tbuckley/cabot-search huggingface dataset:
Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study.
Authors: Elizabeth R. Plimack, Thomas Powles, Jens Bedke, Frédéric Pouliot, Viktor Stus, Tom Waddell, Rustem Gafanov, Dmitry Nosov, Boris Alekseev, Raymond S. McDermott, Maurice Markus, Sophie Tartas, Anna Kryzhanivska, Igor Bondarenko, Cezary Szczylik, Jianxin Lin, Rodolfo F. Perini, L. Rhoda Molife, Michael B. Atkins, Brian I. Rini
Journal: Journal of Clinical Oncology (2021)

327 Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit. Clinical trial information: NCT02853331 .
Primary healthcare for a long term and sustainable vaccination strategy
Authors: Arnaud Chiolero, Stéphane Cullati, Valérie Santschi
Journal: BMJ (2021)

Organising the covid-19 vaccination programme puts enormous pressure on healthcare systems. Two major challenges must be tackled for a long term, sustainable strategy.

Firstly, we need to account for vaccination hesitancy. In 2019 it was listed by the World Health Organization among the top 10 threats to global health1 and hesitancy towards covid-19 vaccines is common in some countries.2

Secondly, the strategy must be tailored to the capacity of healthcare systems. …
Safety and efficacy of hypofractionated stereotactic radiosurgery with anlotinib targeted therapy for glioblastoma at first recurrence: A preliminary report.
Authors: Yun Guan, Huaguang Zhu, Jing Li, Guanghai Mei, Xiaoxia Liu, Chao Li, Xiu Gong, Jiazhong Dai, Li Pan, Yang Wang, Enmin Wang, Xin Wang
Journal: Journal of Clinical Oncology (2021)

e14015 Background: The optimal treatment for recurrent glioblastoma (rGBM) remains uncertain. Hypofractionated stereotactic radiotherapy (HSRT) and anti-vascular endothelial growth factor (VEGF) antibodies (e.g, bevacizumab and anlotinib) have been reported a promising survival benefit and acceptable toxicity in recent studies. This research aimed to investigate the efficacy and safety of hypofractionated stereotactic radiosurgery with anlotinib as a salvage treatment for rGBM within the radiation field at first recurrence. Methods: Between December 2019 and June 2020, rGBM patients treated with CyberKnife (CK) radiosurgery concurrently with anlotinib were retrospectively analyzed. Anlotinib was prescribed 12 mg daily during CK. Adjuvant anlotinib was administered 12mg d1-14 every 3 weeks. The primary endpoint was objective response rate (ORR) using response assessment in neuro-oncology (RANO) criteria, and secondary endpoints included overall survival (OS), progression-free survival (PFS) after salvage treatment, and toxicity. Toxicity was assessed using common terminology criteria for adverse events (CTCAE) 5.0. Results: A total of five patients were included in the study. The median planning target volume (PTV) was 26.94 cm3 (5.53 to 54.41 cm3). The prescribed dose was 25.0 Gy in 5 fractions. The median number of cycles of anlotinib was 9 (4 to 15 cycles). The median baseline Karnofsky Performance Status (KPS) is 80 (70 to 90). The follow-up ranged from 4 to 10 months. Three (60%) patients had the best outcome of partial response (PR), and 2 (40%) achieved complete response (CR), the ORR was 100%. No patient died or had progressive disease (PD) until the last follow-up. Two patients had grade 2 hand-foot syndrome and relieved after dermatology treatments, no other grade 3 or higher toxicities was recorded. Conclusions: Salvage radiosurgery with anlotinib showed a favorable outcome and acceptable toxicity for rGBM patients in this preliminary report. A prospective phase II study (NCT04197492) is ongoing to further investigate the regimen in rHGG. [Table: see text]
Association between prior radical surgery (RS) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).
Authors: Dimitrios Makrakis, Daniel Castellano, Ivan de Kouchkovsky, Joseph J. Park, Mehmet Asim Bilen, Neeraj Agarwal, Yousef Zakharia, Rafael Morales-Barrera, Michael E. Devitt, Ariel Ann Nelson, Benjamin A. Gartrell, Abhishek Tripathi, Aristotelis Bamias, Alejo Rodriguez-Vida, Sandy Liu, Rana R. McKay, Lucia Andrea Alonso Buznego, Jure Murgic, Petros Grivas, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2021)

444 Background: It is unclear whether prior RS of primary tumor is associated with response and outcomes with ICI in aUC. We hypothesized that such response and outcomes would not differ based on prior RS. Methods: We performed a retrospective cohort study including patients (pts) with aUC who received ICI. We compared overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) between pts with vs without RS [cystectomy or (nephro)-ureterectomy]. Analysis was stratified based on ICI therapy line (first-line vs salvage). A separate comparison between pts with prior RS or radiation (RT) only or none was also pursued. ORR was compared between groups using logistic regression, as well OS and PFS using cox regression analysis; a multivariable model was built adjusting for calculated Bellmunt score. P&lt;0.05 was significant. Results: We identified 984 pts from 24 institutions; 682, 704 and 673 were included in OS, PFS and ORR analyses, respectively; 54% of pts had prior RS with median age 68 at ICI initiation with RS vs 71 without RS with similar proportion of men (73-74%) and ever smokers (70-71%). The RS group had higher proportion (%) of white pts (77% vs 71%), lower % of pts with Hb&lt;10g/dL at ICI initiation (23% vs 32%) but not significantly higher % of liver metastasis at ICI initiation (23% vs 17%). Bellmunt score with vs without RS was 16% vs 11%, 50% vs 48%, 27% vs 37%, 7% vs 4% for 0, 1, 2, and 3, respectively. ORR and PFS were not significantly different between groups, while prior RS was associated with longer OS (unadjusted HR 0.8, p=0.03). However, after adjustment for Bellmunt score, this association was not significant (table). Upon stratification based on treatment line, OS was longer with prior RS (0.7, p=0.03) for those treated with salvage ICI but this was not significant after adjusting for Bellmunt score. ORR, PFS and OS were not significantly different between pts receiving prior RT only vs RS vs none. Conclusions: Prior RS was not significantly associated with longer OS in pts with aUC receiving ICI after adjusting for Bellmunt score. Further work is needed to interrogate tumor-host immune interactions and identify biomarkers that can be prognostic and/or predictive of ICI response. [Table: see text]
Abstract PO023: Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube
Authors: Huy Q. Dinh, Xianzhi Lin, Forough Abbasi, Robbin Nameki, Marcela Haro, Claire Olingy, Heidi Chang, Lourdes Hernandez, Simon Gayther, Kelly N. Wright, Paul-Joseph Aspuria, Beth Karlan, Rosario I. Corona, Andrew Li, B.J. Rimel, Matthew Siedhoff, Fabiola Medeiros, Kate Lawrenson
Journal: Cancer Research (2021)

Abstract The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous ‘ovarian’ cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the ‘early secretory’ population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs, a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia. Further computational analyses on fibroblast and immune cells together with tumor single-cell data reveals extended contribution of non-epithelial microenvironment and cell-cell interactions and communications in fallopian tube that potentially drive HGSC progression. Citation Format: Huy Q. Dinh, Xianzhi Lin, Forough Abbasi, Robbin Nameki, Marcela Haro, Claire Olingy, Heidi Chang, Lourdes Hernandez, Simon Gayther, Kelly N. Wright, Paul-Joseph Aspuria, Beth Karlan, Rosario I. Corona, Andrew Li, B.J. Rimel, Matthew Siedhoff, Fabiola Medeiros, Kate Lawrenson. Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO023.
Development of a polycaprolactone/poly(p-dioxanone) bioresorbable stent with mechanically self-reinforced structure for congenital heart disease treatment
Authors: Fan Zhao, Jing Sun, Wen Xue, Fujun Wang, Martin W. King, Chenglong Yu, Yongjie Jiao, Kun Sun, Lu Wang
Journal: Bioactive Materials (2021)

Recent progress in bioresorbable stents (BRSs) has provided a promising alternative for treating coronary artery disease. However, there is still lack of BRSs with satisfied compression and degradation performance for pediatric patients with congenital heart disease, leading to suboptimal therapy effects. Here, we developed a mechanically self-reinforced composite bioresorbable stent (cBRS) for congenital heart disease application. The cBRS consisted of poly(p-dioxanone) monofilaments and polycaprolactone/poly(p-dioxanone) core-shell composite yarns. Interlacing points in cBRS structure were partially bonded, offering the cBRS with significantly higher compression force compared to typical braids and remained good compliance. The suitable degradation profile of the cBRS can possibly preserve vascular remodeling and healing process. In addition, the controllable structural organization provides a method to customize the performance of the cBRS by altering the proportion of different components in the braids. The in vivo results suggested the cBRS supported the vessel wall similar to that of metallic stent. In both abdominal aorta and iliac artery of porcine, cBRS was entirely endothelialized within 1 month and maintained target vessels with good patency in the 12-month follow-up. The in vivo degradation profile of the cBRS is consistent with static degradation results in vitro. It is also demonstrated that there is minimal impact of pulsatile pressure of blood flow and variation of radial force on the degradation rate of the cBRS. Moreover, the lumen of cBRS implanted vessels were enlarged after 6 months, and significantly larger than the vessels implanted with metallic stent in 12 months.
Towards a sensitive and accurate interpretation of molecular testing for SARS-CoV-2: a rapid review of 264 studies
Authors: Kamelia R. Stanoeva, Annemiek A. van der Eijk, Adam Meijer, Laetitia M. Kortbeek, Marion P.G. Koopmans, Chantal B.E.M. Reusken
Journal: Eurosurveillance (2021)

Background Sensitive molecular diagnostics and correct test interpretation are crucial for accurate COVID-19 diagnosis and thereby essential for good clinical practice. Furthermore, they are a key factor in outbreak control where active case finding in combination with isolation and contact tracing are crucial. Aim With the objective to inform the public health and laboratory responses to the pandemic, we reviewed current published knowledge on the kinetics of SARS-CoV-2 infection as assessed by RNA molecular detection in a wide range of clinical samples. Methods We performed an extensive search on studies published between 1 December 2019 and 15 May 2020, reporting on molecular detection and/or isolation of SARS-CoV-2 in any human laboratory specimen. Results We compiled a dataset of 264 studies including 32,515 COVID-19 cases, and additionally aggregated data points (n = 2,777) from sampling of 217 adults with known infection timeline. We summarised data on SARS-CoV-2 detection in the respiratory and gastrointestinal tract, blood, oral fluid, tears, cerebrospinal fluid, peritoneal fluid, semen, vaginal fluid; where provided, we also summarised specific observations on SARS-CoV-2 detection in pregnancy, infancy, children, adolescents and immunocompromised individuals. Conclusion Optimal SARS-CoV-2 molecular testing relies on choosing the most appropriate sample type, collected with adequate sampling technique, and with the infection timeline in mind. We outlined knowledge gaps and directions for future well-documented systematic studies.
Alignment and discordances in perceptions and experiences of shared decision making (SDM) among bladder cancer (BC) patients and their care team.
Authors: Karim Chamie, Sarah P. Psutka, Taral Patel, Manojkumar Bupathi, Breanne Y Farris, Rebecca R Crawford, Jeffrey D. Carter, Tamar Sapir
Journal: Journal of Clinical Oncology (2021)

420 Background: To align BC treatment with patient goals, it is vital that healthcare providers (HCPs) engage their patients (pts) in SDM for treatment planning. We assessed alignment and discordances on aspects of SDM among BC pts and their urology and oncology teams. Methods: Between 05/2020 and 06/2020, surveys were administered to 53 pts with BC (48% female, mean age 68 years) and 23 HCPs, as part of in-clinic and virtual collaborative patient education sessions across 5 US-based practices. Surveys were designed to assess perceptions, preferences, and experiences with regard to SDM during BC care. Results: Survey findings indicated key alignments and discordances in pts’ reported experience and HCPs’ perceptions of the use of SDM in BC care. HCPs and pts identified the same top 2 patient goals for BC care: 1) preventing progression/recurrence (61% pts, 48% HCPs) and 2) maintaining quality of life (35% pts, 78% HCPs). When asked to identify patient’s top challenges for pts in BC care, both pts and HCPs indicated post-treatment aspects as the top challenge, though pts indicated managing side effects/serious worry about side effects from treatment as the top challenge (22%); whereas, HCPs were split evenly between managing side effects from treatment (26%) and managing life changes as a result of urinary diversion (26%). HCPs overestimated the effect that fatigue and worry had on pts capacity for SDM: only 9% of pts indicated worry or fatigue as a barrier to SDM, but 65% of HCPs indicated this as a likely barrier. Furthermore, the patient experience of SDM differed from HCP perception of SDM (Table); for some aspects of SDM, such as explaining different treatment options, explaining pros/cons of treatment options, and overall involvement in treatment decisions, fewer HCPs indicated that these aspects of SDM always or usually occurred as compared to pts. Conclusions: These findings reveal important alignments and discordances between pts and HCPs with regard to BC care and SDM, which may inform future bladder cancer and SDM initiatives. [Table: see text]
Avoiding a Crisis With High-Deductible Insurance Plans
Authors: Jenny A. Shih, Katherine C. Wrenn
Journal: JAMA Internal Medicine (2021)

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Interferon antagonism by SARS-CoV-2: a functional study using reverse genetics
Authors: Simon Schroeder, Fabian Pott, Daniela Niemeyer, Talitha Veith, Anja Richter, Doreen Muth, Christine Goffinet, Marcel A Müller, Christian Drosten
Journal: The Lancet Microbe (2021)

SummaryBackgroundThe COVID-19 agent, SARS-CoV-2, is conspecific with SARS-CoV, the causal agent of the severe acute respiratory syndrome epidemic in 2002–03. Although the viruses share a completely homologous repertoire of proteins and use the same cellular entry receptor, their transmission efficiencies and pathogenetic traits differ. We aimed to compare interferon antagonism by SARS-CoV and SARS-CoV-2.MethodsFor this functional study, we infected Vero E6 and Calu-3 cells with strains of SARS-CoV and SARS-CoV-2. We studied differences in cell line-specific replication (Vero E6 vs Calu-3 cells) and analysed these differences in relation to TMPRSS2-dependent cell entry based on inhibition with the drug camostat mesilate. We evaluated viral sensitivity towards type I interferon treatment and assessed cytokine induction and type I interferon signalling in the host cells by RT-PCR and analysis of transcription factor activation and nuclear translocation. Based on reverse genetic engineering of SARS-CoV, we investigated the contribution of open reading frame 6 (ORF6) to the observed phenotypic differences in interferon signalling, because ORF6 encodes an interferon signalling antagonist. We did a luciferase-based interferon-stimulated response element promotor activation assay to evaluate the antagonistic capacity of SARS-CoV-2 wild-type ORF6 constructs and three mutants (Gln51Glu, Gln56Glu, or both) that represent amino acid substitutions between SARS-CoV and SARS-CoV-2 protein 6 in the carboxy-terminal domain.FindingsOverall, replication was higher for SARS-CoV in Vero E6 cells and for SARS-CoV-2 in Calu-3 cells. SARS-CoV-2 was reliant on TMPRSS2, found only in Calu-3 cells, for more efficient entry. SARS-CoV-2 was more sensitive to interferon treatment, less efficient in suppressing cytokine induction via IRF3 nuclear translocation, and permissive of a higher level of induction of interferon-stimulated genes MX1 and ISG56. SARS-CoV-2 ORF6 expressed in the context of a fully replicating SARS-CoV backbone suppressed MX1 gene induction, but this suppression was less efficient than that by SARS-CoV ORF6. Mutagenesis showed that charged amino acids in residues 51 and 56 shift the phenotype towards more efficient interferon antagonism, as seen in SARS-CoV.InterpretationSARS-CoV-2 ORF6 interferes less efficiently with human interferon induction and interferon signalling than SARS-CoV ORF6. Because of the homology of the genes, onward selection for fitness could involve functional optimisation of interferon antagonism. Charged amino acids at positions 51 and 56 in ORF6 should be monitored for potential adaptive changes.FundingBundesministerium für Bildung und Forschung, EU RECOVER project.
Abstract #5253: Cancer 10-pathway reporter array: An innovative tool to simultaneously measure the activities of ten signaling pathways involved in cancer biology
Authors: Abigail Harris, Vikram Devgan
Journal: Cancer Research (2009)

Most of the cancers are result of de-regulated cell signaling pathways. Typically, more than one signal transduction pathway is involved in cancer pathogenesis and progression. In order to fully understand the physiology of cancer, it is vital to understand the intracellular status of multiple signaling pathways simultaneously. We have developed Cancer 10-Pathway Reporter Array to simultaneously measure the activities of ten key cell signaling pathways, including Notch, Wnt/\#946;-Catenin, TGF\#946;, p53, NFkB, E2F, MAPK (JNK), MAPK (ERK), Myc and HIF-1\#945;, which serve as critical regulators of a cancer biology. In this study, we utilized cancer 10-pathway reporter array to determine the effect of knock down of well known tumor suppressor gene, i.e. p53 on important cancer signaling pathways. Our result showed that the knock down of p53 gene expression down-regulates p53 signaling, while up-regulating Notch, hypoxia and MAPK/ERK signaling in HEK-293 cells. Interestingly, Notch signaling is known to be frequently deregulated in human malignancies. Up-regulation of Notch signaling by p53 RNA interference suggests that Notch may function as a proto-oncogene in HEK-293 cells. Moreover, our data potentiate the ability of reporter array to rapidly, accurately and reproducibly quantify the impact of a given stimulus (RNAi/small chemical molecules/antibodies) on the activities of ten cancer signaling pathways in a single experiment.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5253.