tbuckley/cabot-search huggingface dataset:
Sensitivity of colorectal or pancreatic cancers with high DDX5 and mutations in Kras and p53 genes to FL118 treatment.
Authors: Xiang Ling, Wenjie Wu, Jianqun Liao, Sreevidya Santha, Leman Aljahdali, Jue Wang, Christos Fountzilas, Renuka V. Iyer, Patrick M Boland, Fengzhi Li
Journal: Journal of Clinical Oncology (2020)

e16102 Background: FL118 is a small molecule anticancer drug with novel mechanisms of action, although its chemical structure is similar to camptothecins. Currently, FL118 is completing its IND process to enter clinical trials for patients with advanced colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) cancers. Precision medicine is becoming a trend for modern cancer treatment. Thus, identification of drug efficacy-relevant biomarker(s) for patient selection is critical for enhancing patients’ response rates and avoiding unnecessary treatment in the clinic. Methods: Animal models of CRC and PDAC patient-derived xenograft (PDX) tumors were used to test FL118 efficacy; next generation sequencing (NGS) was used to determine PDX tumor molecular profiles; Western blots (WB) and real time RT-PCR were used to determine gene expression and/or apoptosis; Immunoprecipitation (IP) plus WB was used to determine protein phophorylation. Proteasome inhibitor was used to determine protein expression pathway. FL118 affinity purification was used to identify FL118 binding protein(s). Results: In association with WuXi Apptec, we have completed FL118 CMC and produced a clinical compatible product formulation. In this new product format, FL118 exhibits excess toxicity at a dose of ≥ 7.5 mg/kg via weekly x 4 schedules in mice. However, dosages of ≤ 6 mg/kg via the same schedule are tolerable. FL118 can eliminate the Kras/p53/APC triple-mutated SW620-established CRC tumors in a high percentage of mice at doses of 6 (maximum tolerated dose, MTD), 5, 4, 3, and 2 mg/kg. Tumor elimination under MTD is a typical characteristic of targeted drugs, which do not need MTD but only need the target to be saturated with drug for maximal efficacy. High expression of DDX5 (also called p68), a multifunctional oncogenic transcriptional co-activator and a DEAD-box RNA helicase, is associated with high FL118 efficacy in both CRC and PDAC PDX tumors. Mechanistically, FL118 binds to DDX5 to induce DDX5 tyrosine dephosphorylation and protein degradation without decreasing its mRNA. Tumors with Kras mutation (mKras) and/or TP53/p53 mutation (mp53) possess intrinsic resistance to multiple classic chemotherapeutic agents. However, PDAC PDX tumors with mp53 exhibit higher mKras expression and greater sensitivity to FL118 than tumors with wild type p53 and mKras. Conclusions: DDX5, mKras and mp53 appears to be favorable biomarkers for predicting FL118 high efficacy. However, further studies with a large cohort will be needed for confirmation.
儿童药物性血尿的临床分析及预防对策
Authors: 纪泽泉, 黄翠雯, 李敏
Journal: BMJ (2005)

对33例药物性血尿患儿的临床资料进行回顾性分析.结果示,在引起药物性血尿的药品中,解热镇痛药15例(45.5%),先锋霉素7例(21.2%),氨基糖甙类抗生素5例(15.1%),另外磺胺药2例,苯唑西林1例,氟哌酸1例,中药抗病毒冲剂2例;药物性血尿可能与药物剂量有关,也可能与剂量无关.提示引起药物性血尿的常见原因与不合理用药有关,临床医生应注意药物性血尿发生的危险因素。
Perspectives on the concept of community-based geriatric mental health service
Authors: Zhenjun Guo, Mei Zhao, Xiaozhen Lyu, Qian Zhao, Liang Bi, Xin Yu, Huali Wang
Journal: BMJ (2016)

老年精神健康问题已经成为老龄化社会医疗卫生与社会保障领域的重要课题。我国老年精神卫生知识的知晓率相当低，医疗资源和专业人员十分短缺。在当前国家加强基层卫生服务建设的背景下，值得尝试将老年精神卫生服务与基层医疗卫生加以整合。
Can tumor cells be distinguished from blood cells by mechanical parameters? A label-free CTC detection approach.
Authors: Ivonne Nel, Erik W Morawetz, Josef A Kaes, Bahriye Aktas
Journal: Journal of Clinical Oncology (2020)

e15526 Background: Even years after successful treatment of the primary tumor about 30% of breast cancer patients are suffering from metastatic relapse. One reason might be hematogenous spread. Therefore circulating tumor cells (CTC) in the blood might be interesting and easy accessible surrogate markers for disease monitoring. Due to phenotypical, mechanical and functional changes during cancer progression and treatment response, isolation of CTC subpopulations remains very challenging. Here we focused on the characterization of CTC mechanics to evaluate the utility of mechanical parameters for CTC separation from blood. Methods: For the first time, we investigated the active and passive mechanical CTC properties such as elasticity, viscosity and contractile force exertion using a dual beam trap. For proof of premise we used peripheral blood mononuclear cells (PBMC) from a healthy donor and human GFP-expressing MDA-MB 231 breast cancer cells to mimic a CTC model system and to measure cell type specific mechanical deformation profiles using an optical rheometer. For translational experiments blood samples were collected from patients with mamma or vulvar carcinoma. Hematopoietic cells were depleted using CD45. The remaining cell suspensions were applied to the optical stretcher and rheological parameters were measured in the same manner. Results: We were able to reveal distinct mechanical profiles from hematopoietic cells and breast cancer cells, respectively. The optical deformability was significantly different in both the model and the translational, systems comparing healthy PPMC to MDA-MB 231 cells, respective possible CTC candidates from breast and vulvar carcinoma patients. Evaluation of secondary parameters like viscosity and activity using a machine learning algorithm allowed for a clear distinction between hematopoietic and cancer cells in the model system. CD45-positive and -negative cells from patients with mamma or vulvar carcinoma (n = 7) showed distinct differences in the rheological behavior of both cell populations. Surprisingly, the mechanical profiles of CD45-negative cells from mamma carcinoma samples were severely different from vulvar carcinoma. Conclusions: Together with morphology and cell size, the cellular deformation pattern might be a proper tool for marker-free CTC detection in the peripheral blood of breast cancer patients.
MAP2K1/2 and MAP3K14 as a prognostic biomarker on immunotherapy and correlated with immune infiltrates in melanoma.
Authors: Jing Chen, Ting Ye, Wenzhuan Xie, Mengli Huang, Mengmei Yang
Journal: Journal of Clinical Oncology (2020)

e22104 Background: Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) and MAP3K are two subgroup of Mitogen-activated protein kinase cascade. MAP2K1/2 and MAP3K14 are members of two subgroup, respectively. Previous study revealed that MAP2K1/2 and MAP3K14 may be a promising therapeutic target for melanoma. However, the association between MAP2K1/2 and MAP3K14 mutant and melanoma remains elusive. In this study, we aimed to elucidate the efficacy of immunotherapy of MAP2K1/2 and MAP3K14 mutant for melanoma by integrated bioinformatics analysis. Methods: Whole-exome sequencing data for a cohort of 110 patients with metastatic melanoma from whom pre-treatment tumor biopsies were download from cBioPortal. Associations between MAP2K1/2 and MAP3K14 mutations and prognosis and TMB are analyzed, and tumor-infiltrating level (TIL) of 18 T-cell subtypes and 6 other immune cells were used to investigate the underlying mechanism. Results: Results showed that MAP2K1/2 and MAP3K14 mutations were associated with an increased progression-free survival (PFS; HR, 0.42; 95% CI, 0.18-0.96; P = 0.0342) and a superior overall survival (OS; HR, 0.28; 95% CI, 0.09-0.90; P = 0.0227) in melanoma with significance at borderline level. TMB levels in melanoma patients with MAP2K1/2 and MAP3K14 mutations were higher than in wild-type patients (P = 0.007). Moreover, TIL revealed distinct immune cells features in the different groups, where immune cells related to infiltrating levels of Neutrophil cells and natural arising regulatory T (nTreg) cells were more prominently enriched in the mutation group while the wide-type group had higher enrichment of Mucosal associated invariant T (MAIT) cells and T helper 2 (Th2) cells. Conclusions: MAP2K1/2 and MAP3K14 mutations may be a potential predictor for better prognosis in melanoma on immunotherapy. Identification of MAP2K1/2 and MAP3K14 mutations by genomic profiling provides a potentially novel and convenient approach for these patients to predict the prognosis, and refines patient’s management in clinical practice.
Clinical analysis of 58 cases of amyloidosis
Authors: Ying-jie Ma, Feng-kui Liu, Yu Wang
Journal: BMJ (2008)

Fifty eight patients with amyloidosis diagnosed by biopsy were admitted to Beijing Friendship Hospital from January 1983 to September 2007 and their clinical data were analyzed retrospectively.Twenty of the 58 cases were systemic amyloidosis,and other 38 were local amyloidosis.In 20 cased of systemic amyloidosis,kidney was involved in 75% cases,liver was in 55%,nervous system Was in 55%and heart Was in 50%.The lesion of local amyloidosis was usually limited in one single organ.

Key words: 
Amyloidosis;  Biopsy
A phase Ib study to evaluate the oral selective estrogen receptor degrader GDC-9545 alone or combined with palbociclib in metastatic ER-positive HER2-negative breast cancer.
Authors: Elgene Lim, Komal L. Jhaveri, Jose Alejandro Perez-Fidalgo, Meritxell Bellet, Valentina Boni, Jose Manuel Perez Garcia, Laura Estevez, Aditya Bardia, Nicholas C. Turner, Rafael Villanueva, Sara Lopez-Tarruella Cobo, Seock-Ah Im, Sung-Bae Kim, Mary R. Gates, Sharareh Monemi, Ya-Chi Chen, Heather Moore, Sherene Loi, Joohyuk Sohn
Journal: Journal of Clinical Oncology (2020)

1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .
Early management of patients with ischemic stroke and transient ischemic attack
Authors: Wei Li
Journal: BMJ (2016)

缺血性脑卒中和短暂性脑缺血发作是临床常见病，及时、合理的急性期治疗可以减少死亡率与残疾率，改善预后。近年来，该领域有不少新进展，如急性期血管内介入治疗等。本文对急性期治疗的主要措施进行讨论，帮助指导临床决策，为患者选择合理的治疗方案。
Longitudinal monitoring by next generation sequencing of plasma cell-free DNA in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with ALK tyrosine kinase inhibitors.
Authors: Minsuk Kwon, Bo Mi Ku, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2020)

9603 Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) NSCLC inevitably acquire resistance to ALK inhibitors. We hypothesized that longitudinal monitoring of cell-free plasma DNA (cfDNA) next generation sequencing (NGS) could predict the response and resistance of TKI therapy in ALK+NSCLC Methods: Patients with ALK+ advanced NSCLC determined by standard tissue testing and planned for TKI therapy were prospectively recruited. Plasma was collected before therapy (n = 92), two months post-therapy (n = 58), and at progression (n = 35). Plasma DNA NGS analysis was done retrospectively by Guardant360. Results: From April 2015 to July 2019, 92 patients enrolled; 81 (88.0%) received ALK TKI as first-line (crizotinib, n = 59; alectinib, n = 22), 10 (10.9%) received TKI as second-line (alectinib, n = 6; crizotinib, n = 2; ceritinib, n = 1; brigatinib, n = 1), and 1 (1.1%) was treated in third-line (lorlatinib). At the cut-off date of January 28, 2020, 56 of 92 patients had disease progression. Circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%); among these were 43 ALK fusions (62.3%) and 1 ALK G1202R without fusion (1.4%). Fusions included EML4-ALK v1 (n = 19), EML4-ALK v3 (n = 14), CLTC-ALK (n = 1), TPM3-ALK (n = 1), GCC2-ALK/CLIP4-ALK (n = 1), and other EML4-ALK fusions (n = 7). Eight patients developed ALK resistance mutations after crizotinib therapy: L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co-occurring F1174L, G1202R, and G1269A (n = 1). Two patients developed ALK resistance mutations after ceritinib: G1202R (n = 1), and co-occurring G1202R and T1151R (n = 1). The absence of detectable ctDNA at baseline was associated with longer progression-free survival (PFS; median 36.1 vs 11.6 months, HR 0.432, p = 0.004) and overall survival (OS; median not reached vs 27.9 months, HR 0.418, p = 0.034). Patients with clearance of ctDNA at two months (n = 29) had significantly longer PFS (median 25.4 vs 13.9 months, HR 0.343, p = 0.030) and OS (median not reached vs 25.7 months, HR 0.173, p = 0.035) than those without clearance (n = 22). Patients with co-occurring TP53 alterations and ALK fusions at baseline (n = 9) showed shorter PFS (median 7.0 vs 12.5 months, HR 3.596, p = 0.0154) than those without TP53 alterations (n = 35). Conclusions: NGS of cell-free plasma DNA is useful not only for the detection of ALK fusions and resistance mutations but also for assessing prognosis and monitoring the dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK TKI.
综合医院与社区卫生服务机构联合防控慢性阻塞性肺疾病
Authors: 何权瀛, 张荣葆, 谭星宇
Journal: BMJ (2008)

目前急需对慢性阻塞性肺疾病(COPD)采取新的防控模式,即以社区为平台,实施三级医院与社区医疗机构长期协作,整合社会资源,健全服务网络,创新服务方式,拓展服务领域,强化服务功能,提高服务水平.以稳定期的防治为基础,对全部COPD患者进行全程长期管理和干预,定期随访,建立疾病档案和随访制度。
National estimates of substance use, substance use disorders, and treatment among adolescent and young adult cancer survivors.
Authors: Xu Ji, Janet Cummings, Ann C. Mertens, Hefei Wen, Karen Elizabeth Effinger
Journal: Journal of Clinical Oncology (2020)

7042 Background: Adolescent and young adult (AYA) survivors of cancer are at an elevated risk of early-life morbidity and mortality due to the disease trajectory and treatment. Engagement in risk behaviors, including substance use, can exacerbate survivors’ vulnerabilities and place them at further risk for adverse health outcomes. This study provides national estimates of the prevalence of substance use and misuse, substance abuse or dependence (i.e., substance use disorders [SUD]), and receipt of treatment for SUD among AYA cancer survivors. Methods: We used 2015-2018 National Survey of Drug Use and Health data to identify a nationally-representative AYA sample (aged 12-34 years). Outcomes included past-year alcohol use, marijuana use, other illicit drug use, misuse of any prescription psychotherapeutic drugs (including opioid analgesics, stimulants, sedatives, or tranquilizers), and misuse of prescription opioid analgesics. Outcomes also assessed past-year SUD in aforementioned drug classes. Among those with SUD, we evaluated past-year receipt of SUD treatment. Multiple logistic regressions were estimated to compare outcomes between 846 AYAs who reported a cancer history and 142,870 AYAs who did not, adjusting for sociodemographic and need-related characteristics. Results: In bivariate analyses, AYAs with a cancer history were more likely than noncancer peers to use alcohol (78.6% vs. 63.4%; p&lt; 0.001) and illicit drugs other than marijuana (11.2% vs. 7.8%; p= 0.02), misuse any prescription psychotherapeutic drugs (16.9% vs. 10.6%; p&lt; 0.001) and prescription opioid analgesics (12.0% vs. 5.9%; p&lt; 0.001), and have an illicit drug (other than marijuana) SUD (3.7% vs. 1.3%; p&lt; 0.01) in the past year. In regression analyses, differences in past-year misuse of any prescription psychotherapeutic drug and prescription opioid analgesics persisted ( p= 0.02, p&lt; 0.01, respectively). Among AYAs with SUD, those with a cancer history were more likely than noncancer peers to receive SUD treatment (21.0% vs. 8.1%; p= 0.01) in the past year; this difference persisted in regression analyses ( p= 0.03). Conclusions: AYAs with a cancer history had an elevated risk for misusing prescription psychotherapeutic medications, which was driven by misuse of prescription opioids; yet, only one in five AYAs with a cancer history and SUD received treatment. Our findings underscore the need for future interventions designed to reduce substance use and misuse and improve access to SUD treatment in AYA cancer survivors.
Extent of implementation of low-dose CT in lung cancer screening.
Authors: Merin Jose, Rajesh Desai
Journal: Journal of Clinical Oncology (2020)

e19177 Background: Lung cancer is the leading cause of cancer deaths in the United States with only 15% alive 5 years after diagnosis. In 2013, USPSTF recommended annual screening for LDCT in high risk individuals. Studies had shown a 20% lower mortality (NELSON trial showed significantly lower lung cancer mortality) with LDCT screening. We aimed to assess the extent to which the guideline for lung cancer screening is being adopted in a community clinic. Methods: A retrospective review of electronic medical record of patients aged 55-80 years with no history of lung cancer who visited a primary care provider in a community clinic in New Jersey from October 2014- December 2019 was done. All records with any form of documentation of smoking were identified electronically. The records of those meeting the criteria (30 pack-year smoking history and currently smoking or have quit within the past 15 years) were reviewed manually to check 1) whether they are eligible for screening, 2) if eligible whether low dose CT has been recommended by the provider and 3) once recommended has it been done and followed by the patients. Results: 359 individuals with documented smoking history were identified. Of those 38.8 % (139/359) had a proper documentation (includes both PPD and number of years of smoking) of smoking history based on which high risk individuals could be identified. Of those 37 individuals met the criteria for lung cancer screening. 62% (23/37) had CT chest ordered at some point of time (16.2% for a different indication and the rest for lung cancer screening). Only 52.2% (12/23) of the patients followed the recommendations and got a LDCT done. Among those 50% (6/12) had follow up CT, 50 % (3/6) of those did it on a regular annual basis while the rest 50% (3/6) did it irregularly. 3 patients followed the annual CT screening for lung cancer. Conclusions: Based on these we note that almost half a decade since the recommendation has been established only a small proportion received the care and a still smaller minority followed it. It reflects the dearth of information regarding the guideline among providers and the lack of awareness of the need to follow among patients. This puts forward need for further interventions for implementation of the guidelines at all levels of care for lung cancer prevention. Measures include analyzing the areas of deficiency through questionnaires for patients and providers. Creating awareness on the need for accurate documentation of smoking history and the impact it can have on care delivered. Educating patients about the benefits in health outcome by following the recommendations.
Effect of TP53 mutation on antitumor immunity and responsiveness to immunotherapy in colorectal cancer.
Authors: Zhihao Lu, Lin Shen, Henghui Zhang, Xi Jiao, Yujiao Wang, Huan Chen, Wenbo Han, Chang Liu, Jifang Gong, Jian Li, Xiaotian Zhang, Xicheng Wang, Zhi Peng, Changsong QI, Zhenghang Wang, Yanyan Li
Journal: Journal of Clinical Oncology (2020)

e16014 Background: Although we have approved immune checkpoint inhibitors (ICIs) in microsatellite instability high (MSI-H) or mismatch-repair-deficient (dMMR) colorectal cancer (CRC), more than half of patients did not respond well to ICIs, emphasizing the need for effective biomarkers. Methods: Whole exome sequencing (WES) analysis was performed on a Chinese cohort of MSI-H/dMMR CRC patients (n = 16). We investigated the pertinence between clinic benefit and potential biomarkers, as TP53 mutation and tumor mutational burden (TMB). The open cohort of ICI-treated CRC patients from the Memorial Sloan Kettering cancer center (MSK ICI cohort) further validated the genomic correlation. Besides, we used the colorectal adenocarcinoma (COADREAD) cohort from The Cancer Genome Atlas (TCGA) dataset to explore the effect of TP53 mutation on the genomic and immunogenetic features. Results: In a Chinese cohort of MSI-H/dMMR CRCs receiving ICIs, we found that patients with TP53 mutation (6 out of 16) showed a remarkable lower durable clinic benefit (DCB) rate than TP53 wild-type subgroup (100% vs. 33%, P = 0.008). Moreover, TP53 wild-type patients were associated with prolonged progression-free survival (P = 0.02; HR, 0.11) and overall survival (P = 0.0037; HR, 0.04). However, TMB-high revealed no statistical significant predictive or prognostic value when using top 20%, 40% or 50% as the cutoff values in our cohort. Further, in order to confirm our observation, we analyzed the association of TP53 mutation with clinic outcome in the publicly available MSK ICI-treated CRC cohort. As expected, the TP53 wild-type patients had a better prognosis (P = 0.037; HR, 0.54) versus the TP53 mutant subgroup. Mechanically, we found that the retention of wild-type TP53 in the TCGA COADREAD cohort was associated with improvement of several steps in the cancer immunity cycle. More intriguingly, in the MSI-H subtype, the TP53 wild-type tumors showed enhanced recognition of cancer cells by T cells and a higher proportion of effector memory CD8+ T cells. Finally, TP53 wild-type tumors also showed reduced heterogeneity and decreased burden of copy number variation, but the correlation between TP53 wild-type tumors and TMB was limited due to MSI status. Conclusions: Our study highlights that TP53 mutations in CRC may indicate inhibition of the tumor microenvironment, particularly in MSI-H/dMMR CRCs. Therefore, the assessment of TP53 status may have important significance in predicting the effectiveness of ICIs in CRC patients and their MSI-H /dMMR subgroup.