tbuckley/cabot-search huggingface dataset:
Phase I study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting DLL3, in patients with small cell lung cancer (SCLC).
Authors: Taofeek Kunle Owonikoko, Hossein Borghaei, Stéphane Champiat, Luis G. Paz-Ares, Ramaswamy Govindan, Michael J. Boyer, Melissa Lynne Johnson, Hibiki Udagawa, Horst-Dieter Hummel, Ravi Salgia, Fiona Helen Blackhall, Rene J. Boosman, Wei-Chu Victoria Lai, Afshin Dowlati, Everett E. Vokes, Christine L. Hann, Anne C. Chiang, Marichu Endraca, Neelesh Soman, Marie-Anne Damiette Smit
Journal: Journal of Clinical Oncology (2020)

TPS9080 Background: SCLC is an aggressive neuroendocrine tumor with poor prognosis and few treatment options. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors but minimally expressed in normal tissues. As such, DLL3 may be a promising therapeutic target. AMG 757 is an HLE BiTE immune therapy designed to redirect cytotoxic T cells to cancer cells by binding to DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In addition to its direct antitumor effect, BiTE immune therapy can inflame the tumor microenvironment. Combining AMG 757 with a PD-1 pathway inhibitor may lead to increased antitumor activity by enabling sustained T cell-dependent killing of tumor cells. Methods: NCT03319940 is an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy; the protocol was recently amended to also evaluate AMG 757 in combination with pembrolizumab. The study will include a dose exploration (monotherapy and combination) followed by a dose expansion (monotherapy). Key eligibility criteria: adult patients with relapsed/refractory SCLC whose disease progressed or recurred after at least 1 platinum-based chemotherapy regimen, ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety/tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757 as monotherapy and in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and evaluate preliminary antitumor activity; exploratory objectives are to assess immunogenicity and changes in biomarkers in blood and tumor tissue. In the dose exploration phase, dose escalation/de-escalation decisions will be guided by a Bayesian logistic regression model; backfill enrollment at dose levels deemed safe and tolerable will be allowed. The study is open and recruiting patients. Clinical trial information: NCT03319940.
Allocation and utilization of health resource for elderly in Xicheng district of Beijing
Authors: Qing Song
Journal: BMJ (2017)

Objective
To analyze the allocation and utilization of health resources for the elderly in Xicheng district of Beijing.


Methods
A questionnaire survey on the allocation and utilization for elderly was conducted during March 2016 to December 2016 in Xicheng district of Beijing. The participants were selected from 4 community health service centers (CHS) in the district by stratified cluster random sampling method. The main contents of the questionnaire included chronic diseases prevalence among the elderly residents, health resources utilization, satisfaction and suggestion of the health service system. Two hundred questionnaires were distributed and equal number of questionnaire was received with a retrieval rate of 100.0%.


Results
At the end of 2014, there were 632 medical and health institutions in Xicheng district. The residents aged 60 and over were increased from 292 416 in 2010 to 354 696 in 2014; those aged 65 and over increased from 218 891 to 246 560; those aged over 80 increased from 61 620 to 81 011; and those aged over 100 increased from 74 to 384. Among 200 participants 78.0% (156/200) suffered with chronic diseases, and 29.5% (59/200) had more than 2 kind of chronic diseases; 65.0% (130/200) preferred the first visit in the secondary or tertiary hospitals, while 33.5% (67/200) chose community health service center for their first visit; and 54.0% (108/200)visited tertiary hospitals more than 4 times per year. For the health service, 11.5% (12/200) werevery satisfied, 26.5% (53/200) weresatisfied, 59.5% (119/200) werenot satisfied, and 2.5% (5/200) werevery dissatisfied. Among all participants 81% (162/200) felt too long waiting time; 63.0% (126/200) were dissatisfied with service attitude of medical staff in the secondary or tertiary hospitals, while 6.5% (13/200) were dissatisfied with service attitude of medical staff in community health service centers.


Conclusion
The population of Xicheng district is progressively aging in recent years, the health service demand of elderly is large, the residents prefer to large hospitals for their first visit, and the elderly residents in Xicheng district are less satisfied with the current status of health and medical resources.


Key words: 
The elderly; Health resources; Analysis of supply and demand
Is checkpoint inhibitor pneumonitis underreported in patients with advanced non-small cell lung cancer (NSCLC) on PD-1 inhibitor monotherapy?
Authors: Benjamin Oren Spieler, Gilberto Lopes, Alan Dal Pra, Tejan Diwanji, Raphael Yechieli, Laura M. Freedman, Ivaylo Mihaylov
Journal: Journal of Clinical Oncology (2020)

9579 Background: For patients with advanced non-small cell lung cancer (NSCLC), immunotherapy (ImT) has led to improvements in survival and quality of life. Checkpoint inhibitor pneumonitis (CIP) is an uncommon but sometimes life-threatening adverse event. While CIP is a diagnosis of exclusion, many oncologists believe the incidence of CIP is underreported. Radiomics, an image analysis technique that can extract imperceptible information from radiographic images, has been incorporated into predictive models for many cancers. Recent studies suggest that radiomic analysis of pre-ImT imaging can predict CIP. We hypothesized that for patients with advanced NSCLC treated with Nivolumab monotherapy, the rate of CIP is underreported and radiomics features can identify CIP that was clinically misclassified. Methods: From an IRB-approved database (DB) of 159 patients with advanced NSCLC treated with Nivolumab, chart review identified 8 patients diagnosed with CIP of any grade (5%). 42 additional patients from the same DB without diagnosis of CIP were randomly selected for analysis. For all 50 patients, uninvolved lung in the last pre-ImT CT imaging study was segmented, delineated, and analyzed for radiomics features associated with CIP. A logistic regression model incorporating radiomics assigned a CIP probability score to every patient. Results: Six radiomics features correlated with CIP ( p-values range from 0.02 to 0.03). Each feature had an AUC of ~0.79 (range 0.789 to 0.794) showing large effect size, with odds ratios greater than 3.50 (4 features) or less than 0.3 (2 features). The radiomics-based probability model assigned 7/42 patients (17.5%) without clinical diagnosis of CIP a greater than 50% probability of CIP. Chart review revealed that 6/7 “misclassified” patients exhibited symptoms or radiographic features highly suggestive of CIP within 5 months of initial immunotherapy treatment. These indications originally had been attributed to disease progression, overshadowed by more severe symptoms or simply mislabeled (e.g. a case of recall pneumonitis was described as "radiation pneumonitis"). Conclusions: For patients with advanced NSCLC treated with nivolumab, the incidence of checkpoint-inhibitor pneumonitis (CIP) is underreported and radiomics features can help identify CIP that has been clinically misclassified. Future directions include expansion of this study across the full database, correlation of radiomics features with blood biomarkers, and the inclusion of tumor burden as an additional covariate in the analysis.
Controlled IL-12 in combination with a PD-1 inhibitor subjects with recurrent glioblastoma.
Authors: E. Antonio Chiocca, Rimas Vincas Lukas, Clark C Chen, Ganesh Rao, Christina Amidei, Jill Yannetti Buck, Nira Hadar, Nathan A. Demars, John Miao, Taylor Estupinan, John W. Loewy, Yunxia Wang, Arnold Bruce Gelb, Laurence JN Cooper
Journal: Journal of Clinical Oncology (2020)

2510 Background: Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (“Controlled IL-12”), was shown in a phase 1 study (NCT02026271) to elicit a new and sustained intra-tumoral infiltration of T cells with co-expression of PD-1. We report updated findings following completion of enrollment (with follow-up ongoing) for a phase 1 substudy (NCT03636477) evaluating safety and tolerability of local, Controlled IL-12 in combination with nivolumab (nivo) in adults with recurrent glioblastoma (rGBM). Methods: Multicenter, open label, dose-escalation phase 1 trial to evaluate safety and tolerability of local, Controlled IL-12 with nivo in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 10 11 viral particles, Day 0 at time of resection) plus V (10 or 20 mg) PO QD x 15 with nivo (1 or 3 mg/kg) IV on Days -7, 15, then Q2W. Results: 21 subjects were treated (Cohort 1: V 10 mg, nivo 1 mg/kg, n = 3; Cohort 2: V 10 mg, nivo 3 mg/kg, n = 3; and Cohort 3: V 20 mg, nivo 3 mg/kg, n = 3 + 12 expansion). Safety data were similar to Ad+V monotherapy. Adverse reactions during follow-on nivo dosing were consistent with anti-PD-1 labeling, manageable, and generally reversible with no synergistic toxicities. Focusing on the 20mg V cohort (recommended phase 2 dose), serum IL-12 mean ± SEM (screening, 0.4 ± 0.1 pg/mL; Day 0, 0.6 ± 0.1 pg/mL), increased after Ad+V to 8.7 ± 3.3 pg/mL on Day 3. Similarly, serum IFN-g levels did not increase due to nivo alone (screening, 0 ± 0 pg/mL; Day 0, 0 ± 0 pg/mL), increasing after Ad+V to 6.2 ± 2.3 pg/mL on Day 7. Additionally, nivo alone did not significantly increase circulating T cells (CD3 + CD8 + %) (paired differences comparison, Day 0 to screening) 3.1%, p =0.13, whereas Ad+V significantly increased peripheral T cells (Day 28 - Day 0) 3.6%, p =0.02. Pseudoprogression followed by a decrease in size (SPD) has been shown as evidenced by serial MRIs in a subgroup of subjects. Preliminary overall survival findings will be presented. Conclusions: Controlled IL-12 with PD-1 inhibition is a rational combination with initial data consistent with immune-mediated effects, a favorable safety profile, and early evidence of anti-tumor effects. An additional phase 2 study combining Controlled IL-12 with cemiplimab-rwlc in adults with rGBM is ongoing. Clinical trial information: NCT03636477 .
Risk factors for cardiovascular complications in the elderly patients with dialysis
Authors: Wei Jiang, Xue-zhu Li, Hai-dong Yan
Journal: BMJ (2008)

Objective To investigate the risk factors for cardiovascular complications in the elderly persons undergone with dialysis.Methods One hundred and eighteen patients undergone with hemodialysis(HD)or continuous ambulatory peritoneal dialysis(CAPD)at the Eastern Hospital, Tongji University, Shanghai during January 2002 to December 2006 were retrospectively analyzed.They were divided into four groups based oil their age and mode of dialysis, i.e., 44 patients in the elderly HD group(aged over 60years), 16 patients in the elderly CAPD group(aged over 60), 46 patients in medium-age HD group(aged under 60 years)and 12 patients in the medium-age CAPD group(aged under 60).Routine biochemical parameters were measured for all the patients and their difference was compared among the four groups.Logistic regression analysis was performed for the risk factors of cardiovascular complications.Results Pulse pressure(PP)was(66±21)mm Hg, serum level of triglycerides(TG)was(1.28±0.67)mmol/L, serum level of lipoprotein(a)[LP(a)]was(434±202)mg/L, C-reactive protein was(CRP)(21±15)mg/L, serum phosphorous(P3-)was(2.02±0.77)mmol/L, and product of serum calcium and phosphorous(Ca×P)was(4.3±1.6)mmol2/L2, respectively, in the elderly group with dialysis, all significantly higher than those in the medium-age group with dialysis(t=1.535, 1.016, 2.154, 2.252, 4.676, and 4.534, respectively, P＜0.05).Incidence of cardiovascular events was markedly lower in the CAPD group than that in the HD group(P＜0.05), either in the elderly or medium-aged patients.And, incidence of cardiovascular complications correlated positively with age, PP, LP(a), CRP and Ca×P of the patients with dialysis, but correlated reversely with serum level of albumin(all with P＜0.05).Conclusions There exist a few risk factors for cardiovascular complications in the elderly patients with dialysis, so proper mode of dialysis should be selected for those who need it and adequate intervention should be implemented for them to correct the risk factors.

Key words: 
Dialysis;  Risk factors; Aged
皮肤筛眼状切开术的临床应用探讨
Authors: 吴崇智
Journal: BMJ (2008)

众所周知,临床创伤处理及术中的皮肤组织缝合处理,经常会遇到皮肤缺少,张力过高,在挤挫伤时,局部组织肿胀,影响血运,造成神经、肌肉、软组织进行性缺血、缺氧等问题,医生处理措施不尽相同,然而总的目的为封闭创面、简化手术、缩短疗程,尽量一次性完成手术。
Clinical significance of levels of serum endostatin and vascular endothelial growth factor in smokers
Authors: Wen-bin Zhou, Ming Bai, Yang Jin, Liang Xiong, Yuan Su
Journal: BMJ (2008)

Objective To explore the changes and clinical significance of levels of serum vascular endothelial growth factor(VEGF)and endostatin in smokers. Methods In a case-control study,levels of serum VEGF and endostatin were determined in 82 smokers with lung cancer,82 pair-matched smokers without lung cancer and 20 healthy non-smokers by enzyme-linked immunoabsent assay(ELISA) or competitive enzyme immunoassay.Results The level of serum VEGF in smokers with lung anncer[(16.1±7.9)ng/ml]was markedly higher than that in the other two groups(both P＜0.01).The level of serum VEGF in smokers without lung cancer was significantly higher than that in healthy non-smokers(P＜0.05).The level of serum endostatin in smokers with lung cancer was significantly higher than that in healthy nonsmokers(P＜0.01),but was not significantly different from that in smokers without lung cancer(P＞0.05),and that in smokers without lung cancer was significantly higher than that in healthy non-smokers (P＜0.05).Notably,the ratio of endostatin to VEGF in smokers with lung cancer(1.3±0.5)was significantly lower than that in the other two groups(both P＜0.01).However.there was no significant difference in it between smokers without lung cancer and healthy non-smokers(P＞0.05).The level of serum VEGF correlated significantly to that of endostatin in smokers both with and without lung cancer(P＜0.01).Conclusions These findings suggest that smoking may result in imbalance of levels of serum endostatin and VEGF leading to tumorigenesis.The ratio of endostatin to VEGF can be used as an early diagnostic indicator for lung cancer in smokers.Periodic determination of levels of serum VEGF and endostatin as well as the ratio of endostatin to VEGF is of clinical importance.

Key words: 
Endothelium,vascular;  Endothelial growth factors; Lung neoplasms
呼出气冷凝液检测在肺癌诊断中的研究进展
Authors: 朱云霞, 李凡, 蔡映云
Journal: BMJ (2010)

肺癌标志物检测在肺癌的早期诊断、病情评估、疗效评价、预后估计等方面起重要作用.目前,临床检测肺癌标志物主要以外周血为标本,也可是支气管肺泡灌洗液、胸腔积液和痰液.呼出气冷凝液(exhaled breath condensate,EBC)检测是近年来新出现的一种无创检测呼吸道生化成分的新技术,具有简便易行和重复性好等优点,但相关的研究相对较少,下面对EBC检测肺癌标志物在肺癌诊断方面的研究进展进行综述。
Biomarker analysis from a phase I study using gedatolisib+palbociclib+hormone therapy in ER+/HER2- metastatic breast cancer (mBC).
Authors: Robert Wesolowski, Nuzhat Pathan, Zhou Zhu, Erica Michelle Stringer-Reasor, Hyo S. Han, Elizabeth Claire Dees, Aditya Bardia, Rachel M. Layman, Amy Weise, Peter Kabos, Janice M. Lu, Kenneth Alan Kern, Kristen J. Pierce, Hope S. Rugo
Journal: Journal of Clinical Oncology (2020)

1052 Background: Endocrine therapy with a CDK4/6 inhibitor (CDKi) is standard of care (SOC) for patients (pts) with estrogen-receptor-positive (ER+) metastatic breast cancer (mBC). Resistance to therapy may arise from mutations in ESR1, PIK3CA, and activation of receptor tyrosine kinase signaling pathways. In this study, gedatolisib (G), a PI3KCA/mTOR inhibitor, was added to a CDKi (palbociclib, P) + letrozole (L) or fulvestrant (F) for treatment of pts with ER+/HER2- mBC. Methods: This phase 1b study (NCT02684032) comprises a dose escalation phase evaluating the dose-limiting toxicity and maximum tolerated dose of G+P+L/F and a dose expansion phase assessing the objective response rate of G+P+L/F, compared with historical data for P+L or P+F. Response was assessed using RECIST v1.1. Genomic and transcriptomic analyses were performed on archival pt tumor biopsies. Longitudinal plasma ctDNA analysis was performed on samples taken at baseline, on-treatment, and end-of-treatment. Unsupervised data analysis was conducted. Results: Genomic information was available for 25 of 35 pts with measurable disease (G+P+L: 11; G+P+F: 14). No relationship was observed between responses (1 complete response [CR] and 11 partial responses [PR]) and baseline PIK3CA pathway alterations. Pt tumor tissue analysis (n = 25) confirmed pts with FGF3/4/19 amplification (n = 4) had larger changes in tumor size in response to G+P+L/F (p = 0.029). Of the 6 pts with an ESR1 mutation, 1 pt with an ESR1 Y537S mutation exhibited a partial response (PR) to G+P+L. Longitudinal plasma ctDNA analysis (73-gene panel) revealed that decreases in PIK3CA and PTEN were most associated with clinical response. Plasma sample analysis (n = 21) showed that pts with somatic alterations in EGFR (n = 4) had a greater response to therapy (p = 0.066), compared with pts without somatic EGFR alterations. Transcriptomic profiling also revealed responsive patients had higher levels of EGFR expression. Pts exhibiting CR/PR had a lower somatic tumor mutation burden at Cycle 5 Day 1 compared with baseline (p = 0.0013). Conclusions: The addition of G to SOC endocrine + CDKi therapy may help overcome resistance due to activation of FGFR or EGFR signaling pathways and the ESR1 Y537S mutation. Somatic frequency changes of PI3K pathway alterations were most correlated with clinical response. Genomic data analysis from dose expansion samples is currently ongoing. Clinical trial information: NCT02684032 .
<i>PIK3CA</i> mutation status and progression-free survival in advanced hormone receptor positive (HR+)/ human endocrine receptor negative (HER2–) metastatic breast cancer (mBC): A meta-analysis of published clinical trials.
Authors: James Signorovitch, Fabrice Andre, Ruchuan Wang, Ines Lorenzo, Antonia Ridolfi, Jinhee Park, Mirko Fillbrunn, Akanksha Dua, Hope S. Rugo
Journal: Journal of Clinical Oncology (2020)

1069 Background: Approximately 40% of HR+/HER2- mBC patients harbor PIK3CA mutation. Associations between PIK3CA mutation status and clinical outcomes among patients with HR+/HER2- mBC have been heterogeneous across clinical trials. We synthesized available evidence from clinical trials to estimate the association between PIK3CA status and progression-free survival (PFS) using a meta-analysis adjusting for study design differences. Methods: Randomized clinical trials reporting PFS stratified by PIK3CA status in HR+/HER2- mBC were identified via a systematic literature review. Trial arms receiving PIK3CA targeted therapies were excluded. Median PFS, 6-, 12- and 18-month PFS rates, and data on trial design features were extracted. Associations between PIK3CA status and PFS were estimated adjusting for study follow-up duration, PIK3CA testing method (ctDNA vs tissue ) and study treatment using multi-level random effects meta-regression. Results: The analyzed data included 3,238 patients from 33 study arms across 11 trials ( PIK3CA mutated (MT): 1,386, wild type (WT): 1,852). PIK3CA mutation was overall associated with shorter median PFS (difference [95% CI] (months): -2.15 [-4.14, -0.15]) with substantial heterogeneity across studies ( I 2 = 98.34%). The direction of this association was robust to adjustment for study treatment (-1.27 [-2.22, -0.32]). The association was stronger for ctDNA testing (-2.16 [-3.65, -0.66]; N (total patients): 1,876) than for tissue testing (-0.65 [-2.2, 0.91]; N: 998). Findings were similar for 6-month PFS rates (absolute rate difference -9.17% [-14.22, -4.12], N: 3,179; MT: 1,366, WT: 1,813). Associations were directionally consistent but not statistically significant at 12 months (N = 2,487; MT: 1,056, WT: 1,431) and 18 months (N = 1,745; MT: 811, WT: 934), potentially due to the decreasing precision towards the tails of the PFS curves and significant heterogeneity across studies. Conclusions: Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS, especially when ctDNA testing was used. These findings suggest a negative prognostic value of PIK3CA mutation in patients with HR+/HER2- mBC.
Transplantation tolerance modifies donor-specific B cell fate to suppress de novo alloreactive B cells
Authors: Stella H.W. Khiew, Dharmendra Jain, Jianjun Chen, Jinghui Yang, Dengping Yin, James S. Young, Alexander Dent, Roger Sciammas, Maria-Luisa Alegre, Anita S. Chong
Journal: Journal of Clinical Investigation (2020)

The absence of alloantibodies is a feature of transplantation tolerance. Although the lack of T cell help has been evoked to explain this absence, herein we provide evidence for B cell-intrinsic tolerance mechanisms. Using a murine model of heart tolerance, we showed that alloreactive B cells were not deleted but rapidly lost their ability to differentiate into germinal center B cells and secrete donor-specific antibodies. We inferred that tolerant alloreactive B cells retained their ability to sense alloantigen because they continued to drive T cell maturation into CXCR5+PD-1+ T follicular helper cells. Unexpectedly, dysfunctional alloreactive B cells acquired the ability to inhibit antibody production by new naive B cells in an antigen-specific manner. Thus, tolerant alloreactive B cells contribute to transplantation tolerance by foregoing germinal center responses while retaining their ability to function as antigen-presenting cells and by actively suppressing de novo alloreactive B cell responses.