tbuckley/cabot-search huggingface dataset:
Population Bottlenecks Strongly Influence the Evolutionary Trajectory to Fluoroquinolone Resistance in Escherichia coli
Authors: Linnéa Garoff, Franziska Pietsch, Douglas L Huseby, Tua Lilja, Gerrit Brandis, Diarmaid Hughes
Journal: Molecular Biology and Evolution (2020)

Experimental evolution is a powerful tool to study genetic trajectories to antibiotic resistance under selection. A confounding factor is that outcomes may be heavily influenced by the choice of experimental parameters. For practical purposes (minimizing culture volumes), most experimental evolution studies with bacteria use transmission bottleneck sizes of 5 × 106 cfu. We currently have a poor understanding of how the choice of transmission bottleneck size affects the accumulation of deleterious versus high-fitness mutations when resistance requires multiple mutations, and how this relates outcome to clinical resistance. We addressed this using experimental evolution of resistance to ciprofloxacin in Escherichia coli. Populations were passaged with three different transmission bottlenecks, including single cell (to maximize genetic drift) and bottlenecks spanning the reciprocal of the frequency of drug target mutations (108 and 1010). The 1010 bottlenecks selected overwhelmingly mutations in drug target genes, and the resulting genotypes corresponded closely to those found in resistant clinical isolates. In contrast, both the 108 and single-cell bottlenecks selected mutations in three different gene classes: 1) drug targets, 2) efflux pump repressors, and 3) transcription-translation genes, including many mutations with low fitness. Accordingly, bottlenecks smaller than the average nucleotide substitution rate significantly altered the experimental outcome away from genotypes observed in resistant clinical isolates. These data could be applied in designing experimental evolution studies to increase their predictive power and to explore the interplay between different environmental conditions, where transmission bottlenecks might vary, and resulting evolutionary trajectories.
NeoRAS: Incidence of RAS reversion from RAS mutated to RAS wild type.
Authors: Jason Henry, Jason Willis, Christine Megerdichian Parseghian, Kanwal Pratap Singh Raghav, Benny Johnson, Arvind Dasari, David Stone, Nikeshan Jeyakumar, Oluwadara Coker, Victoria M. Raymond, Richard B. Lanman, Michael J. Overman, Scott Kopetz
Journal: Journal of Clinical Oncology (2020)

180 Background: RAS mutations are found in ~50% of patients (pts) with metastatic colorectal cancer (mCRC) and associated with resistance to anti-EGFR. Circulating tumor DNA (ctDNA) enables detection of resistant RAS MUT arising from RAS WT . Recently there has been interest in defining the converse: RAS MUT tumors that revert to RAS WT , with early results suggesting rates of ~7%. Clinical trials in this population are in development, though the incidence has not been validated with robust methodologies. Methods: 1) We identified 74 mCRC pts with baseline RAS MUT and longitudinal ctDNA or tissue data enrolled in ATTACC (NCT01196130), a prospective genomic matching protocol utilizing paired tissue/ctDNA samples at baseline. We evaluated serial samples for RAS loss. 2) Using an external cohort of pts with mCRC and serial ctDNA with a targeted NGS assay sequencing all KRAS/ NRAS exons (Guardant360, Guardant Health), we screened pts for baseline RAS MUT with no evidence of prior anti-EGFR exposure and evaluated for RAS loss. Results: 74 pts met criteria of RAS MUT CRC with serial samples in ATTACC. Of these, 51 retained RAS MUT . 22 pts had very low or absent levels of other clonal alterations such as APC or TP53 and are therefore unable to reliably detect RAS loss. One patient had true RAS loss with NRAS G13R, APC and TP53 mutations at baseline and persistent high-level APC and TP53 mutations without a detectable NRAS mutation, for an overall rate of RAS loss of 2% (1/52). In the second cohort we identified 162 pts, 34 of which had insufficient ctDNA to assess RAS loss on the serial sample as defined by loss of clonal alterations like APC and TP53. Of the remaining 128 patients, 11 had RAS loss (8.5%, with 1 NRAS, 10 KRAS). We next compared the relative mutant allele frequency (rMAF) between RAS retainers and RAS loss. The median baseline rMAF for pts who lost RAS was 0.74, compared to 0.86 in pts retaining RAS (p = 0.045). Conclusions: RAS reversion in mCRC from RAS MUT to RAS WT is uncommon and occurs at a rate between 2-8% in our two cohorts. RAS reversion is associated with a lower rMAF at baseline, suggesting subclonality. Liquid biopsies must be interpreted carefully, such that a determination of RAS mutation status is most informative in the presence of truncal APC and/or TP53 mutations.
Transcriptional profile of immune microenvironment and their prediction role for the prognosis of esophageal squamous cell carcinoma.
Authors: Jianji Guo, Tao Liu, Xinying Shi, Beibei Mao, Jiao Zhang, Henghui Zhang, Lei Xian
Journal: Journal of Clinical Oncology (2020)

416 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancer in China. The genetic characterizations have already been described in many studies, but the immune microenvironment features were seldom reported. Our study was aimed to explore the relationship between the immune profile in stage IIIa ESCC and patients’ prognosis. Methods: 20 eligible stage IIIa ESCC patients with received surgery and radiotherapy (19 with and 1 without radiotherapy). RNA targeted sequencing was performed on 20 primary tumor specimens. Transcripts of 395 immune-related genes expressed in tumor were analyzed. The univariate and multivariate Cox proportional hazards analyses were examined the relations of 395 genes’ expression and the prognosis. Results: Patients were divided into two groups based on the median expression values of 395 genes. The univariate analyses showed 20 genes were significantly associated with overall survival (OS). Unsupervised hierarchical clustering analysis using 20 gene expression data revealed two distinct clusters (cluster 1 and 2). The cluster1 patients had high level expression of AXL, ADGRE5, CD40, CXCR6, MPO, etc., which were associated with tumor proliferation and migration. However, the cluster2 patients expressed higher NOS2, IL15, IKZF2, TNFRSF18 which were related with T lymphocyte activated. Therefore, the cluster2 patients had significantly longer OS than cluster 1. Moreover, the combined expression of 10 genes (CD40, ADGRE5, CSF1R, CCR1, IGSF6, MPO, MRC1, SRGN, CD63, LRP1) which had high correlation among 20 genes were significantly related to OS and DFS (disease free survival) in univariate analysis. The multivariate analyses demonstrated that 10 genes signature expression was the independent high risk factor for OS, and the low signature value was associated with better prognosis. Conclusions: In IIIa ESCC, the 20 genes can profile the tumor immune microenvironment, and were independently associated with the patients’ OS. The 10 genes’ signature which represents the malignancy and immune activation of tumor was an independent predictive factor for OS, which can identify the patients with favorable or poor prognosis.
Progression-free survival in patients with cholangiocarcinoma with <i>FGFR2</i> fusions or rearrangements: An exploration of response to systemic therapy.
Authors: Kristen Bibeau, Luis Féliz, Scott Barrett, Ling Na, Christine Francis Lihou, Ekatherine Asatiani
Journal: Journal of Clinical Oncology (2020)

588 Background: Most cholangiocarcinoma (CCA) patients (pts) are diagnosed with advanced disease and are ineligible for surgery. FGFR2 fusions or rearrangements are present in 10–16% of pts with intrahepatic CCA (iCCA) and are reported to be oncogenic drivers. However, little data are available on the role of FGFR2 genetic alterations in the response to systemic cancer therapy. FIGHT-202 is a phase 2 study of pemigatinib (a selective, potent, oral FGFR1–3 inhibitor) in pts with previously treated advanced/metastatic CCA (NCT02924376); primary results were reported at ESMO 2019. FIGHT-202 enrolled pts who progressed on ≥1 prior therapy, allowing the examination of the role of FGFR2 alterations on the response to prior therapy. The objective of this post hoc analysis was to evaluate progression free survival (PFS) on standard systemic therapy received prior to study enrollment among pts with CCA harboring FGFR2 fusions or rearrangements ( FGFR2+). Methods: Case report forms were reviewed to determine disease history and exposure to prior lines of systemic cancer therapies (LOSCT) in the advanced setting before receiving pemigatinib. Only pts with sufficient data on prior LOSCT were included in this analysis. Median PFS was calculated using the Kaplan-Meier method. Results: 102 pts were included in this analysis (median age 54.5, 61.8% female). Median PFS on first-line therapy was 5.5 (95% CI: 4.0, 8.0) months. Among the 38 pts (37.3%) with ≥2 prior LOSCT, median PFS on second-line therapy was 4.4 (95% CI: 3.0, 5.3) months. Conclusions: This analysis provides data about PFS on standard systemic therapies for pts with FGFR2+ CCA. Median PFS on first-line therapy was lower than historical published data, and median PFS on second-line therapy was slightly longer than previously reported, in unselected CCA populations. Limitations of this analysis include retrospective examination of investigator reported data, and that clinical trial participants may not truly reflect a general CCA patient population. The short PFS on standard therapies in pts with FGFR2+ CCA highlights the need for development of other options including targeted therapies to improve outcomes.
GINA recommendations in adults with symptomatic mild asthma and a smoking history
Authors: Helen K. Reddel
Journal: European Respiratory Journal (2020)

<b>The 2019 GINA recommendations are supported by clinical trials in &gt;10000 mild asthma patients. For any treatment decision, GINA recommends that clinicians should consider individual patient characteristics/risk factors as part of shared decision making.</b>http://bit.ly/2ZqboJ2
A phase II trial with safety lead-in to evaluate the addition of APX005M, a CD40 agonistic monoclonal antibody, to standard-of-care doxorubicin chemotherapy for the treatment of advanced soft tissue sarcoma.
Authors: Matthew Ingham, Shing Mirn Lee, Sahil Doshi, Susana Hernandez, Shahnaz V. Singh-Kandah, Zoe Singer, Ovidiu C. Trifan, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2020)

TPS85 Background: Soft tissue sarcoma (STS) is a biologically heterogeneous disease for which existing immunotherapy approaches (e.g. anti-PD-1) have shown limited clinical activity. Cytotoxic chemotherapy with doxorubicin (D), an anthracycline, remains standard-of-care treatment for most advanced STS. Combining chemotherapy with immunomodulatory treatments may enhance antigen presentation and favorably impact the immune microenvironment (iME). APX005M (Apexigen; San Carlos, CA) is a novel CD40 agonistic antibody. Preclinically, CD40 ligation plus chemotherapy induced expression of costimulatory and major histocompatibility complex molecules on antigen presenting cells (APCs), shifted the myeloid compartment towards an M 1 phenotype and expanded T-cell receptor clonality, which are characteristics in which the sarcoma iME is deficient (2,3). In phase 1, APX005M showed dose-dependent activation of APCs in peripheral blood and favorable tolerability. We designed a phase II study evaluating D+A as a novel combination for STS. Methods: This is a single-arm, open-label, Simon 2 stage phase II study with safety lead-in evaluating D+A among 27 patients with STS. Pts have advanced STS (excluding GIST and Kaposi sarcoma) for which doxorubicin is appropriate and any prior lines of therapy, including none. Pts receive D 75 mg/m 2 and A 0.3 mg/m 2 IV day 1 in 21 day cycles. Doxorubicin is stopped after cycle 8 but APX005M may continue. The primary endpoint is the objective response rate (ORR). The study design has power of 85% to show an improvement in ORR from 10% (inactive) to 30% (active) with α = 0.04. Secondary endpoints include PFS and safety. Pts undergo collection of stool specimens at baseline and cycle 3 to evaluate composition of the gut microbiome including effects on clinical outcomes and modulation of microbiome by treatment. Pts undergo paired tumor biopsies at baseline and cycle 2 which are evaluated with gene expression and multiplex immunohistochemistry to evaluate effects of D+A on iME. The study opened in 1/2019. Clinical trial information: NCT03719430.
Effect of Hydrocortisone vs Pasireotide on Pancreatic Surgery Complications in Patients With High Risk of Pancreatic Fistula
Authors: Timo Tarvainen, Jukka Sirén, Arto Kokkola, Ville Sallinen
Journal: JAMA Surgery (2020)

Both hydrocortisone and pasireotide have been shown in randomized clinical trials to be effective in reducing postoperative complications of pancreatic surgery, but to date no randomized clinical trial has evaluated the effectiveness of pasireotide compared with hydrocortisone.To assess the noninferiority of hydrocortisone compared with pasireotide in reducing complications after partial pancreatectomy.A noninferiority, parallel-group, individually randomized clinical trial was conducted at a single academic center between May 19, 2016, and December 17, 2018. Outcome collectors and analyzers were blinded. A total of 281 patients undergoing partial pancreatectomy were assessed for inclusion. Patients younger than 18 years, those allergic to hydrocortisone or pasireotide, patients undergoing pancreaticoduodenectomy with hard pancreas or dilated pancreatic duct, and patients not eventually undergoing partial pancreatectomy were excluded. Modified intention-to-treat analysis was used in determination of the results.Treatment included pasireotide, 900 μg, subcutaneously twice a day for 7 days or hydrocortisone, 100 mg, intravenously 3 times a day for 3 days.The primary outcome was the Comprehensive Complication Index (CCI) score within 30 days. The noninferiority limit was set to 9 CCI points.Of the 281 patients (mean [SD] age, 63.8 years) assessed for eligibility, 168 patients (mean [SD] age, 63.6 years) were randomized and 126 were included in the modified intention-to-treat analyses. Sixty-three patients received pasireotide (35 men [56%]; median [interquartile range] age, 64 [56-70] years) and 63 patients received hydrocortisone (25 men [40%]; median [interquartile range] age, 67 [56-73] years). The mean (SD) CCI score was 23.94 (17.06) in the pasireotide group and 30.11 (20.47) in the hydrocortisone group (mean difference, -6.16; 2-sided 90% CI, -11.73 to -0.60), indicating that hydrocortisone was not noninferior. Postoperative pancreatic fistula was detected in 34 patients (54%) in the pasireotide group and 39 patients (62%) in the hydrocortisone group (odds ratio, 1.39; 95% CI, 0.68-2.82; P = .37). One patient in the pasireotide group and 2 patients in the hydrocortisone group died within 30 days. In subgroup analyses of patients undergoing distal pancreatectomy, the CCI score was a mean of 10.3 points lower (mean [SD], 16.03 [11.94] vs 26.28 [21.76]; 2-sided 95% CI, -19.34 to -2.12; P = .03) and postoperative pancreatic fistula rate was lower (37% vs 67%; P = .02) in the pasireotide group compared with the hydrocortisone group.In this study, hydrocortisone was not noninferior compared with pasireotide in patients undergoing partial pancreatectomy. Pasireotide may be more effective than hydrocortisone in patients undergoing distal pancreatectomy.ClinicalTrials.gov identifier: NCT02775227; EudraCT identifier: 2016-000212-16.
A randomized, multicenter, phase II trial of gemcitabine (G), cisplatin (C) +/- veliparib (V) in patients with pancreas adenocarcinoma (PDAC) and a known germline (g)BRCA/ PALB2 mutation.
Authors: Eileen Mary O'Reilly, Jonathan W. Lee, Mark Zalupski, Marinela Capanu, Jennifer Park, Talia Golan, Esther Tahover, Maeve Aine Lowery, Joanne F. Chou, Vaibhav Sahai, Robin Brenner, Hedy L. Kindler, Kenneth H. Yu, Alice Zervoudakis, Shreya Vemuri, Zsofia Kinga Stadler, Richard K. G. Do, Neesha C. Dhani, Alice P. Chen, David Paul Kelsen
Journal: Journal of Clinical Oncology (2020)

639 Background: gBRCA 1,2 mutations occur in 5-8% PDAC. Platinum and poly-ADP ribose polymerase inhibitors (PARPi) effective in BRCA-mut cancers. Phase I GC + V high RR 78%; combination may delay resistance in PDAC (O’Reilly, Cancer, 2018). Herein, we evaluate GC +/- V in a multi-national, randomized phase II trial. Methods: Eligibility: Untreated germline (g)BRCA, PALB2 mut PDAC; measurable stage III/IV; ECOG 0-1. Randomized 1:1 Arm A or B. Treatment: Arm A: G 600 mg/m2 IV, C 25 mg/m2 IV, d3 and 10, V 80 mg PO BID day 1-12, all q 3 weeks or Arm B: GC only. Primary endpoint: RECIST 1.1 response rate (RR). Simon 2-stage per arm: null hypothesis 10% vs promising 28%; type I, II error 10%. Secondary endpoints: progression-free survival (PFS), OS (m), disease control rate (CR+PR+SD), safety and correlative analyses. PFS, OS compared between arms using log-rank test and RR, DCR using Fisher’s exact test between arms. Results: N = 52 enrolled 01/14- 11/18. N = 2 withdrew Arm B. N = 50 for ITT. Male = 22 (44%), Female = 28. Median age = 64 years (range 37-82). BRCA1 N = 12, BRCA2 N = 35, PALB2 N = 3. Stage III N = 8; Stage IV N = 42. Hematologic Toxicity: Arm A vs Arm B: Gd 3-4 neutropenia 13 (48%) vs 7 (30%); Gd 3-4 platelets 15 (55%) vs 2 (9%); Gd 3-4 anemia 14 (52%) vs 8 (35%). Non-hematologic toxicity similar Arm A vs B. Exploratory analyses (combined Arms): Med OS if &gt; 4 m platinum → PARPi: 23 m (95%CI 6.5- 53.9). Med OS by BRCA: BRCA1: 14 m (8.1- 18.5); BRCA2: 20.2 m (12.3- 24.4). Med OS by ECOG: ECOG 0: 23 m (13.8- 24.5); ECOG 1: 14.3 (8.1 vs 16.4). Two-year OS rate for entire cohort: 30.6% and 3-year OS: 17.8%. Conclusions: GC +/- V very active in gBRCA/PALB2 mut PDAC with high RR, PFS, OS with both A, B significantly exceeding threshold RR. Improved DCR arm A vs B, but with greater heme toxicity A vs B. Study confirms GC as reference treatment in gBRCA/PALB2 with durable survival in subset. Funding: National Cancer Institute, CTEP, Lustgarten Foundation, AbbVie. Clinical trial information: NCT01585805 . [Table: see text]
Author Correction: A global overview of pleiotropy and genetic architecture in complex traits
Authors: Kyoko Watanabe, Sven Stringer, Oleksandr Frei, Maša Umićević Mirkov, Christiaan de Leeuw, Tinca J. C. Polderman, Sophie van der Sluis, Ole A. Andreassen, Benjamin M. Neale, Danielle Posthuma
Journal: Nature Genetics (2020)
Sgnlva-005: Open-label, phase II study of ladiratuzumab vedotin (LV) for advanced aerodigestive tract malignancies.
Authors: Ian Churchill Anderson, Yinghui Wang, Zejing Wang, Rachel E. Sanborn
Journal: Journal of Clinical Oncology (2020)

TPS469 Background: LIV-1 is a transmembrane protein with putative zinc transporter and metalloproteinase activity. It has been linked to the epidermal-to-mesenchymal transition that leads to malignant progression and metastasis. Ladiratuzumab vedotin (LV), also known as SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) targeting LIV-1 that is composed of a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable linker. MMAE-linked ADCs can induce mitotic arrest and immunogenic cell death. In a phase 1 study, LV was well tolerated and showed antitumor activity in heavily pretreated patients (pts) with metastatic breast cancer (Modi et al 2017). The current study was initiated to evaluate LV in previously treated pts with advanced upper aerodigestive tract malignancies. Methods: SGNLVA-005 (NCT04032704) is an open-label, phase 2 study evaluating LV monotherapy (2.5 mg/kg IV every 3 weeks) for pts with the following advanced malignancies: gastric and gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC)-squamous, NSCLC-nonsquamous, and head and neck squamous cell carcinoma. Up to approximately 30 pts with unresectable locally advanced or metastatic disease, measurable disease per RECIST v1.1, an ECOG score of 0 or 1, and adequate organ function are enrolling in each of the cohorts. Pts in the gastric and GEJ adenocarcinoma and esophageal squamous cell carcinoma cohorts must have received no more than 1 prior line of platinum-based cytotoxic chemotherapy and pts in the gastric and GEJ adenocarcinoma cohort should have received prior anti-PD(L)1 therapy if indicated. The study consists of a 2-stage design that includes a Bayesian predictive probability of success approach to determine futility criteria. Study objectives include objective response rate (primary); safety and tolerability, disease control rate, duration of response, progression-free and overall survival, and pharmacokinetics and immunogenicity (all secondary); and pharmacodynamics. Study enrollment is ongoing in North America. Pts will also enroll in Europe and Asia. Clinical trial information: NCT04032704.
Impact of HPV vaccine hesitancy on cervical cancer in Japan: a modelling study
Authors: Kate T Simms, Sharon J B Hanley, Megan A Smith, Adam Keane, Karen Canfell
Journal: The Lancet Public Health (2020)

BackgroundFunding for human papillomavirus (HPV) vaccination in Japan began in 2010 for girls aged 12–16 years, with three-dose coverage initially reaching more than 70%. On June 14, 2013, 2 months after formal inclusion in Japan's national immunisation programme, proactive recommendations for the HPV vaccine were suspended following reports of adverse events since found to be unrelated to vaccination, but which were extensively covered in the media. Vaccine coverage subsequently dropped to less than 1% and has remained this low to date. We aimed to quantify the impact of this vaccine hesitancy crisis, and the potential health gains if coverage can be restored.MethodsIn this modelling study, we used the Policy1-Cervix modelling platform. We adapted the model for Japan with use of data on HPV prevalence, screening practices and coverage, and cervical cancer incidence and mortality. We evaluated the expected number of cervical cancer cases and deaths over the lifetime of cohorts born from 1994 to 2007 in the context of the vaccine hesitancy crisis. We assessed a range of recovery scenarios from 2020 onwards, including a scenario in which routine coverage is restored to 70%, with 50% catch-up coverage for the missed cohorts (aged 13–20 years in 2020). To estimate the impact of the vaccine crisis to date, we also modelled a counterfactual scenario in which 70% coverage had been maintained in 12-year-olds from 2013 onwards.FindingsThe vaccine crisis from 2013 to 2019 is predicted to result in an additional 24 600–27 300 cases and 5000–5700 deaths over the lifetime of cohorts born between 1994 and 2007, compared with if coverage had remained at around 70% since 2013. However, restoration of coverage in 2020, including catch-up vaccination for missed cohorts, could prevent 14 800–16 200 of these cases and 3000–3400 of these deaths. If coverage is not restored in 2020, an additional 3400–3800 cases and 700–800 deaths will occur over the lifetime of individuals who are 12 years old in 2020 alone. If the crisis continues, 9300–10 800 preventable deaths due to cervical cancer will occur in the next 50 years (2020–69).InterpretationThe HPV vaccine crisis to date is estimated to result in around 5000 deaths from cervical cancer in Japan. Many of these deaths could still be prevented if vaccination coverage with extended catch-up can be rapidly restored.FundingNational Health and Medical Research Council Australia Centre of Research Excellence in Cervical Cancer Control, Japan Society for the Promotion of Science.