tbuckley/cabot-search huggingface dataset:
Digital pathology to evaluate PD-L1 IHC scoring as a predictor of outcome with second-line avelumab treatment in patients with non-small cell lung cancer (NSCLC).
Authors: Thomas Mrowiec, Elena Svenson, Aslihan Gerhold-Ay, Corinna M Wolf, Hans Juergen Grote, Marcus Otte, P. Alexander Rolfe, Parantu K. Shah, Anja von Heydebreck, Juergen Scheuenpflug, Mary M. Ruisi, Violeta Labarta-Beceiro, Glenn Beeman, Ti Cai
Journal: Journal of Clinical Oncology (2020)

e21539 Background: Assessment of programmed death ligand-1 (PD-L1) protein expression using immunohistochemistry (IHC)-based tests is currently the only approved biomarker guiding treatment of non-small cell lung cancer (NSCLC) with checkpoint inhibitors. Robust scoring guidelines and suitable cut-offs should be defined specifically for each PD-L1 IHC assay and are critical for appropriate treatment decisions. Methods: We retrospectively applied a novel digital pathology (DP) solution that mimics the conventional tumor proportion scoring (TPS) of PD-L1. The exploratory DP solution was developed and validated using samples from 340 patients enrolled in the first- and second-line (1L and 2L) NSCLC cohorts of the avelumab phase 1 JAVELIN Solid Tumor trial (NCT01772004) and 792 patients with NSCLC enrolled in the avelumab phase 3 JAVELIN Lung 200 trial (NCT02395172). Efficacy analyses were conducted for overall survival (OS) and progression-free survival (PFS) using the full analysis set with evaluable imaging data (n = 136 and n = 544, respectively). Results: Comparison of DP and conventional, semiquantitative pathologist scoring resulted in a high correlation overall (Spearman correlation coefficient, 0.86), with comparable performance for prediction of outcome to treatment with avelumab in 2L NSCLC. Consistent with conventional scoring, median OS and median PFS in avelumab-treated patients increased with higher PD-L1 expression cut-offs: in patients with ≥1%, ≥50%, and ≥80% PD-L1 expression on tumors cells, median OS was 10.0 months (95% CI: 8.6-14.3), 13.8 months (95% CI: 9.6-20.4) and 18.5 months (95% CI: 9.6-not estimable), respectively; median PFS, 3.1 months (95% CI: 2.7-4.9), 5.5 months (95% CI: 2.8-8.3) and 5.6 months (95% CI: 2.8-9.9). Conclusions: Our results demonstrate the technical feasibility, robustness, and utility of DP in scoring PD-L1 IHC in clinical trial samples, achieving comparable performance to conventional, semiquantitative pathologist scoring. Furthermore, our study supports the manual pathologist scoring algorithm (TPS scoring) in NSCLC and the selection of higher cut-offs for the PD-L1 IHC Ab clone 73-10.
A novel gene signature for predicting response to chemoradiotherapy in locally advanced esophageal adenocarcinoma.
Authors: Divya Sahu, Ashten N. Omstead, Anastasia Gorbunova, Dennis O’Meally, Madison Salvitti, Vincent K. Lam, Blair A Jobe, Ronan Joseph Kelly, Ajay Goel, Ali Hussainy Zaidi
Journal: Journal of Clinical Oncology (2020)

4571 Background: While neoadjuvant chemoradiotherapy (CRT) has emerged as an important treatment modality in patients with locally advanced esophageal adenocarcinoma (EAC), ~60%-70% of patients do not respond to such treatments; but are exposed to their toxicity nonetheless. This highlights the clinical need for the development of biomarkers that can robustly predict response to CRT and spare others from the toxicity and expense associated with these treatments. Herein, we systematically and comprehensively identified a biomarker signature that predicts response to neoadjuvant therapy in EAC patients. Methods: A cohort of 31 EAC patients treated with chemotherapy or chemoradiotherapy was assembled, with a majority of patients receiving carboplatin, paclitaxel and concurrent radiotherapy. Specifically, we performed a capture based targeted sequencing in paired biopsy specimens obtained at baseline and 3-6 weeks post-treatment. In addition, we also analyzed the predictive potential of a panel of immune-related genes (TIM3, LAG3, IDO1 and CXCL9) in these matched pre- and post-treatment tissues. Results: In our cohort, based upon pathologic response to neoadjuvant CRT, 8 EAC patients were categorized as non-responders, while 23 were deemed as responders to CRT. Among responders, the most frequently mutated genes were MKI67, SYNE1, PCLO, RECQL4, MSH3, NOTCH2, ILR7, CIITA, LRRK2 and EML4, and the overall tumor mutation burden (TMB) was significantly reduced for these genes in post-treatment samples ( P=5.73E-03). Similarly, in non-responders NLRP1, MAP3K1, ASMTL, and ALK harbored frequent mutations, and the TMB was significantly reduced for these genes in post-treatment samples ( P=5.57E-03). We compared responders and non-responders from the pre-treatment samples and identified differentially mutated genes including EPHA5, ZNF217, RELN, PALB2 and MYO18A. Similarly, responders had all four immune-related genes significantly up-regulated in post-treatment samples than pre-treatment samples. We constructed a risk-stratification model that comprised of mutational score from 5 differentially mutated genes, together with 4 immune-related genes, which achieved an AUC of 0.96 in predicting response to CRT in EAC patients ( P=1.03E-04). Conclusions: Using a systematic biomarker discovery approach, we have developed a novel biomarker signature that robustly predicts response to CRT in EAC patients and has a significant potential for personalized management of locally advanced EAC patients.
Change in serum resistin level and its clinical significance in patients with systematic inflammatory response syndrome
Authors: 黄友敏, 周永勤, 宋静, 张厚毅
Journal: BMJ (2007)

目的 观察全身炎症反应综合征(SIRS)患者血清中抵抗素在疾病不同程度分组中的差异及与感染存在的相关性.方法 符合SIRS诊断标准的患者60例,入院后做可疑感染分泌物、排泄物等细菌培养,同时肘静脉穿刺取血进行抵抗素定量测定和急性生理和慢性健康评估Ⅱ(APACHE-Ⅱ)评分.根据疾病严重程度分为3组:轻度SIRS组、重度SIRS组和休克组.再根据细菌培养结果分为脓毒症组和非脓毒症组,并设对照组60例.结果 轻度SIRS组、重度SIRS组、休克组抵抗素含量与对照组之间的差异具有统计学意义(P＜0.01);重度SIRS组和休克组抵抗素含量与轻度SIRS组之间的差异具有统计学意义(P＜0.01);而重度SIRS组和休克组之间的差异无统计学意义(P＞0.05).APACHE-Ⅱ评分在3组之间的差异均具有统计学意义(P＜0.01).脓毒症组和非脓毒症组抵抗素含量之间的差异具有统计学意义(P＜0.01),两组与对照组之间的差异均具有统计学意义(P＜0.01).结论 抵抗素可作为判断SIRS患者疾病的严重程度和预后指标,也可作为区分脓毒症和非脓毒症SIRS的参考指标。
Understanding the treatment effect modification of mono- or combination PD-1/PD-L1 inhibitor therapies on survival outcomes in patients with metastatic renal cell carcinoma: What does the literature say?
Authors: Neha Sati, Devon J Boyne, Darren Brenner, Paul Arora
Journal: Journal of Clinical Oncology (2020)

e17097 Background: PD-1/PD-L1 inhibitors are immune checkpoint inhibitors widely used in the treatment of metastatic renal cell carcinoma (mRCC) and other cancers. There is a lack of understanding regarding which factors predict response to these therapies. To address this gap, a systematic literature review and meta-analyses were conducted. The objectives of this study were to a) conduct a systematic literature review of studies examining factors that modify the clinical efficacy of PD-1 or PD-L1 inhibitors among patients diagnosed with mRCC and b) quantitatively synthesize the magnitude to which each predictive factor modifies the effect of PD-1/PD-L1 inhibitors. Methods: Electronic databases MEDLINE and COCHRANE were searched for studies published in English from 2006 onwards. We included all phase II/III randomized trials that provided subgroup analyses of any baseline characteristics regarding the effect of PD-1/PD-L1 inhibitors, alone or as part of a combination therapy, with respect to overall or progression-free survival among patients with mRCC. We developed a novel quantitative approach to synthesize subgroup findings across trials. The ratio of the subgroup-specific hazard ratios (HRs) from each study were pooled using a random effects meta-analysis whereby ratios of 1.00 would indicate that the subgroup-specific HRs were equal in magnitude. Results: From an initial 662 studies, five trials were judged to be eligible for inclusion. Meta-analyses suggested the treatment effect of PD-1/PD-L1 inhibitors in mRCC patients was modified by age (overall survival: ratio of HR age &gt; 75 vs. HR age &lt; 65 = 1.51; 95% CI:1.01-2.26; I 2 = 0%, p= 0.04), PD-L1 expression (progression-free survival: ratio of HR PD-L1 &gt; 10% vs. HR PD-L1 &lt; 1% = 2.21; 95% CI:1.14-4.27; I 2 = 2.26%; p= 0.01), and sarcomatoid tumor presence (progression-free survival: HR no sarcomatoid differentiation vs. HR sarcomatoid differentiation = 1.54; 95% CI:1.07-2.21; I 2 = 0%; p= 0.02). Conclusions: Evidence suggests that older age, lower levels of PD-L1 expression, and absence of sarcomatoid tumour differentiation diminish the clinical efficacy of anti-PD-1/PD-L1 immunotherapies among mRCC patients.
增强全科医生培训内容的实用性
Authors: 郑永腾
Journal: BMJ (2010)

在全科医生培训注重实践方面目前尚存在不少问题,表现在:仍以专科医生培养模式来培养全科医生;带教医生对全科医生如何在缺少现代诊疗设备的条件下有效诊治常见疾病缺乏深入的思考和指导;培训教材内容没有体现整体思维和社区适宜诊治方法,基本沿用其他专科的培训教材;缺少降低医疗成本意识的教育. 我认为,针对这些不足,需要对目前的培训方式进行必要的改进或调整,大幅度增加社区基地实践的时间;同时,从教材编撰到对师资教学方式都应该有相应改变。
Screening and intervention of resistant hypertension in the community
Authors: Xiaoling Xu, Wei Yu, Jing Yan, Fang Ding, Shiyun Hu
Journal: BMJ (2019)

Objective
To assess the screening and intervention techniques for resistant hypertension in the community.


Methods
Random sampling method was used to recruit 1 171 hypertensive patients from two communities in Hangzhou and Zhuji cities of Zhejiang province form October 2015 to september 2016. Among them, 97 patients with resistant hypertension were identified with the Three-steps-flow screening method and the individualized intervention was given. The standardized treatment and lifestyle changes were compared before and after intervention.


Results
Among 97 patients with resistant hypertension, 7 cases of pseudo resistant hypertension were detected; there were 2 cases with thyroid disease history, 48 cases with snoring history and 1 case with sleep apnea syndrome. The life style intervention and standardized medication guidance were given to 90 patients with resistant hypertension according to the individual risk factors. After one year of intervention, the results showed that the rate of normalized blood pressure was 83.5% (75/90) and the rate of standardized medication increased from 14.4%(13/90) to 90.0%(81/90), the rate of medication compliance increased from 46.7%(42/90) to 95.6%(86/90),the blood pressure control rate increased from 12.2%(11/90) to 77.8%(70/90), and the average systolic blood pressure and diastolic blood pressure levels were decreased by 20.4 mmHg (1 mmHg=0.133 kPa) and 15.5 mmHg. The life style of patients with resistant hypertension was remarkably changed, 56.7%(51/90) of patients took exercise regularly, high salt/high calorie diet decreased from 37.8%(34/90) to 11.1%(10/90), the proportion of the obese went down to 16.7%(15/90).


Conclusion
With the application of resistant hypertension screening and intervention, there are remarkable improvement in blood pressure control and life style changes for patients with resistant hypertension in the community.


Key words: 
Hypertension, resistant; Community; Screening and intervention
Association of characteristics of patients visiting fever clinic with different air quality index in Beijing
Authors: Xiaoguang Li, Yunhao Zheng
Journal: BMJ (2016)

Objective
To examine the association of characteristics of patients visiting fever clinic with different air quality index in Beijing.


Methods
Six days with highest ambient air quality index (AQI) (polluted weather group) and 6 days with lowest AQI (clear weather group) during February 1st to March 31th 2014 were selected as study period. The clinical data of patients, who visited in fever clinic of Peking University Third Hospital during the selected 12 days, were retrospectively analyzed.


Results
There were 417 patients in clean weather group and 481 in polluted weather group. There were no significant differences in duration of fever [(2.30±2.51)d vs. (2.18±2.58) d, χ2=0.701, P=0.484] and highest body temperature [(38.60±0.65)℃ vs. (38.57±0.66)℃, χ2=0.545, P=0.586] between two groups. The symptoms of cough, sore throat in pollution group were higher than those in clear group (52.39% vs. 45.56%, χ2=4.166, P=0.041; 50.52% vs. 42.21%, χ2=6.203, P=0.013, respectively). The proportion of cases diagnosed as influenza-like illness in polluted weather was higher than that in clear weather group (53.85% vs. 46.76%, χ2=4.484, P=0.034).


Conclusion
The results indicate that the symptoms cough and sore throat and influenza-like illness are increased in polluted weather in Beijing.


Key words: 
Air pollution; Pneumonia; Influenza-like illness
Parietal-Prefrontal Feedforward Connectivity in Association With Schizophrenia Genetic Risk and Delusions
Authors: Danielle L.B. Greenman, Michelle A.N. La, Shefali Shah, Qiang Chen, Karen F. Berman, Daniel R. Weinberger, Hao Yang Tan
Journal: American Journal of Psychiatry (2020)

Conceptualizations of delusion formation implicate deficits in feedforward information updating across the posterior to prefrontal cortices, resulting in dysfunctional integration of new information about contexts in working memory and, ultimately, failure to update overfamiliar prior beliefs. The authors used functional MRI and machine learning models to address individual variability in feedforward parietal-prefrontal information updating in patients with schizophrenia. They examined relationships between feedforward connectivity, and delusional thinking and polygenic risk for schizophrenia.The authors studied 66 schizophrenia patients and 143 healthy control subjects during performance of context updating in working memory. Dynamic causal models of effective connectivity were focused on regions of the prefrontal and parietal cortex potentially implicated in delusion processes. The effect of polygenic risk for schizophrenia on connectivity was examined in healthy individuals. The authors then leveraged support vector regression models to define optimal normalized target connectivity tailored for each patient and tested the extent to which deviation from this target could predict individual variation in severity of delusions.In schizophrenia patients, updating and manipulating context information was disproportionately less accurate than was working memory maintenance, with an interaction of task accuracy by diagnosis. Patients with delusions also tended to have relatively reduced parietal-prefrontal feedforward effective connectivity during context updating in working memory manipulation. The same connectivity was adversely influenced by polygenic risk for schizophrenia in healthy subjects. Individual patients' deviation from predicted "normal" feedforward connectivity based on the support vector regression models correlated with severity of delusions.These computationally derived observations support a role for feedforward parietal-prefrontal information processing deficits in delusional psychopathology and in genetic risk for schizophrenia.
Clinical and molecular characteristics of TSC1/2 mutant lung cancer.
Authors: Yanye Wang, Song Xu, Shikang Zhao, Shuai Zhu, Xiongfei Li, Xi Lei, Jun Chen, Gang Chen
Journal: Journal of Clinical Oncology (2020)

e21647 Background: Tumor suppressor genes TSC1 and TSC2 inhibit cell growth through inactivation the function of mTORC1. Previous studies have demonstrated that loss of function mutation of either TSC1 or TSC2 gene result in formation of neoplasm in multiple tissues. However, the clinical significance of TSC1 and TSC2 in non-small-cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the clinical and molecular characteristics of TSC1 and TSC2 mutation in NSCLC patients. Methods: We retrieved the clinical and genomic information of 1144 NSCLC from the Pan-Lung cancer dataset through the cBioportal ( www.cbioportal.org) . The cohorts of TSC1 and TSC2 mutant patients were identified. We compared baseline characteristics of patients with the Fisher exact test for categorical data and the Mann-Whitney U test for continuous variables. Overall survival (OS) was estimated with Kaplan-Meier curves, and differences were compared with the log-rank test. Results: Among 1144 patients, 27(2.36%) of them had TSC1 mutation and 40 (3.50%) had TSC2 mutation. Most patients with TSC1 and TSC2 mutations coexisted with other oncogenic gene alterations. TP53 was the most frequent concurrent gene (n = 53), followed with ERBB family genes (n = 24) and KRAS (n = 15). Compared to squamous cell carcinoma, TSC1/2 mutation was slightly more common in adenocarcinoma (53.7% vs 46.3%). 61.2% TSC1/2 mutant patients were male and 88.1% patients had former/current smoking history. Kaplan–Meier analysis showed that the patients harboring TSC1 mutation had a median OS of 14.1 months, whereas patients with TSC2 mutation had a median OS 110.6 months. However, there was not a statistically difference (P = 0.201). Conclusions: TSC1/2 mutation may define a unique population of NSCLC, which often coexists with other oncogenic gene alterations such as TP53 mutation. The function of TSC1/2 mutation and the value of TSC1/2 as therapeutic target in NSCLC are under investigation.
Randomized phase III study of irinotecan/cisplatin (IP) versus etoposide/cisplatin (EP) for completely resected high-grade neuroendocrine carcinoma (HGNEC) of the lung: JCOG1205/1206.
Authors: Hirotsugu Kenmotsu, Seiji Niho, Masahiro Tsuboi, Masashi Wakabayashi, Genichiro Ishii, Kazuo Nakagawa, Haruko Daga, Hiroshi Tanaka, Haruhiro Saito, Keiju Aokage, Toshiaki Takahashi, Toshi Menju, Takashi Kasai, Ichiro Yoshino, Koichi Minato, Morihito Okada, Hiroshi Katayama, Hisao Asamura, Yuichiro Ohe, Shun-ichi Watanabe
Journal: Journal of Clinical Oncology (2020)

9006 Background: In the WHO classification, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are considered as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Although there were no randomized trials evaluating adjuvant chemotherapy for patients (pts) with resected HGNEC, EP was considered to be a standard regimen for this population. A phase III study showed the superiority of IP to EP in pts with extensive stage SCLC (JCOG9511). Methods: Pts with completely resected HGNEC were randomized in a 1:1 ratio to receive either etoposide (100 mg/m 2 , days 1-3)/cisplatin (80 mg/m 2 , day 1) or irinotecan (60 mg/m 2 , days 1, 8, 15)/cisplatin (60 mg/m 2 , day 1), using the minimization method according to sex, pathologic stage, histology and institution. The primary endpoint was changed from overall survival (OS) to relapse-free survival (RFS) during the study period. We assumed a 3-year RFS of 59% of EP arm and 72% of IP arm (hazard ratio (HR) of 0.623). Planned sample size was 220 in total to give a power of 80% with a one-sided alpha of 5%, an accrual period of 6 years and a follow-up period of 3 years. Results: Between April 2013 and October 2018, 221 pts with a median age of 66 years, pathological stage I (54%), SCLC (53%), were randomly assigned to the EP arm (n = 111) or the IP arm (n = 110). In the second interim analysis, the predictive probability that IP would be superior to EP at the time of the primary analysis was 15.9%, which led to early termination of the trial. With a median follow-up of 24.1 months, 3-year RFS was 65.4% versus 69.0% with HR of 1.076 (95% CI, 0.666-1.738; log-rank test, one-sided P= 0.619). In the subgroup analyses of histology, 3-year RFS in SCLC was 65.2% versus 66.5% with HR of 1.029 (95% CI, 0.544-1.944), and 3-year RFS in LCNEC was 66.5% versus 72.0% with HR of 1.072 (95% CI, 0.517-2.222). Overall survival at 3 years was 84.1% versus 79.0% with HR of 1.539 (95% CI, 0.760-3.117). Proportions of treatment completion were 87.4% (EP) and 72.7% (IP). Incidences (EP/IP) of grade 3 or 4 febrile neutropenia (20.2/3.7%) or neutropenia (97.2/35.8%) were more common in EP. Grade 3 or 4 diarrhea (0.9/8.3%) or anorexia (6.4/11.1%) were more common in IP. One treatment-related death due to tracheal bleeding was observed in IP. Conclusions: This study failed to show the superiority of IP to EP in RFS for pts with completely resected HGNEC. EP is still a standard treatment for this population. Clinical trial information: UMIN000010298.
KEYNOTE-199 cohorts (C) 4 and 5: Phase II study of pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC).
Authors: Christopher J. Hoimes, Julie N Graff, Scott T. Tagawa, Clara Hwang, Deepak Kilari, A. J. Ten Tije, Aurelius Omlin, Raymond S. McDermott, Ulka N. Vaishampayan, Tony Elliott, Winald R. Gerritsen, Haiyan Wu, Jeri Kim, Charles Schloss, Johann S. De Bono, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2020)

5543 Background: Initial evidence suggests activity of pembro + enza in patients (pts) resistant to enza. We present results from the multicohort phase II study KEYNOTE-199 (NCT02787005) in chemotherapy-naive pts with mCRPC treated with pembro + enza after progression with enza and who had RECIST-measurable (C4) or bone-predominant (C5) disease. Methods: Pts who did or did previously receive abiraterone and for whom enza treatment failed after clinically meaningful response received pembro 200 mg Q3W, with continuation of enza for up to 2 y or until progression, toxicity, or withdrawal. End point was ORR per RECIST v1.1 (C4) by blinded independent central review (primary); DOR (C4), time to PSA progression, rPFS, OS, and safety. Results: A total of126 pts (C4, 81; C5, 45) were treated. Median (range) PSA was 31 ng/mL (0.4-1667) in C4 and 19 ng/mL (1-1750) in C5.Median (range) time from enrollment to data cut off was 15 mo (7-21) in C4 and 19 mo (7-21) in C5. In C4, ORR (95% CI) was 12% (6-22; 2 CRs, 8 PRs) and median (range) DOR was 6 mo (3+ to 13); 60% of pts had DOR ≥6 mo. DCR (CR + PR + SD) was 51% in C4 and C5. Median (95% CI) time to PSA progression was 4 mo (4-4) in C4 and 4 mo (4-4) in C5. Median (95% CI) rPFS was 4 mo (3-6) for C4 and 4 mo (3-6) for C5; 12-mo rPFS rate was 17% in C4 and 23% in C5. Median (95% CI) OS was NR (16-NR) in C4 and 19 (14-NR) mo in C5; 12-mo OS rate was 70% in C4 and 75% in C5. Shorter median OS was more associated with prior enza treatment &lt;6 mo than with prior enza treatment ≥6 mo. Liver metastasis was associated with shorter median OS however, median OS in visceral disease subgroups appeared longer than expected. Any-grade/grade ≥3 treatment-related AEs occurred in 75%/26% of pts in C4 and 69%/24% in C5. Two pts in C5 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Any-grade/grade 3/4 rash (regardless of relatedness) was higher than that in prior reports for individual agents (33%/6%). Conclusions: Pembro + enza after enza resistance had manageable safety and showed antitumor activity for RECIST-measurable and bone-predominant mCRPC. This combination is being evaluated in an ongoing phase III combination trial. Clinical trial information: NCT02787005 . [Table: see text]