tbuckley/cabot-search huggingface dataset:
Determinants of enhanced vulnerability to Covid-19 in U.K. cancer patients: Results from the OnCovid study.
Authors: David James Pinato, Lorenza Scotti, Alessandra Gennari, Emeline Colomba, Ailsa Sita-Lumsden, Angela Loizidou, Alberto Zambelli, Mark Bower, Ramon Salazar Soler, Alexia Francesca Bertuzzi, Joan Brunet, Daniele Giulio Generali, Salvatore Grisanti, Gianpiero Rizzo, Diego Ottaviani, Eudald Felip, Aleix Prat, Josep Tabernero, Nikolaos Diamantis, Alessio Cortellini
Journal: Journal of Clinical Oncology (2021)

1574 Background: Despite high contagiousness and rapid spread, SARS-Cov-2 has led to heterogeneous outcomes across affected nations. Within Europe, the United Kingdom is the most severely affected country, with a death toll in excess of 100.000 as of February 2021. We aimed to compare the national impact of Covid-19 on the risk of death in UK cancer patients versus those in continental Europe (EU). Methods: We performed a retrospective analysis of the OnCovid study database, a European registry of cancer patients consecutively diagnosed with Covid-19 in 27 centres from February 27 to September 10, 2020. We analysed case fatality rates and risk of death at 30 days and 6 months stratified by region of origin (UK versus EU). We compared patient characteristics at baseline, oncological and Covid-19 specific therapy across cohorts and tested these in multivariable Cox regression models to identify predictors of adverse outcome in UK versus EU patients. Results: Compared to EU patients (n = 924), UK patients (n = 468) were characterised by higher case fatality rates (40.38% versus 26.5%, p &lt; 0.0001), higher risk of death at 30 days (hazard ratio, HR 1.64 [95%CI 1.36-1.99]) and 6 months after Covid-19 diagnosis (47.64% versus 33.33%, p &lt; 0.0001, HR 1.59 [95%CI 1.33-1.88]). UK patients were more often males, of older age and more co-morbid than EU counterparts (p &lt; 0.01). Receipt of anti-cancer therapy was lower in UK versus EU patients (p &lt; 0.001). Despite equal proportions of complicated Covid-19, rates of intensive care admission and use of mechanical ventilation, UK cancer patients were less likely to receive anti-Covid-19 therapies including corticosteroids, anti-virals and interleukin-6 antagonists (p &lt; 0.0001). Multivariable analyses adjusted for imbalanced prognostic factors confirmed the UK cohort to be characterised by worse risk of death at 30 days and 6 months, independent of patient’s age, gender, tumour stage and status, number of co-morbidities, Covid-19 severity, receipt of anti-cancer and anti-Covid-19 therapy. Rates of permanent cessation of anti-cancer therapy post Covid-19 were similar in UK versus EU. Conclusions: UK cancer patients have been more severely impacted by the unfolding of the Covid-19 pandemic despite societal risk mitigation factors and rapid deferral of anti-cancer therapy. The increased frailty of UK cancer patients highlights high-risk groups that should be prioritised for anti-SARS-Cov-2 vaccination. Continued evaluation of long-term outcomes is warranted.
Risk factors of metachronous peritoneal carcinomatosis after potentially curative gastric cancer resection in the CRITICS trial.
Authors: Irene A Caspers, Karolina Sikorska, Astrid E. Slagter, Elma Meershoek – Klein Kranenbarg, Cornelis J.H. Van De Velde, Pehr A. Lind, Marianne Nordsmark, Edwin PM Jansen, Marcel Verheij, Johanna W. van Sandick, Annemieke Cats, Nicole C.T. van Grieken
Journal: Journal of Clinical Oncology (2021)

4053 Background: Peritoneal carcinomatosis (PC) is accountable for over 50% of metastatic spread in gastric cancer (GC). Little is known about factors contributing to the risk of metachronous PC as a single site of metastases after preoperative chemotherapy and potentially curative resection. An accurate prediction model of risk factors identifying high risk populations may pave the way for new treatment strategies, such as intraperitoneal chemotherapy. In this analysis, risk factors for the development of isolated metachronous PC after preoperative chemotherapy and surgical resection were investigated. Methods: In the CRITICS trial, 788 patients with resectable GC were randomized for preoperative chemotherapy and gastrectomy followed by either chemotherapy or chemoradiotherapy. Patients who underwent a potentially curative resection without peritoneal metastases at time of surgery were included in this analysis. Univariate and multivariate analyses were performed using a competing risk model. Results: In total, 617 patients met the inclusion criteria. Overall, 97 of 617 (16%) patients developed metachronous PC. The peritoneum was the first site of recurrence in 64 of 617 (10%) patients. Diffuse or mixed type GC, ypT4 stage and ypN3 stage or a lymph node ratio (LNR) with &gt;20% tumor positivity were independent predictors of isolated PC in both univariate and multivariate analyses with hazard ratios (HR) of 2.90, 2.63 and 2.31, respectively (Table). ypT4 and ypN3 stage or a LNR &gt;20% were also independent predictors of distant recurrence or death with HR of 1.46 and 2.34, respectively. Patients in whom all predictors were present had the highest 2 year cumulative incidences of both isolated PC development and other events of 39.6% and 48.8%, respectively. Conclusions: Diffuse or mixed tumor type, ypT4 and ypN3 or a LNR &gt;20% were identified as independent risk factors for metachronous PC as a single site of metastases in a large cohort of patients treated with preoperative chemotherapy followed by surgical resection. The combination of these factors might identify a subgroup that could benefit from preventive treatment strategies.[Table: see text]
Phase (Ph) 1b/2 evaluation of olaratumab in combination with gemcitabine and docetaxel in advanced soft tissue sarcoma (STS).
Authors: Steven Attia, Victor Manuel Villalobos, Nadia Hindi, Brian Andrew Van Tine, Andrew J. Wagner, Bartosz Chmielowski, Donna Elise Levy, Matteo Ceccarelli, Robin Lewis Jones, Mark Andrew Dickson
Journal: Journal of Clinical Oncology (2021)

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m 2 , d1 and d8) and D (75 mg/m 2 , d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]
LGG-04. MULTIOMIC ANALYSIS OF MAPK PATHWAY ACTIVITY IN PEDIATRIC PILOCYTIC ASTROCYTOMA
Authors: Romain Sigaud, Florian Selt, Thomas Hielscher, Anja Stefanski, Nina Overbeck, Diren Usta, Daniela Kocher, Marc Remke, Daniel Picard, Stefan M Pfister, David T W Jones, Tilman Brummer, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2021)

Abstract Introduction Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by MAPK pathway alterations, leading to its constitutive activation and modulating the balance between cell proliferation and the oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP) factors. This makes PA suitable for MAPK inhibitor (MAPKi) therapies, showing encouraging results in phase 1/2 clinical trials. Little is known about the molecular implications of MAPK downregulation in the proliferating and senescent compartments. Methods DKFZ-BT66 PA cells derived from a primary KIAA:BRAF-fusion positive PA cell line, were used as model system. Gene expression and phospho-proteomic datasets were generated from DKFZ-BT66 cells, in both the proliferative and senescent states, and treated with the MEKi trametinib for different time-spans. A time course analysis based on differentially expressed genes was performed, followed by a single-sample gene set enrichment analysis (ssGSEA). Analysis of the phospho-proteomic data is ongoing. Results Differential gene expression analysis revealed that MEK inhibition leads to the inhibition of the OIS-SASP gene program in senescent DKFZ-BT66. ssGSEA showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including FGFR, NTRK and TGFB pathways) were upregulated, in both proliferating and senescent DKFZ-BT66. Genes regulated by the MAPK pathway and involved in OIS-SASP were identified by analyzing genes differentially regulated between proliferating and senescent DKFZ-BT66, and modulated upon MEKi treatment. Conclusion This data suggests that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators in proliferating and senescent PA cells, identifying putative co-targets that could help prevent growth rebound upon MAPKi withdrawal. Furthermore, the identification of the MAPK-related OIS-SASP genes provide insight about the regulation of OIS-SASP by the MAPK pathway. Validation of this data with the ongoing phospho-proteomic analysis and in primary samples is needed.
The future of the GMC: an interview with Donald Irvine, the new president
Authors: R. Smith
Journal: BMJ (1995)

Donald Irvine is the first general practitioner to be elected president of the General Medical Council (GMC). Richard Smith spoke to him half an hour after he completed his last ever surgery at his practice in Ashington, Northumberland.

RS: What are the key problems facing the GMC at the moment?

DI: The first is getting its image and its relationship right with the outside world. It must be seen to be interested in good practice and to be connecting with patients' concerns. It shouldn't be seen just as a punitive body that does or doesn't work depending on your point of view.

RS: Is it seen largely as a punitive body?

DI: Many doctors don't know what the GMC actually does. It's just something in London to be avoided at all costs.

The importance of “Good Medical Practice”

RS: Do you think that you might change that?

DI: The council has been tending to emphasise the positive side of practice in the past few years. This changing attitude led to the standards committee producing Good Medical Practice, which was approved by the council last week.1 It's a major reorientation. [Good Medical Practice lays down the essential skills, behaviours, and attitudes that constitute good practice. Sir Donald, as chairman of the standards committee of the GMC, played a central part in its creation.]

RS: Because it's positive rather than just negative?

DI: It's more than that. It makes explicit the link with registration, which gives doctors privileges and benefits, including the right to earn their living as doctors. But it's also a privilege to be associated with a profession that is held in such high esteem by the British public. In many parts of the world the grasping image of doctors has taken over from the caring image.

The flipside …
A phase 1b study of personalized neoantigen vaccine plus pembrolizumab in adults with advanced cancer.
Authors: Aaron Miller, Zeynep Kosaloglu-Yalcin, Luise Westernberg, Leslie Montero, Milad Bahmanof, Angela Frentzen, Ashmitaa Logandha Ramamoorthy Premlal, Jason Greenbaum, Gregory Seumois, Roxanne Habbaba, Amanda Natsuhara, Kim McConnell, Elaine Eng, Alessandro Sette, Bjoern Peters, Stephen Philip Schoenberger, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2021)

2615 Background: Neoantigens (NeoAg) are key targets for personalized immunotherapy but efficient methods for their systematic identification and therapeutic targeting remain elusive. We developed a methodology to reliably identify and verify somatic alteration-derived neoantigens based on natural T cell responses against them which formed the basis of an individualized therapeutic vaccine strategy. Methods: This is a phase Ib study to assess the immunogenicity, safety and early clinical activity of personalized synthetic long peptides (PSLP) cancer vaccines in combination with pembrolizumab for patients with treatment refractory metastatic solid tumors or PSLP vaccine alone as an adjuvant treatment with patients with no evidence of disease (NED) that incorporates patient-specific NeoAg identified by an HLA-agnostic, functional T-cell assay (see table). Results: At the time of data cutoff, a total of 5 patients had been treated on ARM-A, 5 patients on ARM-C and 2 patients on ARM-D. AES possibly attributed to personalized vaccine (PSLP), or pembrolizumab, or both include: Grade 1: Arthralgia (1); Diarrhea (1); Fever (4); Fatigue (7); Generalized muscle weakness (1); Headache (2); Nausea (1); Confusion (1); Injection site reaction (5); Rash maculo-papular (3); Flu like symptoms (5); Myalgia (1); and Grade 2: Diarrhea (1); Fatigue (1); Hyperhidrosis (1); Hypothyroidism (1); Injection site reaction (1); Proteinuria (1); Renal and Urinary – other (1); and Grade 3: Colitis (1). For the 9 patients with at least 1 radiographic assessment at the time of analysis 6 had a best response of stable disease (SD) and 3 had progressive disease (PD). Immune monitoring of peripheral blood specimens consistently demonstrated that NeoAg-specific T cell responses were enhanced following administration of PSLP vaccine. On-treatment biopsies demonstrated immune-editing with the variant allele frequency of targeted mutations decreasing following administration of the PSLP vaccine. Conclusions: Taken together, these data meet the trial primary endpoint by demonstrating PSLP vaccines targeting NeoAg identified using the HLA-agnostic pipeline augment effector T cell function against these targets. Clinical trial information: NCT02287428. [Table: see text]
Prevalence of Angina Among Primary Care Patients With Coronary Artery Disease
Authors: Daniel M. Blumenthal, Sidney E. Howard, Jennifer Searl Como, Sandra M. O’Keefe, Steven J. Atlas, Daniel M. Horn, Neil W. Wagle, Jason H. Wasfy, Robert W. Yeh, Joshua P. Metlay
Journal: JAMA Network Open (2021)

Angina pectoris is associated with morbidity and mortality. Angina prevalence and frequency among contemporary US populations with coronary artery disease (CAD) remain incompletely defined.To ascertain the angina prevalence and frequency among stable outpatients with CAD.This cross-sectional survey study involved telephone-based administration of the Seattle Angina Questionnaire-7 (SAQ-7) between February 1, 2017, and July 31, 2017, to a nonconvenience sample of adults with established CAD who receive primary care through a large US integrated primary care network. Data analysis was performed from August 2017 to August 2019.SAQ-7 administration.Angina prevalence and frequency were assessed using SAQ-7 question 2. Covariates associated with angina were assessed in univariable and multivariable regression.Of 4139 eligible patients, 1612 responded to the survey (response rate, 38.9%). The mean (SD) age of the respondents was 71.8 (11.0) years, 577 (35.8%) were women, 1447 (89.8%) spoke English, 147 (9.1%) spoke Spanish, 1336 (82.8%) were White, 76 (4.7%) were Black, 92 (5.7%) were Hispanic, 974 (60.4%) had Medicare, and 83 (5.2%) had Medicaid. Among respondents, 342 (21.2%) reported experiencing angina at least once monthly; among those, 201 (12.5%) reported daily or weekly angina, and 141 respondents (8.7%) reported monthly angina. The mean (SD) SAQ-7 score was 93.7 (13.7). After multivariable adjustment, speaking a language other than Spanish or English (odds ratio [OR], 5.07; 95% CI, 1.39-18.50), Black race (OR, 2.01; 95% CI, 1.08-3.75), current smoking (OR, 1.88; 95% CI, 1.27-2.78), former smoking (OR, 1.69; 95% CI, 1.13-2.51), atrial fibrillation (OR, 1.52; 95% CI, 1.02-2.26), and chronic obstructive pulmonary disease (OR, 1.61; 95% CI, 1.18-2.18) were associated with more frequent angina. Male sex (OR, 0.63; 95% CI, 0.47-0.86), peripheral artery disease (OR, 0.63; 95% CI, 0.44-0.90), and novel oral anticoagulant use (OR, 0.19; 95% CI, 0.08-0.48) were associated with less frequent angina.Among stable outpatients with CAD receiving primary care through an integrated primary care network, 21.2% of surveyed patients reported experiencing angina at least once monthly. Several objective demographic and clinical characteristics were associated with angina frequency. Proactive assessment of angina symptoms using validated assessment tools and estimation of patients at higher risk of suboptimally controlled angina may be associated with reduced morbidity.
FLORA-5: Front-line chemoimmunotherapy (Paclitaxel-Carboplatin-Oregovomab [PCO] versus chemotherapy (Paclitaxel-Carboplatin-Placebo [PCP]) in patients with advanced epithelial ovarian cancer (EOC)—Phase III double-blind placebo controlled multinational study.
Authors: Angeles Alvarez Secord, Sunil Gupta, Cathy Reddick, Jyoti Chauhan, Sarah Gill, John O. Schorge, Michael Gold, Devansu Tewari, Christopher A Breed, Patricia S. Braly, Dennis Yi-Shin Kuo, Susan C. Modesitt, Robert W. Holloway
Journal: Journal of Clinical Oncology (2021)

TPS5606 Background: Oregovomab binds tumor-associated CA125 rendering the target antigen CA125 more immunogenic or “neoantigen-like” through altered and enhanced antigen processing and presentation to specific T cells. This phenomenon is hypothesized to bypass tumor-associated immune suppression when administered in combination with chemotherapy. In a randomized phase II study, immunization with oregovomab in a schedule-dependent combination with paclitaxel and carboplatin induced tumor immunity and demonstrated significant improvement in PFS (median (months) 41.8 PCO vs 12.3 PCP, HR 0.44 p = 0.0027, and OS median N.E. PCO vs 43.2 PCP HR O.34 (p = 0.0077)) in patients with previously untreated EOC. The FLORA-5, the definitive confirmatory global registration trial, is currently recruiting patients in the front-line setting. Methods: The study is a phase 3, multicenter, double-blind, placebo-controlled clinical trial. Optimally debulked patients with FIGO III/IV EOC and serum CA125 &gt; 50 U/ml receiving adjuvant (Cohort 1) or neoadjuvant (Cohort 2) chemotherapy will be randomized post-surgery to paclitaxel and carboplatin with or without oregovomab. Patients with germline BRCA1/2 mutations will be excluded. Chemotherapy will be administered every 3 weeks in both cohorts. Oregovomab/placebo is administered simultaneously at cycles 1, 3, and 5 of chemotherapy with a single maintenance dose at 12 weeks following cycle 5 in Cohort 1. Neoadjuvant patients (Cohort 2) will be administered oregovomab/placebo post interval debulking surgery at cycles 4 and 6 with maintenance doses at 6- and 18-weeks following cycle 6. No other post front-line maintenance therapy is permitted. The primary objective is PFS determined by RECIST 1.1 criteria. Cohort 1 will recruit 372 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.65 when 252 PFS events have been observed. Cohort 2 will be analyzed separately recruiting 232 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.60 when 165 PFS events have been observed. An interim analysis for futility will be performed. Secondary objectives include OS, frequency and severity of adverse events, and quality of life. Exploratory objectives include iRECIST, TFST, TSST, PFS2, and evaluation of potential biomarkers. The study is actively enrolling in the US with 9 patients enrolled at time of submission. Centers in Europe, South America and Asia are expected to begin accruing shortly. Clinical trial information: NCT04498117.
Impact of vaccination on new SARS-CoV-2 infections in the UK
Authors: E Pritchard, P C Matthews, N Stoesser, D Eyre, O Gethings, K Vihta, J Jones, T House, H VanSteenHouse, I Bell, J I Bell, J N Newton, J Farrar, I Diamond, E Rourke, R Studley, D Crook, T Peto, A S Walker, K B Pouwels
Journal: Nature Medicine (2021)