tbuckley/cabot-search huggingface dataset:
Etiology, clinical profile and prognosis of pregnancy-related acute kidney injury in critically ill obstetric patients
Authors: Yaogui Ning, Minwei Zhang, Jinlong Chen, Jing Guo, Yanqiong Wu, Jianhua Yu, Na Li
Journal: BMJ (2015)

Objective
To investigate the etiology, clinical profile and prognosis of pregnancy-related acute kidney injury (PR-AKI) in critically ill obstetric patients.


Methods
Data of the critically ill obstetric patients admitted to ICU from January 2011 to March 2014 were collected and analyzed retrospectively.PR-AKI patients were screened according to the clinical diagnostic criteria of AKI.The etiological diseases, laboratory indicators, urine output, length of ICU stay, prognosis of PR-AKI were documented and analyzed; and the risk factors of PR-AKI was assessed with logistic regression analysis.


Results
A total of 124 critically ill obstetric patients were enrolled, and AKI occurred in 46 of them (37.1%) under kidney disease: Improving Global Outeomes Acute kidney injury(KDIGO-AKI) criteria.The main causes of PR-AKI included pre-eclampsia(41.3%, 19/46), hemorrhagic shock(21.7%, 10/46), hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome (17.4%, 8/46), acute fatty liver of pregnancy (AFLP) (15.2%, 7/46). Of the 46 PR-AKI patients, 3 died (6.5%), and the causes of death was cerebral hemorrhage, cerebral venous sinus thrombosis and multiorgan failure (MOF). There were 23 cases in stage 1, 13 cases in stage 2 and 10 cases in stage 3 according to KIDGO-AKI stage criteria.Ten patients received renal replacement treatment: 1 in stage 1, 2 in stage 2 and 7 in stage 3.Complete, partial and no renal recovery was observed in 73.9% (34/46), 17.4%(8/46) and 8.7%(4/46) of the patients, respectively.Complete renal recovery was observed 91.3% (21/23) in stage 1, 9/13 in stage 2, 4/10 in stage 3, respectively.On logistic regression, pregnancy-induced hypertension, hemorrhagic shock and HELLP syndrome were risk factors of PR-AKI.


Conclusions
The incidence of PR-AKI in critically ill obstetric patients is high.A variety of etiological factors and risk factors are related to PR-AKI.Early detection and effective therapeutic measures are important to PR-AKI.The prognosis of PR-AKI is related with severity of AKI.


Key words: 
Acute kidney injury; Etiology; Pregnancy; Risk factors
他汀类药物引起的肌病一例
Authors: 李欣, 高鑫
Journal: BMJ (2004)

患者男,29岁,既往体健,不嗜烟酒,因进行性乏力10天就诊.患者因肥胖于3周前在当地医院发现总甘油三酯7.23 mmol/L,胆固醇4.71 mmol/L,高密度脂蛋白1.26 mmol/L,低密度脂蛋白2.0 mmol/L,开始服用舒降(simvastatin)10 mg/d,后改用来适可(lovastatin)20 mg/d治疗.服药后2周开始四肢乏力,呈进行性加重.无肌肉疼痛、发热、关节痛等.无高血压、冠心病家族史。
Progress in noninvasive assessment of fluid responsiveness
Authors: Jiguang Li, Yuanfeng Shi, Caihong Gu, Shiqi Lu
Journal: BMJ (2019)

Fluid infusion is one of the most common therapeutic measures in clinical practice. With the development of medical technology, the assessment of fluid responsiveness before fluid infusion has become simpler and less invasive. The assessment of fluid responsiveness is based on three aspects: cardiopulmonary interaction, volume-loading test and endogenous volume-loading test. This article reviews the progress in the assessment of fluid responsiveness with the application of ultrasound and noninvasive continuous cardiac output monitoring, and the prospect of future improvement.


Key words: 
Noninvasive; Ultrasound; Continuous cardiac output monitoring; Fluid responsiveness
Preclinical evaluation of LX-086, a small molecule as a selective inhibitor of PI3K.
Authors: Jiaqiang Dong, Tie-Lin Wang, Jingjie Huang, Ji Zhou, Ye Tan, Tao Yu, Chengde Wu, Shuhui Chen
Journal: Journal of Clinical Oncology (2020)

e15662 Background: PI3K/Akt signaling pathway plays a key role in a series of cellular functions related to cell growth, proliferation, survival and differentiation. PI3Kα is ubiquitously expressed, and associates with angiogenesis and glucose homeostasis. Gain of function mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common somatic alterations in solid tumors. The purpose of this study is to investigate the in vitro/ in vivo antitumor activity, and safety of LX-086, a small molecule of PI3Kα selective inhibitor, in preclinical models of solid cancer with PIK3CA mutation or amplification. Methods: Kinase inhibitory activity and selectivity of LX-086 were determined with PI3K kinase assays. Cellular pAkt S473 inhibitory activity and selectivity were evaluated in BT-474, MDA-MB-468, RAW264.7 and Jeko-1 cell lines (cell lines PI3Kα/β/γ/δ are specifically highly expressed respectively). The antitumor activity of LX-086 was evaluated in vivo in PIK3CA amplified or mutant breast cancer BT-474, T47D and ovarian cancer SK-OV-3 cell-derived mouse xenograft (CDX) models. Results: LX-086 displayed potent kinase inhibitory activity for WT PI3Kα, PI3Kα E545K , PI3Kα H1047R with IC 50 1.80 nM/1.13 nM/0.69 nM, respectively. LX-086 inhibited cell pAkt S473 in BT-474 cells with IC 50 35.4 nM. The selectivity of LX-086 in PI3Kα over PI3Kβ/δ/γ is similar with that of alpelisib, which had been approved by FDA in 2019. LX-086 showed antitumor efficacy in HER2+/HR+, PIK3CA amplified breast cancer BT-474 CDX model (TGI = 106% @40 mpk, QD), as well as in the HER2-/HR+, PIK3CA H1047R breast cancer T47D CDX model ( TGI = 84.7%@ 40 mpk, QD) and PIK3CA H1047R ovarian cancer SK-OV-3 CDX model ( TGI = 69.2%@ 40 mpk, QD). The 28-days toxicity study in dog also indicated that LX-086 had similar therapeutic index with alpelisib, with low risk of hyperglycemia. Conclusions: We have identified a novel potent and safe PI3Kα inhibitor LX-086. Preclinical studies show antitumor efficacy of LX-086 in PIK3CA mutant and amplified solid cancer models. LX-086 represents a promising clinical candidate for the treatment of solid cancers with PIK3CA mutation or amplification.
Genomic characterization of preclinical models derived from primary and metastatic sites from rapid autopsy patients in PDMR.
Authors: Li Chen, Rajesh Patidar, Biswajit Das, Yvonne A Evrard, Chris Alan Karlovich, Tomas Vilimas, Nikitha Nair, Amanda Peach, Anna Lee Fong, Luis Romero, Shahanawaz Jiwani, Lindsay Dutko, Kelly Benauer, Marianne Radzyminski, Kelly Dougherty, Michelle Eugeni, Dianne Newton, Melinda G. Hollingshead, Paul M. Williams, James H. Doroshow
Journal: Journal of Clinical Oncology (2020)

e13506 Background: The National Cancer Institute has developed a repository of preclinical models [Patient-Derived Models Repository (NCI PDMR, https://pdmr.cancer.gov )] including patient derived xenografts (PDXs), organoids (PDOrgs) and in vitro tumor cultures (PDCs) from patients with solid tumor cancer histologies. A subset of these preclinical models is derived from post-mortem collections from rapid autopsies representing the end point in disease progression. Clinical annotations and genomic datasets associated with these models provide a unique opportunity to study tumor evolution, mechanistic insights into the metastatic process, and treatment resistance. Methods: To date, 43 PDXs, 21 PDCs, and 23 PDOrgs using rapid autopsy specimens from 8 primary and 35 metastatic sites of 18 patients have been developed by the Biological Testing Branch (DTP, DCTD, NCI Frederick, MD) for the PDMR. Whole exome (WES) and total transcriptome (RNASeq) data were processed to generate mutation, copy number alteration (CNA) and gene expression data. Multi-model lineage trees were reconstructed based on putative somatic variants for all the models derived from all patients. The fraction of the genome affected by CNA was compared both within and across PDX models. Results: Most of the rapid autopsy PDX models (32/43) are derived from pancreatic adenocarcinoma (PAAD) patients (13/18), with metastatic specimens originating from sites including liver, colon, omentum, and lung. Driver mutations are present in all preclinical model specimens derived from the same patient. For instance, KRAS p.G12D is present in all patient-derived model specimens derived from PAAD patient 521955. The fraction of the genome affected by CNA remains stable within a PDX model across passages (n = 24, mean = 6.39%, sd = 5.90%). However, we found that this increased when comparing PDX models derived from metastatic sites versus the primary site (n = 19, mean = 16.92%, sd = 10.46%). This indicates presence of tumor heterogeneity between metastatic and primary sites. The lineage tree for models from patient 521955 indicates that one liver metastasis has a unique seeding event compared to the other 4 metastatic sites. Unsupervised clustering analysis on gene expression data also confirms the observed tumor site relationships. Conclusions: Our data demonstrate the potential use of these preclinical models available from the NCI PDMR. These models provide a unique resource for preclinical studies in tumor evolution, metastatic spread mediators, and drug resistance.
Ultrasonography in differential diagnosis of benign and malignant endometrial lesions in postmenopausal women
Authors: Ning Zhao
Journal: BMJ (2016)

The transvaginal ultrasonography, sonohyterography and intravenous contrast-enhanced ultrasonography are main ultrasonographic methods in evaluation of endometrial lesions. This article introduces the procedures, limitations, advantages and disadvantages of these three ultrasonographic methods in differential diagnosis of benign and malignant endometrial lesions in postmenopausal women.


Key words: 
Endometrium; Ultrasonography; Endosonography
Phase II trial of adjuvant mFOLFOX6 after metastasectomy for pulmonary metastasis of colorectal cancer: WJOG5810G.
Authors: Nozomu Machida, Takehiro Okumura, Junji Kishimoto, Narikazu Boku, Tomohiro Nishina, Koichi Suyama, Yasuhisa Ohde, Katsunori Shinozaki, Hideo Baba, Shinya Tokunaga, Hisato Kawakami, Takashi Tsuda, Masahito Kotaka, Hiroyuki Okuda, Hisateru Yasui, Tadamichi Denda, Kentaro Yamazaki, Shuichi Hironaka, Kei Muro, Ichinosuke Hyodo
Journal: Journal of Clinical Oncology (2020)

4097 Background: Resection of pulmonary metastasis (PM) is widely accepted to improve the prognosis in selected patients (pts) with metastatic colorectal cancer (CRC). However, the clinical implication of adjuvant chemotherapy after metastasectomy of PM is unknown. We conducted a multi-center phase 2 trial of adjuvant chemotherapy with mFOLFOX6 after metastasectomy of PM-CRC. Methods: Main eligibility criteria were first curative metastasectomy of 4 or less PMs and no prior chemotherapy except for adjuvant chemotherapy with fluoropyrimidine monotherapy after curative resection of primary or extrathoracic CRC metastasis. The study treatment was 12 courses of mFOLFOX6 (oxaliplatin 85 mg/m 2 , l-leucovorin 200 mg/m 2 , 5-fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 continuous infusion, every 2 w). The primary endpoint was overall survival (OS). The secondary endpoints included disease-free survival (DFS), adverse events (AEs), and recurrence sites. The sample size was determined to be 93 expecting 5-year OS rate of 50% with threshold 35% (90% power, alpha error 5%). Results: Fifty-two pts from 34 institutions were enrolled between July 2011 and July 2014. Patient enrollment was closed prematurely because of slow accrual. Four patients were ineligible after enrollment and the safety and efficacy cohort comprised 52 and 48 patients, respectively. Patient backgrounds were as follows: gender (male/female) 31/21, median age (range) 63 (42-75) years, ECOG PS (0/1) 48/4, primary site (colon/rectum) 18/34, number of PM (1/2/3/4) 36/9/5/2, synchronous/metachronous PM 11/41, and unilateral/bilateral PM 40/12. With the median follow-up time of 6.0 (1.8-7.7) years, 5-year OS rate was 86% (95% CI: 72-93) and 5-year DFS rate was 59% (95% CI: 43-71). Tumors recurred in 19 patients (13 lung, 3 liver and 7 others). Total 41 pts (79%) completed 12 courses of mFOLFOX6 (reasons for discontinuation: AEs in 3, refusal due to AEs in 8). AEs ( &gt; Grade 3) were neutropenia 50%, fatigue 8%, peripheral sensory neuropathy 8%, appetite loss 4%, diarrhea 4%, febrile neutropenia 2% and allergic reaction 2%. There was no treatment related death. Conclusions: Adjuvant mFOLFOX6 is feasible and may be effective after metastasectomy for PM-CRC, considering much better OS than we had expected. Clinical trial information: UMIN000005693 .
Role of mutant KRAS as a biomarker in FL118-induced apoptosis, reactive oxygen species (ROS) production and inhibition of survivin, Mcl-1 and XIAP in human bladder cancer.
Authors: Sreevidya Santha, Ieman Aljahdali, Sailee Suryakant Rasam, Xue Wang, Xiang Ling, Jianqun Liao, Jue Wang, Christos Fountzilas, Qingyong Li, Jun Qu, Fengzhi Li
Journal: Journal of Clinical Oncology (2020)

e15651 Background: Effective treatment of bladder cancer patients has not been realized over the past two decades due to heterogeneity with key oncogenic and tumor suppressor gene mutations, which is a major hurdle for effective treatment of the disease. Methods: Cancer cell growth/viability was determined using MTT assays; protein gene expression profiles were determined by both Western blots and proteomics technologies; PARP cleavage were determined by Western blots; genetic modulation of protein gene expression was realized by shRNA silencing or forced expression of the gene; reactive oxygen species (ROS) production was measured using a ROS assay kit; and human bladder xenograft tumor growth was determined using animal models. Results: Our study indicated that FL118, an innovative small molecule, exhibits differential anticancer efficacy in high-grade bladder cancer cell lines (HT1376, T24, UMUC-3). FL118 is highly effective at inhibiting the viability of T24 and UMUC-3 bladder cancer cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 with wild-type Ras exhibits insensitivity to FL118-mediated inhibition of cell viability. Consistently, FL118 strongly induced PARP cleavage (hallmark of apoptosis) and inhibited the expression of survivin, XIAP and/or Mcl-1 in both T24 and UMUC-3 cells but not in the HT1376 cells. Our studies further indicated that the constitutive AKT and ERK1/2 signaling does not play a major role in these FL118-mediated effects. Instead, mutant Kras appeared to be involved in FL118 efficacy and played a positive role in mediating FL118 effects. Silencing of mutant Kras via shRNA reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC-3 cells, suggesting mutant Kras is required for FL118 to exhibit high efficacy. FL118 increases ROS production in T24 and UMUC-3 cells but not in HT1376 cells. Silencing of mutant Kras with shRNA in UMUC-3 cells significantly reduced FL118-mediated ROS generation. Additionally, proteomics analyses of UMUC3 and HT1376 cell protein profiles after FL118 treatment support the obtained results described above. Consistent with these in vitro results, in vivo studies indicated that UMUC3 is highly sensitive and HT1376 is highly resistant to FL118 treatment. Conclusions: Our studies suggest that mutant Kras is a favorable biomarker for FL118 targeted treatment in human bladder cancer.
The prognostic value of neutrophil-to-lymphocyte ratio in patients with epidermal growth factor receptor mutated advanced non-small cell lung cancer (NSCLC).
Authors: Nicole Yun, Sherin Juliet Rouhani, Brendan Gilmore, Ethan M. Ritz, Christine M. Bestvina, Imad Tarhoni, Marta Batus, Jeffrey Allen Borgia, Philip D. Bonomi, Mary J. Fidler
Journal: Journal of Clinical Oncology (2020)

e21675 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) indicates a poor prognosis across multiple cancers, including non-small cell lung cancer (NSCLC). Our study aims to validate these findings in EGFR-mutated NSCLC patients receiving tyrosine kinase inhibitor (TKI) therapy, and to evaluate other factors that may impact NLR. Methods: We retrospectively analyzed 95 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and The University of Chicago Medical Center from August 2011 to August 2018. The prognostic value of NLR was assessed at the start of therapy, and after 6 and 12 weeks of treatment. The median progression free survival (mPFS) and median overall survival (mOS) were calculated by the Kaplan-Meier method and compared with the log rank test. Spearman rank correlation was used to correlate number of disease sites with NLR at diagnosis. T test analysis compared mean NLR between patients with high grade (≥ 3) toxicity versus low or no (grades 0-2) toxicity. The relationship between NLR and body mass index (BMI) changes were analyzed using Pearson correlation. Results: At therapy start, patients with NLR &lt; 5 (n = 57) had a mPFS of 15.3 months and a mOS of 56.7 months, while those with NLR ≥ 5 (n = 35) had a mPFS of 13.8 months ( p= 0.024) and mOS of 40.0 months ( p= 0.0056). After 6 weeks of treatment, patients with NLR &lt; 5 (n = 69) had a mPFS of 14.6 months and mOS of 56.2 months, while those with NLR ≥ 5 (n = 23) had a mPFS of 10.0 months ( p= 0.052) and a mOS of 37.74 months ( p= 0.049). After 12 weeks of treatment, patients with NLR &lt; 5 (n = 66) had a mPFS of 14.2 months and mOS of 54.8 months, while those with NLR ≥ 5 (n = 17) had a mPFS of 3.0 months ( p= 0.0016) and a mOS of 22.4 months ( p= 0.0012). Patients who had a decrease in NLR did not have significantly better mPFS or mOS compared to patients whose NLR increased at either 6 or 12 weeks. Baseline number of disease sites and BMI did not correlate with NLR at diagnosis. Changes in BMI did not correlate with a change in NLR at 6 weeks or at 12 weeks. There was no significant difference in NLR between patients with high grade (≥ 3) versus no or low grade (0-2) drug toxicities. Conclusions: NLR can be used as a prognostic factor to predict which EGFR mutated NSCLC patients on TKI therapy may have worse PFS or OS outcomes. Closer monitoring and potential therapeutic escalation may be beneficial in patients with elevated NLR ≥ 5. Further work studying NLR in patients being treated with a larger osimertinib cohort is ongoing.
Mutation spectrum of <i>EGFR</i> in 21,324 patients with non-small cell lung cancer successfully tested by multiple platforms in a CAP-accredited laboratory.
Authors: Linlin Mao, Weiwei Zhao, Xiaoxia Li, Shangfei Zhang, Changhong Zhou, Danyan Zhou, Xiaohua Ou, Yanyan Xu, Yuanxiao Tang, Changming Hu, Pifu Luo, Shihui Yu
Journal: Journal of Clinical Oncology (2020)

e13637 Background: Genotyping epidermal growth factor receptor ( EGFR) gene in patients with advanced non-small cell lung cancers (NSCLC) is essential to identify those patients who may benefit from targeted treatments. However, the testing methodology is still a puzzle for many clinicians. This study retrospectively reviewed the EGFR data from testing patients with NSCLC in our laboratory in 10 years. Methods: A total of 21,324 NSCLC cases successfully underwent EGFR genotyping in our laboratory for clinical therapeutic purpose, including 5,244 cases tested by Sanger sequencing, 13,329 cases tested by real-time PCR, and 2,751 tested by next generation sequencing-NGS. Results: 54.6%, 20% and 2.3% samples were recorded with tumor cell content (TCC) of &lt; 40%, &lt; 20% and 1% respectively. The average EGFR mutation rate was 45.1%, with 40.3% identified by Sanger sequencing, 46.5% by real-time PCR and 47.5% by NGS. Comparable EGFR mutation rates were observed in cases with 1%-20% TCC from real-time PCR and NGS platforms. In these cases with EGFR mutations, 93.3% of them carried a single EGFR mutation (92.1% with a classical mutation as 19del or L858R, and 7.9% with an uncommon mutation) and 6.7% harbored complex EGFR mutations. 65.3% of the cases carrying EGFR mutations identified by NGS also have tumor related variants in other genes. 26.5% more cases were found to have oncogenic driver mutations with therapeutic significance beyond EGFR by NGS. Conclusions: NGS may be the most optimal methodology to detect EGFR mutations in patients with NSCLC compared with Sanger sequencing and real-time PCR platforms from accuracy and comprehensiveness aspects, but some other issues, such as Turn Around Time (TAT), still should be considered in clinical practice.
Assessment of the risk of tumor progression in different subtypes of breast cancer.
Authors: Liubov Yu Vladimirova, Elena M. Frantsiyants, Natalia Yu. Samaneva, Anna E. Storozhakova, Valeria A. Bandovkina, Natalia D. Cheryarina, Elena A. Sheiko, Marina M. Sergeeva, Oleg I. Kit, Aleksandr E. Lisutin, Evgeniya M. Nepomnyashchaya
Journal: Journal of Clinical Oncology (2020)

e12551 Background: Breast cancer (BC) is still one of the main causes of death in women due to the tumor recurrence and/or resistance to anticancer therapy. The criteria to assess the risk of tumor progression in breast cancer after 2 chemotherapy cycles are required. The purpose of the study was to analyze blood levels of TGFβ, TGFR2, TNF, TNFα, TNFR1, TNFR2, MMP-9 and CD-44 in patients with various BC subtypes before and after 2 chemotherapy cycles. Methods: The study included 42 patients with various BC subtypes: luminal A, luminal B and triple-negative BC (TNBC). Levels of TGFβ, TGFR2, TNF, TNFR1, TNFR2, CD-44, MMP-9 were measured by ELISA in the blood of all patients prior to anticancer therapy and after 2 chemotherapy cycles. Statistical processing of results was performed using the Statistika 6.0 software by the Student’s t-test. Results: Levels of TGFβ, TGFR2, TNF, TNFα, TNFR1, TNFR2, CD-44, MMP-9 in patients with all BC subtypes were high before the treatment. After 2 chemotherapy cycles, the values decreased statistically significantly in all BC subtypes: CD-44 decreased by 25.2%, 30% and 54.7% in luminal A, luminal B and TNBC, respectively; TNFα – by 26.2%, 48.3% and 50.8%, respectively; TNFα-R1 – by 52.1%, 39.2% and 50.3% respectively; TNFα-R2 – by 31.7%, 32.8% and 41.9% respectively; MMP-9 – 35.3%, 32.6% and 43.3% respectively. The patients remained in remission for 3 years. When the levels were high or did not differ from initial values, the tumor progressed. Conclusions: We identified a set of criteria allowing with high probability to determine the growth and progression of tumors in various subtypes of breast cancer after two cycles of chemotherapy. A decrease in the levels of TGF-β, TNF, MMP-9, and CD-44 demonstrates remission; stabilization or increase of these indicators leads to further early progression of the disease.
Surgical treatment of soft tissue defect with medial sural artery perforator pedicled flap or muscle flap
Authors: Gong-lin Zhang, Ming Zhang, Ao Guo, Ling-zhi Zhang, Hao Jing, Jin-fu Zhang, Ai-jun Ling
Journal: BMJ (2008)

This article was to discuss the effectiveness of medial sural artery perforator pedicled flap or muscle flap in the treatment of soft tissue defect. Since 2002, 21 patients(14 males and 7 females)with prepatellar(n=7)or pretibial(n=14)defect had underwent soft tissue reconstruction. Ten of them obtained medial sural artery perforator pedicled flap and the rest received muscle flap. All the medial sural artery perforator pedicled flaps and muscle flaps survived well and the clinical outcomes were satisfactory. No remarkable donor site morbidity was found. According to our data. medial sural artery perforator pedicled flap or muscle flap may seem to be highly vascularized and have constant vascular anatomy and long vascular pedicle. They could be useful in the treatment of prepatellar or pretibial soft tissue defect. 

Key words: 
Surgical flaps; Tissue transplantation