tbuckley/cabot-search huggingface dataset:
Serum-based multiplex protein assay for early detection of colorectal cancer and precancerous lesions in a FIT positive population.
Authors: Herbert A. Fritsche, Jason Lee Liggett, Hong Zhang, Linnea Ferm, Ib Jarle Christensen, Hans J. Nielsen
Journal: Journal of Clinical Oncology (2020)

e16145 Background: Colorectal cancer (CRC) is the second leading cancer worldwide in terms of incidence, 5-year prevalence and mortality for both women and men ages 45 years old and up. The current screening method for many countries with organized screening programs is the FIT test for fecal occult blood; however, this test can result in false positive rates as high as 65%. A FIT reflex test could reduce unnecessary colonoscopies while reducing wait times for those patients that need confirmatory colonoscopies the most. Methods: Danish FIT positive colonoscopy confirmed serum samples (n = 1,499) were divided into training and validation sets maintaining approximately equivalent percentages of clean colonoscopy (40%), low risk adenomas (16%), medium risk adenomas (19%), high risk adenomas (13%), stage I CRC (5%), stage II CRC (2%), stage III CRC (4%), and stage IV CRC (0.5%). Proteins were quantified by custom 16-plex immunoassays utilizing the Luminex xMAP platform. A support vector machine supervised machine learning algorithm was trained with the 16 biomarkers plus age and FIT concentration using 1,291 samples for the outcome medium risk adenoma, high risk adenoma, and CRC. Then this algorithm was tested on a blind 208 sample validation set. Results: The training set was 90% sensitive and 27% specific (AUC = 0.68) and the validation set was 93% sensitive and 21% specific (AUC = 0.63). The sensitivities of the validation by risk/stage was as follows: medium risk adenoma 91%, high risk adenomas 92%, stage I CRC 100%, stage II CRC 100%, stage III CRC 100%, stage IV CRC 93%. Conclusions: This study demonstrates feasibility of a novel blood-based multiplex protein immunoassay for use as a reflex to FIT positive results in population wide screening. It detected nearly all adenomas and carcinomas while reducing FIT false positives and thus unnecessary colonoscopies by more than 20%. A FIT reflex test could alleviate endoscopy burden experienced in countries with organized cancer screening programs, while providing better patient outcomes by detecting polyps and early-stage CRC with high sensitivity.
Alterations of Raman profiles of nasopharyngeal carcinoma cells after treated with chemodrugs detected by laser tweezer Raman spectroscopy.
Authors: Miaomiao Li, Xiaochuan Chen, Ting Lin, Zongwei Huang, Shihong Wu, Wei Liu, Duo Lin, Lurong Zhang, Sufang Qiu
Journal: Journal of Clinical Oncology (2020)

e15513 Background: To explore the metabolic alterations of nasopharyngeal carcinoma (NPC) cells after treated with chemodrugs, the Raman profiles were characterized with laser tweezer Raman spectroscopy. Methods: Two NPC cell lines (CNE2 and C666-1) were treated with gemcitabine, cisplatin, and paclitaxel, respectively. The high-quality Raman spectra of cells without or with treatments were recorded at the single-cell level with label-free laser tweezers Raman spectroscopy (LTRS) and analyzed for the differences of alterations of Raman profiles. Results: Tentative assignments of Raman peaks indicated that the cellular specific biomolecular changes associated with drug treatment, including changes in protein structure (e.g. 1655 cm −1 ), changes in DNA content and structure (e.g. 830 cm −1 ), destruction of DNA base pairs (e.g. 785 cm −1 ), and reduction in lipids (e.g. 970 cm −1 ). Besides, both principal components analysis (PCA) combined with linear discriminant analysis (LDA) and the classification and regression trees (CRT) algorithms were employed to further analyze and classify the spectral data between control group and treated group, with the best discriminant accuracy of 96.7% and 90.0% for CNE2 and C666-1 group treated with paclitaxel, respectively. Conclusions: This exploratory work demonstrated that LTRS technology combined with multivariate statistical analysis has promising potential to be a novel analytical strategy at the single-cell level for the evaluation of NPC-related chemotherapeutic drugs.
PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis
Authors: Yun Zhang, Lichong Shen, Honglin Zhu, Katja Dreissigacker, Diana Distler, Xiang Zhou, Andrea Hermina Györfi, Christina Bergmann, Xianyi Meng, Clara Dees, Thuong Trinh-Minh, Ingo Ludolph, Raymund Horch, Andreas Ramming, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2020)

Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc).Expression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α.The expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFβ), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFβ and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFβ receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis.PGC-1α is upregulated in SSc and promotes autophagy to foster TGFβ-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.
QT assessments in oncology drug development and related labels.
Authors: Nan Zheng, Hong Zhao, Mike Li, Lilian Wanjiku Adeojo, Visesh Uppoor, Christine Garnett
Journal: Journal of Clinical Oncology (2020)

e14127 Background: A thorough QT (TQT) study, designed to evaluate whether a new drug excludes a small mean increase in the QTc interval (i.e., &gt; 10 ms) which is considered to have low proarrhythmic risk, is often not feasible for oncology drugs. Alternative designs that assess the QTc changes in cancer patients are used to exclude large mean increases (i.e., &gt; 20 ms) for drugs where the expected benefit outweighs the small proarrhythmic risk. A retrospective analysis was conducted to evaluate QT study designs and the consistency of QT labeling for oncology drugs. Methods: This analysis included FDA approved oncology drugs with QT studies reviewed by CDER’s Interdisciplinary Review Team as of 10/01/2019. Information collected included the clinical study design (i.e., TQT, alternative designs such as a sub-study in a Phase 2/3 trial), primary analysis (i.e., central tendency or concentration-QTc [CQT] analysis), QT findings at the therapeutic dose (i.e., the mean [M] and the upper bound of 90% confidence interval [UCI] of QTc changes), supportive data (i.e., nonclinical cardiac safety data, if applicable), conclusion of the QT assessment, and labeling statements in Section 12.2 (Pharmacodynamics) and Section 5 (Warnings &amp; Precautions) of the product labels. Baseline QTc values in these alternative studies were compared to those in TQT studies across different therapeutic areas. Results: The analysis included 72 oncology drugs. The mean baseline QTc value is 411.2 ms in male patients (n = 6951) and 394.6 ms in male healthy volunteers (n = 22288), and 414.3 ms in female patients (n = 6412) and 408.8 ms in female healthy volunteers (n = 15682). Alternative study designs were used for 63 (87.5%) drugs while TQT study was only used for 9 (12.5%) drugs. CQT was used as the primary analysis for 11 (15.3%) drugs. Among the 72 product labels, 8 labels do not have QT information in Section 12.2 and 9 labels inconsistently describe the results of an alternative study. Warnings and Precautions for QT Prolongation in Section 5 of the labels were triggered by positive signals in the QT assessment or clinical trial safety monitoring experience. Conclusions: Cancer patients had higher QTc and less sex difference at baseline than healthy volunteers. QT labeling consistency in Section 12.2 could be improved by standardizing the description of study results based on QT study designs. Disclaimer: The contents reflect the views of the authors and should not be construed to represent the FDA's views or policies.
Actionable alterations (AA) in gastrointestinal (GI) cancers: Rate of detection and receipt of matched therapies (MT).
Authors: Megan Greally, Yaelle Tuvy, Brittanie M Millang, Eileen Mary O'Reilly, Rona Yaeger, Leonard B. Saltz, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2020)

e15677 Background: Next generation sequencing (NGS) is widely used in pts with advanced cancer to personalize care. Current NCCN guidelines endorse Her2, PD-L1 and MSI testing in esophagogastric cancer (EGC), RAS, BRAF, Her2 and MSI testing in colorectal cancer (CRC) and germline, somatic and MSI testing in pancreas cancer (PC). The proportion of GI cancer pts who receive MT based on NGS is unclear. Methods: We identified pts with advanced EGC (2016-18), PC (2017) and CRC (2016) who underwent NGS with MSK-IMPACT. We assessed the proportion of pts with ≥1 AA as defined by OncoKB (at the time of analysis, levels 1/2a were accepted practice and levels 2b/3/4 were investigational; Chakravaty, JCO PO 2017), those who received MT on trial or off label and 3 and 6 months (mos) progression-free survival (PFS). Results: We identified 260 EGC, 357 PC and 438 CRC pts. After excluding pts who had ongoing benefit from standard therapy (tx), were treated elsewhere or had no active stage IV disease, potential level 2/3/4 AAs occurred in 37% (n = 97) of EGC pts, 32.5% (n = 116) of PC pts and 26.7% (n = 117) of CRC pts (Table). 10, 1 and 17 pts with EGC, PC and CRC respectively were MSI. 1 pt in each subtype had an NTRK fusion (OncoKB level 1). In EGC, 6 pts (6.2% of those with AAs) received MT: 2 pts with MET amplification (a) and 1 each with BRCA2 mutation (m), TSC2m, ERBB2m and EGFRa. The pts with METa treated with crizotinib achieved 3 but not 6 mos PFS. In PC, 11 pts (9.5%) got MT: 10 pts for BRCAm and 1 for NTRK3 fusion. 9 pts with BRCAm treated with PARP inhibitors (i) achieved ≥3 mos PFS and 5 pts reached ≥6 mos PFS. The pt treated with NTRKi progressed rapidly. In CRC, 5 pts with ERBB2a and 9 pts with BRAFm received MT (12%). 3 pts and 2 pts treated with anti-Her2 tx achieved ≥3 and ≥6 mos PFS respectively. Of 6 pts treated with BRAF/MEKi plus irinotecan or anti-EGFR tx, all achieved ≥3 mos PFS; 3 reached ≥6 mos PFS. 3 pts received novel BRAF and ERK1/2i; none reached 3 mos PFS. Conclusions: NGS frequently identified OncoKB level 2 AAs. Few pts received MT, and of those, some achieved ≥6 mos PFS. Pts with CRC and PC received MT which subsequently became standard NCCN recommendations; therefore, a more current analysis may show increased MT use. Still, MT for level 3 and 4 alterations were rare, suggesting expectations of NGS must be managed appropriately. [Table: see text]
Genomic landscape of head and neck cancers.
Authors: Anand Subash, Vishal Uchila Shishir Rao
Journal: Journal of Clinical Oncology (2020)

e18530 Background: Head and neck squamous cell carcinoma (HNSCC) encompasses a heterogeneous group of tumours. In India it accounts for about 40% of all the malignancies. HNSCC in the subcontinent behaves differently as compared to the western world. As heterogenous as they are so are their response to treatment. Deciphering the human genome has indeed been one of the biggest contribution to science. Genomic profiling would help identify the variants that separate these HNSCC patients and facilitate development of newer targeted therapeutic strategies. Methods: At Healthcare Global Cancer Centre, Bangalore we retrospectively analysed 35 cases of Head and Neck squamous cell carcinoma as a pilot. Whole exome analysis of the patient samples were done using the Illumina Hi-Seq 2500 machine with a depth of 70-100X. Results: Of the 35 patients, 27 were oral cavity squamous cell carcinoma. About 2/3 rd of these patients had history of tobacco or alcohol use. At the time of analysis 20 patients were alive and disease free,3 were alive with disease,11 were dead and 2 were lost to follow up. It was observed that the maximum number of variations were mis-sense mutations. Known oncogenic proteins like TP53 and NOTCH1 showed a mutation frequency of more than 50%, while DNA damage and repair genes like XRCC1 and ERCC2 were seen to have almost 90% mutation frequency, some of which have not been previously documented in literature. Conclusions: The preliminary data has brought to light some very novel mutations, many of them until now unknown to be implicated in HNSCC. This study holds the potential to predict response to treatment and factors which contribute to this. We have classified these novel mutations into different pathways so that specific targeted therapies can be developed in future.
Sickness absence and disability pension among Swedish women before breast cancer relapse.
Authors: Hedayati Elham, Sofie a.m. Gernaat, Aina Johnsson, Ulla m Wilking, Renske Altena
Journal: Journal of Clinical Oncology (2020)

e14121 Background: Sickness absence (SA) and disability pension (DP) from diagnosis of primary breast cancer (BC) among patients who in a later stage will develop a recurrence or metastatic disease is unknown. This study explores the prevalence and risk factors of SA and DP in this study population before and after primary breast cancer diagnosis. Methods: Longitudinal register data on 1,310 female patients living in Sweden (age 20 to 63 years) diagnosed with primary BC between 1996 to 2011, were analyzed for annual prevalence of SA days and DP starting 2 years pre- to 5 years postdiagnosis. Logistic regressions were used to explore associations between primary BC characteristics and future SA. Results: 579 (44.2%) had loco-regional recurrence after a median of 2.5 years (interquartile range (IQR) = 1.3-4.3) and 731 (55.8%) had a metastatic disease after a median of 2.3 years (IQR = 1.3-4.1). 320 (24.4%) of 1,310 were still relapse-free 5 years postdiagnosis. SA was high during year 1 postdiagnosis but decreased steadily through year 5 (67.9%, 40.3%, 29.0%, 23.9%, 19.4%, respectively), while DP steadily increased during this time period (16.4%, 17.5%, 19.7%, 24.9%, 28.7%, respectively). The annual prevalence of SA over 180 days among patients who later were diagnosed with metastatic disease was constantly higher compared to patients who later were diagnosis of loco-regional recurrence. Pre-diagnosis SA, age &lt; 50 years at the time of diagnosis, higher tumor stage, chemotherapy and future metastatic disease were associated with higher odds ratios for SA (odds ratio range, 1.56 to 4.42) Conclusions: In conclusion, longitudinal rates of SA and DP in a cohort of women with early BC, of whom a part developed disease relapse during follow-up were higher compared to previous studies. These are unique findings as previously published studies excluded patients with disease relapse. Patients at increased risk for SA, should be assessed and triaged to optimize chances for a smooth transition to return to work after oncological treatment.
Genome-wide association study of steady-state letrozole concentration in patients with breast cancer.
Authors: Daniel Louis Hertz, Julie Douglas, Kelley M. Kidwell, Christina L Gersch, Zeruesenay Desta, Anna Maria Storniolo, Vered Stearns, Todd C. Skaar, Daniel F. Hayes, Norah Lynn Henry, James M. Rae
Journal: Journal of Clinical Oncology (2020)

538 Background: Letrozole is a non-steroidal aromatase inhibitor (AI) used to treat hormone receptor positive (HR+) breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including CYP2A6. The objective of this genome-wide association study (GWAS) was to identify genetic variants that affect steady state letrozole concentrations. Methods: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized 503 post-menopausal patients with HR+ non-metastatic breast cancer to exemestane or letrozole treatment. Germline DNA was collected pre-treatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole concentration via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array to the Haplotype Reference Panel ( &gt; 2 million variants). The association of each polymorphism with square-root transformed letrozole concentration was tested in self-reported white patients via linear regression using the standard alpha for genome-wide significance (α = 5x10 −8 ) assuming an additive genetic model and correcting for age and body mass index. Results: 228 patients met inclusion criteria and had all necessary data. Each variant allele of rs7937 a patient carried increased their letrozole concentration ~22.9 ng/mL (standard error = 4.01, p = 3.51x10 −8 , Table) and this variant explained 13% of the variability in letrozole concentrations. rs7937 is located ~50 kB upstream of CYP2A6, and has previously been identified in GWAS of CYP2A6-related phenotypes, including nicotine metabolism and lung cancer. Conclusions: This GWAS confirmed that steady-state letrozole concentrations are partially determined by germline polymorphisms affecting CYP2A6 activity. If letrozole concentrations affect treatment efficacy or toxicity, CYP2A6 genetics may be useful to individualize letrozole dosing to improve clinical outcomes in patients with HR+ breast cancer. [Table: see text]
Clinical response and biomarker analysis of POLARIS-02 a phase II study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with metastatic nasopharyngeal carcinoma.
Authors: Fenghua Wang, Xiao-Li Wei, Jifeng Feng, Qi Li, Nong Xu, Xichun Hu, Wangjun Liao, Yi Jiang, Xiaoyan Lin, Qingyuan Zhang, Xianglin Yuan, Haixin Huang, Ye Chen, Guanghai Dai, Jianhua Shi, Lin Shen, Shujun Yang, Yongqian Shu, Yunpeng Liu, Rui-hua Xu
Journal: Journal of Clinical Oncology (2020)

6542 Background: Metastatic nasopharyngeal cancer (mNPC) patients progressed after standard therapy have limited treatment options. This study is to evaluate the clinical efficacy and safety of toripalimab in mNPC patients refractory to standard chemotherapy treatment (Clinical trial ID: NCT02915432). Methods: Patients receive 3 mg/kg toripalimab Q2W via IV infusion until disease progression, unacceptable toxicity, or voluntary withdrawal. Clinical response is assessed every 8 weeks according to RECIST v1.1. Tumor PD-L1 expression, plasma EBV titer and other biomarkers will be evaluated for correlation with clinical response. Results: From Dec 2016 to Feb 2019, 190 mNPC patients were enrolled from 17 participating centers in China. The median age was 46 years with 83% male. Patients were heavily pretreated with a median of 2 lines of prior systemic treatments. By the cutoff date of Jan 17, 2020, 97% patients experienced treatment related adverse events (TRAE). Most common TRAE included anemia, hypothyroidism, AST increased, proteinuria and fever. Grade 3+ TRAE occurred in 28% patients. Among 190 patients assessed by Independent Review Committee per RECIST v1.1, 6 CR, 33 PR and 40 SD were observed for an ORR of 20.5% and a DCR of 41.6%. The median DOR was 12.9 months. The median PFS and median OS were 1.9 months and 18.6 months respectively. PD-L1+ patients (n=48) had higher ORR than PD-L1- patients (n=134), 27.1% versus 19.4%. By tumor histology, ORR was higher in keratinizing NPC (n=8) than non-keratinizing NPC (n=168), 62.5% versus 19.0%. 144 patients had valid plasma EBV titer measured every 28 days during the study. An average drop of 101-fold plasma EBV titer from baseline was observed in patients with objective responses. Patients with 2-fold+ drop in plasma EBV titer on day 28 (n=60) went on to have 48.3% ORR and 76.7% DCR, whereas patients with less than 2-fold drop (n=88) had 5.7% ORR and 25.0% DCR. 14 responding patients who later developed progressive disease had at least 2-fold+ increase of plasma EBV tier 3-months (median) before radiographic identification of disease progression. Conclusions: Toripalimab demonstrated encouraging clinical activity with a manageable safety profile in mNPC patients refractory to standard chemotherapy. Patients with 2-fold+ drops in plasma EBV titer on day 28 from baseline had favorable clinical response of 48.3% ORR, which might be used as a predictive biomarker. Clinical trial information: NCT02915432 .
华北油田社区卫生服务人员紧急避孕知识现状与影响推广因素的调查
Authors: 刘学伟, 赵学英, 管嬿, 闫瑞平, 黄立钊
Journal: BMJ (2006)

调查社区卫生服务人员紧急避孕知识水平和影响开展此项服务的主要因素.162 份有效调查问卷显示,人员紧急避孕知晓率为72.8 %,及格率为8.6 %.从事妇幼卫生专业人员、护士与其他人员之间紧急避孕知识得分差异有统计学意义,不同文化程度的调查对象得分差异无统计学意义.影响社区开展此项服务的最主要因素是需求不足.提示加强卫生服务内容的宣传,提高人员的相关知识水平是目前社区开展紧急避孕服务的重点。
Assessing dose-response effects of national essential medicine policy in China: comparison of two methods for handling data with a stepped wedge-like design and hierarchical structure
Authors: 任燕, 杨珉, 李茜, 潘杰, 陈飞, 李晓松, 孟群, 程亮亮
Journal: BMJ (2017)

目的
利用具有层次结构的阶梯设计试验数据，建立多水平重复测量模型与多水平双重差分模型，用以评价政策干预时长与结局间的线性关系（即剂量反应效应）。


方法
中国基本药物制度（基药）效果评价数据来源于国家卫生计生统计信息中心，共收集2008—2012年间31个省份2 675个县的34 506家基层医疗卫生机构监测数据。该制度实施过程类似于阶梯设计试验。本研究以基层医疗卫生机构的门诊服务量结局指标为例，解释如何用多水平重复测量模型和多水平双重差分模型来评价基药制度的剂量反应效应。


结果
通过建立4个多水平双重差分模型，估计出基本药物制度的剂量反应效应为0.015；多水平重复测量模型估计其效应为0.012。2种模型均估计出从2009—2012年门诊服务量增加了2.5倍，但多水平双重差分模型的随机效应系数标准误比多水平重复测量模型大2~4.3倍。多水平重复测量模型能根据数据评价剂量反应效应在省份、县和机构水平的变异，从而判断哪个省份/县/机构实施的效果最好或最差。


结论
基于多个时间点和层次结构的类阶梯试验数据，评价其政策干预的剂量反应效应时，多水平重复测量模型比多水平双重差分模型更为方便、高效且获得信息更丰富。