tbuckley/cabot-search huggingface dataset:
Prognostic value of CD8+ tumor-infiltrating lymphocyte density and PD-L1 expression in tumor cells in thymic epithelial tumors.
Authors: Yuki Katsuya, Hidehito Horinouchi, Yasushi Goto, Shintaro Kanda, Yutaka Fujiwara, Hiroshi Nokihara, Noboru Yamamoto, Shun-ichi Watanabe, Noriko Motoi, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2017)

21 Background: The prognostic significance of CD8+ tumor-infiltrating lymphocytes (TILs) in thymic epithelial tumors (TETs; thymoma [TM] and thymic carcinoma [TC]) is unknown. We examined whether the density of CD8+ TILs and the PD-L1 expression level in TETs were correlated with patient outcome. Methods: Immunohistochemistry and a semi-automated software quantification analysis were used to examine formalin-fixed paraffin-embedded specimens from patients with TET who had been treated with chemotherapy. The density of CD8+ TILs was evaluated at two representative sites: within the tumor nest (intratumoral CD8), and at the invasive margin (stromal CD8, if evaluable). The average density of CD8+ TILs was used as the cut-off value, while an H-score of 5% was used as the cut-off for PD-L1 expression. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate prognostic factors. Results: Twenty-six patients (TM/TC 9/17) were evaluated. A high intratumoral CD8 density was correlated with a superior outcome in terms of both PFS (median, 7.6 vs 27.7 months; P = 0.002) and OS (median, 54.3 months vs not reached; P = 0.022) among the patients with TM, and a similar tendency was seen among the patients with TC, although the correlations were not statistically significant. PD-L1 expression was not significantly correlated with patient outcome in the TM and TC groups. Univariate and multivariate analyses demonstrated that a high intratumoral CD8 density was a significant predictive factor for PFS (Hazard ratio, 0.25 [95%CI 0.08–0.75]; P = 0.014) and OS (Hazard ratio, 0.06 [95%CI 0.007–0.44]; P= 0.006), whereas PD-L1 expression was not. The tendency for a change in the intratumoral CD8 density in pre/post-chemotherapy TM specimens was not consistent. The proportion of stromal CD8 density to intratumoral CD8 density in the TC specimens was not correlated with survival. Conclusions: A high intratumoral CD8 density had a positive prognostic impact for patients with TETs, especially those with TMs. The impact of this immune-related factor should be validated in a larger cohort.
TRRAP is essential for regulating the accumulation of mutant and wild-type p53 in lymphoma
Authors: Alexander Jethwa, Mikołaj Słabicki, Jennifer Hüllein, Marius Jentzsch, Vineet Dalal, Sophie Rabe, Lena Wagner, Tatjana Walther, Wolfram Klapper, Hanibal Bohnenberger, Mandy Rettel, Junyan Lu, Arne H. Smits, Frank Stein, Mikhail M. Savitski, Wolfgang Huber, Yael Aylon, Moshe Oren, Thorsten Zenz
Journal: Blood (2018)
Ministers seek to stop GPs charging victims of domestic abuse for information
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The government is considering recommending changes to the GP contract to block practices from charging victims of domestic abuse for letters to help them access legal aid or housing, The BMJ has found.

The move comes after MPs and peers raised concerns about the issue with the Department of Health and Social Care, after reports that some practices charge people £100 (€116; $143) to confirm to authorities that they were a victim of domestic violence.

The general medical services contract does not currently fund general practices for issuing such letters, and practices are permitted to charge patients.

But MPs and peers said that charging a vulnerable group of patients in this way was …
Arterial Venous Differentiation for Vascular Bioengineering
Authors: Laura Niklason, Guohao Dai
Journal: Annual Review of Biomedical Engineering (2018)

The development processes of arteries and veins are fundamentally different, leading to distinct differences in anatomy, structure, and function as well as molecular profiles. Understanding the complex interaction between genetic and epigenetic pathways, as well as extracellular and biomechanical signals that orchestrate arterial venous differentiation, is not only critical for the understanding of vascular diseases of arteries and veins but also valuable for vascular tissue engineering strategies. Recent research has suggested that certain transcriptional factors not only control arterial venous differentiation during development but also play a critical role in adult vessel function and disease processes. This review summarizes the signaling pathways and critical transcription factors that are important for arterial versus venous specification. We focus on those signals that have a direct relation to the structure and function of arteries and veins, and have implications for vascular disease processes and tissue engineering applications.
Targeting the glucose metabolism of monocytic myeloid-derived suppressor cells to stimulate cancer immunity.
Authors: Jaspreet Singh Grewal, Numan Al-Rayyan, Jamaal Ritchie, Paxton Schowe, Cam Falkner, Sucheta Telang, Kavitha Yaddanapudi, Jason Alan Chesney
Journal: Journal of Clinical Oncology (2017)

126 Background: Myeloid derived suppressor cells (MDSCs) inhibit the expansion of tumor antigen-specific effector CD8+ T cells via different mechanisms including increased expression of arginase, transforming growth factor – β (TGF – β) and indoleamine 2,3-dioxygenase (IDO). Recently, MDSCs were found to over-express hypoxia inducible factor 1 alpha (HIF-1α) which is required for their differentiation. An essential transcriptional target of HIF-1α is 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) which synthesizes fructose 2,6-bisphosphate, an allosteric stimulator of glycolysis and of proliferation via stimulation of cyclin dependent kinase-1 (CDK1). We hypothesized that MDSCs might over-express PFKFB3 which in turn might be required for their function as T cell suppressors. Methods: We used monocytic MDSCs (M-MDSCs) induced by co-culture with A375 melanoma cells, M-MDSCs from metastatic melanoma patients, murine bone marrow MDSCs and splenic M-MDSCs from B16 F10 tumor bearing mice for our studies. T cell suppression assays were performed to analyze M-MDSC suppression and reversal following PFKFB3 blockade. Results: We found that M-MDSCs have increased PFKFB3 expression. We also found that PFK-158 administration in B16 (wild-type) melanoma-bearing mice results in a marked reduction in MDSCs and a simultaneous increase in CD8+ T cell infiltration in the tumors. We analyzed three advanced cancer patients for circulating MDSCs before and after PFK-158 administration as part of a multi-center phase 1 clinical trial. And, we found that the MDSCs were markedly reduced in each patient. In addition, we have generated data for MDSC suppressive activity following in vitro treatment with PFK-158 showing reversal of suppressive activity. Conclusions: Taken together, these data indicate that selective inhibition of PFKFB3 may be a novel approach to target MDSCs and combinations of PFKFB3 inhibitors with immunotherapies may be a rational strategy to promote durable immune-mediated remissions in cancer patients.
An immunologically relevant rodent model demonstrates safety of therapy using a tumour‐specific IgE
Authors: D. H. Josephs, M. Nakamura, H. J. Bax, T. S. Dodev, G. Muirhead, L. Saul, P. Karagiannis, K. M. Ilieva, S. Crescioli, P. Gazinska, N. Woodman, C. Lombardelli, S. Kareemaghay, C. Selkirk, H. Lentfer, C. Barton, S. Canevari, M. Figini, N. Downes, D. Dombrowicz, C. J. Corrigan, F. O. Nestle, P. S. Jones, H. J. Gould, P. J. Blower, S. Tsoka, J. F. Spicer, S. N. Karagiannis
Journal: Allergy (2018)

Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans.
Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin‐2 and neutrophil extracellular traps
Authors: Hongjie Li, Dechun Feng, Yan Cai, Yudong Liu, Mingjiang Xu, Xiaogang Xiang, Zhou Zhou, Qiang Xia, Mariana J. Kaplan, Xiaoni Kong, Bin Gao
Journal: Hepatology (2018)

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), a key antibacterial protein, is highly elevated in patients with end-stage liver disease that is often associated with bacterial infection. LCN2 is expressed at high levels in both hepatocytes and neutrophils; however, how hepatocyte-derived and neutrophil-derived LCN2 cooperate to combat bacterial infection remains unclear. Here, by studying hepatocyte-specific and myeloid-specific Lcn2 knockout mice in two models of systemic and local Klebsiella pneumoniae infections, we demonstrated that hepatocytes played a critical role in controlling systemic infection by secreting LCN2 protein into the circulation following intraperitoneal injection of bacteria, whereas neutrophils were more important in combating local lung infection by carrying LCN2 in their specific granules to the local infection site following intratracheal intubation of bacteria. Both hepatocyte-derived and myeloid cell-derived LCN2 were required against bacterial infection in the peritoneal cavity and liver necrotic areas following intraperitoneal injection of Klebsiella pneumoniae. LCN2/NGAL protein was detected in neutrophil extracellular traps (NETs) in activated neutrophils from mice and humans. Disruption of the Lcn2 gene in neutrophils abolished LCN2 on NETs, whereas deletion of this gene in hepatocytes did not affect LCN2 protein on NETs. Genetic deletion of the Lcn2 gene globally or specifically in neutrophils did not affect NET formation but reduced the bactericidal effect of NETs in vitro. Finally, NGAL-positive NETs were detected in the liver from patients with various types of liver diseases.Both hepatocytes and neutrophils combat bacterial infection through the production of LCN2; extracellular LCN2 secreted by hepatocytes limits systemic bacterial infection, whereas neutrophils carry LCN2 protein to the local site and against local bacterial infection through NETs. (Hepatology 2018).
Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study
Authors: Gregor Warnecke, Dirk Van Raemdonck, Michael A Smith, Gilbert Massard, Jasleen Kukreja, Federico Rea, Gabriel Loor, Fabio De Robertis, Jayan Nagendran, Kumud K Dhital, Francisco Javier Moradiellos Díez, Christoph Knosalla, Christian A Bermudez, Steven Tsui, Kenneth McCurry, I-Wen Wang, Tobias Deuse, Guy Lesèche, Pascal Thomas, Igor Tudorache, Christian Kühn, Murat Avsar, Bettina Wiegmann, Wiebke Sommer, Arne Neyrinck, Marco Schiavon, Fiorella Calabrese, Nichola Santelmo, Anne Olland, Pierre-Emanuel Falcoz, Andre R Simon, Andres Varela, Joren C Madsen, Marshall Hertz, Axel Haverich, Abbas Ardehali
Journal: The Lancet Respiratory Medicine (2018)
3PD Co-targeting PIM1 or Src to overcome the limits of single MET inhibition
Authors: I. Attili, N. Karachaliou, J. Bracht, J. Berenguer, C. Codony-Servat, M. Ito, M. Rugge, P.F. Conte, L. Bonanno, R. Rosell
Journal: Journal of Thoracic Oncology (2018)
M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with advanced solid tumors.
Authors: Yutaka Fujiwara, Takafumi Koyama, Christoph Helwig, Morihiro Watanabe, Toshihiko Doi
Journal: Journal of Clinical Oncology (2018)

762 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report results in Asian patients (pts) with advanced solid tumors. Methods: NCT02699515 is a phase 1, open-label, 3 + 3 dose-escalation study. Pts receive M7824 at 3, 10 or 20 mg/kg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics (PK), immunogenicity and best overall response per RECIST v1.1. Results: As of 28 February 2017, 14 heavily pretreated pts (85.7% received ≥3 prior therapies) received M7824 for a median duration of 5.9 weeks (range: 2-40 weeks). Grade (gr) ≥3 treatment-related adverse events occurred in 3 pts (21.4%): 1 pt (3 mg/kg) had gr 4 hyponatremia and gr 3 hypopituitarism; 1 pt (20 mg/kg) had gr 3 intracranial tumor hemorrhage (dose-limiting toxicity; treatment discontinued [TD]); 1 pt (20 mg/kg) had gr 3 increased blood creatine phosphokinase, hyponatremia and hypoacusis (TD). PK data showed a dose-linear increase in exposure. Signs of efficacy were seen across all dose levels: 2 pts (colorectal cancer [CRC] associated with Lynch syndrome [3 mg/kg] and ovarian cancer [20 mg/kg]) achieved a confirmed partial response (PR) and 3 pts (gastric/gastroesophageal junction cancer [3 mg/kg], gastric cancer [3 mg/kg] and adenoid cystic carcinoma of the tongue [10 mg/kg]) achieved stable disease. Durations of response were 1.1+ months (ovarian; PR occurred after TD, with no further anticancer therapy) and 7.0+ months (CRC; treatment ongoing); both PRs were ongoing beyond the data cutoff. Conclusions: M7824 had a manageable safety profile in Asian pts with heavily pretreated advanced solid tumors; the MTD was not reached. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.
Molecular ablation of tumor blood vessels inhibits therapeutic effects of radiation and bevacizumab
Authors: Viveka Nand Yadav, David Altshuler, Padma Kadiyala, Daniel Zamler, Andrea Comba, Henry Appelman, Patrick Dunn, Carl Koschmann, Maria G Castro, Pedro R Löwenstein
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is an aggressive and highly vascular tumor with median survival below 2 years. Despite advances in surgery, radiotherapy, and chemotherapy, survival has improved modestly. To combat glioma vascular proliferation, anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) were introduced. Preclinically these agents were effective, yet they did not improve overall survival in phase III trials. We tested the hypothesis that ganciclovir (GCV)-mediated killing of proliferating endothelial cells expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) would have direct antitumor effects, and whether vessel ablation would affect the antitumor activity of anti-VEGF antibodies and radiotherapy.Proliferating endothelial cells were eliminated using GCV-mediated killing of proliferating endothelial cells expressing HSV1-TK (in Tie2-TK-IRES-GFP mice). Syngeneic NRAS/p53 (NP) gliomas were implanted into the brains of Tie2-TK-IRES-GFP mice. Endothelial proliferation activates the Tie2 promoter and HSV1-TK expression. Administration of GCV kills proliferating tumor endothelial cells and slows tumor growth. The effects of endothelial cell ablation on anti-angiogenic therapy were examined using anti-VEGF antibodies or irradiation.GCV administration reduced tumor growth and vascular density, increased tumor apoptosis, and prolonged survival. Anti-VEGF antibodies or irradiation also prolonged survival. Surprisingly, combining GCV with irradiation, or with anti-VEGF antibodies, reduced their individual therapeutic effects.GCV-mediated killing of proliferating endothelial cells expressing HSV1-TK, anti-VEGF antibodies, or irradiation all reduced growth of a murine glioma. However, elimination of microvascular proliferation decreased the efficacy of anti-VEGF or irradiation therapy. We conclude that, in our model, the integrity of proliferating vessels is necessary for the antiglioma effects of anti-VEGF and radiation therapy.
Re: Jose Luis Perez-Gracia, Yohann Loriot, Jonathan E. Rosenberg, et al. Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens. Eur Urol 2018;73:462–8
Authors: Francesco Massari, Vincenzo Di Nunno
Journal: European Urology (2018)
130O Real-world prevalence of PD-L1 expression in locally advanced or metastatic non-small cell lung cancer (NSCLC): The global, multicentre EXPRESS study
Authors: M. Dietel, N. Savelov, R. Salanova, P. Micke, G. Bigras, T. Hida, B. Piperdi, T. Burke, S. Khambata-Ford, A. Deitz
Journal: Journal of Thoracic Oncology (2018)
Abstract 12707: HIV Infection and Heart Failure Outcomes in Women
Authors: Sumbal A Janjua, Virginia A Triant, Balint Szilveszter, Daniel Addison, Susan Regan, Pedro Staziaki, Ravi V Shah, Grinspoon K Steven, Udo Hoffmann, Markella V Zanni, Tomas G Neilan
Journal: Circulation (2016)

Introduction: Women with HIV have an increased risk of incident heart failure (HF). Whether HF outcomes differ by HIV status in women has not been established. Methods: We performed a US health care system-based cohort study analyzing data from 1388 HIV-infected women initially matched 1:10 on age, race/ethnicity with uninfected women. The presence of HF was ascertained by ICD-9-CM codes and adjudicated by physicians blinded to HIV status. After adjudication, cohorts were re-matched 1:3 so that age, race/ethnicity would be similar in the final cohort. The primary outcome was incident HF hospitalization rate. Secondary outcomes included HF hospitalization length of stay, all cause and cardiovascular mortality. Results: The final HF cohort consisted of 34 HIV-infected and 102 uninfected women (mean age 59 years). There were no significant differences in the LVEF (54±15 vs. 52±14%, HIV+ vs. HIV-, p=0.48) or prevalence of HFrEF (EF&lt;50%) (29 vs. 35%, HIV+ vs. HIV-, p=0.67). HIV-infected women with HF had more cocaine use (23 vs. 6%, p=0.006), lower BMI (28±5 vs. 33±8 kg/m 2 , p=0.002), increased QRS (113±19 vs. 97±20 msec, p &lt;0.0001) and higher PASP (49±10 vs. 35±10 mmHg, p&lt;0.0001). Over a median follow-up of 5 years (IQR 4.0-7.5), HIV-infected women with HF had 2.5 times the rate of incident HF hospitalization, adjusted for age, HTN, DM, sleep apnea, CAD, ACE I/ARB and LVEF (HR: 2.5 (1.54-4.29), p&lt;0.0001) (Figure). HIV-infected women with HF also had an increased HF hospitalization length of stay (8 vs. 5 days, p&lt;0.001), and higher all-cause (53 vs. 21%, p&lt;0.001) and cardiovascular mortality (83 vs. 33%, p&lt;0.006). In sub-group analysis, HIV-infected women with HFrEF had lower use of guideline-recommended HF therapy (40 vs. 83%, p=0.01). Conclusions: As compared with matched uninfected women with HF, HIV-infected women with HF had a lower use of HF therapies, increased HF hospitalization rate, HF hospitalization length of stay, and all-cause and cardiovascular mortality.
Appropriate Time for Chronic Dialysis Initiation
Authors: Zijin Chen, Chi-yuan Hsu
Journal: JAMA Internal Medicine (2018)

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UK will invest £75m in research to improve prostate cancer care
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The prime minister, Theresa May, has launched a major drive to improve diagnosis and treatment of prostate cancer in the UK. The government will recruit over 40 000 men to new research studies over the next five years, backed by £75m (€86m; $106m) of investment.

Prostate cancer currently kills more than 11 000 men every year in the UK.

Announcing the initiative during a visit to an NHS hospital in Cambridgeshire, May said that the government was focused on achieving quicker diagnosis and treatment. Ahead of the visit, she said, “Our cancer treatments are world …
198TiP Afatinib plus EGF pathway targeting immunization (EGF-PTI) as first line therapy for EGFR mutant NSCLC: The EPICAL study
Authors: N. Karachaliou, A. Cardona Zorrilla, D. Rodríguez-Abreu, M. Cobo Dols, N. Reguart Aransay, S. Viteri, J. Codony-Servat, M.A. Molina-Vila, E. D'Hondt, R. Rosell
Journal: Journal of Thoracic Oncology (2018)
Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.
Authors: J. Randolph Hecht, Miklos Pless, Antonio Cubillo, Aitana Calvo, Steven Raman, Chunxu Liu, Emily Chan, Jason Alan Chesney, Aleix Prat
Journal: Journal of Clinical Oncology (2018)

438 Background: T-VEC is a genetically modified HSV-1 oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF, and stimulate anti-tumor immune responses. This study evaluates the safety of intrahepatic injection (inj) of T-VEC in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated dose. Eligible pts were ≥ 18 years (y) old, had progressive HCC or breast cancer (BC), colorectal cancer (CRC), gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 10 6 plaque-forming units (PFU)/mL followed by up to 4 mL of 10 7 PFU/mL (cohort 1) or 10 8 PFU/mL (cohort 2) every 21 (±3) days (Q21D), or up to 8 mL of the maximum tolerated concentration (MTC) Q21D (cohort 3). Inj volume was based on lesion size. Results: Results from cohorts 1 and 2 of group A are reported. 14 pts were treated; 12 (3 BC, 9 CRC) were DLT-evaluable: Median age was 65.5 y (range: 33, 73); median number of inj was 3; 1 pt received all 12 inj. MTC was 10 8 PFU/mL. There was 1 DLT, grade 3 aspartate aminotransferase (AST)/grade 2 bilirubin increase (inc), after 1 dose. In all treated pts, 4 (28.6%) had grade 3/4 treatment-related adverse events (TRAEs): anemia and inc gamma-glutamyltransferase, alanine aminotransferase (ALT), and AST. There were 2 deaths attributable to disease. Incidence of serious AEs (SAEs) is shown (Table). Conclusions: The MTC was 10 8 PFU/mL Q21D after initial inj at 10 6 PFU/mL. Repeated intrahepatic inj of T-VEC at the FDA-approved concentration for intralesional inj of melanoma was deemed tolerable and feasible in pts with liver mets. Additional investigation in combination with a PD-1 inhibitor is planned. Clinical trial information: NCT02509507. [Table: see text]