tbuckley/cabot-search huggingface dataset:
Clinical conundrums: Developing a strategy for discerning TP53-associated chip and coherent clinical care.
Authors: Jeffrey N. Weitzel, Judy Ellen Garber, Danielle Castillo, Sharon Sand, Rosa Mejia, Aleck Cervantes, Samantha Stokes, Janet Mokhnatkin, Kar Wing Kevin Tsang, Jinhui Wang, Xiwei Wu, Josef Herzog, Bita Nehoray, Thomas Paul Slavin
Journal: Journal of Clinical Oncology (2020)

1514 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However, approximately 20% of commercial laboratory multigene panel test (MGPT)-detected pathogenic TP53 variants represent aberrant clonal expansion (ACE), rather than a germline finding, and are often detected in individuals that lack classic features of LFS. Clonal hematopoiesis (CH) is a form of ACE, and in the absence of an abnormal hemogram is termed Clonal hematopoiesis of indeterminate potential (CHIP). CHIP is often associated with a pathogenic variant (PV) in hematopoietic pathway gene(s) at a variant allele frequency (VAF) less than expected for a heterozygous germline finding. The prevalence increases with age and exposure to chemotherapy. The presence of a skewed VAF is usually noted in a comment on a genetic test result, however, clinicians without genetic training often lack understanding of the comment and need strategies to discern the difference between germline findings, CHIP, and post-zygotic mosaicism. Our studies illuminate possible strategies for discernment for clinicians. Methods: Among 113 cases with MGPT-detected TP53 PVs, enrolled in the Clinical Cancer Genomics Community Research Network registry, we obtained additional tissues, family history and complete blood count (CBC) reports on 42 cases. DNA extracted from formalin fixed paraffin embedded (FFPE) tumor/normal tissues, blood, saliva, eyebrow plucks, was analyzed using a previously validated custom myeloid and CH gene (n = 79) amplicon-based QIAseq panel. PVs with VAF &gt; 2% were included in analyses. Results: Germline status was confirmed for 6 cases (one with a CH PV), post-zygotic mosaicism was supported for 5 cases and 2 were indeterminant. 12 had results supporting ACE/CH, with additional CH-associated PV(s) identified in 5/12 (41%); n = 2 of each TET2, ATM, TP53; and increasing VAF over time for the driver TP53 PV was noted in 2. Of these 2 one was identified to have a hematopoietic malignancy identified through analysis of the CBCs and bone marrow biopsy in parallel with the increasing VAF. Additional results are pending for 7 cases. Conclusions: With the use of our multi-tissue NGS strategy, serial sampling of suspected ACE/CH cases, family history and CBC analyses we were able to discern the status of most TP53 genetic findings. This work has direct translational impact, refining risk estimation and improving the clinical care of patients with TP53 PVs, while avoiding unnecessary LFS-related care and enabling appropriate care for those with ACE.
Intratumor immunotherapy utilizing real time radiological image guidance: Early experience from a tertiary cancer center.
Authors: Ravi Murthy, Rahul Sheth, Vivek Subbiah, Filip Janku, Aung Naing, Jordi Rodon, Timothy A Yap, Adi Diab, Sapna Pradyuman Patel, Alda Tam, Sanjay Gupta, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2020)

e15223 Background: Intratumoral (IT) delivery of immunotherapeutic agents is a compelling approach to overcoming the systemic barriers of toxicity and lack of efficacy associated with many novel agents. In this context, the application of IT delivery is growing rapidly, however the feasibility and safety profile of these interventions for lesions that require real time radiological image-guidance remains unknown. Methods: Patients who underwent IT injections of immunotherapeutic agents across several clinical trials over a 5 year period at a single tertiary cancer center were included in this analysis. Technical success &amp; procedure related adverse events of the IT injection and the frequently accompanying concomitant or sequential image-guided biopsy of injected (adscopal) and non-injected (abscopal) sites were analyzed. Results: A total of 256 patients with metastatic &amp;/or unresectable solid malignancies underwent a total of 1096 (median 5) image-guided IT investigational agent injections during the study period. There were no adverse events attributable to the technical component of the procedure, specifically during the needle insertions or 3862 concomitant biopsies. Soft tissue and nodal lesions in the extraparietal locations &amp; visceral lesions in deeper, intraparietal locations and solid organs were also injected (adrenal, liver and lung). The median injected lesion tumor length was 3.3cm. Serious adverse events (NCI CTC AE ≥ 3) including dyspnea and severe flu-like symptoms developing within 24 hours of the injection &amp; required hospitalization following 1.5% of injections. Conclusions: Intratumoral immunotherapeutic injections &amp; tissue sampling with real time radiological image guidance are feasible across a wide range of regions and organs irrespective of agent and histology. Post-delivery anticipated &amp; adverse events were rare &amp; manageable.
Diagnosis and management of acute lower gastrointestinal bleeding
Authors: Dong Wu
Journal: BMJ (2017)

消化道出血根据病变部位分为三类：部位在食管、胃和十二指肠为上消化道出血；部位在空肠和回肠为中消化道出血；部位在结直肠为下消化道出血。急性下消化道出血好发于老年人，多数患者出血自限，但严重时也可危及生命。我国下消化道出血的主要病因是结直肠肿瘤、慢性结肠炎、肛门直肠疾病和炎症性肠病，与西方人群有一定差异。病史和体格检查是确定出血病因和评估病情严重度的重要依据。CT血管成像、核素显像和血管造影是常用的影像学检查。结肠镜兼有诊断和治疗作用，已成为下消化道出血的首选诊疗方法。
Pharmacokinetics and safety following a single oral dose of niraparib in patients with moderate hepatic impairment.
Authors: Mehmet Akce, Anthony B. El-Khoueiry, Sarina Anne Piha-Paul, Emeline Bacque, Peng Pan, Zhi-Yi Zhang, Reginald Ewesuedo, Divya Gupta, Ashley Milton, Patricia Judson, Cindy L. O'Bryant
Journal: Journal of Clinical Oncology (2020)

6054 Background: Niraparib is approved for the maintenance treatment of adult patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, or with similar cancers but advanced, associated with homologous recombination deficiency (HRD) and have been treated with ³3 prior chemotherapy regimens. Niraparib is extensively metabolized in the liver and eliminated via both hepatobiliary and renal routes. Objectives of this study included characterization of niraparib pharmacokinetics (PK) and safety in pts with normal hepatic function vs. pts with moderate hepatic impairment. Methods: This phase I, open-label, parallel-group, single-dose study enrolled pts with advanced solid tumors into 2 groups: normal hepatic function and moderately impaired hepatic function, defined as bilirubin &gt;1.5 to 3 times the upper limit of normal and any aspartate aminotransferase elevation. Pts received a single 300-mg dose and underwent PK sampling for 7 days. Exposure parameters included maximum concentration (C max ), area under the concentration-time curve calculated to last measured concentration (AUC last ), and extrapolated to infinity (AUC inf ). PK parameters were determined using a non-compartmental analysis in WinNonlin. Results: Seventeen pts were enrolled; 9 with normal hepatic function and 8 with hepatic impairment. Niraparib C max was 7% lower in pts with moderate hepatic impairment compared with pts with normal hepatic function (Table). Overall exposure was increased in pts with moderate hepatic impairment, with niraparib AUC last and AUC inf increased 45% and 60%, respectively. Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic impairment experienced increased niraparib exposure which did not noticeably alter the toxicity profile in this population. Clinical trial information: NCT03359850. [Table: see text]
A nomogram to predict the probability of breast intraductal tumors in patients with nipple discharge: A report based on our 13-year clinical experience.
Authors: Siyuan Jiang, Bin Wang, Lizhe Zhu, Shibo Yu, Yu Ren
Journal: Journal of Clinical Oncology (2020)

e13582 Background: Nipple discharge is a common symptom of breast disease. Our aim was to perform a descriptive statistical analysis of the cases we collected and to establish a model to predict intraductal tumors. Methods: We conducted a retrospective study of patients from 2007 to 2019. The variables were analyzed by the c2 test. Univariate binary logistic regression was used to analyze the relationship between clinical features of patients. Receiver operating characteristics (ROC) were used to assess the sensitivity and specificity of the predictive ability of the model. Results: Patients with spontaneous, single duct, bloody discharge and smooth ductal wall were more likely to diagnose with tumor by ductoscopy. A model was established based on seven variables: age, side of discharge, spontaneous or not, duration of discharge, ductal wall and characteristics of discharge. It was subsequently validated in 178 patients with complete data on variables in the validation cohort. The area under ROC curve (AUC) were calculated to be 0.7024 indicating a good predictive ability. Conclusions: Patients with clinical characteristics of unilateral, bloody, single duct, spontaneous discharge and smooth ductal wall were more likely to have intraductal tumors by ductoscopy. Our nomogram can effectively predict intraductal tumors in patients with nipple discharge.
COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study
Authors: Lennard YW Lee, Jean-Baptiste Cazier, Vasileios Angelis, Roland Arnold, Vartika Bisht, Naomi A Campton, Julia Chackathayil, Vinton WT Cheng, Helen M Curley, Matthew W Fittall, Luke Freeman-Mills, Spyridon Gennatas, Anshita Goel, Simon Hartley, Daniel J Hughes, David Kerr, Alvin JX Lee, Rebecca J Lee, Sophie E McGrath, Christopher P Middleton, Nirupa Murugaesu, Thomas Newsom-Davis, Alicia FC Okines, Anna C Olsson-Brown, Claire Palles, Yi Pan, Ruth Pettengell, Thomas Powles, Emily A Protheroe, Karin Purshouse, Archana Sharma-Oates, Shivan Sivakumar, Ashley J Smith, Thomas Starkey, Chris D Turnbull, Csilla Várnai, Nadia Yousaf, Rachel Kerr, Gary Middleton
Journal: The Lancet (2020)
Clinical significance of CTC enumeration on the Epic Sciences platform in metastatic castration-resistant prostate cancer (mCRPC) patients treated with AR signaling inhibitors (ARSi).
Authors: Joseph Schonhoft, Audrey Gill, Ryon P Graf, Adam Jendrisak, Ethan Barnett, Hannah Benoliel, Emily Carbone, Alisa Tubbs, Sarah Orr, Jiyun Byun, Rick Wenstrup, Howard I. Scher
Journal: Journal of Clinical Oncology (2020)

5571 Background: Circulating Tumor Cell (CTC) number, enumerated using the analytically valid FDA cleared Cell Search (Menarini Silicon Biosystems) platform has been shown to be prognostic for survival pre- and post-therapy, and used as an aid to monitoring breast, colorectal and prostate cancers. The assay uses antibody-based capture and defines a CTC as an EpCAM+ and CD45- intact cell. In contrast, with the Epic sciences CTC detection platform red blood cells are first lysed and all nucleated cells deposited on pathology slides, fixed, and imaged. There is no affinity selection and CTCs for this analysis were defined in silico as any cytokeratin (CK)+, CD45- cell with an intact DAPI+ nucleus. Here we report the prognostic significance of the CK+ CTCs detected on the EPIC Sciences platform in mCRPC patients prior to treatment with an AR signaling inhibitor. Methods: A pre-treatment blood sample was collected from 181 unique patients with progressing mCRPC about to start an ARSI as 1st, 2nd or 3rd line therapy at MSKCC. CTCs were enumerated on the Epic Sciences platform and verified by a trained human technician. Results: At least 1 CTC was detected (median = 1, 0-711 CTCs/ml) in 134 (74%) of cases, with higher counts observed in patients with visceral or multiple osseous sites relative to those with lymph node only disease. Counts increased by line of therapy. The table shows the associated risk of death for CTCs modeled as a continuous variable. Conclusions: The results support the clinical validity of CTC number determined on the Epic Sciences platform as a significant baseline prognostic factor. In multivariate modeling CTC number was found to be the most significant blood-based predictor of poor OS with each doubling representing a 20% greater risk of death observed with adjustment for therapy line, LDH, PSA, and ALK. [Table: see text]
Advantages of intraoperative digital specimen radiography (IDSR) in breast surgery.
Authors: Lyudmila Zhukova, Nikita Maksimov, Gurami Kvetenadze, Evgeniy Shivilov, Khalil Arslanov, Anton Smirnov
Journal: Journal of Clinical Oncology (2020)

e12613 Background: Breast cancer is in first place among malignant diseases in women in Russia. We can provide, in most cases, breast-conserving surgery (BCS), due to progress in early diagnosis. Evaluation of positive margins is still one of the most important objectives in breast-conserving surgery. Objectives: To assess the benefits of IDSR in BCS of patients with “carcinoma in situ”. Methods: The results of treatment of 55 patients with breast cancer “carcinoma in situ” in our clinic were evaluated in two comparable groups. Group A included 28 patients, who were operated on from January 2019 to June 2019 and had breast-conserving surgery without IDSR. Group B included 27 patients, who were operated on from June 2019 to January 2020 and had breast-conserving surgery with the evaluation of margins by IDSR. Results: In a planned histological examination positive margins were detected in group A in 4 cases (14%) and required reoperation. In group B all margins were clear. After IDSR, 6 (22%) patients out of 27 in this group showed microcalcifications in the resection margins or at a distance of less than 1 mm and required intraoperative additional excision to obtain clean margins. Conclusions: IDSR reduces the frequency of reoperation due to increased detection of positive margins, allows to correct scope and duration of surgery because of impact on the time of the surgical decision-making process.
Survival analysis of prognostic associated factors in the maintenance hemodialysis patients
Authors: Xiao-zhou Hu, Shao-ting Wang, Jin Zhang, Yong-shen Lu, Yan Zhang, Hong Yang
Journal: BMJ (2011)

One hundred and twenty one patients on maintenance hemodialysis ( MHD) from Januaury 2004 to Januaury 2009 in our hospital were enrolled in the study. Demographic characteristics, clinical data and causes of disease were documented, the survival probability was estimated with Kaplan-Meier method and the prognostic factors were analyzed with Cox regression model. The median follow-up duration was 28. 9 months. The 1,3, 5-year survival rates were 93. 0% , 66. 5% and 45. 8% respectively. By Kaplan-Meirie analysis, cardiovascular disease (x2 =6. 582, P =0. 010) , age of starting dialysis (x2= 12.439, P= 0.002), urea clearance index Kt/V ( x2 =7.633, P=0.006) and albumin levels ( x2 = 4.512, P= 0.034) were closely related to prognosis. Cox regression analysis showed Kt/V, cardiovascular disease and age of starting dialysis were independent prognostic factors ( relative risk were 3. 204, 2. 994, 2. 543 respectively).

Key words: 
Hemodiafiltration;  Survival analysis
中华医学会全科医学分会年会会议纪要
Authors: 中华医学会全科医学分会
Journal: BMJ (2007)

2007年9月14日至17日,中华医学会全科医学分会在杭州市举行了2007年度学术年会,与会代表200余人.15位全科医学专家、相关领域专家及卫生行政部门的领导与会并做了学术报告,近60篇学术论文在会上交流,内容涉及全科医学的各个方面,与会代表皆感收获甚多。
Analysis of signaling pathway activity in desmoid-type fibromatosis (DF) to identify druggable pathways.
Authors: Anja Van De Stolpe, Martijn Akse, Eveline den Biezen-Timmermans, Jean-Yves Blay, Nicolas Penel
Journal: Journal of Clinical Oncology (2020)

e23558 Background: DF are locally invasive soft tissue tumors of fibroblast origin, with unpredictable course. CTTNB1 mutations are a hallmark of DF. Molecular-targeted therapies are lacking. Recently developed OncoSignal (www.philips.com/oncosignal) pathway activity tests enable quantitative measurement of activity of clinically relevant oncogenic signal transduction pathways (estrogen, progesterone &amp; androgen receptors; PI3K, MAPK-AP1, TGFβ, Notch, Hedgehog, Wnt pathways), based on computational interpretation of expression levels of direct target genes of the pathway-associated transcription factor. Methods: OncoSignal was used to measure activity of signaling pathways on Affymetrix transcriptome data from sporadic DF (n = 128), generated before in our center (GEO database: GSE58697), and from presumably healthy fibroblasts (n = 63) derived from a number of different tissue types (public dataset GSE63626). Pathway activity was expressed on a normalized scale 0-100 (min and max pathway activity score depend on the cell/tissue type analyzed). Comparisons used Mann Whitney test. Results: Mean Notch (43.2+/-7.2 vs 11.2 +/- 5.2; p &lt; .0001), PI3K (54.6 +/- 10.0 vs 48.1 +/- 6.6, p &lt; .0001) and androgen receptor (AR) pathway activities (32.8 +/- 3.7 vs 21.7 +/- 2.4, p &lt; .0001) were increased in DF compared to fibroblasts. MAPK-AP1 pathway activity was lower in DF (40.8+/-6.0 vs 70.2 +/- 9.5; p &lt; .0001). Mean Wnt (p = 0.7), HH (p = 0.8) pathway activities were not different between DF and fibroblasts, however the range in Wnt pathway activity scores was larger in DF (median score 24.1, range 5.3-41.7) than in normal fibroblasts (median 26.0, range 14.6-33.0). Conclusions: The increased activity of Notch, PI3K pathways in DF is consistent with the mesenchymal nature. We confirm here the key role of AR pathway. The wide range of Wnt pathway expression was larger, suggesting the heterogeneity in TD biology, possibly related to the type of CTTNB1 mutations. Overall, the large inter-patient variation in pathway activities is in line with variety of TD course. We identified signaling pathways which may provide novel options for targeted drug treatment.
Intervention model of smoking cessation and its implementation
Authors: Jiangdong Liu
Journal: BMJ (2017)

Over the years, the sociological and medical researchers have worked together on smoking cessation intervention model and conducted extensive programs to improve the confidence of smokers, to overcome the withdrawal symptoms and other difficulties in quitting, and to improve the success rate of smoking cessation. This paper reviews the major intervention models of smoking cessation and their implementation in recent years, including psychological intervention, behavior intervention, drug intervention and combined intervention; and also some intervention methods including acupuncture therapy, nicotine vaccine and others. The systematic implementation of smoking cessation model facilitates the success of smoking cessation.


Key words: 
Smoking cessation; Intervention
Methods of hepatic vascular exclusion on recovery of postoperative liver function in patients undergoing hepatectomy
Authors: Ming Yang, Yun-cheng Li, De-guang Sun, Rui Liang, Qin-long Liu, Asef Tagiyev
Journal: BMJ (2013)

One hundred and ten patients with primary hepatocellular carcinoma underwent hepatectomy from 2005 to 2010. Different methods of hepatic exclusion were applied in the surgery, including 54 patients with total hepatic vascular exclusion, 22 with half hepatic vascular exclusion and 34 with regional hepatic vascular exclusion. The recovery of postoperative liver function was retrospectively analyzed. The results showed that the postoperative liver function of regional hepatic vascular exclusion [ALT (311±80) U/L, total bilirubin(TB) (22.2±8.3)μmol/L at 1st day and ALT (58±17) U/L, TB (11.3±3.1)μmol/L at 7th day] was better than that of total hepatic vascular exclusion [ALT (874±299) U/L, TB (42.9±19.1)μmol/L at 1st day (P 0.05), indicating that regional hepatic vascular exclusion can effectively reduce hepatic injury during the operation and promote recovery of liver function after operation.


Key words: 
Hepatectomy; Hepatic vascular exclusion
循证医学在检验医学中的应用
Authors: 苏建荣, 裴双
Journal: BMJ (2007)

近年来,循证医学(evidence-based medicine,EBM)已成为医学界的热门话题并在医学实践中积极推广.现代循证医学的思想是英国流行病学家、内科医生Archie Cochrane在20世纪70年代提出的[1],1992年在Iain Chalmers博士的领导下,由英国国家卫生服务部资助,成立了以Cochrane姓氏命名的世界上第1个循证医学中心--英国Cochrane中心。
臀下动脉断裂一例
Authors: 常建琪, 张子峰, 庞军, 张文生, 王忻, 高敏
Journal: BMJ (2004)

患者男,44岁.以刀刺伤致臀部出血、昏迷6 h转入院.查体:血压未测出,心率180次/min,意识不清,面色苍白.左臀部有长度4 cm的已缝合伤口.入院诊断:重度失血性休克,臀部大血管损伤.经抗休克治疗,生命体征恢复正常.同时反复查臀部伤口及腹盆腔无出血,下肢感觉、循环正常,故未急诊手术.伤后 15 d患者行走时突感伤口胀痛,穿刺抽出新鲜血液,急诊行臀部伤口探查、血管结扎术.术中见伤口快速出血,考虑左臀部大血管损伤,先经腹腔行左髂内动脉结扎术,然后再扩大左臀部伤口,仔细探查见臀下动脉断裂,可靠结扎.术后诊断:左臀下动脉断裂。
FDA analysis of ECOG performance status and safety outcomes.
Authors: Harpreet Singh, Yutao Gong, Pourab Roy, Bellinda King-Kallimanis, Vishal Bhatnagar, Richard Pazdur, Paul Gustav Kluetz
Journal: Journal of Clinical Oncology (2020)

12024 Background: Patients with poor performance status are often excluded from clinical trials. The FDA has published several guidances on modernizing oncology clinical trial eligibility criteria to more accurately reflect the patient population. Many patients receiving novel oncology therapeutics are heavily pretreated, and often have comorbidities, organ dysfunction, and frailty syndromes. Little is known about the safety of novel therapeutics in patients with poor performance status. Methods: Data from six randomized trials (n=4465) leading to registration for several solid tumor and malignant hematologic cancers, including multiple therapeutic mechanisms of action, such as EGFR TKI’s, immune checkpoint inhibitors (ICI), and chemotherapy, were pooled. Cumulative incidence of Grade 3-5 adverse events and serious adverse events at Days 30, 90, and 180 were evaluated based on ECOG 0-2. Rates of treatment discontinuation by ECOG was also examined. Results: Cumulative incidence of toxicity events at days 30, 90, and 180 are shown in Table. Patient dropout rates due to death were 3.9%, 6.7%, and 10.9%; dropout rates due to disease progression were 66.5%, 66.6% and 56.9%; and dropout rates due to reasons other than progression or death were 29.7%, 26.7% and 32.1% for ECOG PS 0, 1 and 2, respectively. Conclusions: This FDA exploratory analysis of safety outcomes in registration trials based on ECOG suggests increasing rates of adverse events and rates of treatment discontinuation due to death with worsening performance status. Discontinuation rates due to disease progression and other reasons did not appear to be worse for ECOG 2 compared to 0-1. These findings were consistent across therapies (targeted therapy, ICI, chemotherapy). All trials in the analysis led to FDA approval, thus inclusion of patients with ECOG 2 did not adversely affect the trial outcome for this set of FDA approved agents. ECOG performance status eligibility criteria should be evaluated and modified on a frequent basis during drug development. Additional analysis of trials which enroll patients with ECOG 2 is needed. [Table: see text]