tbuckley/cabot-search huggingface dataset:
Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma
Authors: Zi Mei, Junwen Huang, Bin Qiao, Alfred King-yin Lam
Journal: International Journal of Oral Science (2020)

With the understanding of the complex interaction between the tumour microenvironment and immunotherapy, there is increasing interest in the role of immune regulators in the treatment of head and neck squamous cell carcinoma (HNSCC). Activation of T cells and immune checkpoint molecules is important for the immune response to cancers. Immune checkpoint molecules include cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), T-cell immunoglobulin mucin protein 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), T cell immunoglobin and immunoreceptor tyrosine-based inhibitory motif (TIGIT), glucocorticoid-induced tumour necrosis factor receptor (GITR) and V-domain Ig suppressor of T cell activation (VISTA). Many clinical trials using checkpoint inhibitors, as both monotherapies and combination therapies, have been initiated targeting these immune checkpoint molecules. This review summarizes the functional mechanism and use of various immune checkpoint molecules in HNSCC, including monotherapies and combination therapies, and provides better treatment options for patients with HNSCC.
Circulating tumor DNA (ctDNA) using Guardant360 to predict response in BRAF V600 WT metastatic melanoma (MM) patients (pts) receiving immune checkpoint inhibitors (ICI).
Authors: Jenny HJ Lee, Matteo S. Carlino, Alexander M. Menzies, Justin Iver Odegaard, Martina Lefterova, Richard A. Scolyer, Georgina V. Long, Helen Rizos
Journal: Journal of Clinical Oncology (2020)

10050 Background: ctDNA detected by ddPCR predicts ICI response in MM, although its utility is limited to pts with known recurring mutations eg. BRAF, NRAS, KIT. We sought to overcome this limitation by using a next generation sequencing approach in BRAF V600 wild type (WT) MM pts. Methods: Plasma was collected at baseline and Week (wk) 6 in 35 BRAF V600 WT MM pts treated with ICI. Cell free (cf)DNA was analyzed using Guardant360 and only somatic non-synonymous and promoter variants were considered. Pts who failed cfDNA extraction at baseline were excluded (n = 3). Favorable ctDNA was defined as undetectable ctDNA at wk 6 and unfavorable ctDNA defined as detectable ctDNA at wk6. Response was according to RECIST at first restaging. Results: Of the evaluable 32 pts (64 plasma samples), median baseline cfDNA quantity was 33ng (range 4-657ng) and ctDNA was detected in 29/32 pts (91%). All 3 pts with undetectable baseline ctDNA had less than 10ng cfDNA compared to only 1/29 pts with detectable baseline ctDNA. Number of mutations identified in the 29 ctDNA-positive pts was 4 per pt (range 1-22). Response assessment was performed on 30 evaluable pts. Candidate driver mutation(s) in BRAF, NF1, or N/K/HRAS were identified in 26/30 pts. These mutations were often detected with other established mutations involved in tumorigenesis (eg. TERT promoter), or passenger mutations (eg. clonal hematopoiesis). Analysis of driver mutations revealed a sensitivity and specificity in predicting treatment failure of 92% and 93%, respectively (table). When all mutations identified were evaluated for treatment response, 9/18 responding pts retained some ctDNA at wk 6, although this never included TERT variants. The resulting sensitivity and specificity in predicting treatment failure changed to 100% and 50%, respectively, when all cfDNA variants were included. Conclusions: The extensive coverage of Guardant360 improves ctDNA detection in BRAF V600 WT MM pts, allowing non-invasive, rapid, and longitudinal assessment of response in a broader population. The expanded coverage also identifies passenger variants of potential non-MM origin, eg. clonal hematopoiesis, and with significant overlap with ctDNA, it is not possible to distinguish between the two in the circulation. We therefore recommend identification and monitoring of known cancer driver mutations only. [Table: see text]
Clinical management of residual cystic duct stones post laparoscopic cholecystectomy: report of one case
Authors: Xi Chen, Hongbing Zhou
Journal: BMJ (2016)

报道1例腹腔镜胆囊切除术(LC)后长期腹痛患者，经仔细询问患者病史，结合磁共振胰胆管造影检查并排除其他疾病后予以再次手术剖腹探查，诊断为LC术后胆囊管残留结石。避免胆囊管残留过长或胆囊管残余结石应重在预防。
急性缺血性脑卒中和短暂性脑缺血发作的治疗
Authors: 徐蕾, 龚涛
Journal: BMJ (2012)

结合《中国急性缺血性脑卒中诊治指南2010》介绍缺血性脑卒中(ischemic stroke,IS)和短暂性脑缺血发作(transient ischemic attack,TIA)的急性期治疗,包括抗栓治疗(溶栓、抗血小板聚集、抗凝、降纤治疗等)、维持血容量、神经保护治疗、中医中药及并发症处理。
慢性酒精中毒后酒精戒断反应41例分析
Authors: 张春红, 张春英
Journal: BMJ (2008)

酒精戒断反应是指长期大量饮酒的酒精依赖者,中断饮酒后出现震颤、幻觉、植物神经功能紊乱、抽搐、意识障碍等一系列精神神经症状.近年来以酒精中毒人院的患者人数呈逐年上升趋势,本文对2000年1月至2006年12月41例慢性酒精中毒后患者酒精戒断反应进行分析,以期对诊断和治疗提供依据。
Extraesophageal manifestation of gastroesophageal reflux disease
Authors: Xiaohong Sun
Journal: BMJ (2016)

胃食管反流病(GERD)是由多种因素造成的消化道动力障碍性疾病，是消化系统的常见病和多发病。除了烧心和反酸的典型症状外，GERD还可表现为胸痛、咳嗽、声嘶、哮喘等食管外表现。这些病人往往首诊于全科医师而非消化专科。全科医师熟悉GERD的食管外表现对提高其临床诊治水平有重要意义。
Hyperimmunoglobulin E syndrome in adult patients: a case report and literature review
Authors: Na Xu, Hongwei Fan, Jing Zhao, Peng Wang, Hongmei Song, Xuejun Zeng
Journal: BMJ (2017)

The clinical manifestations, laboratory test results, treatments and prognoses of 5 adult patients with hyperimmunoglobulin E syndrome (HIES) were retrospectively analysed. All 5 patients experienced disease onset within 1 year of birth and had recurrent multiple infections, all had recurrent rash and 4 had skeletal abnormalities. Recurrent infections lasted for a mean of 19.6 years and predominantly affected the skin and respiratory tract. Other manifestations included chronic otitis media, renal abscess and osteomyelitis. Two cases had skin abscess (methicillin-susceptible Staphylococcus aureus infection), which was alleviated after antibiotic treatment and abscess drainage. Two cases had respiratory tract infection and one case had a foot skin ulcer, and all symptoms improved after antibiotic treatment. HIES should be suspected when an adult patient experiences repeated infection since birth, particularly when skeletal abnormalities and a history of neonatal rash is also present. Early diagnosis facilitates targeted anti-infection therapy, leading to earlier remission and an improved prognosis.


Key words: 
Hyperimmunoglobulin E; Infection
Phase II preoperative window study of SAR439859 versus letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer.
Authors: Mario Campone, Christina Isabella Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling
Journal: Journal of Clinical Oncology (2020)

TPS1108 Background: Endocrine therapy targeting ER signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER2- breast cancer. This study is a 14-day preoperative non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods: This international, open-label, Phase II randomized study (NCT04191382; ACT16106) evaluates SAR439859 at two dose levels versus the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing Phase I/II study (NCT03284957; TED14856) in metastatic breast cancer (Campone. SABCS 2019. P5-11-02). Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0–1 and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological Complete Response will also be assessed. The study is currently recruiting; target enrollment: n = 126. Clinical trial information: NCT04191382 .
Green tea extract to prevent colorectal adenomas in men and women: Results of the MIRACLE trial.
Authors: Thomas Jens Ettrich, Julia Stingl, Stefan Menzler, Helmut Messmann, Gerhard Kleber, Alexander Zipprich, Stefanie Frank-Gleich, Hana Algül, Klaus Metter, Frank Odemar, Theodor Heuer, Ullrich Hügle, Rüdiger Behrens, Andreas Berger, Catharina Scholl, Katharina Schneider, Lukas Perkhofer, Friederike Rohlmann, Rainer Muche, Thomas Seufferlein
Journal: Journal of Clinical Oncology (2020)

1551 Background: Prevention of colorectal adenomas (CA) can reduce colorectal cancers (CRC). Epidemiological and experimental data suggest that the green tea catechin epigallocatechingallate has an antineoplastic effect in the large bowel. MIRACLE is the largest trial so far to examine the effect of three-year daily intake of green tea extract (GTE) on the incidence of metachronous CA in a Caucasian population. Methods: Prospective, parallel group, double-blinded, placebo-controlled, randomized multicenter trial (40 German centers, recruitment 11/2011-6/2015). Patients (n = 1001, age 50-80y), polypectomy ≤ 6 months and tolerating GTE well (one-month run-in) were randomized to receive decaffeinated GTE standardized to EGCG (150 mg bid, capsules) or placebo (P) for 3 years. Primary endpoint: Incidence of metachronous CA at the 3-year follow-up colonoscopy. Secondary endpoints: Occurrence, number, localization, size, histological subtype of CA, frequency of CRC, biomarker and safety. Strata: study center, low-dose aspirin (≤100 mg/d). Results: Clinical parameters were well balanced. CA incidence at the 3-year follow-up colonoscopy was analyzed in the modified ITT set (modITT; n = 309 patients (GTE), n = 323 (placebo), timely follow up colonoscopy) and the per protocol set (PP, modITT set without major protocol violations). Incidence of CA was 55.7 % (P) and 51.1% (GTE), (modITT, adj. RR 0.905, one sided, p = 0.081), respectively 54.3 % (P) and 48.3% (GTE) (PP, adj. RR 0.883, one sided, p = 0.058). These differences did not reach statistical significance. In the preplanned exploratory analysis regarding gender incidence of CA in females was 47.9% (P) and 47.6% (GTE) in the modITT-set (adj. RR 0.989; 95%-CI: 0.753,1.299; p = 0.935), respectively 45.4% (P) and 46.9% (GTE) in the PP-set (adj. RR 1.014; 95%-CI: 0.748, 1.373; p = 0.930). In contrast, in the male population incidence of CA in the follow-up colonoscopy was 60.4% (P) and 52.9% (GTE) in the modITT-set (adj. RR 0.846; 95% CI 0.717, 0.999); p = 0.048), respectively 59.1% (P) and 49.1% (GTE) in the PP-set (RR 0.803, 95% CI: 0.666, 0.969; p = 0.022). Thus, GTE intake was associated with a significant, 12.4 relative and 7.5% absolute reduction of metachronous CA in the male modITT population. There were no differences with respect to safety between the groups. Conclusions: GTE reduced the incidence of metachronous CA. However, a significant effect was only observed in the in the male population whereas there was no effect in the female population. Clinical trial information: NCT 01360320.
Prevalence of uncommon epidermal growth factor receptor (<i>EGFR</i>) alterations detected in circulating tumor DNA (ctDNA) of non-small cell lung cancer (NSCLC) patients from East Asia.
Authors: Beung-Chul AHN, Herbert H. F. Loong, Oscar Siu-Hong Chan, Michelle Mei Lin Lee, Steven R. Olsen, Byoung Chul Cho, Tony S. K. Mok
Journal: Journal of Clinical Oncology (2020)

e21608 Background: EGFR is the most commonly altered biomarker in East Asian NSCLC patients. Common driver mutations (L858R or exon 19 deletions (del)) are the focus of conventional hotspot testing which may overlook less common activating alterations such as single nucleotide variants (SNVs) in the tyrosine kinase or extracellular domain as well as exon 20 insertions (ins). We investigated the prevalence of uncommon EGFR mutations in ctDNA from NSCLC patients in East Asia tested by a commercially available comprehensive next generation sequencing (NGS) assay (Guardant360). This assay identifies SNVs, ins and del, fusions, and amplifications (amp), with complete exon sequencing of EGFR. Methods: Guardant360 test results from Hong Kong, Korea, Japan, Taiwan, and Southeast Asia were reviewed (cut-off December 2019). We identified cases with a diagnosis of “lung cancer,” excluding pure squamous, small cell, neuroendocrine, carcinoid and sarcomatoid histology. Patients enrolled in certain prospective clinical trials were excluded at the investigators’ request. Clinically relevant biomarkers were mutations in EGFR, BRAF (V600E), ERBB2, or KRAS; MET amp or exon 14 skipping; and ALK, ROS1, or RET fusions. Uncommon EGFR mutations were defined as those other than L858R, exon 19 del, or resistance SNV in codons 790-797; synonymous mutations and amp were excluded. Results: Plasma from 820 non-squamous NSCLC patients was tested. Samples came from 436 women and 384 men, median age 61 years. ctDNA was identified in samples from 701 patients (85% detection rate). Alterations in at least one clinically relevant gene were detected in 75% of the ctDNA positive cases: EGFR (54%), KRAS (8%), ALK (5%), ERBB2 (5%), RET (2%), MET (2%), BRAF (1%), ROS1 ( &lt; 1%). Uncommon EGFR alterations were found in 115 samples (16%), with 63 (9%) potentially actionable (exon 19 ins (1); exon 20 ins (22); activating SNV (40), some with multiple mutations, including L718Q (6), L718V (5), G719A (5), L861Q (5), S768I (4), and others) and 52 (7%) variants of unknown significance. Uncommon EGFR mutations were the only clinically relevant biomarker in 53 samples (8%). Conclusions: Uncommon, potentially actionable EGFR mutations were found in 9% of plasma samples from East Asian NSCLC patients. In this clinical practice dataset, uncommon EGFR mutations were more prevalent than actionable biomarkers in other genes. These data support the use of NGS testing methods to identify NSCLC patients for appropriate EGFR-targeted therapy.
FOLFIRINOX versus sequential 5-FU, oxaliplatin, and irinotecan-based regimens in patients with recurrent pancreatic cancer (rPDAC).
Authors: Hasan Rehman, Jeffrey Chi, Nausheen Hakim, Jyothi Jose, Linda Moriarty, Carol Lamont, Wasif M. Saif
Journal: Journal of Clinical Oncology (2020)

e16791 Background: There is a paucity of data to guide treatment for rPDAC after curative resection and gemcitabine-based adjuvant chemotherapy. Our aim was to investigate whether combination treatment upfront with all active agents is better than sequential administration of these drugs in patients with rPDAC following curative therapy. Methods: We retrospectively analyzed overall survival (OS), progression-free survival (PFS), response rate (RR), and adverse events (AEs) in patients treated for rPDAC. Patients received FOLFIRNOX upfront versus sequential therapy in the following order based on patient’s presence of toxicities (FOLFOX —&gt; FOLFIRI, FOLFOX—&gt; liposomal irinotecan/5FU, liposomal irinotecan/5FU —&gt; FOLFOX). Each treatment was administered per NCCN guidelines with regulated staging scans, blood work, and office visits. Data was collected about chemotherapy dose, ECOG performance status (PS), RR, PFS, OS, and AEs. Results: 55 patients were identified with ECOG PS ≤ 2 and male:female ratio 35:20. Results for FOLFIRINOX, FOLFOX followed by FOLFIRI, FOLFOX followed by liposomal irinotecan/5FU, and vice versa are as follows respectively: PFS 4.0, 3.5, 3.5, and 3.0 months; OS 8.0, 7.5, 7.0, and 8.3 months; RR 10%, (8%, 3%), (9%, 4%), and (3%, 5%). One of the patients in the mFOLFIRINOX was able to undergo metastasectomy. The table summarizes the toxicities and dose modifications seen. Conclusions: Upfront FOLFIRINOX versus sequential regimens of oxaliplatin and irinotecan-containing regimens resulted in similar PFS and OS but higher AEs as expected. However, surgery was only possible in patients receiving FOLFIRINOX. Our findings support the use of sequential treatment in rPDAC who are not potential surgical candidates. Further investigative work is warranted to optimize sequencing of active agents in this setting where prognosis has historically been poor. [Table: see text]
Emerging trends and utilization of patient-reported outcomes (PROs) in clinical trials of chimeric antigen receptor (CAR) T-cell therapies.
Authors: Anthony John Messina, Vasily Andrianov, Daniel Mazzolenis, Liat Vidal-Fisher
Journal: Journal of Clinical Oncology (2020)

e19142 Background: Patient-reported outcomes (PROs) are an important tool to assess the impact of new therapies on health-related quality of life (HRQoL). This study aimed to describe if and what PRO instruments are currently being utilized in CAR-T cell therapy studies in solid and hematological malignancies while assessing the patterns of inclusion and trends of HRQoL data reporting. Methods: We used Citeline to search for clinical trials between Jan 2008 - Jan 2020, excluding planned or terminated studies, non-oncology, non-treatment, and duplicates. Reviewers extracted various parameters for included trials, then cross-matched data with EU Clinical Trials Register, Clinical trials.gov, trial protocols (when available), and Google. The reporting of PRO data was then assessed for those Closed/Completed trials that included a PRO via PubMed/MEDLINE, Sponsor, and Google. Results: A sample of 664 CAR-T trials was identified. PROs were included in only 6.17% (41/664) studies. Of the 41 trials that included a PRO, 63.41% (26/41) utilized more than one PRO, with the generic EORTC QLQ-C30 and the EQ-5D being used predominately. Median HRQoL follow-up was 5-years on most trials. No studies used PROs as primary endpoints. The majority of PROs were observed to be utilized in early phase trials (phase I, 12; Phase I/II, 17). PROs were first incorporated in CAR-T trials beginning in 2014, and the utilization rate has increased steadily, except for 2019. PROs were included in 3 first line trials, 22 second line, 5 third line, and 11 fourth line or greater. PRO utilization between solid tumor trials and hematologic malignancies was comparable (6.04% [9/149], and 6.26% [32/511]). Of the completed/closed trials, 28.57% (3/14) published PRO data and met at least eight of the CONSORT-PRO quality indicators. Conclusions: The utilization of PROs in CAR-T trials (6.17%) is under the industry average of 27%, despite the growing importance of HRQoL and its impact on value-based care. The findings from this review reflect the overall increased attention to CAR-T as a new therapeutic entity and the continued deficiency of including and reporting of PROs in trial designs.
Abstract 17988: Autotaxin Inhibition Reduces Cardiac Inflammation and Mitigates Adverse Cardiac Remodeling After Myocardial Infarction: Potential Therapeutic Targets for Ischemic Heart Disease
Authors: Himi Tripathi, Lakshman Chelvarajan, Ahmed Al-Darraji, Shaojing Ye, Bryana Levitan, J. Anthony Brandon, Andrew J Morris, Susan S Smyth, Ahmed Abdel-Latif
Journal: Circulation (2017)

Introduction and Hypothesis: Myocardial infarction (MI) is a leading cause of death and is associated with increased inflammatory response and circulating monocytes (monocytosis) in peripheral bloo...
Epidermal growth factor receptor expression as a molecular determinant of glioblastoma response to the dopamine receptor D2 antagonist, ONC201.
Authors: Yuyu He, Jun Ma, Sanjay Dhawan, Tomoyuki Koga, Frank Furnari, Varun Vijay Prabhu, Joshua E. Allen, Clark C Chen
Journal: Journal of Clinical Oncology (2020)

e14552 Background: Durable response in glioblastoma patients have been reported in phase I/II clinical trials for the blood-brain penetrant dopamine receptor D2 (DRD2) antagonist, ONC201. Here we examine potential molecular determinants of response to DRD2 inhibition. Methods: The Cancer Genome Atlas (TCGA) glioblastoma database and other published mRNA profiles were used to analyze the DRD2 expression pattern. In vitro and in vivo responses to ONC201 were determined using patient derived xenograft glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from phase I/II clinical trials involving ONC201. Results: For the majority of clinical glioblastoma specimens in both the TCGA and non-TCGA dataset, epidermal growth factor receptor (EGFR) expression was inversely correlated with DRD2. This observation was recapitulated in a panel of patient-derived glioblastoma lines. In this panel of DRD2 expressing lines, high EGFR expression was associated with poor response to ONC201 in vitro and in vivo. Moreover, ectopic expression of EGFR reduced DRD2 expression and ONC201 sensitivity, suggesting functional redundancy between DRD2 and EGFR. In cell lines and clinical glioblastoma samples, DRD2 expression closely associated with the expression of rate-limiting enzymes for dopamine synthesis, suggesting dependency of a subset of glioblastomas on autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (p = 0.037). All patients who exhibited progression free survival beyond 200 days showed low to no EGFR expression. Conclusions: Our results suggest EGFR expression as a determinant of response to ONC201 in glioblastoma patients and should inform the design of future clinical trials.