tbuckley/cabot-search huggingface dataset:
The landscape of <i>MAP3K1</i>/<i>MAP2K4</i> alterations in gastrointestinal (GI) malignancies.
Authors: Matthew K Stein, Andrew Elliott, Jimmy J. Hwang, Emil Lou, Moh'd M. Khushman, Aaron James Scott, John Marshall, Davendra Sohal, Benjamin Adam Weinberg, Richard M. Goldberg, Mohamed E. Salem, Wolfgang Michael Korn, Axel Grothey
Journal: Journal of Clinical Oncology (2020)

4113 Background: Inactivating alterations in MAP3K1/MAP2K4 occur in various solid tumors, sensitize cancer models to MEK inhibitors, and have co-mutation partners which may enable therapeutic targeting. Methods: We retrospectively reviewed 20290 GI malignancy patients (pts), comprised of 9986 colorectal carcinoma (CRC) and 10304 non-CRC, whose tumors were profiled with Caris Life Sciences from 2015-2019. Profiling included immunohistochemistry (IHC) with programmed death ligand-1 (PD-L1), next-generation sequencing (NGS), tumor mutational burden (TMB) and deficient mismatch repair or microsatellite instability-high status (dMMR/MSI-H). Results: MAP3K1/MAP2K4-alteration ( MAP3K1/MAP2K4-MT) was more frequent in CRC than non-CRC pts (2.0% v. 1.2%, p&lt;0.0001), with truncating mutations representing the majority of lesions along both genes. While MAP3K1/MAP2K4-MT CRC pts were similar in age and gender to wild-type (WT), mutated non-CRC pts were older (median age 69 v. 65 years) and more likely female (51% v. 42%) compared to WT (both p&lt;0.05). MAP3K1/MAP2K4-MT CRC (25% v. 7%) and non-CRC (30% v. 3%) were more frequently dMMR/MSI-H than WT pts (both p&lt;0.0001). MAP3K1/MAP2K4-MT CRC cases were affiliated with higher TMB and similar rate of PD-L1 expression compared to WT. A higher rate of MAP3K1/MAP2K4-MT CRC pts were right-sided (36% v. 22%, p&lt;0.0001) and transverse (8% v. 4%, p&lt;0.05) compared to WT, whereas a higher frequency of WT cases were left-sided (20% v. 28%, p&lt;0.05) and rectal (15% v 23%, p&lt;0.05). Of microsatellite stable (MSS) CRC pts, those with MAP3K1/MAP2K4-MT were more likely PIK3CA (26% v. 17%) and APC (85% v. 78%) and less-likely TP53 (64% v. 77%) co-mutated versus WT MSS pts (all p&lt;0.05); no difference was seen in BRAF V600E, ERBB2/ ERBB3 or KRAS co-mutation rate in MSS pts. In both all-comers and MSS CRC, MAP3K1/MAP2K4-MT pts were more frequently co-mutated than WT with ARID1A, POLE, ATM, BRCA2 and PIK3R1 (all ≥7% of MAP3K1/MAP2K4-MT pts, p&lt;0.0001). A higher frequency of all-comer non-CRC GI malignancy pts with MAP3K1/MAP2K4-MT were co-mutated with PIK3CA (13% v. 6%), ERBB2/ERBB3 (8% v. 3%) or APC (13% v. 5%) compared to WT (all p&lt;0.01). For MSS non-CRC GI cases, ARID1A (50% v. 30%) and SMAD4 (21% v. 12%) were more frequently co-mutated in MAP3K1/MAP2K4-MT versus WT pts (all p&lt;0.05). Conclusions: Truncating MAP3K1/MAP2K4 alterations occur in nearly 2% of GI malignancy pts and are more commonly associated with dMMR/MSI-H than WT. Potentially targetable co-mutation partners implicated in MAPK and PI3K pathways as well as POLE, BRCA2 and ATM warrant further evaluation.
NHS launches Race and Health Observatory after <i>BMJ</i> ’s call to end inequalities
Authors: Zosia Kmietowicz
Journal: BMJ (2020)

A new NHS centre to investigate the effects of race and ethnicity on people’s health has got the go ahead after a special issue of The BMJ in February focused on the continuing problem of racism in medicine.

Earlier this year Mala Rao and Victor Adebowale, who guest edited the special issue (bmj.com/racism-in-medicine), called for an independent “observatory” to “inform action towards the overarching NHS race equality goals.”1

Simon Stevens, NHS England’s chief executive, has now approved the NHS Race and Health Observatory after agreeing to establish the centre “in principle” at The BMJ ’s event to launch the special issue, at which he joined a panel discussion …
PD-L1 and neutrophil to lymphocyte ratio (NLR) as predictive panel of prognosis in bladder cancer.
Authors: Tao Qin, Hao Yu, Bo Wang, Cui Tan, Huangming Hong, Hai Hu, Herui Yao
Journal: Journal of Clinical Oncology (2020)

e17040 Background: PD-1/PD-L1 blockade significantly improved survival for bladder cancer. PD-L1 expression might not be an ideal marker for patient selection in isolation. Several studies demonstrated that alternative markers such as NLR, a biomarker of systemic inflammation response to therapy, correlated with outcomes in a variety of cancers including bladder cancer, might be a predictor for patient selection and the response to immunotherapy. However, no reporters have been made combination of NLR and PD-L1 in predicting prognosis in bladder cancer. Methods: Suitable tissue of 100 FFPE blocks of bladder cancer patients treated in Sun Yat-Sen Memorial Hospital Sun Yat-sen University were stained with PD-L1 antibody. Clinicopathological data and pretreatment complete blood count were retrospectively collected. All patients were classified into high NLR group and low NLR group at cut-off 3.0. Kaplan-Meier and Cox proportional hazard models analyses were used to assessed the predictor of combined PD-L1/NLR for disease-free survival (DFS) and overall survival (OS). Results: Patients were mostly male (79%) with high grade () lymph node positive (21%), T3-4 (33%) . The positivity of PD-L1 expression was 22% (22/100) at cut-off 1%. Univariate analysis showed that PD-L1 expression was positively associated with larger tumor size, higher grade, positive lymph node metastases. Median DFS and OS were 35 months and 37 months, respectively. Both PD-L1 expression and NLR were associated with DFS and OS. COX analysis model showed that PD-L1 and NLR were independent prognostic factors for tumor prognosis. Of interest, when patients were divided in two groups based on PD-L1/NLR: patients with PD-L1+/high NLR as group 1 and other patients as group 2, group1 had significantly shorter DFS and OS (DFS, X 2 = 4.146, P = 0.042; OS, X 2 = 10.274, P = 0.001). COX proportional hazards regression models indicated that PD-L1+/high NLR was correlated with a significantly shorter DFS and OS (DFS, hazard ration [ HR] = 2.572, P = 0.05; OS, HR = 3.811, P = 0.003). Conclusions: The study indicated that combined use of PD-L-1/ NLR as predictive biomarker for survival. This feasible panel may be optional maker applied to select patients for immunotherapy.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and receptors in type 1, type 2 and type 17 inflammation in cross-sectional asthma study
Authors: Michelle Marks, Chad Steele, Wendy C Moore, Deborah A Meyers, Brian Rector, Elizabeth Ampleford, Eugene R Bleecker, Annette T Hastie
Journal: Thorax (2020)

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) reportedly promotes, or conversely, resolves inflammation in asthma. In this study of TRAIL and cell receptors in sputum, bronchoalveolar lavage and biopsy from subjects in the Severe Asthma Research Program at Wake Forest, the high TRAIL group had significant increases in all leucocytes, and was associated with increased type 1, type 2 and type 17 cytokines, but not type 9 interleukin 9. Two variants at loci in the TRAIL gene were associated with higher sputum levels of TRAIL. Increased TRAIL decoy receptor R3/DcR1 was observed on sputum leucocytes compared with death receptor R1/DR4, suggesting reduced apoptosis and prolonged cellular inflammation.
Key points in the clinical pathway for dyspnea
Authors: Hong Zhang
Journal: BMJ (2017)

呼吸困难是一种异常不舒服的呼吸感觉，是一种警告，是患者就医的主要原因之一。呼吸困难是一种混合了多种因素的主观感受，程度与疾病的严重度可能不一致，而且可导致呼吸困难的疾病众多，导致其诊断和治疗复杂。全面的病史询问、体格检查和适当的辅助检查有助于呼吸困难的识别、鉴别和有效治疗。对于急性呼吸困难应着重于发现致死性的严重病因，及时抢救；对于慢性呼吸困难着重于发现病因，对因治疗。
Safety of nivolumab/pembrolizumab in hepatitis B surface antigen-positive non-small cell lung cancer (NSCLC) patients.
Authors: Chongrui Xu, Hai-Yan Tu, Yue-Li Sun, Yang-Si Li, Bing-Fei Xu, Bin-Chao Wang, Hua-Jun Chen, Zhen Wang, Qing Zhou, Jin-Ji Yang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2020)

e21670 Background: Chronic hepatitis B virus infection patients are noted about 7% in Chinese population who are excluded from the clinical trials of the nivolumab or pembrolizumab in non-small cell lung cancer (NSCLC). However, in clinical practice these patients received checkpoint inhibitors as well. Limited evidence exist on the safety of the checkpoint inhibitors in hepatitis B surface antigen positive NSCLC patients. Methods: From January 1, 2018 to September 30, 2019, clinical information of advanced non-small cell lung cancer patients who received nivolumab or pembrolizumab ± chemotherapy as routine clinical practice in Guangdong Lung Cancer Institute were collected according to a standardized procedure. Gender, histology, treatment regimens, experimental test, respose rate, and adverse events were recorded. Status of hepatitis B surface antigen (HBsAg) were tested for every patient before the treatment and data of the positive patients were accessed for this research. Adverse events were assessed according to Common Terminology Criteria for Adverse Events v5.0. Results: Among 232 eligible patients, HBsAg were found positive in 17 patients(7.3%). Clinical characteristics were list in the table. The median age was 55.2 years (range 39-72) and transaminase and bilirubin of all the patients were normal before treatment. The median treatment cycle was 7 (95%CI 4.6-10.3) and the median time to discontinuation was 4.4 months (95%CI 2.8-7.1). 8 patients received anti-virus therapy including entecavir and adefovir during the treatment. Grade 1 transaminase or bilirubin elevation were noted in 6 patients during the treatment. Grade 3 transaminase and grade 4 bilirubin elevation were found in 1 patient without evidence of viral reactivation. Conclusions: Nivolumab or pembrolizumab are safety treatment options for HBsAg positive NSCLC patients. [Table: see text]
欢呼全科医生制度出台迎接全科医学的春天
Authors: 张愈
Journal: BMJ (2011)

2011年6月22日国务院常务会议决定在我国建立全科医生制度，这是深化医疗卫生体制改革进程中的又一重大举措，是对改善城乡居民健康水平，降低医疗费用和合理利用卫生资源，提高基层医疗卫生服务水平，缓解“看病难、看病贵”的治本之策；这项制度的推出顺应医学模式的转变，必将促进医学人才教育培养模式和医疗卫生服务模式的转变；这项制度的建立必将为覆盖城乡的基本医疗卫生制度的实现提供可靠的人力和人才保障。
Timing of US Food and Drug Administration (FDA) cancer drug approvals relative to publication of clinical trial results.
Authors: Ali Raza Khaki, Aakash Desai, Martin W. Schoen, Bishal Gyawali, Eddy J. Chen, Peter C. Yang, Jeremy Lyle Warner
Journal: Journal of Clinical Oncology (2020)

2071 Background: Publication of clinical trial results in peer reviewed literature is essential to inform clinicians regarding the use of new anti-cancer treatments, which often have a low therapeutic ratio and require careful assessment of risks and benefits. Publication of registration trials should precede FDA approval to facilitate evaluation and implementation of new therapies. The timing of trial publication relative to FDA drug approvals has not been systematically investigated. Methods: We collected all FDA drug approvals for a cancer indication between 2000-19. Trials were identified using FDA labels as well as drugs and publications indexed on HemOnc.org. Approvals for generics/biosimilars, non-oncology indications and label revisions without supportive evidence were excluded. Dates of approval, the approval pathway, approval type (new vs expansion), and the first full publication related to the registration were recorded. Trials and approvals were matched using available metadata. We calculated the proportion of drugs approved prior to publication overall and for those receiving accelerated approval (AA). We used logistic regression to compare rates of pre-publication approval by approval pathway and by new vs expanded approval. Results: Among a total of 378 drug approvals, 139 (37%) had pre-publication approval. Of these, the median overall time from approval to publication was 140 days (IQR 64-281 days). For those with approval after publication, median time from publication to approval was 157 days (IQR 72-359 days). The number of drugs approved pre-publication rose by 27% between the first and last quarters of the study period, though, the proportion decreased as more anti-cancer drugs have been approved in recent years (Table). More drugs were approved pre-publication through AA than regular approval (46% vs 34%, OR 1.66 [95% CI 1.03-2.70], p=0.04) and as new approvals vs. expanded approvals (45% vs 32%, OR 1.76 [95% CI 1.15-2.70], p=0.01). Conclusions: A substantial minority of FDA approvals occur before trial results are published, with the odds being higher for drugs receiving AA and for new approvals. Since clinicians rely upon published results to inform risk/benefit decisions, efforts are needed to ensure trial results are published by the time of FDA approval of new cancer drugs and indications. [Table: see text]
TOAST subtypes, risk factors and recurrence of ischemic stroke
Authors: Li-hong Zhao, Jie Han
Journal: BMJ (2009)

Objective To analyse subtyping of iscbemic stroke by the criteria of Trial of Org 10 172 in Acute Stroke Treatment (TOAST), its distribution, and relationship between TOAST subtypes, its risk factors and recurrence. Methods Clinical data of 441 patients of ischemic stroke were collected prospectively during October 1, 2006 to September 30, 2007. All the patients were classified by TOAST criteria into five major subtypes and followed-up for one year since its first episode. Dates of its recurrence and death due to recurrence were recorded. Results All the 441 patients with ischemic stroke could be subtyped etiologically according to TOAST criteria as follows: etiology undetermined in 42.3 percent, small-vessel occlusion in 30.9 percent, large-artery atherosclerosis in 17.3 percent, cardioembolism in 9.3 percent, and others in 0.2 percent, without statistically significant difference in its gender and age distributions. Recurrence rate of iscbemic stroke in one year since its first episode for varied subtypes was 33.3 percent for cardioembolism, 14. 6 percent for etiology undetermined, 13.7 percent for large-artery atherosclerosis and 6.9 percent for small-vessel occlusion, respectively. There was no significant difference in risk factors for varied subtypes of iscbemic stroke, including history of smoking, hypertension, diabetes, cardiac disease, and serum levels of total cholesterol, low-density lipoprotein cholesterol, fihrinogen and glucose. Conclusions Varied subtypes of iscbemic stroke had different risk factors and recurrence rate by TOAST criteria, which can be used as an etiologic classification for its secondary prevention. 

Key words: 
Cerebrovascular accident;  Subtype;  Risk factors
Correlation of tumor mutational burden (TMB) with molecular profiling and clinical characteristics in patients with bladder cancer.
Authors: Divya Natesan, Henry Martell, Patrick Devine, Bradley A. Stohr, James P. Grenert, Jessica Van Ziffle, Nancy M. Joseph, Boris C. Bastian, Sarah E Umetsu, Courtney Onodera, Emily Chan, Arpita Desai, Anthony C. Wong, Sima P. Porten, Jonathan Chou, Terence W. Friedlander, Eric Jay Small, Lawrence Fong, Eric Alejandro Sweet-Cordero, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2020)

e17025 Background: Bladder cancers (BC) are frequently highly mutated. Next generation sequencing (NGS) can both shed light on mutational burden and the specific alterations that provide insights into the underlying biology of individual tumors. Methods: We retrospectively reviewed BC cases assessed with UCSF500, an institutional NGS assay that uses hybrid capture enrichment of target DNA to interrogate approximately 500 frequently mutated cancer genes. Hypermutated tumors were defined as having TMB &gt; 10 mutations/Mb. Fisher’s exact test was used to compare patients (pts) with hypermutated (HM) and non-hypermutated (NHM) tumors. Results: From 2015 to 2019, 74 pts with BC underwent UCSF500 testing; 48 pts were evaluable for TMB, of which 19 pts (40%) had HM tumors. 17/19 pts were evaluable for mutational signatures; all 17 had APOBEC signatures. Signatures were not assessed in NHM tumors due to low TMB. Clinicopathologic characteristics and most common alterations in the two groups are listed in the table. More HM pts had responses to immunotherapy (IO) treatment (86% vs 40%, p = 0.13). Conclusions: In this single-institution BC cohort, HM tumors were common and APOBEC mutational signature was the common underlying biology in HM tumors. There were relevant differences in common alterations between HM and NHM tumors, including more FGFR3 mutations in NHM tumors. HM status and APOBEC signature were suggested as relevant predictive biomarkers of response to IO, which should be investigated further in larger BC cohorts. [Table: see text]
一个发热的小病人
Authors: 周仲华, 金世红
Journal: BMJ (2010)

我有一个小病人,现在刚满1岁半.他的父母一直是我忠实的病人,一家人无论有什么健康问题都首先来找我.他妈妈在怀他之前就来我们全科门诊做孕前咨询,怀孕后也是一直由我做产前检查,足月临产后我协助安排她住进产科,并陪她在产房中分娩.孩子出生后,妈妈的产后访视及孩子的定期健康体检也都是我做的,这种连续性的照顾使得我对这家人及这个孩子的健康状况都很了解。
Correlation of pathogenic POLE mutations with clinical benefit to immune checkpoint inhibitor therapy.
Authors: Benjamin Garmezy, Jinesh S. Gheeya, Kyaw Zin Thein, Patrick Glen Pilie, Wanlin Wang, Jordi Rodon Ahnert, Kenna Rael Shaw, Funda Meric-Bernstam, Timothy A Yap
Journal: Journal of Clinical Oncology (2020)

3008 Background: Mutations in DNA polymerase epsilon ( POLE) may induce DNA replication errors, increasing neoantigen load and potentially enhancing clinical benefit to immune checkpoint inhibitors (ICI). We present a clinicopathologic analysis of patients (pts) with advanced cancers harboring POLE mutations and their response to ICI therapy at MD Anderson Cancer Center. Methods: We used targeted exome sequencing via CLIA-certified next generation sequencing assays to identify pts with POLE-aberrant tumors and their co-occurring mutations. The pathogenicity of each POLE mutation was annotated utilizing InterVar and ClinVar databases. Chi-square analysis was performed. Results: Tumors from 12,947 pts were analyzed and 448 (3.5%) pts had a mutation or copy number variation in POLE (3.5%), comparable to the TCGA PanCancer Atlas (4.0%). Clinical data were available for 293 pts; the most common cancers were colorectal (14.7%), non-small cell lung (13.7%), cholangiocarcinoma (13.3%) and melanoma (10.2%). There were 267 unique co-mutations, including KRAS (23.0%), ARID1A (21.5%), BRCA2 (18.7%), ATM (18.4%), CDKN2A (17.5%), BRAF (15.3%), EGFR (15.3%), ATRX (12.6%), CREBBP (11.7%), APC (11.3%), ATR (11.0%), BRCA1 (11.0%) and CDK12 (10.4%). POLE variants were annotated in all pts: pathogenic/likely pathogenic (n = 34, 11.6%), benign/likely benign (61, 20.8%), and variant of unknown significance (198, 67.6%). 104 (35.8%) of 293 pts with POLE mutations received PD-1/L1 inhibitors as monotherapy or in combination. 93 (88.4%) of 104 pts were evaluable for response: Radiological CR 4.3% (n = 4), PR 26.9% (n = 25), SD 22.6% (n = 21), PD 46.2% (n = 43), for a clinical benefit rate (CR + PR + SD) of 53.8%. Pathogenic status of POLE mutation was associated with clinical benefit to PD-1/L1 inhibitors (p = 0.04). TMB (p = 0.44), PD-L1 (p = 0.11), and MSI (p = 0.66) status were not associated with pathogenic status. MSI-H status was not over-represented in pts with ICI clinical benefit (p = 0.36). Conclusions: Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutations as a predictive biomarker. Multiple co-occurring DNA damage response mutations were found, which may contribute to ICI clinical benefit.
Updated analysis of the inducible T-cell co-stimulatory receptor (ICOS) agonist, GSK3359609 (GSK609), combination with pembrolizumab (PE) in patients (pts) with anti-PD-1/L1 treatment-naïve head and neck squamous cell carcinoma (HNSCC).
Authors: Eric Angevin, Stefanie L. Groenland, Annette May Ling Lim, Juan Martin-Liberal, Victor Moreno, Jose Manuel Trigo, Christophe Le Tourneau, Matthen Mathew, Daniel C. Cho, Aaron Richard Hansen, David Vicente, Michele Maio, Antoine Italiano, Jessica Ruth Bauman, Michael Jon Chisamore, Helen Zhou, Catherine Elizabeth Ellis, Marc S. Ballas, Axel Hoos, Danny Rischin
Journal: Journal of Clinical Oncology (2020)

6517 Background: INDUCE-1 (NCT02723955) is a first-in-human study investigating GSK609, an IgG4 ICOS agonist non-T-cell depleting antibody, as monotherapy and combination therapy with anti-cancer agents that includes PE. A range of GSK609 dose levels (≥0.1–1 mg/kg) having biological and clinical activity were identified and evaluated in the expansion phase with GSK609 0.3 mg/kg selected as the dose for further investigation. Results from the HNSCC expansion cohorts (ECs) showed GSK609 has single agent activity in pts with relapsed/refractory disease, and early clinical activity in combination with PE in pts with anti-PD-1/L1 treatment-naïve disease (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). Updated results from the GSK609/PE HNSCC EC are presented. Methods: Eligible pts for the HNSCC EC had anti-PD-1/L1 treatment-naïve disease, ≤5 prior lines of therapy, measurable disease, and no active autoimmune disease. Pts received GSK609 0.3 mg/kg + PE 200 mg every 3 weeks (wks) until disease progression or unacceptable toxicity, up to 2 years (yrs)/35 cycles. Disease assessments were performed every 9 wks through wk 54 then every 12 wks thereafter. Pts were followed for survival and subsequent anti-cancer therapy. Results: As of 11 October 2019, 34 pts were enrolled and evaluable for efficacy analyses. The median age of this population was 61.5 yrs (range: 37–77); 85% were male; 53% received ≥1 prior line of therapy in the metastatic setting. ORR was 26% (95% CI: 12.9, 44.4; n = 9 with 4 complete and 5 partial responses); disease control rate was 68% (95% CI: 49.5, 82.6; n = 23). Among pts with PD-L1 IHC status by 22C3 pharmDx assay (n = 24; 71%), the majority of pts with a response or stable disease (SD) had PD-L1 CPS status &lt; 20 (11 of 15 pts including 1 SD pt with CPS &lt; 1). Median PFS was 5.6 months (95% CI: 3.9, 6,2). Median OS was not reached at time of analysis (95% CI: 8.2, NR); 6-month OS rate was 84% (95% CI: 66, 93). Treatment-related adverse events were reported in 66% of pts; the majority of events were Grades 1 or 2 with &lt; 10% of pts experiencing ≥ Grade 3 events. Conclusions: This updated analysis with a more mature dataset shows promising clinical activity that supports further randomized investigation of GSK609 in combination with PE with an OS endpoint in HNSCC. Clinical trial information: NCT02723955 .