tbuckley/cabot-search huggingface dataset:
Towards patient-centric drug discovery: Drug action in malignant pleural effusions and ascites using high content imaging and deep learning.
Authors: Nikolaus Krall, Robert Sehlke, Christina Taubert, Isabella Alt, Florian Rohrer, Elisabeth Fuchs, Bojan Vilagos, Michael Schumacher, Dominik Maurer, Klaus Hackner, Judith Lafleur, Lukas Hefler, Christoph Minichsdorfer, Thorsten Fuereder, Gregory Ian Vladimer
Journal: Journal of Clinical Oncology (2020)

e21633 Background: Many anticancer drugs found to be active in preclinical development later do not show desired effect clinically. This suggests that currently used preclinical models do not fully recapitulate the complexity of the disease. The study of drug activity in primary samples could provide a more immediate picture of a molecule’s activity in a patient. Factors that have so far hampered the use of primary tissue samples for drug discovery and development include access in sufficient quantity as well as robust analytical methods. We hypothesised that malignant pleural effusions and ascites (MPAs) of solid tumour patients are a promising model system to study preclinical drug activity. MPAs are easily accessible and contain cancer cells as well as recruited immune cells. Following previous successes in studying drug action in primary tissues of patients with haematological malignancies with automated microscopy (Snijder et al 2017, Lanc Haem, NCT03096821) we describe advances in using high content imaging and deep learning-based image analysis to study drug action in MPAs of solid tumour patients. Methods: MPAs from patients with metastatic breast, pancreatic and ovarian cancer (at least n = 10 of each) were collected. The response of EpCam+/CD45- and CD45+ cells against small molecule drugs was evaluated using high content microscopy. Drug response was quantified at single cell resolution using regional convolutional neural networks (R-CNNs) comprising object detection and single cell classification. Results: MPAs contain both cancer cells and recruited myeloid and lymphoid immune cells with varying activation. Ex vivo drug responses from each patient sample were measured and the EC50 of each molecule determined by curve fitting. Sensitivity mirrored drug approvals for some indications, and also revealed drugs with potential off label use. On target and off-target response curves, along with integrative scores are used to visualize the effects. Conclusions: Single-cell phenotypic analysis of MPAs enables the study of anticancer drug action in a setting that is one step closer to the clinic than cell line or outgrown organoid models of solid tumor. While initial response patterns can be observed that mirror current approvals, further biological and clinical validation must occur to understand in how far these data can be used for drug discovery and translational research purposes.
Underrepresentation of genitourinary cancers in studies of venous thromboembolism (VTE) prophylaxis.
Authors: Max S Perlmutt, Tracy L Rose, Vaibhav Kumar, Matthew I. Milowsky
Journal: Journal of Clinical Oncology (2020)

e17115 Background: Significant advances in the management of VTE in cancer have led to a recent ASCO clinical practice update for VTE prophylaxis and treatment in patients with cancer. Genitourinary (GU) cancers (including bladder, kidney, prostate, testicular) have a high incidence of VTE, but also frequent bleeding complications, and it is not clear if patients with GU cancers are adequately represented in studies of VTE prophylaxis. We sought to determine the frequency of inclusion of patients with GU cancers in prospective studies of VTE prophylaxis. Methods: A systematic review of the literature using MEDLINE (inception to January 2020) was conducted. We included randomized controlled trials that compared thromboprophylaxis to placebo or best supportive care in patients with an established diagnosis of cancer. Observational studies, case series, and case reports were excluded. The primary outcome was proportion of patients with GU malignancies included within the trials. Results: A total of 137 articles were identified under the original search and 7 underwent full text review. A total of 6066 patients were included in 7 thromboprophylaxis trials, of which only 119 (2.0%) had a defined GU malignancy (Table). Given the heterogeneity of the GU cancers represented in each study, and the small numbers of patients included with GU cancers, a patient-level meta-analysis among GU patients in this population was not performed. Conclusions: In spite of the high risk for VTE in GU cancers, in particular bladder and testicular cancer, GU cancers are underrepresented in prospective randomized trials investigating VTE prophylaxis. To ensure appropriate decision making for each individual patient, future prospective trials must ensure adequate representation of patients with GU cancers to better understand the potential role for VTE prophylaxis in this high-risk population.[Table: see text]
Factors influencing infusion-related reactions following dosing of reference rituximab (RTX) and PF-05280586, a RTX biosimilar.
Authors: Jocelyn Courville, Loretta J. Nastoupil, Nitin Kaila, John M. Kelton, Pilar Nava-Parada, Sandeep Parsad, Jeffrey Zhang, Ann Alcasid, Peter Lee
Journal: Journal of Clinical Oncology (2020)

e20049 Background: Rituximab (RTX) is an effective therapy for some patients with CD20 positive (CD20+), B-cell malignancies. Infusion-related reactions (IRRs) are the most common adverse event (AE) associated with infusion of RTX. The objective of this analysis was to assess if IRRs were correlated with infusion rates of the first dose of the RTX biosimilar PF-05280586 (RTX-PF) or reference RTX sourced from the EU (RTX-EU). Methods: This analysis incorporates data from a randomized, double-blind comparative trial of 394 patients (RTX-PF, n = 196; RTX-EU, n = 198) with low tumor burden follicular lymphoma. RTX was administered at a dose of 375 mg/m 2 on days 1, 8, 15 and 22 (one cycle), with a follow-up period through 52 weeks. Logistic regression analysis was performed with infusion rate and treatment or maximum serum concentration (C max ) as independent variables. Treatment or C max was excluded from the model if not significant. Descriptive statistics of baseline CD20+ B-cell level, baseline anti-drug antibody (ADA) status and baseline tumor burden (Ann Arbor stage and bone marrow biopsy lymphoma results) were summarized by occurrence of IRR (yes/no). Results: The median RTX infusion duration on day 1 was 3.50 h for each of the two treatments. There was a significant positive correlation between infusion rate and all-grade IRR AEs occurring within 24 h after infusion (p &lt; 0.0001). The estimated probability of developing an IRR was 0.16 and 0.29 at infusion rates of 189 mg/h and 227 mg/h, respectively. The estimated odds ratio with an increase in rate of 100 mg/h was 7.7. Treatment (RTX-PF or RTX-EU) was not a significant covariate and was excluded from the model. There was a non-significant trend between C max of RTX and developing an IRR; the estimated probability of developing an IRR was 0.26 at the median C max (196.5 μg/mL) of RTX. Patients who developed IRRs had a higher median baseline CD20+ B-cell level. The trough plasma concentration (C trough ), collected before the second dose, and baseline tumor burden did not correlate with increased IRR incidence. Baseline ADA status did not predict IRR outcome. Conclusions: The results of this analysis suggest that higher infusion rates of RTX, administered as RTX-PF or RTX-EU, are positively correlated with IRR after the first dose. Clinical trial information: NCT02213263 .
The advancement of pharmacological management of pain
Authors: 水源, 樊碧发
Journal: BMJ (2008)

疼痛是人类最原始、最普遍存在的一种痛苦.急性疼痛通过治疗原发疾病大部分患者的疼痛能够缓解,而慢性疼痛远非如此简单,2002年7月完成的我国六城市慢性疼痛调查结果显示,在短短1个月内,六城市中到医院就诊的慢性疼痛患者多达13.6万人,大多数疼痛患者均经过一个以上专科的诊断或治疗后仍不能有效地减轻疼痛.因此,对于慢性疼痛患者需要疼痛专科医生对其做出专业诊断和治疗,药物治疗是疼痛治疗中非常重要的部分。
Characteristics and outcomes of real-world (RW) patients (pts) with microsatellite instability-high (MSI-H) solid tumors treated with pembrolizumab monotherapy (P) after FDA approval.
Authors: Tamara Snow, Akshay Swaminathan, Jeremy Snider, Alexa Betzig Schrock, Gerald Li, Brian Michael Alexander, Gaurav Singal, Emily Castellanos, Margaret Elizabeth McCusker
Journal: Journal of Clinical Oncology (2020)

3060 Background: The first tumor-agnostic, biomarker-based FDA approval in oncology was P in May 2017 for pts with MSI-H or mismatch repair (MMR) deficient tumors. 1 yr overall survival (OS) was &gt;70% for colorectal cancer (CRC) and &gt;60% for non-CRC in P-treated MSI-H clinical trial pts (Le 2019; Marabelle 2019). As tumor-agnostic therapies are a new paradigm, it is important to assess their use and effectiveness in routine clinical practice. We examined characteristics and outcomes of RW pts with MSI-H solid tumors who received P after May 2017. Methods: Pts with MSI-H solid tumors who received P after May 2017 were selected from the Flatiron Health-Foundation Medicine (FH-FMI) clinico-genomic database, a nationwide de-identified EHR-derived database linked to comprehensive genomic profiling (CGP) data. Pts with 2+ visits in the FH network from 01/2011-09/2019 with CGP prior to P use were included. Clinical characteristics were assessed at first P use. Time to treatment discontinuation (TTD) and OS from first P use were estimated with Kaplan-Meier analyses of all pts and the largest tumor types. Results: 33,395 pts had a solid tumor tested for MSI by CGP, of which 557 (1.7%) were MSI-H (median age 68 yrs; 34% male). 129 MSI-H pts across 33 tumor types received first P after May 2017. CRC (N=36) and Endometrial cancer (N=39) were most common. 52 pts (40%) had a concurrent MMR alteration (MLH1, MSH2, MSH6 or PMS2); median TMB was 32.2 mut/mb (IQR 20.9-47.5). Median number of therapies prior to P was 1; median time from CGP to first P use was 3 mos. Table shows OS and TTD. Conclusions: In this RW study, P use was observed across 33 MSI-H tumor types. Median OS exceeded 1 yr across all pts and in CRC, Endometrial, and Other cohorts. 1 yr OS rate was consistent with P trial outcomes. Further study should evaluate whether effectiveness differs across diseases, MSI testing method, or other genomic attributes to improve treatment selection. [Table: see text]
A phase I/II study of PI3Kinase inhibition with copanlisib combined with the anti-PD-1 antibody nivolumab in relapsed/refractory solid tumors with expansions in MSS colorectal cancer.
Authors: Christopher Jakubowski, Natalie B Collins, Elizabeth Ann Sugar, Maureen Berg, Haihui Cao, Marios Giannakis, Elizabeth M. Jaffee, Nilofer Saba Azad
Journal: Journal of Clinical Oncology (2020)

TPS4114 Background: Certain somatic mutations are thought to promote immune evasion and resistance to immunotherapy. PIK3CA was identified in an in vivo genomic screen for mechanisms of resistance to anti-PD1 therapy. MC38 cells (murine colon adenocarcinoma) were engineered to express a library of human cancer-associated mutations from TCGA. Resultant tumors in vivo were exposed to immune pressure with anti-PD1 therapy. Cells that proliferated were then analyzed for mutations that impart immune resistance. Multiple activating mutations in PIK3CA conferred resistance to anti-PD1 therapy. Coadministered PI3K inhibition reversed this resistance. Multiple studies have shown the impact of the phosphatidylinositol 3-kinase (PI3K) pathway on the tumor microenvironment, and 20% of colorectal cancer (CRC) tumors have an activating mutation of PI3K. Methods: A multi-center, open-label, phase I/II study with the combination copanlisib and nivolumab, a PD1 inhibitor, in relapsed/refractory solid tumors with expansions in relapsed/refractory microsatellite-stable (MSS) CRC was developed. Copanlisib is an inhibitor of PI3K and exhibits its most potent inhibitory effect on the isoforms PI3Kα and PI3Kδ. The first phase seeks to determine the maximum tolerated dose (MTD) of copanlisib with fixed dose nivolumab of 480 mg given every 4 weeks. Following determination of the MTD the second phase seeks to determine the 6-month objective response rate of the combination in MSS CRC patients and contains two cohorts 1) PIK3CA wildtype, 2) PIK3CA mutated. The study is planned with 21 evaluable subjects per cohort and allows early termination for lack of efficacy. Tumor assessments will be made using RECIST 1.1. Patients will have a pre-treatment biopsy followed by nivolumab on Day 1 of each 4 week cycle and copanlisib on Day 1, 8 and 15. A second biopsy will occur after six weeks. Eligibility criteria includes completed NGS for PI3K status, and patients must have received at least 2 prior lines of standard therapy. Patients can not have received a prior checkpoint inhibitor or PI3K inhibitor. Secondary and exploratory objectives, in addition to survival and safety outcomes, include exploring immune cell subsets in the local tumor microenvironment and in the peripheral circulation, as well as investigating immune activation and suppressive pathways through RNA expression and additional NGS techniques. The clinical study was activated in January 2019 (NCT03711058). Clinical trial information: NCT03711058 .
Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019
Authors: Adeel S. Zubair, Lindsay S. McAlpine, Tova Gardin, Shelli Farhadian, Deena E. Kuruvilla, Serena Spudich
Journal: JAMA Neurology (2020)

<h3>Importance</h3> Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing human coronavirus disease 2019 (COVID-19), which has now spread into a worldwide pandemic. The pulmonary manifestations of COVID-19 have been well described in the literature. Two similar human coronaviruses that cause Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV-1) are known to cause disease in the central and peripheral nervous systems. Emerging evidence suggests COVID-19 has neurologic consequences as well. <h3>Observations</h3> This review serves to summarize available information regarding coronaviruses in the nervous system, identify the potential tissue targets and routes of entry of SARS-CoV-2 into the central nervous system, and describe the range of clinical neurological complications that have been reported thus far in COVID-19 and their potential pathogenesis. Viral neuroinvasion may be achieved by several routes, including transsynaptic transfer across infected neurons, entry via the olfactory nerve, infection of vascular endothelium, or leukocyte migration across the blood-brain barrier. The most common neurologic complaints in COVID-19 are anosmia, ageusia, and headache, but other diseases, such as stroke, impairment of consciousness, seizure, and encephalopathy, have also been reported. <h3>Conclusions and Relevance</h3> Recognition and understanding of the range of neurological disorders associated with COVID-19 may lead to improved clinical outcomes and better treatment algorithms. Further neuropathological studies will be crucial to understanding the pathogenesis of the disease in the central nervous system, and longitudinal neurologic and cognitive assessment of individuals after recovery from COVID-19 will be crucial to understand the natural history of COVID-19 in the central nervous system and monitor for any long-term neurologic sequelae.
Enzymatic tissue disintegration leads to the loss of immunophenotype of breast cancer stem cells.
Authors: Aleksandr B. Sagakyants, Anastasia O. Sitkovskaya, Tatiana V. Shamova, Svetlana Yu. Filippova, Elena S. Bondarenko, Elena Yu. Zlatnik, Inna A. Novikova, Larisa N. Vashchenko, Emma E. Kechedzhieva, Tatiana V. Ausheva, Elena A. Andreyko, Natalya S. Saforyan, Irina R. Dashkova, Iuliana S. Shatova, Liubov Yu Vladimirova, Aleksandr E. Lisutin, Oleg I. Kit
Journal: Journal of Clinical Oncology (2020)

e13089 Background: Cancer stem cells (CSC) are a population in the complex hierarchy of tumor tissue responsible for growth, metastasis and resistance to chemotherapy and radiotherapy. The purpose of the study was to reveal the effect of the enzymatic disintegration of breast cancer (BC) tissue on the CSC immunophenotype. Methods: BC tumor samples obtained during surgery were placed for 2 hours in a sterile Hanks’ solution immediately after collection. Samples were fragmented to 1 mm in diameter, the fragments were evenly distributed into 4 Petri dishes with (6 cm diameter) and placed in DMEM medium (Gibco, USA) without collagenase and with the addition of collagenase (Biolot, Russia) to a final concentration of 150, 300 and 450 units/ml. Samples were cultured for 48 hours at 37°C and 5.5% CO 2 . On day 2, the samples incubated in collagenase were grinded by passing through tips of decreasing diameter; the reference sample was grinded in the Medimachine system (BD, USA). The effect of enzymatic tissue disintegration on the preservation of BC SC immunophenotype (CD24 low/- CD44 + ) was evaluated using the BD FacsCanto II flow cytometer (BD, USA) and PE Mouse Anti-Human CD24 (clone ML5; BD, USA) and FITC Mouse Anti-Human CD44 (clone G44-26; BD, USA) antibodies. Results: The total number of isolated cells increased almost exponentially with increasing collagenase concentration. The trypan blue test showed that cell viability did not change significantly with an increase in collagenase concentration and was approximately 50%, being an order of magnitude higher compared to mechanical dissociation (4%). However, 48 h incubation in a collagenase solution led decreased the number of CD44+ cells in proportion to the enzyme concentration by 3 to 10 times in comparison with the control. Similarly, inhibition of CD24 expression was observed compared with the control, inevitably leading to a decreased purity of the isolated subpopulation with the CD24 low/- CD44 + phenotype. Conclusions: Despite an increase in the yield of viable cells, prolonged incubation in a collagenase solution leads to a loss of the immunophenotype of BC SC.
Precision medicine, genetics and genomics in a community cancer clinic.
Authors: Sourat Darabi, David R. Braxton, Jeanne Homer, Chelsey Weatherill, Taylor Brodie, Luanna Buchanan, Michael J. Demeure
Journal: Journal of Clinical Oncology (2020)

e13511 Background: With advances in technology and the decreasing cost of next generation sequencing (NGS) to identify both germline and somatic pathogenic variants, there is a critical need for curation and interpretation of these results. Clinicians often order the tests simultaneously. Our objective was to analyze results of NGS testing in a community cancer care clinic setting with a coordinated precision medicine program. Methods: In a retrospective review, we analyzed the germline NGS results from patients who were seen by the Hereditary Cancer Program (HCP) at Hoag Family Cancer Institute since 2001. Additionally, we compared those who had both positive genetic testing results and had tumor molecular profiling. Results: A total of 8,239 patients were seen by HCP, 6,100 had germline testing done, approximately 50% had multi gene panel testing (MGPT). 15% of the patients with germline testing had a pathogenic or likely pathogenic mutation. Of those with the positive results, 71% were breast and ovarian cancer and 29% were other cancer types. We also analyzed NGS results for 713 tumors tested through a commercial laboratory in one year. All cases were subjected to our secondary annotation, resulting in additional recommendations in 40% of cases, beyond what was in the commercial report and additional clinical trial options in 30%. Based on a new initiative in the past year, we examined tumor profiling results for indications of possible germline mutations. By analyzing those results, we made recommendations for genetic counseling in 91 (12.8%) cases. Conclusions: The data show the importance of genetic counseling and MGPT in a community setting in patients with personal and/or family history of cancer. Adoption of somatic and germline testing is increasing at our cancer center due to demonstrated benefit to patients and increased physician understanding of the clinical utility of molecular testing.
Does radiation increase the risk of immunotherapy related pneumonitis in cancer patients with thorax radiotherapy combined immune checkpoint inhibitors: A meta-analysis.
Authors: Yamin Jie, Anxin Gu, Pingfu Fu, Feng-Ming Spring Kong
Journal: Journal of Clinical Oncology (2020)

e15099 Background: Thorax radiotherapy (TRT) combined with immunotherapy has shown promising results. However, it remains unclear whether TRT would increases the risk of immunotherapy related pneumonitis (IRP). Here, we performed a meta-analysis to compare the rates of IRP in patients treated with TRT to patients treated without TRT. Methods: A meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Two individual researchers conducted the platform searches on the PubMed upto Nov. 4th, 2019. Quality of studies was assessed independently by two researchers using the Cochrane Collaboration's tool for randomized clinical trials, and the Newcastle-Ottawa Scale for cohort studies. Any disagreements encountered were settled through senior authors. The single rate of pneumonitis along with the corresponding 95% confidence interval (CI) was estimated. The odds ratio (OR) and its 95% CI were computed using random-effects model after checking the heterogeneity across studies using the Cochran Q chi-square test and the I 2 statistic. Data analyses were performed using R version 3.6.2, meta and metafor packages. Results: A total of 62 studies including 14648 patients on IRP were first selected. Thirteen studies had two arms data, 501 patients were in TRT arm, 1185 patients were in non-TRT arm. Two studies including 557 patients were treated with immunotherapy and concurrent/sequential TRT. The remaining 47 studies had no TRT patients or TRT data were unavailable. The pooled rate of any grade IRP of all 62 studies (14648 patients) was 6% (95% CI: 5%-8%). All grades IRP was significantly higher among patients treated with immunotherapy and TRT arm when compared to the non-TRT arm (OR = 1.44, 95% CI: 1.04-2.00, P = 0.030). In the subgroup analysis, no significance difference in IRP rate was found between patients with various cancer types or various types of immune checkpoint inhibitors (p = 0.7033, p = 0.7522, respectively). The rate of IRP in all TRT patients was 18% (95% CI: 13%-24%), comparing to 5% (95% CI: 4%-6%) in control group. Conclusions: This meta-analysis demonstrates that TRT combined immunotherapy had an elevated incidence of IRP compared to non-TRT (OR = 1.44, 95% CI: 1.04-2.00, P = 0.030). There remains a lack of data on risk factors of IRP in TRT patients, and future large-scale studies are warranted. To our knowledge, this is the first comprehensive meta-analysis of IRP for TRT patients.