation for head and neck cancer: insights from NRG Oncology experience.","authors":"Luana G Sousa,James Edward Bates,Payal Anand,Jimmy J Caudell,A Dimitrios Colevas,Christina L Runge,Jeffrey D Sharon,Musaddiq Awan,Beth M Beadle,Jennifer H Choe,Paul W Gidley,Paul M Harari,Christina Henson,Jed A Katzel,Nancy Y Lee,Lachlan Mcdowell,Loren K Mell,Marc-Elie Nader,Soumon Rudra,Kaiwen Wang,George Yang,Sue S Yom,Trisha M Wise-Draper","doi":"10.1093/jnci/djaf343","DOIUrl":"https://doi.org/10.1093/jnci/djaf343","url":null,"abstract":"BACKGROUNDCisplatin remains the cornerstone radiosensitizer for definitive and adjuvant chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). However, despite decades of clinical use, many practical aspects of cisplatin administration remain unstandardized in clinical practice and trials.METHODS AND FINDINGSDrawing on the collective experience of the NRG Oncology Head and Neck Working Group, this consensus manuscript provides practical guidance on the administration of cisplatin during radiation therapy. We review and propose recommendations regarding the timing of chemotherapy and radiation initiation, premedication and hydration regimens by dose, monitoring and grading of cisplatin-induced ototoxicity, and management strategies during cisplatin shortages. Our guidance is informed by clinical trial protocols, retrospective and prospective data, and multidisciplinary expert consensus. We emphasize the importance of protocol flexibility to support equitable trial accrual, minimize treatment delays, and improve patient-centered outcomes.CONCLUSIONThis manuscript offers a unified framework to optimize the use of cisplatin in chemoradiation protocols, improve adherence, reduce toxicity, and preserve oncologic efficacy. Our recommendations are particularly timely in the context of evolving clinical practices and recent cisplatin shortages. Insights from the NRG Oncology collaborative group aim to inform future trial designs and clinical practice guidelines, ensuring consistent and equitable care for patients with head and neck cancer.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674343","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}
Dawn L Hershman,Cathee Till,Michael Leblanc,Scott Ramsey,Joseph M Unger
BACKGROUNDpatients with advanced cancer are at risk for unplanned Emergency Department (ED) visits and hospital stays (HS). The purpose was to develop and validate a risk prediction model to identify patients at the highest risk for acute care use.METHODSWe identified advanced cancer patients ≥65 years treated on SWOG trials from 1999-2014 using data linked to Medicare claims. The primary outcome was acute care use (ED visits or HS). A 60% random sample training set was used to identify candidate variables. An adverse risk model was built by summing adverse factors and creating high vs low-risk groups by splitting at the median. This risk model was tested in the 40% validation set.RESULTSAmong N = 1397 patients from 6 trials, 839 comprised the training set. The proportion of patients with ≥1 HS/ED visit was 67.5%. Adverse risk factors were performance status (0 vs.≥1), coronary artery disease, hypertension, and liver disease. Patients with ≥2 factors (high-risk; 57.3%) vs. 0/1 risk factor (low-risk; 42.7%) were more likely to experience acute care (79.6% vs. 51.1%), corresponding to a > 3-fold increase in odds (OR = 3.38, 95%CI , 2.48-4.62). Results were similar in the test set, indicating successful validation. Among all patients, quartile-level proportions were 48.9% for zero risk factors vs. 84.0% for 3/4 risk factors. The C-statistic was 0.703.CONCLUSIONSA limited set of 4 variables predicted a threefold increased risk of acute care use in older patients with advanced cancer. Personalized interventions aimed at preventing acute care use could improve the quality of cancer care.
背景：晚期癌症患者出现计划外急诊科（ED）就诊和住院（HS）的风险较大。目的是开发和验证一个风险预测模型，以确定患者在急性护理使用的最高风险。方法：我们从1999-2014年的SWOG试验中选取≥65岁的晚期癌症患者，使用与医疗保险索赔相关的数据。主要结局是急诊使用（ED或HS）。使用60%随机样本训练集来识别候选变量。将不利因素相加建立不利风险模型，并在中位数处划分高风险组和低风险组。该风险模型在40%的验证集中进行了测试。结果6项试验的1397例患者中，839例纳入训练集。HS/ED就诊≥1次的患者占67.5%。不良危险因素为运动状态（0 vs.≥1）、冠状动脉疾病、高血压和肝脏疾病。≥2个危险因素（高危，57.3%）与0/1个危险因素（低危，42.7%）的患者更有可能经历急性护理（79.6% vs. 51.1%），对应于bb0 3倍的优势增加（OR = 3.38, 95%CI, 2.48-4.62）。测试集的结果相似，表明验证成功。在所有患者中，零危险因素的四分位数比例为48.9%，而3/4危险因素的四分位数比例为84.0%。c统计量为0.703。结论：一组有限的4个变量预测老年晚期癌症患者使用急性护理的风险增加了3倍。旨在预防急性护理使用的个性化干预措施可以提高癌症护理的质量。
{"title":"Development and validation of a risk prediction model for acute care use among older advanced cancer patients on clinical trials.","authors":"Dawn L Hershman,Cathee Till,Michael Leblanc,Scott Ramsey,Joseph M Unger","doi":"10.1093/jnci/djaf342","DOIUrl":"https://doi.org/10.1093/jnci/djaf342","url":null,"abstract":"BACKGROUNDpatients with advanced cancer are at risk for unplanned Emergency Department (ED) visits and hospital stays (HS). The purpose was to develop and validate a risk prediction model to identify patients at the highest risk for acute care use.METHODSWe identified advanced cancer patients ≥65 years treated on SWOG trials from 1999-2014 using data linked to Medicare claims. The primary outcome was acute care use (ED visits or HS). A 60% random sample training set was used to identify candidate variables. An adverse risk model was built by summing adverse factors and creating high vs low-risk groups by splitting at the median. This risk model was tested in the 40% validation set.RESULTSAmong N = 1397 patients from 6 trials, 839 comprised the training set. The proportion of patients with ≥1 HS/ED visit was 67.5%. Adverse risk factors were performance status (0 vs.≥1), coronary artery disease, hypertension, and liver disease. Patients with ≥2 factors (high-risk; 57.3%) vs. 0/1 risk factor (low-risk; 42.7%) were more likely to experience acute care (79.6% vs. 51.1%), corresponding to a > 3-fold increase in odds (OR = 3.38, 95%CI , 2.48-4.62). Results were similar in the test set, indicating successful validation. Among all patients, quartile-level proportions were 48.9% for zero risk factors vs. 84.0% for 3/4 risk factors. The C-statistic was 0.703.CONCLUSIONSA limited set of 4 variables predicted a threefold increased risk of acute care use in older patients with advanced cancer. Personalized interventions aimed at preventing acute care use could improve the quality of cancer care.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"203 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674393","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}
Simon Pahnke,Karine Alcala,Connie Bulos Salim,Ricardo Cortez Cardoso Penha,Hanla A Park,James Mckay,Mattias Johansson
BACKGROUNDElevated absolute lymphocyte cell (ALC) count is often used as a first indication for diagnostic investigation of chronic lymphocytic leukaemia (CLL). The absolute risk of CLL as a function of age, sex and ALC has not been described.METHODSWe used information on pre-diagnostic ALC on 475,399 longitudinally followed research participants from UK Biobank, with a median follow-up of 11.6 years during which 854 participants were diagnosed with CLL. A CLL risk model was developed based on sex, age at recruitment, and pre-diagnostic ALC using flexible parametric survival modelling.RESULTSCompared to research participants with ALC below 2 x109 cells/L, the risk of CLL was almost 8 times higher for those with ALC of 3 to 4x109 cells/L (HR 7.76, 95% CI: 6.24-9.65). The absolute risk of CLL was two-fold higher in males than in females. For 60-year-olds with ALC of 5x109 cells/L, 10-year CLL risk was estimated at 6.5% (95% CI: 5.6%-7.5%) for men and 3.5% (3.0%-4.1%) for women. The 10-year risk of CLL for participants with ALC of 5x109 cells/L varied between 0.91% (95% CI: 0.68-1.2%) for a 40-year-old female and 12% (95% CI: 11-15%) for a 70-year-old male.CONCLUSIONThe absolute risk of CLL is strongly influenced by age, sex and ALC. A crude ALC cut-off to indicate further investigation for CLL without taking age and sex into consideration will identify some individuals who are at low risk. These results may be considered when establishing guidelines for clinical management of patients with elevated ALC.
{"title":"Lymphocyte count and risk of chronic lymphocytic leukaemia.","authors":"Simon Pahnke,Karine Alcala,Connie Bulos Salim,Ricardo Cortez Cardoso Penha,Hanla A Park,James Mckay,Mattias Johansson","doi":"10.1093/jnci/djaf338","DOIUrl":"https://doi.org/10.1093/jnci/djaf338","url":null,"abstract":"BACKGROUNDElevated absolute lymphocyte cell (ALC) count is often used as a first indication for diagnostic investigation of chronic lymphocytic leukaemia (CLL). The absolute risk of CLL as a function of age, sex and ALC has not been described.METHODSWe used information on pre-diagnostic ALC on 475,399 longitudinally followed research participants from UK Biobank, with a median follow-up of 11.6 years during which 854 participants were diagnosed with CLL. A CLL risk model was developed based on sex, age at recruitment, and pre-diagnostic ALC using flexible parametric survival modelling.RESULTSCompared to research participants with ALC below 2 x109 cells/L, the risk of CLL was almost 8 times higher for those with ALC of 3 to 4x109 cells/L (HR 7.76, 95% CI: 6.24-9.65). The absolute risk of CLL was two-fold higher in males than in females. For 60-year-olds with ALC of 5x109 cells/L, 10-year CLL risk was estimated at 6.5% (95% CI: 5.6%-7.5%) for men and 3.5% (3.0%-4.1%) for women. The 10-year risk of CLL for participants with ALC of 5x109 cells/L varied between 0.91% (95% CI: 0.68-1.2%) for a 40-year-old female and 12% (95% CI: 11-15%) for a 70-year-old male.CONCLUSIONThe absolute risk of CLL is strongly influenced by age, sex and ALC. A crude ALC cut-off to indicate further investigation for CLL without taking age and sex into consideration will identify some individuals who are at low risk. These results may be considered when establishing guidelines for clinical management of patients with elevated ALC.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"125 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644900","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}
Dylan Williams,Chandni Patel,Kate Murray,Lucy Oldfield,Benjamin Small,Lawrence N Barrera,Rachel O'Sullivan,James Birch-Ford,Anthony Evans,Fiona Campbell,Pedro A Perez-Mancera,Christopher M Halloran,Daniel Palmer,William Greenhalf,Ian M Copple,Chris Goldring,Thilo Hackert,Richard Jackson,John P Neoptolemos,Christoph Springfeld,Markus W Büchler,Christoph W Michalski,Paula Ghaneh,Eithne Costello
BACKGROUNDNAD(P)H Quinone Dehydrogenase 1 (NQO1), a detoxification enzyme regulated by the Nrf2 cytoprotective pathway, is overexpressed in pancreatic ductal adenocarcinoma (PDAC). NQO1 levels are also influenced by the C609T single nucleotide polymorphism (SNP). We hypothesised that elevated NQO1 would confer chemoresistance in PDAC and predict poor patient outcome.METHODSNQO1 tumor levels and germline C609T SNP status were assessed in archival samples from the European Study Group for Pancreatic Cancer (ESPAC) trials. NQO1 expression (H-score) was treated as continuous for survival regression analyses and dichotomised for visual summaries. Nrf2 or downstream gene induction was assessed in Nrf2 reporter mice or in PDAC cells following exposure to gemcitabine (Gem), 5-fluorouracil (5-FU) or the capecitabine (Cap) metabolite 5-Fluoro-5'-deoxyuridine (5'-DFUR). Colony formation following NQO1 depletion was assessed.RESULTSNQO1 tumor levels correlated with germline C609T SNP status (p < .001). Contrary to our hypothesis, high NQO1 expression was associated with improved survival in ESPAC-4 patients randomised to GemCap (HR 0.87 (0.751, 0.999); P = .049), and had no association to outcome in the Gem-only treated arm [HR: 0.98 (0.78, 1.23) P = .867]. Including genotype data did not improve predictive model performance. Neither Gem nor 5-FU induced Nrf2 in vivo. At high concentrations they suppressed Nrf2/NQO1 in PDAC cells, an effect not mitigated by co-treatment with 5'-DFUR. NQO1 depletion experiments revealed that NQO1 inhibits colony formation. The strongest inhibition was observed when NQO1-positive cells were co-treated with Gem and 5'-DFUR, supporting our clinical data from ESPAC.CONCLUSIONHigh tumor NQO1 predicts better outcome following GemCap therapy.
{"title":"NQO1 as a predictor of response to adjuvant GemCap treatment for pancreatic cancer.","authors":"Dylan Williams,Chandni Patel,Kate Murray,Lucy Oldfield,Benjamin Small,Lawrence N Barrera,Rachel O'Sullivan,James Birch-Ford,Anthony Evans,Fiona Campbell,Pedro A Perez-Mancera,Christopher M Halloran,Daniel Palmer,William Greenhalf,Ian M Copple,Chris Goldring,Thilo Hackert,Richard Jackson,John P Neoptolemos,Christoph Springfeld,Markus W Büchler,Christoph W Michalski,Paula Ghaneh,Eithne Costello","doi":"10.1093/jnci/djaf345","DOIUrl":"https://doi.org/10.1093/jnci/djaf345","url":null,"abstract":"BACKGROUNDNAD(P)H Quinone Dehydrogenase 1 (NQO1), a detoxification enzyme regulated by the Nrf2 cytoprotective pathway, is overexpressed in pancreatic ductal adenocarcinoma (PDAC). NQO1 levels are also influenced by the C609T single nucleotide polymorphism (SNP). We hypothesised that elevated NQO1 would confer chemoresistance in PDAC and predict poor patient outcome.METHODSNQO1 tumor levels and germline C609T SNP status were assessed in archival samples from the European Study Group for Pancreatic Cancer (ESPAC) trials. NQO1 expression (H-score) was treated as continuous for survival regression analyses and dichotomised for visual summaries. Nrf2 or downstream gene induction was assessed in Nrf2 reporter mice or in PDAC cells following exposure to gemcitabine (Gem), 5-fluorouracil (5-FU) or the capecitabine (Cap) metabolite 5-Fluoro-5'-deoxyuridine (5'-DFUR). Colony formation following NQO1 depletion was assessed.RESULTSNQO1 tumor levels correlated with germline C609T SNP status (p < .001). Contrary to our hypothesis, high NQO1 expression was associated with improved survival in ESPAC-4 patients randomised to GemCap (HR 0.87 (0.751, 0.999); P = .049), and had no association to outcome in the Gem-only treated arm [HR: 0.98 (0.78, 1.23) P = .867]. Including genotype data did not improve predictive model performance. Neither Gem nor 5-FU induced Nrf2 in vivo. At high concentrations they suppressed Nrf2/NQO1 in PDAC cells, an effect not mitigated by co-treatment with 5'-DFUR. NQO1 depletion experiments revealed that NQO1 inhibits colony formation. The strongest inhibition was observed when NQO1-positive cells were co-treated with Gem and 5'-DFUR, supporting our clinical data from ESPAC.CONCLUSIONHigh tumor NQO1 predicts better outcome following GemCap therapy.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644879","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}
Gloria D Coronado,Richard M Hoffman,Josheili Llavona-Ortiz,Carolyn M Rutter
The May 2021 Centers for Medicare and Medicaid Services (CMS) coverage determination allowed reimbursement for blood-based biomarker tests and other tests for colorectal cancer (CRC) screening that meet minimum 74% sensitivity and 90% specificity thresholds. However, these performance benchmarks fail to account for the importance of detecting precancerous lesions and the impact of the recommended testing interval on the effectiveness of screening. We review the limitations of the CMS criteria, summarize supporting evidence for stool-based testing and colonoscopy as effective and cost-efficient screening modalities, and offer recommendations to strengthen CMS coverage decisions to better align with public health goals in CRC prevention.
{"title":"The Centers for Medicare and Medicaid Services and others misunderstand stool testing for colorectal cancer.","authors":"Gloria D Coronado,Richard M Hoffman,Josheili Llavona-Ortiz,Carolyn M Rutter","doi":"10.1093/jnci/djaf341","DOIUrl":"https://doi.org/10.1093/jnci/djaf341","url":null,"abstract":"The May 2021 Centers for Medicare and Medicaid Services (CMS) coverage determination allowed reimbursement for blood-based biomarker tests and other tests for colorectal cancer (CRC) screening that meet minimum 74% sensitivity and 90% specificity thresholds. However, these performance benchmarks fail to account for the importance of detecting precancerous lesions and the impact of the recommended testing interval on the effectiveness of screening. We review the limitations of the CMS criteria, summarize supporting evidence for stool-based testing and colonoscopy as effective and cost-efficient screening modalities, and offer recommendations to strengthen CMS coverage decisions to better align with public health goals in CRC prevention.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"218 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644898","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}
Eunji Choi, Wanting Zhai, Jaeil Ahn, Tim A Ahles, Ashley L Artese, Iwalola Awoyinka, Judith E Carroll, Harvey J Cohen, Kathleen Van Dyk, Deena Graham, Heather S L Jim, Brenna C Mcdonald, Zev M Nakamura, Sunita K Patel, Kelly E Rentscher, James C Root, Andrew J Saykin, Brent J Small, Yiwey Shieh, Jeanne S Mandelblatt, Traci N Bethea
Background Neighborhood characteristics can affect aging and health. We tested effects of neighborhood deprivation on deficit accumulation frailty scores in a prospective cohort of breast cancer survivors vs. controls aged 60-98. Methods Newly diagnosed, non-metastatic breast cancer survivors (477) and frequency-matched controls (434) were enrolled from 2010-2023, with up to 5-year follow-up through 2024. Deficit accumulation was measured with a 48-item index (scores 0-1); a clinically meaningful deficit increase was defined by a 0.06 score increase. Neighborhood deprivation was assessed using area deprivation index (ADI) at enrollment census block group and categorized into tertiles. Cause-specific Cox models tested the association between ADI and risk of deficit accumulation increase. Results Participants living in more deprived areas (2nd and 3rd tertiles of ADI) had higher risks of increased deficit accumulation (adjusted hazard ratios [aHR] 1.38 [1.01-1.89; P = .04] and 1.46 [1.07-1.94; P = .01] vs. 1st tertile, respectively). Independent of ADI, being a survivor (vs. control) was associated with greater risk of increased deficit accumulation (aHR = 1.69 [1.32-2.17, P<.001]). There were different patterns of cumulative incidence rates of increased deficit accumulation by ADI survivors treated with chemotherapy (+/- hormonal therapy) living in more vs. less deprived areas had a 20% higher incidence of increased deficit accumulation within 1 year (P = .004), while survivors receiving hormonal therapy alone and non-cancer controls had their most pronounced differences by 4 years (10%; P = .32 and 10%; P = .05, respectively). Conclusions Neighborhood deprivation may increase deficit accumulation, with an apparent acceleration of effects among older breast cancer survivors treated with chemotherapy.
{"title":"Neighborhood deprivation on increasing deficit accumulation in older breast cancer survivors and non-cancer controls","authors":"Eunji Choi, Wanting Zhai, Jaeil Ahn, Tim A Ahles, Ashley L Artese, Iwalola Awoyinka, Judith E Carroll, Harvey J Cohen, Kathleen Van Dyk, Deena Graham, Heather S L Jim, Brenna C Mcdonald, Zev M Nakamura, Sunita K Patel, Kelly E Rentscher, James C Root, Andrew J Saykin, Brent J Small, Yiwey Shieh, Jeanne S Mandelblatt, Traci N Bethea","doi":"10.1093/jnci/djaf337","DOIUrl":"https://doi.org/10.1093/jnci/djaf337","url":null,"abstract":"Background Neighborhood characteristics can affect aging and health. We tested effects of neighborhood deprivation on deficit accumulation frailty scores in a prospective cohort of breast cancer survivors vs. controls aged 60-98. Methods Newly diagnosed, non-metastatic breast cancer survivors (477) and frequency-matched controls (434) were enrolled from 2010-2023, with up to 5-year follow-up through 2024. Deficit accumulation was measured with a 48-item index (scores 0-1); a clinically meaningful deficit increase was defined by a 0.06 score increase. Neighborhood deprivation was assessed using area deprivation index (ADI) at enrollment census block group and categorized into tertiles. Cause-specific Cox models tested the association between ADI and risk of deficit accumulation increase. Results Participants living in more deprived areas (2nd and 3rd tertiles of ADI) had higher risks of increased deficit accumulation (adjusted hazard ratios [aHR] 1.38 [1.01-1.89; P = .04] and 1.46 [1.07-1.94; P = .01] vs. 1st tertile, respectively). Independent of ADI, being a survivor (vs. control) was associated with greater risk of increased deficit accumulation (aHR = 1.69 [1.32-2.17, P&lt;.001]). There were different patterns of cumulative incidence rates of increased deficit accumulation by ADI survivors treated with chemotherapy (+/- hormonal therapy) living in more vs. less deprived areas had a 20% higher incidence of increased deficit accumulation within 1 year (P = .004), while survivors receiving hormonal therapy alone and non-cancer controls had their most pronounced differences by 4 years (10%; P = .32 and 10%; P = .05, respectively). Conclusions Neighborhood deprivation may increase deficit accumulation, with an apparent acceleration of effects among older breast cancer survivors treated with chemotherapy.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575290","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}
Noor Wortelboer, Seamus Kent, Hedwig M Blommestein, Annemiek van Ommen-Nijhof, Vincent van der Noort, Esther van den Pol, Cristina Guerrero Páez, Aart Beeker, Karin Beelen, Lisanne C Hamming, Joan B Heijns, Aafke H Honkoop, Paul C de Jong, Quirine C van Rossum-Schornagel, Christa van Schaik- van de Mheen, Jolien Tol, Cathrien S Tromp-van Driel, Suzan Vrijaldenhoven, A Elise van Leeuwen-Stok, Gabe S Sonke, Agnes Jager, Inge R Konings
Background The SONIA trial demonstrated that addition of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) to first-line endocrine therapy (aromatase-inhibitor) was not superior in terms of progression-free survival after two treatment lines (PFS2) compared to addition to second-line (fulvestrant), while first-line use increased toxicity (74% more grade ≥3 adverse events) and costs. Understanding the impact of both treatment strategies on health-related quality of life (HRQoL) is critical to inform patient-centered treatment decisions. Methods HRQoL was assessed using the FACT-B and EQ-5D-5L questionnaires at up to 11 time points over the course of both treatment lines (follow-up) until SONIA treatment discontinuation. FACT-B total and subscale scores—including physical (PWB), social (SWB), emotional (EWB), functional well-being (FWB) and the breast cancer subscale (BCS) – along with EQ-5D-5L scores were compared between treatment strategies using mixed linear regression models. Clinically meaningful differences were predefined as 7 points for the FACT-B total score and 2 points for subscales. Results Questionnaire completion rates for FACT-B were 88% at baseline and 75% during follow-up. No clinically or statistically significant differences in HRQoL were observed between treatment arms during follow-up. The estimated mean difference in FACT-B total score (CDK4/6i in second-line as reference) was -0.66 (95% CI -2.14 to 0.82; p = .39). Differences for subscales were similarly small. Conclusion HRQoL was comparable between patients receiving CDK4/6i in first- versus second-line across all measures, despite differences in toxicity rates. Clinical Trial Registration ClinicalTrials.gov (NCT03425838)
索尼亚试验表明，在一线内分泌治疗（芳香酶抑制剂）中添加周期蛋白依赖性激酶4和6抑制剂（CDK4/6i）在两条治疗线（PFS2）后的无进展生存方面并不优于添加二线（氟维司汀），而一线使用增加了毒性（≥3级不良事件增加74%）和成本。了解两种治疗策略对健康相关生活质量（HRQoL）的影响对于为以患者为中心的治疗决策提供信息至关重要。方法采用FACT-B和EQ-5D-5L问卷，在两条治疗线（随访）过程中多达11个时间点评估HRQoL，直到SONIA治疗停止。使用混合线性回归模型比较治疗策略之间的FACT-B总得分和子量表得分-包括身体（PWB），社会（SWB），情感（EWB），功能幸福感（FWB）和乳腺癌子量表(BCS) -以及EQ-5D-5L得分。临床意义差异预先定义为FACT-B总分7分，亚量表2分。结果基线时FACT-B问卷完成率为88%，随访时为75%。随访期间，两组患者HRQoL无临床或统计学差异。FACT-B总分（二线CDK4/6i作为参考）的估计平均差异为-0.66 （95% CI -2.14至0.82;p = 0.39）。亚量表的差异同样很小。结论：尽管毒性率存在差异，但接受CDK4/6i治疗的一线和二线患者的HRQoL具有可比性。临床试验注册ClinicalTrials.gov （NCT03425838）
{"title":"Health-related quality of life with first- vs second-line CDK4/6 inhibitor use in advanced breast cancer: results from the SONIA trial","authors":"Noor Wortelboer, Seamus Kent, Hedwig M Blommestein, Annemiek van Ommen-Nijhof, Vincent van der Noort, Esther van den Pol, Cristina Guerrero Páez, Aart Beeker, Karin Beelen, Lisanne C Hamming, Joan B Heijns, Aafke H Honkoop, Paul C de Jong, Quirine C van Rossum-Schornagel, Christa van Schaik- van de Mheen, Jolien Tol, Cathrien S Tromp-van Driel, Suzan Vrijaldenhoven, A Elise van Leeuwen-Stok, Gabe S Sonke, Agnes Jager, Inge R Konings","doi":"10.1093/jnci/djaf334","DOIUrl":"https://doi.org/10.1093/jnci/djaf334","url":null,"abstract":"Background The SONIA trial demonstrated that addition of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) to first-line endocrine therapy (aromatase-inhibitor) was not superior in terms of progression-free survival after two treatment lines (PFS2) compared to addition to second-line (fulvestrant), while first-line use increased toxicity (74% more grade ≥3 adverse events) and costs. Understanding the impact of both treatment strategies on health-related quality of life (HRQoL) is critical to inform patient-centered treatment decisions. Methods HRQoL was assessed using the FACT-B and EQ-5D-5L questionnaires at up to 11 time points over the course of both treatment lines (follow-up) until SONIA treatment discontinuation. FACT-B total and subscale scores—including physical (PWB), social (SWB), emotional (EWB), functional well-being (FWB) and the breast cancer subscale (BCS) – along with EQ-5D-5L scores were compared between treatment strategies using mixed linear regression models. Clinically meaningful differences were predefined as 7 points for the FACT-B total score and 2 points for subscales. Results Questionnaire completion rates for FACT-B were 88% at baseline and 75% during follow-up. No clinically or statistically significant differences in HRQoL were observed between treatment arms during follow-up. The estimated mean difference in FACT-B total score (CDK4/6i in second-line as reference) was -0.66 (95% CI -2.14 to 0.82; p = .39). Differences for subscales were similarly small. Conclusion HRQoL was comparable between patients receiving CDK4/6i in first- versus second-line across all measures, despite differences in toxicity rates. Clinical Trial Registration ClinicalTrials.gov (NCT03425838)","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567296","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}
Giancarlo Di Giuseppe,Arif Jetha,Petros Pechlivanoglou,Jason D Pole
BACKGROUNDCancer in adolescents and young adults (AYAs) emerges during critical transitional phases, resulting in lasting effects on financial well-being. It remains uncertain whether cancer in AYAs exhibits differences in financial impact on income based on gender and diagnosis age over time.METHODSWe linked Canada's national cancer registry to personal tax records to identify AYAs (15-39 years) diagnosed between 1994 and 2013. In the year before diagnosis, survivors were variable-ratio matched to 10 cancer-free individuals on several sociodemographic characteristics. Participants were followed longitudinally up to 10-years post-diagnosis or until 2015. Relative and absolute income changes were estimated using doubly-robust difference-in-differences. We categorized age into three groups: adolescents (15-17 years), emerging young adults (18-29 years), and young adults (30-39 years), reflecting the different AYA life stages. Analyses were stratified by gender and diagnosis age.RESULTSThere were 60,240 women and 33,085 men survivors matched to 490,645 and 274,595 cancer-free participants, respectively. Overall, men and women had 6.9% (95%CI: 5.1%-8.6%) and 4.5% (95%CI: 3.1%-5.8%) income reductions, respectively. Adolescent men had the largest reduction of 23.7% (95%CI: 1.9% to 40.6%), while a lack of significance was observed in women of the same age. Income was reduced for varying magnitudes and durations across the different intersections of gender and diagnosis age, with men experiencing longer periods of income reductions.CONCLUSIONSCancer impacts income generation differently for AYA men and women, and at various diagnosis ages over time. Men, particularly younger men, are most vulnerable to income reductions.
{"title":"Income After Cancer Across Gender and Age Among Canadian Adolescents and Young Adults.","authors":"Giancarlo Di Giuseppe,Arif Jetha,Petros Pechlivanoglou,Jason D Pole","doi":"10.1093/jnci/djaf333","DOIUrl":"https://doi.org/10.1093/jnci/djaf333","url":null,"abstract":"BACKGROUNDCancer in adolescents and young adults (AYAs) emerges during critical transitional phases, resulting in lasting effects on financial well-being. It remains uncertain whether cancer in AYAs exhibits differences in financial impact on income based on gender and diagnosis age over time.METHODSWe linked Canada's national cancer registry to personal tax records to identify AYAs (15-39 years) diagnosed between 1994 and 2013. In the year before diagnosis, survivors were variable-ratio matched to 10 cancer-free individuals on several sociodemographic characteristics. Participants were followed longitudinally up to 10-years post-diagnosis or until 2015. Relative and absolute income changes were estimated using doubly-robust difference-in-differences. We categorized age into three groups: adolescents (15-17 years), emerging young adults (18-29 years), and young adults (30-39 years), reflecting the different AYA life stages. Analyses were stratified by gender and diagnosis age.RESULTSThere were 60,240 women and 33,085 men survivors matched to 490,645 and 274,595 cancer-free participants, respectively. Overall, men and women had 6.9% (95%CI: 5.1%-8.6%) and 4.5% (95%CI: 3.1%-5.8%) income reductions, respectively. Adolescent men had the largest reduction of 23.7% (95%CI: 1.9% to 40.6%), while a lack of significance was observed in women of the same age. Income was reduced for varying magnitudes and durations across the different intersections of gender and diagnosis age, with men experiencing longer periods of income reductions.CONCLUSIONSCancer impacts income generation differently for AYA men and women, and at various diagnosis ages over time. Men, particularly younger men, are most vulnerable to income reductions.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545346","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}
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