tbuckley/cabot-search huggingface dataset:
Economic evaluation of the oncotype DX test for hormone receptor positive (HR+) early-stage breast cancer (BC) from the Brazilian societal perspective.
Authors: Andre Mattar, Guilherme Ribeiro Fonseca, Murilo Barato Agudo Romão, Jorge Yoshinori Shida, Debbie M Jakubowski, Calvin Y. Chao, Sergio C Oliveira, Luiz Henrique Gebrim
Journal: Journal of Clinical Oncology (2020)

e19380 Background: Selecting appropriate patients for AC (adjuvant chemotherapy) remains an important issue in BC treatment. Although AC improves clinical outcomes toxicity and economic burden is substantial. The Oncotype DX test identifies high-risk patients likely to benefit from AC who otherwise might not be identified through standard parameters (SP), and low-risk patients unlikely to benefit from AC, avoiding toxicities and inherent risks. This study estimated the incremental cost-effectiveness ratio and budget impact (BI) of Oncotype DX testing from the perspective of the Brazilian Public Health System. Methods: A Markov transitional state model was developed with 3 states: recurrence free, distant recurrence, and death. The model compared the scenario in which patients are screened by SP with a proposed scenario with Oncotype DX testing. Changes in therapeutic recommendations and cost of treatment were obtained from a prospective clinical survey at Pérola Byington Hospital. Additional data was obtained from literature. As a societal perspective analysis, medical costs (test, AC, and adverse events), costs of productivity loss, transportation and employment leave were considered. Population was estimated from BC incidence, proportion of early stage cases, and HR expression. An incremental proportion of 10% per year of patients using Oncotype DX testing was assumed. BI analysis had a 5-year horizon and cost-effectiveness a lifetime horizon (5% annual discount). Results: Oncotype DX results as identifier of a subgroup at higher risk of relapse and greater benefit with AC was dominant over SP. Oncotype DX testing resulted in clinical benefits in terms of life-years gained (0.62) and quality-adjusted life years (0.54), related to lower incidence of distant recurrence and use of AC, both of which greatly impacted quality of life. Testing resulted in economic benefits, with lower average cost per patient (−BRL 3,855). Incorporation of Oncotype DX testing resulted in potential savings reaching BRL 107 million in the 5th year stemming from the decrease in AC and consequent decrease in indirect costs. Conclusions: Patients with HR+, HER2− early stage BC may present different risks of relapse and likelihoods of benefiting from AC. With high clinical impact for patients and high economic impact for the health system, a tool that safely and accurately identifies the subgroup of patients who really needs AC is essential. Oncotype DX test incorporation in the Brazilian Public Health System should be considered.
Bioinformatic analysis of selinexor-induced gene expression in patient-derived-chordomas to reveal mechanisms of action leading to tumor growth inhibition.
Authors: Christopher James Walker, Hua Chang, Leah Henegar, Trinayan Kashyap, Thaddeus J Unger, Sharon Shacham, Patricia Cogswell, Stacy Fechner, Michael Wick, Joan Levy, Yosef Landesman
Journal: Journal of Clinical Oncology (2020)

e23502 Background: Selinexor is a selective inhibitor of nuclear export that inhibits XPO1 from shuttling its cargo from the nucleus to the cytoplasm. This leads to accumulation of tumor suppressor proteins in the nucleus, activation of cell cycle checkpoints, cell cycle arrest and apoptosis in cancer cells. Chordomas are rare cancers emanating from the skull base and spine that originate from remnants of the notochord. Patients with chordomas have poor prognosis with limited treatment options. To investigate the in vivo efficacy and assess molecular effects of selinexor treatment in chordoma, two patient-derived xenograft (PDX) mouse models were tested. Methods: Murine chordoma PDX models of recurrent clival chordoma (SF8894) and metastatic sacral chordoma (CF466) were treated with selinexor (5mg/kg PO, 4x weekly). Tumor volume was monitored for 6 weeks of treatment, then excised tumors were used for immunohistochemistry (IHC) analysis and RNA sequencing. Results: Selinexor treatment significantly reduced the tumor volume of mice bearing CF466-derived tumors (5 mice/group; 57.6% reduction in volume compared to control; P = 0.031), and SF8894-derived tumors (4 mice/group; 76.2% reduction; P &lt; 0.001). Differential gene expression between selinexor and vehicle treated samples showed significant differences in 428 genes and 156 genes in the CF466 and SF8894 tumors, respectively (adjusted P-value [Padj] &lt; 0.01). In both models, XPO1 protein levels were markedly decreased and expression of the tumor suppressors TP53 (CF466: Padj = 1.4x10 −17 ; SF8894: Padj = 0.002) and ARRDC3 (CF466: Padj = 2.2x10 −72 ; SF8894: Padj = 2.9x10 −12 ) were increased. In the CF466 chordoma model, selinexor reduced SOX9 (Padj = 1.6x10 −18 ), SMAD4 (Padj = 0.019), and SHH (Padj = 0.028), which were confirmed to be reduced at the protein level by IHC. The SF8894 model showed reduction in EZH2 expression (Padj = 0.0012). Pathway analysis of both models showed activated TP53 signaling (CF466: z-score = 0.82; SF8894: z-score = 2.16) and apoptosis (CF466: P = 5.2x10 −8 ; SF8894: P = 1.2x10 −8 ). G2/M checkpoint regulators were upregulated in the CF466 model (z-score = 2.83). Conclusions: Selinexor treatment led to reduction in tumor growth in two PDX models of chordoma. Both models showed upregulation of TP53 signaling and apoptosis upon treatment, with downregulation of distinct oncogenic pathways. Further investigation of selinexor as a treatment option for chordoma is warranted.
Bone mineral density reference standards for Chinese children aged 3-18: cross-sectional results of the 2013-2015 China Child and Adolescent Cardiovascular Health (CCACH) Study
Authors: 刘军廷, 王亮, 孙景辉, 刘功姝, 严卫丽, 席波, 熊丰, 丁文清, 黄贵民, Heymsfield Steven, 米杰
Journal: BMJ (2017)

目的
骨骼是构成人体的支架，是儿童青少年正常生长发育的基础。人体骨量在20岁左右达到峰值，骨峰值的80%在青少年时期形成。研究证明，峰值骨量决定了中老年的骨量丢失和发生骨质疏松的风险。正确评价儿童的骨密度对于评价正常儿童的生长发育，发现偏移、运动不足及营养相关导致的骨量不足以及继发性（原发病引起和药物引起）骨质疏松具有重要意义。目前，中国没有基于全国数据的儿童青少年骨密度参照标准，本研究旨在建立中国3~18岁儿童青少年骨密度参照值。


方法
数据来源于2013—2015年中国儿童青少年心血管健康横断面研究，采用双能X线（dual energy X-ray absorptiometry，DXA）骨密度仪对7省、自治区、直辖市的10 818名3~18岁儿童青少年进行了骨密度检测。采用LMS曲线平滑技术对年龄别/身高别骨密度百分位曲线进行平滑，得出中国3~18岁儿童青少年年龄别/身高别骨密度参照标准。


结果
东北地区的吉林省儿童青少年平均去头骨密度（total body less head bone mineral density，TBLH BMD）最高，华东地区山东省儿童最低。TBLH BMD随着年龄和身高的增长而增加，男童的TBLH BMD高于女童。与美国儿童TBLH BMD对比发现，不论年龄别、身高别TBLH BMD，美国儿童在每个百分位均高于中国儿童；中美两国儿童身高别TBLH BMD存在很大差异，美国儿童显著高于中国儿童，其中中位数和第3百分位差距最大。


结论
本研究建立的标准是首个基于中国3~18岁儿童青少年的大样本、广地域人群的骨密度参照标准。以TBLH BMD低于平均水平0~1倍标准差（相当于第51百分位~第15.9百分位）和1~2倍标准差（相当于第15.8百分位~第2.3百分位）作为骨量发育不足和骨量发育严重不足的评价标准，不足者可通过生活方式和饮食干预；以低于2倍标准差（相当于低于第2.2百分位）作为骨量发育异常的评价标准，骨量发育异常者需结合临床进行干预。
A personalized prediction model for hospital readmission risk for cancer patients.
Authors: Jacob Tyler Shreve, Sarah Lee, Christina Felix, Rachel Benish Shirley, Cameron Beau Hilton, Nathan Radakovich, James Stevenson, Alberto J. Montero, Aziz Nazha
Journal: Journal of Clinical Oncology (2020)

7057 Background: Cancer patients (pts) are at high risk of unplanned hospital readmissions. Predicting which cancer patients are at higher risk of readmission would improve post-discharge follow-up/navigation, decrease cost, and improve pt outcomes. Methods: We conducted a retrospective cohort study of non-surgical cancer pts hospitalized at our center between 12/2014 to 7/2018. A machine learning algorithm was trained on 348 medical, sociodemographic and cancer-specific variables with a total of 1,801,944 data points. The cohort was randomly divided into training (80%) and validation (20%) subsets. Prediction performance was measured by area under the receiver operator characteristic curve (AUC). Results: A total of 5,178 hospitalizations were included, of which 45.1% were women, and 27.6% experienced an unplanned readmission within 30 days. The most frequently represented cancers were hematologic malignancies (30.5%), followed by GI (18.1%), lung (13.7%), and GU (10.9%). Significant variables that impacted the algorithm decision are ranked from the most to the least important, including: days from last admission; planned index chemotherapy admission; number of vascular access lines, drains, and airways in use; length of stay; cancer diagnosis; total ED visits in past 6 months; age; discharge lab values (sodium, albumin, alkaline phosphatase, bilirubin, platelets); number of prior admissions; and discharge disposition. The AUC for the validation subset was 0.80. To ease the translation of this model into the clinic, we developed a web application whereby users can supply the aforementioned variables to the model and receive a personalized prediction that highlights those variables most affecting a subject’s readmission risk status: www.Cancer-Readmission.com. Conclusions: A cancer-specific readmission risk model with high AUC for 30-days unplanned readmission has been developed. The model is embedded in a freely available web application that provides personalized, patient-specific predictions. Programs that integrate this model can identify cancer patients with a greater risk for unplanned hospital readmission, thus providing a personalized approach to prevent future unplanned readmissions.
Risk factors of falls in the elderly
Authors: Zhi Zhou, Tao Gong
Journal: BMJ (2016)

跌倒的危险因素包括机体内在的危险因素和外在的环境和社会因素，老年人跌倒多为内在因素和外在因素相互作用的结果。通过结合国外研究现状，对老年人跌倒的危险因素进行阐述，以帮助临床医师提高对其的认识，从而早期识别高危人群，及早进行干预，减少跌倒的发生。
Spatial proximity of CD8 T cells to tumor cells as an independent biomarker for response to anti-PD-1 therapy.
Authors: Maarten Slagter, Elisa A. Rozeman, Huiwen Ding, Judith M. Versluis, Mesele Valenti, Dennis Peters, Annegien Broeks, Charlotte van Rooijen, Hugo Horlings, John B. A. G. Haanen, Erik Hooijberg, Lodewyk F. A. Wessels, Christian U. Blank, Ton N. Schumacher
Journal: Journal of Clinical Oncology (2020)

10038 Background: Only a subset of advanced melanoma patients respond to anti-PD-1 (aPD1) monotherapy. Upfront identification of (non-)responsiveness would help guide first-line treatment decisions, prevent overtreatment and unnecessary risk for toxicities. T cell density and expression of T cell related genes have been associated with response to aPD1, but are imperfect predictors. We investigated whether spatial proximity of CD8 T cells to tumor cells improves upon the predictive value of T cell density alone. Methods: Pretreatment tumor specimens from melanoma patients treated with aPD1 in the Netherlands Cancer Institute were stained for DAPI, SOX10/Melan-A, CD4, CD8, FOXP3 and PD-1 by multiplex immunofluorescence. Sections were imaged on Vectra and analyzed using HALO to optimize marker thresholds and demarcate tumor and stroma. T cell proximity to tumor cells was evaluated as difference in area under the curve between i) a spatial G-function quantifying T cell density around tumor cells in tumor areas and ii) analogous null distributions obtained by random permutation of cell labels. This assessment of co-clustering is independent of cell density and heterogeneity therein and does not reflect repulsion of T cells to stromal/marginal areas. Clinical characteristics, RECIST response and survival were collected from patient records. Associations between T cell density, T cell proximity to Sox10/Melan-A + tumor cells, other clinical biomarkers (LDH, M stage and WHO performance status) and response were examined in a Bayesian hierarchical logistic regression. Results: Tumor specimens of 98 patients were included, of whom 45 were treated with aPD1 as first-line therapy and 33 had an objective response. CD8 T cell proximity to tumor cells was associated with response in an independent, comparatively strong, and tissue dependent manner (cutaneous tissue: 2.78 [2.45, 3.17], visceral: 2.30 [1.95, 2.72], lymphoid: 2.12 [1.88, 2.40], format: maximal posteriori odds ratio [89% equal-tailed credibility interval]), in a multivariate model correcting for CD8 T cell density (1.74 [1.62, 1.88]), LDH (1.93 [1.72, 2.16]), M stage (0.92 [0.87, 0.98]) and WHO performance status (0.79 [0.72, 0.88]). Our model achieved an area under the ROC curve of 77.7%, whereas an analogous model omitting the proximity variable achieved 73.1%. Conclusions: Our analyses show that spatial proximity of CD8 T cells to tumor cells functions as an independent biomarker for response to aPD1 and suggests that preexisting CD8 T cell tumor reactivity is reflected by this spatial proximity.
酒精性肝病的诊断与治疗
Authors: 施军平, 范建高
Journal: BMJ (2007)

酒精性肝病(ALD)是由于长期大量饮酒所致的肝脏疾病.初期通常表现为脂肪肝,进而可发展成酒精性肝炎、肝纤维化和肝硬化;严重酗酒时可诱发广泛肝细胞坏死甚或急性肝衰竭.ALD是我国常见的慢性肝病之一,其发病率呈增长趋势且有年轻化和女性化倾向[1-6].为此,中华肝脏病学会2006年2月修定了 [4]。
Of Mice and Men: NAD+ Boosting with Niacin Provides Hope for Mitochondrial Myopathy Patients
Authors: Eduardo Nunes Chini
Journal: Cell Metabolism (2020)

In this issue of Cell Metabolism, Pirinen et al. (2020) show that disruption in NAD+ homeostasis is a key component of the pathogenesis of mitochondrial myopathy in humans that can be targeted by the administration of the NAD+ precursor niacin, identifying NAD+ boosting as a potential treatment for this devastating disease.
A phase I study of ADXS-503 alone and in combination with pembrolizumab in subjects with metastatic squamous or non-squamous non-small cell lung cancer (NSCLC).
Authors: Suresh S. Ramalingam, Tom Stinchcombe, Gregory James Gerstner, Missak Haigentz, Surya Vangala, Megan Parsi, John W. Heyburn, Victor Kabala, Tuhina Prasad, Andres A. Gutierrez, Jonathan Wade Goldman
Journal: Journal of Clinical Oncology (2020)

e21682 Background: ADXS-503 (A503) is an off-the-shelf, attenuated Listeria monocytogenes (Lm)-based immunotherapy bioengineered to elicit potent T cell responses against 22 tumor antigens commonly found in NSCLC (i.e., 11 hotspot mutations and 11 tumor-associated antigens, TAAs). Pembrolizumab (Pembro) is a programed death receptor-1 (PD-1)- blocking antibody with proven efficacy in NSCLC. A503 and Pembro have complementary mechanisms of immune activation and reversal of immune tolerance. Methods: This is a phase I study of A503 ± Pembro in patients (pts) with metastatic squamous or non-squamous NSCLC. Dose escalation with A503 alone has been tested at two dose levels (i.e., 1 and 5 x10 8 CFU) in Part A in pts refractory or intolerant to prior systemic therapy. In dose escalation Part B, A503 is being evaluated at the same dose levels (DLs) in combination with Pembro in pts with disease progression on Pembro. Part C will be a dose expansion cohort with A503 + Pembro as first-line treatment in the metastatic setting. A503 ± Pembro (200 mg) will be infused intravenously every 3 weeks until disease progression or limiting toxicity. Main endpoints include safety, tolerability and immune-correlative data. Results: Nine patients have been treated: 7 with A503-alone in Part A and two pts with A503+ Pembro in Part B-DL1. No pts in Part A experienced dose-limiting toxicities at the 2 DLs tested. Two Grade 3 adverse events occurred in one pt related to the infusion: hypertension and flu-like syndrome. A transient and manageable SAE (Grade 2 acute kidney injury) was possibly related to A503 alone at 5 x10 8 CFU. A503+ Pembro have been well tolerated in 2 pts in Part B-DL1. Four pts achieved a best overall response of stable disease, three in Part A and one in Part B. A503 alone induced immune responses in pts so far evaluated in Part A. Conclusions: ADXS-503 alone has demonstrated a manageable safety profile and immune responses in Part A. The 1x10 8 CFU was identified as the recommended phase II dose. Dose escalation with A503+ Pembro is ongoing and dose expansion in first line treatment is due to start shortly. Clinical trial information: NCT03847519.
Centrally mediated abdominal pain syndrome: an old problem in a new perspective
Authors: Dong Wu
Journal: BMJ (2017)

中枢介导的腹痛综合征曾被称为慢性特发性腹痛、功能性腹痛综合征，持续腹痛是其突出表现。本病临床并不少见，诊疗有一定的难度。其发病机制与中枢性疼痛调节障碍密切相关，常合并焦虑、抑郁等心理疾患。病史和体格检查对诊断有重要的提示意义。建议在充分沟通的基础上给予针对性的评估，避免过度检查。良好的医患关系是成功诊治本病的基础，基于多学科协作的药物治疗、认知行为治疗及心理治疗对本病有效。
正确对待临床辅助检查
Authors: 许玉韵
Journal: BMJ (2005)

患者女,46岁,因风湿性心脏病重度二尖瓣狭窄(瓣口面积0.9 cm2)于2个月前行二尖瓣置换术.术后1个月又感心悸气短,近1周来逐步加重伴不能平卧,以心功能不全入院治疗.体检:体温正常,血压116/74 mm Hg(15.4/9.8 kPa),心率96次/min,律齐,心前区可闻及3/6全收缩期杂音,广泛传导至左腋下及左胸骨缘;两肺底可闻及湿啰音;肝在肋下1 cm有触痛;双下肢轻度凹陷性水肿.
主动脉夹层三例误诊分析
Authors: 高宏健, 王晓云
Journal: BMJ (2005)

例1 男,53岁,因突发背部疼痛2 h就诊.2 h前患者扫地时突发背部剧烈疼痛,不能忍受,伴烦躁不安.体格检查:左上肢血压160/90 mm Hg(1 mm Hg=0.133 kPa),右上肢180/100 mm Hg.双肺无啰音,心浊音界无扩大,心率76次/min,律齐,未闻及杂音.心电图示完全性右束支传导阻滞.血清肌酸激酶(CK)516 U/L,肌酸激酶同工酶(CK-MB)未查.超声心动图(UCG)未见异常.临床诊断为急性心肌梗死(AMI),予吸氧、静脉滴注硝酸甘油、酚妥拉明扩管降压、肌注度冷丁止痛等治疗,患者疼痛无明显缓解,并出现腹痛.至入院第3天心电图一直无变化,胸部、腹部CT检查示主动脉夹层(AD)(Ⅲ型).加用倍他乐克降压治疗,患者疼痛减轻,转上级医院手术治疗。
GBM AGILE: A global, phase II/III adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.
Authors: Meredith Becker Buxton, Brian Michael Alexander, Donald A. Berry, Webster K. Cavenee, Howard Colman, John Frederick De Groot, Benjamin M. Ellingson, Gary B. Gordon, Mustafa Khasraw, Andrew B. Lassman, Wenbin Li, Michael Lim, Ingo K. Mellinghoff, James R. Perry, Erik P. Sulman, Kirk Tanner, Michael Weller, Patrick Y. Wen, W. K. Alfred Yung, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2020)

TPS2579 Background: Glioblastoma (GBM) is an aggressive brain tumor with few effective therapies and is invariably fatal. Developing new therapies for patients with GBM requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. Industry is wary of developing drugs for GBM due to the high failure rate and high cost of drug development. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase II/III development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research (GCAR), a non-profit organization. GCAR’s mission is to speed the discovery and development of treatments for patients with rare and deadly diseases by serving as sponsor of innovative trials. Methods: GBM AGILE is an international, seamless phase II/III platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs/drug combinations from different pharmaceutical companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, enrolling its first patient in June 2019. Site activation is ongoing in the US, with approximately 40 US planned. The trial received CTA approval from Health Canada in January 2020. Expansion to Europe, China, and Australia is also underway. Clinical trial information: NCT03970447 .
谁是真正的冠心病患者
Authors: 曾昭耆
Journal: BMJ (2006)

有一位病人,女性,49岁,2年来频发胸闷憋气,在其他医院做心电图显示有ST-T改变,已确诊为冠心病.但用过各种抗心绞痛药,效果均不佳.来我院心内科门诊,由一位主任医师给做了详细的心脏科检查,包括24 h心电监测、平板运动试验、心脏核素扫描等,均未发现异常.但病人仍不相信自己无病,故意要求医生写一份诊断书给她.
Identification of new lesion with disease progression in Ovarian cancer per RECIST 1.1.
Authors: Manish Sharma, Oliver Bohnsack, Rudresh Jarecha, Jayant Narang, Anitha Singareddy, Surabhi Bajpai
Journal: Journal of Clinical Oncology (2020)

e18058 Background: Metastasis is the leading cause of ovarian cancer (OC) related death with more than 70% of OC patients diagnosed with metastasis with five-year survival rates below 45%. OC cells mainly metastasize within the peritoneal cavity at presentation and throughout the course of the disease in 85% of the patients which involves exfoliation from the primary tumor, followed by survival and transport in the peritoneal fluid and finally metastatic colonization of the organs within the peritoneal cavity. There is a tendency of conventional imaging to underestimate the frequency of peritoneal spread. The purpose of the study was to obtain the frequency of organ involvement in OC metastasis and identify the most common route of OC metastasis. Methods: Retrospective study and analysis of two randomized double-blind trials was performed in patients with OC. Data was analyzed from these studies using blinded independent central review using RECIST 1.1 involving a total of 895 subjects, 528 and 367 respectively. A double read with adjudication by independent radiologists was performed for each scan based on the RECIST 1.1 criteria. Baseline tumor burden was assessed for all subjects using RECIST 1.1 criteria. At follow-up visits, data was specifically analyzed for New lesions. The readers had to select New lesion location from a pre-defined location list from a drop-down menu. Data was tabulated with frequency of subjects with New lesion per each location. Results: With both studies combined involving 895 subjects, total subjects with new metastasis observed in decreasing order for various organs were peritoneum/omentum (406), lymph nodes (315), ascites (207), liver (94), pleural effusion (65), pelvis (52) &amp; lung (56). Other less common locations for new metastasis was abdominal wall, pleural deposits, spleen, brain, retroperitoneum and adrenal. We also looked at the possibility of disagreement between 2 readers in identifying such lesions leading to progression as below. Conclusions: It can be concluded that subjects with ovarian cancer tend to develop metastasis leading to progression per RECIST 1.1 in peritoneum / omentum, lymph nodes, liver and lung. Due to significant variability in identification of such discrete, ill-defined and/or small nature of lesions, targeted awareness and training should be incorporated to improve clinical outcome. [Table: see text]