tbuckley/cabot-search huggingface dataset:
Abstract 4123: Clinical significance and the difference between programmed death-1 ligand-1 and ligand-2 in patients with esophageal cancer
Authors: Kazuo Okadome, Yoshifumi Baba, Taisuke Yagi, Yuki Kiyozumi, Kojiro Eto, Yukiharu Hiyoshi, Yohei Nagai, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2019)

Abstract Background: Immunotherapies targeting the PD-1/PD-L1 pathway have emerged as promising therapeutic strategies for many cancers. PD-L1 and PD-L2 are ligands of PD-1 on T-cells and prevent T-cells activation and proliferation. There have been reported that PD-L1 and PD-L2 are expressed on not only antigen-presenting cells but also some types of tumors. Clinical and prognostic features of the PD-L1 have been widely reported for many types of cancers but those of PD-L2 remain unclear in esophageal cancer. The aim of this study was to analyze the clinical significance and the difference between PD-L1 and PD-L2 in esophageal cancer. Methods: Using a database of 437 curatively resected esophageal cancer from April 2005 to March 2016, we evaluated PD-L1 and PD-L2 expression in tumor cells by immunohistochemical staining and analyzed the association between those with clinicopathological features. Double immunohistochemical staining for PD-L1 and PD-L2 was performed to confirm the localization of each positive cell. Results: Out of 437 cases of esophageal cancer, 69 cases (15.8%) showed PD-L1 positive and 71 cases (16.2%) showed PD-L2 positive expression. There was no significant relationship between PD-L1 and PD-L2 positive cases (p=0.18). In both PD-L1 and PD-L2 positive cases, double immunohistochemical staining for PD-L1 and PD-L2 showed that there was a heterogeneity for PD-L1 and PD-L2 positive tumor cell. PD-L1 positive cases were significantly associated with tobacco use (p=0.013), pathological stage (p=0.001), and preoperative therapy present cases (p=0.015). In the other hand, PD-L2 positive cases were significantly associated with younger age (p=0.029). Thus PD-L1 and PD-L2 patient characteristics were likely different. Overall survival rates of the patients with PD-L1 or PD-L2 positive were significantly worse than those with PD-L1 or PD-L2 negative (p=0.009 and p=0.013, respectively). Conclusion: There was no significant relationship between PD-L1 and PD-L2 expression, and patient characteristics of those were different in patients with esophageal cancer. But both PD-L1 and PD-L2 expression were significantly associated with prognosis, supporting their roles as prognostic biomarkers. Citation Format: Kazuo Okadome, Yoshifumi Baba, Taisuke Yagi, Yuki Kiyozumi, Kojiro Eto, Yukiharu Hiyoshi, Yohei Nagai, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Clinical significance and the difference between programmed death-1 ligand-1 and ligand-2 in patients with esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4123.
Compulsory vaccination: case isolation is likely to be more effective
Authors: Mark Temple
Journal: BMJ (2019)

Draeger mentions herd immunity while discussing compulsory vaccination.1 The concept of herd immunity arises from ordinary differential equation models, with the population at risk mixing randomly. The model assumes that children in rural Scotland, Wales, or Cornwall have the same chance of contact with a person with measles in London as do children in Westminster.

Keeling and Eames showed that the structure of contact networks …
Abstract 17005: Endomyocardial Biopsies for Diagnostic Evaluation of Specific Cardiomyopathies: A Contemporary Single-Center Experience
Authors: Sulaiman M Mapara, Randall C Starling, Carin Grobolsek, Carmela D Tan, E. Rene Rodriguez, Mazen A Hanna, Guilherme H Oliveira, David O Taylor, W. H. Wilson Tang
Journal: Circulation (2012)

Background: Endomyocardial biopsy (EMBx) has been utilized to identify underlying etiologies of specific cardiomyopathies. The evolution of indications and diagnostic outcomes of EMBx in the contem...
Abstract 994: Combining ruthenium metallo-intercalators and targeted radionuclide therapy for EGFR-overexpressing oesophageal cancer
Authors: Martin R. Gill, Jyothi U. Menon, Robert Carlisle, Katherine A. Vallis
Journal: Cancer Research (2019)

Abstract Targeted radionuclide therapy (TRT) combines the specificity of molecular targeting with the potent cytotoxicity of ionising radiation. An emerging question is how to most effectively integrate TRT with radiosensitizing small molecules [1]. Auger electron-emitting radionuclides such as 111In are well-suited as the therapeutic radionuclide as their short-range reduces “cross fire” damage to neighbouring cells. As a novel chemical class of radiosensitizing agent, we have found ruthenium polypyridyl complexes (RPCs) that intercalate between DNA base pairs such as Ru(phen)2(tpphz)2+ (phen = 1,10 phenanthroline, tpphz = tetrapyridophenazine) act to stall replication forks and impede mitotic progression in human oesophageal cancer cells [2,3]. This dual mechanism of action results in preferential growth inhibition of rapidly-proliferating oesophageal cancer cells with elevated mitotic indices. In contrast to cisplatin and other DNA-damaging agents, relatively low DSB levels are generated in response to RPC metallo-intercalation and reduced cytotoxicity towards non-cancer cells is observed. In addition to this, treatment is able to enhance cancer cell sensitivity to IR by increasing IR-induced DNA double-strand break (DSB) damage, decreasing cell survival in a synergistic manner. Based on these discoveries, we explore how nanoparticle-mediated delivery of Ru(phen)2(tpphz)2+ and the Auger electron emitting radionuclide 111In can achieve localised cytotoxicity enhancement specifically in EGFR-overexpressing oesophageal cancer cells, thereby demonstrating both a combinational effect alongside molecular targeting for this novel combination [4]. References:[1] M. R. Gill, N. Falzone, Y. Du and K. A. Vallis, Lancet Oncol, 18, e414 (2017).[2] M. R. Gill, S. N. Harun, S. Halder, R. A. Boghozian, K. Ramadan, H. Ahmad and K. A. Vallis, Sci. Rep., 6, 31973 (2016).[3] M. R. Gill, P. J. Jarman, S. Halder, M. G. Walker, H. K. Saeed, J. A. Thomas, C. Smythe, K. Ramadan and K. A. Vallis, Chem. Sci., 9, 841 (2018).[4] M. R. Gill, J. U. Menon, P. J. Jarman, J. Owen, I. Skaripa-Koukelli, S. Able, J. A. Thomas, R. Carlisle, K. A. Vallis, Nanoscale, 10, 10596 (2018). Citation Format: Martin R. Gill, Jyothi U. Menon, Robert Carlisle, Katherine A. Vallis. Combining ruthenium metallo-intercalators and targeted radionuclide therapy for EGFR-overexpressing oesophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 994.
Abstract 1469: Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration
Authors: Hilary McElwaine-Johnn, Sam Illingworth, Rochelle Lear, Richard Brown, Brian Champion
Journal: Cancer Research (2019)

Abstract Background:EnAd is a tumor-selective oncolytic adenovirus with highly selective replication and cell killing in a broad range of carcinoma cell lines. Following intravenous dosing in clinical studies, uptake and replication of EnAd, associated with CD8+ cell infiltration, has been shown. It is currently in combination studies with nivolumab and paclitaxel. Intravenous delivery of EnAd stimulates an acute response characterised by an increase in cytokines in peripheral blood. As previously reported (ESMO IO 2017, abstr 203), the MTD of EnAd (3x1012 viral particles (vp) Days 1, 3 and 5, flat dosing schedule) has been determined primarily based on AEs occurring on first dose (C1D1), with the cytokine response, including interleukin-6 (IL-6), to subsequent doses of EnAd appearing attenuated when delivered within a few days of the first dose. Methods: The effect of the first EnAd dose on subsequent acute particle-mediated cytokine (IL-6) responses in mice was investigated following administration of systemic doses equivalent to between 5.5 x 1012 vp and 5.5 x 1013 vp in humans. Results: The magnitude of IL-6 response to a low first dose, which itself induces very low or undetectable levels of IL-6 cytokine, is sufficient to attenuate the response to subsequent high doses (10 times more vp). When administered as first dose these high doses induced a significant elevation in systemic IL-6. Conclusions: Tolerability of EnAd is primarily determined by C1D1, correlating with the cytokine response across the patient cohort. The data from this in vivo pharmacology study support the concept of delivering a lower dose of enadenotucirev on Day 1 and administering higher doses thereafter, with the aim to deliver a higher viral load to tumour tissue and potentially optimise the overall risk:benefit of EnAd administration. This type of dosing regimen (low-high-high) has been successfully implemented in clinical studies of other systemically administered oncolytic viruses (Clin Cancer Res 2006;12:2555-2562) and is under clinical investigation as part of the ongoing combination study with nivolumab. (EudraCT:2013-001276-38). Citation Format: Hilary McElwaine-Johnn, Sam Illingworth, Rochelle Lear, Richard Brown, Brian Champion. Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1469.
Abstract 1117: The molecular basis of LIF-mediated NPC metastasis
Authors: Shu-Chen Liu
Journal: Cancer Research (2019)

Abstract Distant metastasis and local recurrence are frequently observed in nasopharyngeal carcinoma (NPC) but the mechanisms remain largely unclear. Here, we report that higher levels of leukemia inhibitory factor (LIF) and LIF receptor (LIFR) are correlated with poorer metastasis/recurrence-free survival. LIF reprograms the invasive mode from collective to mesenchymal migration via acquisition of EMT and invadopodia-associated characteristics. Higher cytoplasmic LIF enhances cancer vascular dissemination and local invasion mechanistically, both in vitro and in vivo, through modulation of LIFR-YAP1-focal adhesion signaling. Pharmaceutical intervention with AZD0530 markedly reverses LIF-mediated cancer dissemination and local invasion through promotion of cytoplasmic accumulation of YAP1 and suppression of focal adhesion kinases. Given the significant role of LIF/YAP1-focal adhesion signaling in cancer progression, targeting of this pathway presents a promising opportunity to block metastasis. Citation Format: Shu-Chen Liu. The molecular basis of LIF-mediated NPC metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1117.
Authors’ reply to Crawford
Authors: Naomi J Fulop, Angus I G Ramsay
Journal: BMJ (2019)

We thank Crawford for his constructive response to our article.12 His argument—that changes to the organisation and delivery of care should undergo rigorous evaluation, with a focus on effects on access to care—is well made. We have urged similar in previous commentaries,34 emphasising the importance of using meaningful measures of impact and remaining open to whether such changes are …
Abstract 2117: Different sensitivities of four protein tyrosine kinase inhibitors towards drug-resistant RET mutations
Authors: Xuan Liu, Tao Shen, Qingling Huang, Teng Peng, Frank Hilberg, Jianfeng Cai, Blaine H. Mooers, Jie Wu
Journal: Cancer Research (2019)

Abstract The RET protein tyrosine kinase (PTK) is a clinically validated target of therapy in non-small cell lung cancer (NSCLC) and thyroid cancer. Mutations in the targeted PTKs is a mechanism of drug resistance in cancer therapy with tyrosine kinase inhibitors (TKIs). Mutation-sensitive secondary drugs have been used successfully to overcome acquired drug-resistance to the first line TKIs. Cabozantinib, lenvatinib, vandetanib, and nintedanib are FDA-approved multikinase TKIs with anti-RET activity. Using RET kinase-dependent BaF3/KIF5B-RET cells, we isolated thirteen mutations resistant to one of these TKIs. Cross-analysis of sensitivities of these four TKIs on these drug-resistant RET mutants and the RETM918T mutant, which is found in medullary thyroid carcinoma, revealed different TKI resistance-sensitivity profiles. In particular, the RETM918T mutant was resistant to cabozantinib, lenvatinib, and vandetanib but did not affect the potency of nintedanib. RETL881V was isolated as a vandetanib-resistant mutation. The RETL881V mutation also induced resistance to cabozantinib and lenvatinib but did not affect the nintedanib sensitivity. Examination of the RET-vandetanib co-crystal structure and the chemical structures of vandetanib and nintedanib suggested that a phenyl group in nintedanib, which corresponds to a methoxy group in vandetanib, may form hydrophobic interaction with the shorter side chain of Val881 and thus allows nintedanib to inhibit RETL881V. To test this possibility, we synthesized two nintedanib analogs (Compound 1 and Compound 2) without the phenyl group and tested their activities. The data showed that RETL881V was resistant to Compound 1 and Compound 2, supporting a role of the phenyl group of nintedanib in mediating inhibition of RETL881V. Taken together, we have identified 13 RET mutations that display different resistance-sensitivity profiles against four anti-RET TKIs. Moreover, nintedanib is effective in inhibiting RETM918T and RETL881V mutants that are resistant to the other three TKIs. Citation Format: Xuan Liu, Tao Shen, Qingling Huang, Teng Peng, Frank Hilberg, Jianfeng Cai, Blaine H. Mooers, Jie Wu. Different sensitivities of four protein tyrosine kinase inhibitors towards drug-resistant RET mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2117.
Health-Related Workplace Absenteeism Among Full-Time Workers — United States, 2017–18 Influenza Season
Authors: Matthew R. Groenewold, Sherry L. Burrer, Faruque Ahmed, Amra Uzicanin, Sara E. Luckhaupt
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

During an influenza pandemic and during seasonal epidemics, more persons have symptomatic illness without seeking medical care than seek treatment at doctor's offices, clinics, and hospitals (1). Consequently, surveillance based on mortality, health care encounters, and laboratory data does not reflect the full extent of influenza morbidity. CDC uses a mathematical model to estimate the total number of influenza illnesses in the United States (1). In addition, syndromic methods for monitoring illness outside health care settings, such as tracking absenteeism trends in schools and workplaces, are important adjuncts to conventional disease reporting (2). Every month, CDC's National Institute for Occupational Safety and Health (NIOSH) monitors the prevalence of health-related workplace absenteeism among full-time workers in the United States using data from the Current Population Survey (CPS) (3). This report describes the results of workplace absenteeism surveillance analyses conducted during the high-severity 2017-18 influenza season (October 2017-September 2018) (4). Absenteeism increased sharply in November, peaked in January and, at its peak, was significantly higher than the average during the previous five seasons. Persons especially affected included male workers, workers aged 45-64 years, workers living in U.S. Department of Health and Human Services (HHS) Region 6* and Region 9,† and those working in management, business, and financial; installation, maintenance, and repair; and production and related occupations. Public health authorities and employers might consider results from relevant absenteeism surveillance analyses when developing prevention messages and in pandemic preparedness planning. The most effective ways to prevent influenza transmission in the workplace include vaccination and nonpharmaceutical interventions, such as staying home when sick, covering coughs and sneezes, washing hands frequently, and routinely cleaning frequently touched surfaces (5).
Abstract 17527: Intestinal Barrier Dysfunction and Elevated Right Atrial Pressure in Patients With Advanced Heart Failure
Authors: Takeshi Kitai, Ina Nemet, Timothy Engelman, Rommel Morales, Kathryn Kiefer, Stanley L Hazen, W. H. Wilson Tang
Journal: Circulation (2017)

Background: Altered intestinal function is prevalent and has been increasingly recognized as a contributor to disease progression in patients with heart failure. A structural disruption of the inte...
CMV reactivation in allogeneic hematopoietic stem cell transplant patients receiving post-transplant cyclophosphamide.
Authors: Paul Markowski, Dale G. Schaar, Catherine Wei, Anne Tyno
Journal: Journal of Clinical Oncology (2019)

e18533 Background: Post transplant cyclophosphamide (PTCY) has been shown to be an effective treatment for prevention of graft versus host disease (GVHD). However, this increased immune suppression rates may increase the risk of CMV reactivation. There is limited published data addressing CMV reactivation in this patient population. Additionally there is no data on the efficacy of prophylactic letermovir in the patients who have received PTCY. In this study we analyzed the incidence of CMV reactivation in patients treated with PTCY and those not treated with PTCY, as well as the efficacy of letermovir in preventing CMV reactivation in the PTCY population. Methods: We conducted a retrospective review of MUD, MRD, and haploidentical stem cell transplant patients at our institution from 1/1/2014 until 12/10/2018. We analyzed the incidence of CMV reactivation (PCR &gt; 137 DNA IU/ml), peak of CMV PCR titer and time to reactivation within the first 100 days post-transplant. Results: There were 150 patients with at least 60 days of follow-up that were included in this study. These patients were split into three groups: No post-transplant cyclophosphamide (NPTCY) (N = 64), received post-transplant cyclophosphamide (PTCY) (N = 70), and received PTCY and letermovir prophylaxis. (L-PTCY) (N = 15). The incidence of CMV reactivation was increased in the PTCY patients when compared to the NPTCY (44% vs 29%). In the NPTCY patients the donor (D) serostatus increased the risk of CMV reactivation (Recipient (R)+ D+ 73% vs R+D-36%) conversely in the PTCY group the donor CMV status did not influence reactivation rates (R+D+ 52% vs R+D- 81%). The CMV reactivation rate in the L-PTCY patients was lower when compared to the PTCY patients (21% vs 44%), additionally the L-PTCY patients had much lower peak CMV titers compared to PTCY group (445 vs 2112 IU/ml). Conclusions: This study demonstrates that there is an increased incidence of CMV reactivation in patients who receive PTCY. Additionally, the donor CMV serostatus does not appear to influence the incidence of CMV reactivation in patients receiving post-transplant CY. Although the number of patients in the L-PTCY group is small, it does appear to be an effective prophylactic treatment in patients receiving PTCY.
Immune Checkpoint Blockade Enhances Shared Neoantigen-Induced T-cell Immunity Directed against Mutated Calreticulin in Myeloproliferative Neoplasms
Authors: Cansu Cimen Bozkus, Vladimir Roudko, John P. Finnigan, John Mascarenhas, Ronald Hoffman, Camelia Iancu-Rubin, Nina Bhardwaj
Journal: Cancer Discovery (2019)

Somatic frameshift mutations in the calreticulin (CALR) gene are key drivers of cellular transformation in myeloproliferative neoplasms (MPN). All patients carrying these mutations (CALR + MPN) share an identical sequence in the C-terminus of the mutated CALR protein (mut-CALR), with the potential for utility as a shared neoantigen. Here, we demonstrate that although a subset of patients with CALR + MPN develop specific T-cell responses against the mut-CALR C-terminus, PD-1 or CTLA4 expression abrogates the full complement of responses. Significantly, blockade of PD-1 and CLTA4 ex vivo by mAbs and of PD-1 in vivo by pembrolizumab administration restores mut-CALR-specific T-cell immunity in some patients with CALR + MPN. Moreover, mut-CALR elicits antigen-specific responses from both CD4+ and CD8+ T cells, confirming its broad applicability as an immunogen. Collectively, these results establish mut-CALR as a shared, MPN-specific neoantigen and inform the design of novel immunotherapies targeting mut-CALR. SIGNIFICANCE: Current treatment modalities for MPN are not effective in eliminating malignant cells. Here, we show that mutations in the CALR gene, which drive transformation in MPN, elicit T-cell responses that can be further enhanced by checkpoint blockade, suggesting immunotherapies could be employed to eliminate CALR + malignant cells in MPN.This article is highlighted in the In This Issue feature, p. 1143.
Abstract 11724: Premature Atrial Contraction Frequency is not Associated With Cerebral Infarcts: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Lin Y Chen, Sunil K Agarwal, Faye L Norby, Rebecca F Gottesman, Laura R Loehr, Elsayed Z Soliman, Thomas H Mosley, Aaron R Folsom, Josef Coresh, Alvaro Alonso
Journal: Circulation (2015)

Background: Premature atrial contractions (PACs) have been shown to predict incident atrial fibrillation (AF). However, the association between PAC frequency and risk of ischemic stroke is less well-characterized. We evaluated the cross-sectional association between PAC frequency and cerebral infarcts on brain MRIs in a sample of participants from the ARIC study, a community-based prospective cohort study. Hypothesis: We hypothesized that higher PAC frequency is associated with higher odds of cerebral infarcts. Methods: We included 323 (mean age [SD], 78.8 [5.1] years; 52.9% female) participants who underwent brain MRI scans, and ≥2 days of heart rhythm recording using the Zio ® Patch (a non-invasive, 2-week continuous ECG monitor) in July 2013-March 2014. PAC frequency was defined as the number of PACs per hour, averaged over the entire monitoring period. Definitions of MRI-diagnosed brain infarcts are given in the Table . We used multivariable logistic regression to assess the association of PAC frequency tertiles with cerebral infarcts on MRI scans. Results: The mean wear and analysis time of the Zio ® Patch were 13.1 [2.1] and 12.7 [2.3] days, respectively. Twenty-six (8%) participants had AF detected by the Zio ® Patch. Higher PAC frequency was not associated with higher odds of cerebral infarcts (Table). A sex- and age-adjusted logistic regression modeling PAC frequency with a restricted cubic spline confirmed the lack of association with cerebral infarcts. Conclusions: Although PACs are a precursor to AF, and the risk factors for PACs are largely similar to AF, higher PAC frequency is not related to higher odds of cerebral infarcts. This finding suggests that the disorganized rhythm of AF or the presence of some other factor such as left atrial enlargement or dysfunction may be necessary for the pathogenesis of ischemic stroke.