tbuckley/cabot-search huggingface dataset:
Pivotal trial endpoints and prices of cancer drugs in the US and Europe.
Authors: Kerstin Noëlle Vokinger, Paola Daniore, Thomas J Hwang, ChangWon C Lee, Aaron S Kesselheim
Journal: Journal of Clinical Oncology (2020)

2077 Background: A key clinical outcome for new cancer drugs is improvement in overall survival (OS), defined as time from the date of randomization to the death from any cause. However, many cancer drugs are approved by regulators based on changes to surrogate measures of OS, such as progression-free survival or overall response rate. When surrogate measures are not validated, they can provide misleading information about drug efficacy. We categorized pivotal trial endpoints for recently-approved cancer drugs in the US and Europe as showing improvements in OS vs non-OS surrogates, and evaluated the correlation with drug prices. Methods: We identified new drugs FDA-approved between 2009 and 2018 that were indicated to treat solid and hematologic tumors in adults and that had also been approved by the EMA and Swissmedic by December 2019. Launch prices were extracted and adjusted to average sales prices for monthly treatment costs in the US and compared to currency-adjusted ex-factory monthly treatment costs in Germany, Switzerland, and England. Pivotal clinical trial primary endpoints were collected from the drug labeling and FDA medical reviews for the US, and the EMA public assessment reports for Europe, and categorized as OS in any trial vs. not. Pearson’s correlation tests assessed the association between launch prices and OS vs non-OS endpoints in each country. Results: 54 drugs were approved by the FDA, EMA, and Swissmedic during the study period. In the US, 30 (56%) were approved based on OS by contrast to 35 (65%) in the EMA. The number of cancer drugs approved by the FDA based on OS decreased in the past years. By contrast, the number of approved cancer drugs by the EMA based on OS were stable. There was no association for the US (p = 0.05), Germany (p = 0.13) and England (p = 0.12), while Switzerland revealed an association (p = 0.03) between OS endpoint and price. Conclusions: Reductions in use of OS endpoints as the basis for cancer drug approval in the US is concerning. Drug pricing should be better aligned with the benefit that drugs provide to patients, as measured by clinical trial outcomes such as OS.
Clinical features of drug-induced liver injury: a review of Chinese literatures 2007–2011
Authors: Jia-yao Lin
Journal: BMJ (2013)

Objective
To analyze the clinical characteristics of drug-induced liver injury(DILI) from Chinese literatures published in Chinese Periodical Full-text Database (CNKI) from 2007 to 2011.


Methods
Using drug-induced liver injury as key words, the literatures in CNKI were searched, and the data of age, gender, medication, clinical manifestation and prognosis were analyzed.


Results
In search of CNKI, 281 literatures were collected; finally 111 relevant papers were obtained. Total 10 693 cases of DILI were included with a male/female ratio of 1.14∶1 and a mean age of 45.6 y ranging from 7 months to 93 y. Among 1093 cases with the age grouped, the highest incidence of DILI was in age 41-60 y(38.52%)and 20.68% patients were over 60 y. Among 6592 cases with clinical manifestation recorded, 43.51% patients were asymptomatic and abnormal liver function was detected in health check-up; and others presented non-specific gastrointestinal symptoms, including fatigue, nausea, vomiting and jaundice. In 9340 cases with medication recorded, the 6 most common drugs inducing DILI were antituberculotics (32.74%), Chinese herbs(22.12%), antibiotics(9.18%), antineoplastics(6.34%), NSAIDs (4.80%)and antithyroid drugs(4.37%). The most common type of toxicity was hepatocellular injury(63.66%, 4438/6971). In general the prognosis was good with a fatality rate of 1.67%.


Conclusions
Antituberculotics and Chinese herbs are the main causes of DILI. Some DILI patients have occult onset and others have nonspecific gastrointestinal symptoms. Most patients have good prognosis if they are treated timely.


Key words: 
Hepatitis, chronic, drug-induced; Review literature; Retrospective studies
Castleman's disease:a report of 45 cases and literature review
Authors: De-chang Diao, Jun-sheng Peng, Zu-li Yang, Xiao-bin Wu, Jun Xiang, Hong-lei Chen, Hu Song
Journal: BMJ (2011)

Clinical features and related information on diagnosis and treatment of 45 cases of Castleman's disease (CD) were retrospectively analyzed.Based on the clinical classification, localized CD (LCD) was found in 26 cases, multicentric CD (MCD) was found in 19 cases.Most cases of LCD presented the symptoms of compression, while MCD had complicated and non-specific clinical manifestations, making the early diagnosis more difficult.All 26 cases with LCD underwent surgery, among which only 2 cases relapsed.Sixteen out of 19 patients with MCD were treated with glucocorticoids or combined chemotherapy, and 14 cases achieved complete or partial remission.The results show that patients with CD have variant manifestation and the diagnosis depend on CT scan or histopathology examination.Most LCD can be cured by complete surgical resection, and MCD can achieve remission by the treatment with glucocorticoids or combined chemotherapy.

Key words: 
Giant lymph node disease;  Therapy
反复胸腔积液
Authors: 吴东, 王玉, 方卫纲
Journal: BMJ (2010)

患者男,64岁,因反复胸腔积液2个月入院.2个月前因冠心病、三枝病变、不稳定性心绞痛,心功能Ⅲ级在外院行冠状动脉搭桥术(CABG),手术顺利.术后4 d感胸闷、气短,X线胸片示右侧胸腔积液(图1).胸腔穿刺引流血性胸腔积液约2000 ml,呼吸困难明显缓解,胸水未做检查。
The role of tumor markers for relapse detection in central nervous system non-germinomatous germ cell tumors (CNS-NGGCT): A pool analysis of cooperative group clinical trials.
Authors: Adriana Fonseca, Cecile Faure-Conter, Matthew Murray, Jason R. Fangusaro, Stewart Goldman, Shivani Bailey, Gabriele Calaminus, Soumen Khatua, Didier Frappaz, Girish Dhall, James Nicholson, Eric Bouffet, Ute Katharina Bartels
Journal: Journal of Clinical Oncology (2020)

2503 Background: CNS-NGGCT are rare tumors that have been successfully treated with multimodal therapies. With a 5-yr EFS and OS of 72-84% and 82-93% respectively, surveillance and relapse detection is essential. Tumor marker (TM) elevation has proven to be a highly sensitive method of relapse detection in extra-cranial-NGGCT. We aim to determine the role of TM for relapse surveillance in children and adolescents with CNS-NGGCTs. Methods: European and North American data from germ cell tumor trials (SIOP GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients treated in the UK, Germany and France under strict protocol-guidelines were included. Details regarding imaging, pathology and TM elevation at diagnosis and relapse were collected. We report the proportion of relapses detectable by TM elevation. Results: Four-hundred and eighty-four patients enrolled in prospective cooperative group CNS-NGGCT trials from 1989 to 2016 were pooled for analysis. One-hundred and thirteen (23%) patients experienced a relapse/progression (SIOP GCT96: n = 57; SFOP TGM TC 90-92 n = 23, COG-ACNS0122 n = 16 &amp; COG-ACNS1123 n = 17) and constitute the population of this report. Median age at diagnosis was 13 (range:1-30) years. The most common primary location was pineal in n = 60 (53%) patients. The site of relapse was available for 100 patients, 48 patients relapsed locally, 36 relapsed with distant disease, combined relapses were seen in 22 patients and 4 patients relapsed with TM elevation alone. TM in serum and/or CSF at diagnosis was available in 93(82%) patients, and in 90(80%) patients at the time of relapse. Eighty-four patients had TM available at both timepoints. At diagnosis 81 (96%) patients had TM elevation and 3 (4%) had negative TM. At relapse, 74(94%) patients with positive TM at diagnosis had TM elevation, while 7(6%) had TM negative. Conversely, 2/3 patients with negative TM at diagnosis, relapsed with elevated TM. Conclusions: Herein, we have assembled the largest prospective cohort to date of relapsed intracranial germ cell tumors. TM are highly sensitive detecting relapse/progression in CNS-NGGCT patients with elevated TM at diagnosis. The routine use of TM for relapse surveillance in patients with CNS-NGGCT can decrease the frequency of cross-sectional imaging, therefore, reducing lengthy hospital visits, sedation procedures and decreasing health-care costs.
KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53<sup>WT</sup>) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy.
Authors: Michael K.K. Wong, Ciara Marie Kelly, Melissa Amber Burgess, Karl Lewis, Jaspreet Singh Grewal, Anthony J. Olszanski, Jesse McGreivy, Wayne Rothbaum, Hope Qamoos, James A. DeCaprio
Journal: Journal of Clinical Oncology (2020)

10072 Background: MCC is an aggressive neuroendocrine skin cancer with very poor prognosis. Immune checkpoint inhibition was recently shown to benefit some patients (pts). There are few effective treatments (tx) and no standard of care for those who relapse on or are refractory to anti-PD-1/L1 agents (R/R). In p53 WT MCC, oncoproteins from the Merkel cell polyomavirus can inhibit p53 tumor suppressor functions via L-MYC/EP400-dependent activation of MDM2. KRT-232, a potent, selective, orally available MDM2i, is being evaluated in pts with p53 WT MCC who are R/R to anti-PD-1/L1 tx. Methods: In stage 1 of this open-label, multicenter, phase 2 study (NCT03787602) pts initially received KRT-232 240mg QD days 1-7 of a 21 day (d) cycle (cy). This cohort was closed due to Grade (Gr) 3/4 cytopenias and pts were moved to 240mg QD days 1-5 of a 28d cy to allow for hematologic recovery. Two new arms were opened: 240mg and 180mg QD days 1-5 of a 28d cy. The primary endpoint is objective response rate (ORR) by RECIST 1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, and safety and tolerability of KRT-232. Results: At the time of this analysis, 11 pts were treated with KRT-232: 6 on the 240mg 7/21d, 3 on the 240mg 5/28d and 2 on the 180mg 5/28d schedules. Median age was 66; 46% of pts had ECOG 1 (range 0-1), the median prior lines of systemic therapy was 3 (range 1-4) and 82% had prior radiation tx. Treatment-emergent adverse events (AEs), regardless of grade or causality, were reported in all pts: 55% had Gr 3-4 AEs and 36% had serious AEs (SAEs). The most common AEs included neutropenia (55%), anemia, leukopenia and thrombocytopenia (each 45%), diarrhea, nausea and fatigue (each 36%), and lymphopenia, hypomagnesaemia, lipase increase and sinus tachycardia (each 27%). SAEs were mainly due to cytopenias. One Gr 5 AE of respiratory failure/ascites was attributed to progression. Median time on study was 11.3 wks (range 1.3-20.9). Two of 11 pts on active tx have not yet reached the first response assessment (wk 6). Of the 9 pts who have reached wk 6, 2 PRs and 1 SD (converted to PR at wk 12) were reported. At the second response assessment (wk 12), 2 PRs were reported; one of the PRs at wk 6 has not yet reached wk 12. The ORR was 33% (3/9 pts) . Conclusions: KRT-232 demonstrates promising monotherapy activity in MCC p53 WT pts who failed anti-PD-1/L1 tx. This is the first clinical proof-of-concept for inhibiting the MDM2 pathway in MCC. Safety and efficacy continue to inform KRT-232 dose and schedule optimization. Clinical trial information: NCT03787602.
不同性别糖尿病合并急性心肌梗死患者的临床特点
Authors: 张迅英, 徐庆国, 张琴, 张奇志, 孙守生
Journal: BMJ (2005)

对66例糖尿病合并急性心肌梗死患者进行回顾性分析.结果显示,绝经后女性患病比例高于男性;男性患者吸烟比例高于女性(P<0.01);平时未监测血糖、患高脂血症的比例女性高于男性(P<0.01);心力衰竭、心源性休克、死亡的比例女性高于男性(P<0.05)。
A national investigation on status of general practitioners in China
Authors: 全国全科医学专业技术队伍现状研究课题组
Journal: BMJ (2009)

Objective To learn general account for general practitioners all over the country to provide evidence for related policy decision-making. Methods Questionnaire survey and focus group discussion were conducted in health administrations of 31 provinces, autonomous regions and municipalities under direct jurisdiction of the State Council, as well as Xinjiang Production and Construction Corps, to collect information about their qualification examinations or evaluations, education and training, registration for permit to practise medicine and other related-policies for general practitioners (GPs). Results ①By October 2007, national qualification examinations for medium-level health professional title of general practice were taken place in all 32 province-level regions. Appraisal for senior professional title of general practice was carried out in 13 province-level regions. There are, in nationwide total, 10 670 GPs, 9826 of them with medium level professional title and 844 with senior professional one, and 97.0% of those with senior professional title working in east part of the country. ②Post training for GPs has been conducted in 31 provinces-level regions and 112 528 GPs received training. Standardized training for GPs has been developed in 9 province-level regions, and 1474 GPs have been trained.③Registration for permit to practise medicine has been developed in 19 provinces-level regions, including all provinces, autonomous regions and municipalities under direct jurisdiction of the State Council in east part of the country. There are 6321 physicians registered as GPs for permit to practise medicine all over the country. Conclusions ①Workforce of GPs has commenced to develop, and related policies have preliminarily been in place, but unbalanced among east, central and west parts of the country; ②Workforce of GPs is in short and unstable, with poor quality, non-standardized appellation and inconsistent statistics; ③Qualification for junior professional title for GPs has not been set and appraisal for senior professional title of GPs has been conducted in only a few areas; ④Registration as GPs for permit to practise medicine has been implemented in a few areas with small number of GPs registered; ⑤Effectiveness of post training for GPs is not satisfactory, and standardized training is very difficult to develop; and ⑥Government should further increase financial input for development of GPs suitable for the country.

Key words: 
Questionnaires;  Interviews;  Community health services;  General practitioners
Immune-related adverse events (irAEs) among urothelial carcinoma (UC) patients treated with PD-1 VS PD-L1 inhibitors: A real-world observational study.
Authors: Saby George, Elizabeth Bell, Nicole Engel-Nitz, John C White, Lincy S. Lal, Frank Xiaoqing Liu, Ruth Kim, Stan Krulewicz, Vijay Kasturi, Ying Zheng
Journal: Journal of Clinical Oncology (2020)

e17017 Background: Anti-PD-1/PD-L1 agents are US FDA-approved for patients with advanced or metastatic UC, but limited information exists on real world irAEs among this patient population. We examined the rates and time to onset of select irAEs in UC patients receiving PD-L1s vs PD-1s in the real world. Methods: This observational study included US commercial and Medicare Advantage health plan members from Optum Research Database with UC and treated with a PD-1 or PD-L1 agent between 01-Sep-14 and 30-Apr-19. Baseline characteristics were assessed ≤ 6-months prior to the first claim for anti-PD-1/PD-L1. 21 irAEs were chosen a priori based on the ASCO clinical guideline on irAE management, clinical input, frequency, and cost of treatment. Patients were followed for newly occurring irAEs, based on claims ICD codes, during the PD-1/PD-L1 therapy and up to 180 days after if no new treatment, study period end, death, or disenrollment. Kaplan-Meier method was utilized to calculate time to onset of irAEs. Results: The study included 240 patients receiving PD-L1s and 317 receiving PD-1s. Baseline demographics were similar (Table). The most common irAEs were 1) thyroid disorders, 2) impaired ventricular function with heart failure and vasculitis, 3) rash, and 4) nephritis. UC patients receiving PD-L1s had a lower rate of irAEs vs PD-1s, mainly driven by lower rates of hematologic and endocrine toxicities (Table). UC patients receiving a PD-L1 also had longer time to irAE onset (p-value = 0.05). Conclusions: UC patients receiving PD-L1s had a lower incidence rate of irAEs and longer time to irAE onset than patients on PD-1s. Findings suggest patients receiving PD-1s may require more intense monitoring for irAEs than patients taking PD-L1s. [Table: see text]
Social media and gynecologic cancers: The impact of Twitter #GYNCSM.
Authors: Christina Lizaso, Dorinda Sparacio, Shannon Neville Westin, Richard Mark Boulay, Sarah Madhu Temkin
Journal: Journal of Clinical Oncology (2020)

e14113 Background: Patients (pts) with gynecologic malignancies look for support and information outside traditional clinical settings. We report the results of a needs assessment of the GYN Cancer Social Media (#gyncsm) Twitter community. Methods: An online needs assessment was publicized on Twitter using the #gyncsm hashtag in 2019 for 23 days. Percentages were calculated to provide observational data. Results: Of 33 respondents, 26 (79%) were pts, 7 (21%) healthcare providers, 2 (6%) cancer researchers, and 1 (3%) caregiver. 15 (60%) pts reported having ovarian cancer; 6 (24%) endometrial/uterine cancer; 2 (8%) sarcoma; 2 (8%) breast cancer; and 1 (4%) vulvar cancer. Participating providers were gynecologic oncologists 3 (21%); pharmacists 2 (14%); medical and radiation oncologist, researcher, social worker therapist and genetic counselor 1 (7%) each. 41% (13) reported tweeting and retweeting #gyncsm tweets; 22% (11) read the blog posts or transcripts of a twitter chat; 28% (9) followed or participated in a twitter chat. Chat topics with importance are shown in the Table. Pts reported that #gyncsm twitter chat helped them advocate for themselves (9, 60%); learn about genetic testing (7, 46%); and investigate clinical trials (4, 26%). Conclusions: Social media has a role in healthcare, especially in pt education and empowerment. Side effects, toxicity, and communication were topics of interest. Inclusion of cervical cancer pts and rare malignancies should be a priority. [Table: see text]
多巴反应性肌张力障碍误诊二例
Authors: 李宝栋, 闫瑞萍, 白晶
Journal: BMJ (2007)

例1女,12岁.因活动后双足内翻、行走困难3年,于2006年7月2日就诊于神经科门诊.患者于3年前无明显诱因出现双下肢僵硬感,活动时出现双足内翻,行走明显受限,症状具有波动性,活动后加重而休息后减轻,呈进行性加重。
Granzyme B PET imaging of immune-mediated tumor killing as a tool for understanding immunotherapy response
Authors: Thomas LaSalle, Emily E Austin, Grant Rigney, Eric Wehrenberg-Klee, Sarah Nesti, Benjamin Larimer, Umar Mahmood
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Cancer immunotherapy research is expanding to include a more robust understanding of the mechanisms of treatment response and resistance. Identification of drivers of pro-tumor and anti-tumor immunity during treatment offers new strategies for effective alternative or combination immunotherapies. Currently, tissue or blood samples are collected and analyzed, then dichotomized based on clinical end points that may occur months or years after tissue is collected. While overall survival is ultimately the desired clinical outcome, this dichotomization fails to incorporate the nuances that may occur during an anti-tumor response. By failing to directly measure immune activation at the time of sampling, tumors may be misclassified and potentially obscure important biological information. Non-invasive techniques, such as positron emission tomography (PET), allow for global and quantitative measurements of cancer specific processes and are widely used clinically to help manage disease. Methods We have previously developed a novel PET agent that can non-invasively quantify granzyme B release in tumors and have demonstrated its ability to predict response to checkpoint inhibitor therapy in multiple murine models of cancer. Here, we used the quantitative measurement of granzyme B release as a direct and time-matched marker of immune cell activation in order to determine immune cell types and cytokines that correlate with effective checkpoint inhibitor therapy in both tumors and tumor-draining lymph nodes. Results Through PET imaging, we were able to successfully distinguish distinct microenvironments, based on tumor type, which influenced immune cell subpopulations and cytokine release. Although each tumor was marked by functionally distinct pathways of immune cell activation and inflammation, they also shared commonalities that ultimately resulted in granzyme B release and tumor killing. Conclusions These results suggest that discrete tumor immune microenvironments can be identified in both responsive and non-responsive tumors and offers strategic targets for intervention to overcome checkpoint inhibitor resistance.
Efficacy and safety of Danhong injection in treatment of angina pectoris: a Meta-analysis
Authors: Ying Sheng
Journal: BMJ (2013)

To analyze the efficacy and safety of Danhong injection in treatment of angina pectoris. Literatures of randomized controlled trials on efficacy comparison of Danhong injection and its components in the single herb pharmaceutical preparations (Danshen injection, safflower injection and compound Danshen injection) for patients with angina pectoris due to coronary heart disease were extracted from database including Wan Fang, CNKI, VIP, for all medical publications between 2000 and 2010. Meta-analysis was performed. The Meta-analysis included total 1306 patients in the treatment group of Danhong injection and 1280 patients in the control group from 28 clinical trials. The results showed that clinical effect and electrocardiogram efficacy in Danhong injection group were significantly better than those in control group (RR=1.23, 95%CI: 1.19-1.27 and RR=1.29, 95%CI: 1.22-1.37, respectively). The homogeneity of the total effective rate was good; however, there had a great variation in hemorrheologic and the serum lipids indices. Thirteen literatures reported that there was no obvious adverse reaction found in Danhong injection group; 9 literatures did not report adverse reaction. Danhong injection has a significant therapeutic effect and safety in patients with angina pectoris due to coronary heart disease.


Key words: 
Angina pectoris; Meta-analysis; Danhong injection