tbuckley/cabot-search huggingface dataset:
The impact of Tfh cell/ B cell pathway-related genetic variants in metastatic colorectal cancer patients with bevacizumab-based chemotherapy.
Authors: Ryuma Tokunaga, Shu Cao, Wu Zhang, Alberto Puccini, Martin D Berger, Madiha Naseem, FRANCESCA BATTAGLIN, Shivani Soni, Michelle McSkane, Sebastian Stintzing, Fotios Loupakis, Volker Heinemann, Alfredo Falcone, Joshua Millstein, Heinz Josef Lenz
Journal: Journal of Clinical Oncology (2018)

651 Background: B cells are recognized for their immune activation and lymph-angiogenesis, which attract us to clarify the correlation between B cells and the effect of bevacizumab in cancer patients. We thus investigated whether genetic polymorphisms in Tfh cell/ B cell pathway could predict clinical outcomes in metastatic colorectal cancer (mCRC) patients with bevacizumab-based chemotherapy in first-line treatment. Methods: Genomic DNA was extracted from 451 samples of three independent cohorts: a discovery cohort of 215 patients with bevacizumab plus FOLFIRI in TRIBE (NCT00719797); a validation cohort of 107 patients with bevacizumab plus FOLFIRI in FIRE-3 (NCT00433927); a control cohort of 129 patients with cetuximab plus FOLFIRI in FIRE-3. The OncoArray including 530K single nucleotide polymorphisms (SNPs) from Illumina was used in this study. The correlation between selected SNPs in Tfh cell/ B cell pathway ( CCL19, CCL21, CCR7, CXCL13, CXCR5, and S1PR2) and clinical outcomes were analyzed. Results: In the discovery cohort, patients with any CXCL13 rs355687 C allele had shorter OS than those with T/T variant (22.9 vs. 30.8 months, HR 1.36, 95%CI: 1.00–2.86, P = 0.050), which remained significant in multivariable analysis (HR 1.51, P = 0.013); they also showed a trend of lower response rate (51 vs. 63%, P = 0.093); patients with any CCL21 rs11574915 C allele had shorter OS than those with A/A variant (25.6 vs. 27.9 months) in both univariate (HR 1.43, 95%CI: 1.01–2.02, P = 0.043) and multivariable analyses (HR 1.50, P = 0.030). In the validation cohort, patients with any CXCL13 rs355687 C allele had a trend which showed lower response rate than those with T/T variant (56 vs. 71%, P = 0.099). The findings were not detected in the control cohort. Conclusions: Genetic polymorphisms of CXCL13 and CCL21 may impact the angiogenic environment and patients survivals. They are impacting efficacy of bevacizumab-based chemotherapy in first-line treatment.
Expansion of Lox-1<sup>+</sup>CD15<sup>+</sup> myeloid-derived suppressor cells in hepatocellular carcinoma patients.
Authors: Xing Li, Qing-Jian Ye, Yan-Fang Xing, Jin-Xiang Lin, Qu Lin, Xiang-yuan Wu
Journal: Journal of Clinical Oncology (2017)

124 Background: The top issue in the field of myeloid deprived suppressor cell (MDSC) was lack of specific markers. Lox-1 was reported to be a novel marker for polymorphonuclear MDSC (PMN-MDSC) in whole blood of head and neck cancer and lung cancer patients. The present study is aimed to detecting the lox-1 PMN-MDSC in whole blood. Methods: In the present study, a series of 24 hepatocellular carcinoma (HCC) patients and 12 healthy donors were analyzed investigating frequencies of PMN-MDSC (Lox-1 + CD15 + ) in whole blood. The immunosuppressive function of MDSC were evaluated using T cell proliferation and activation tests. The underly mechnisms were determined using inhibitors, genes expression and activity tests. The association between MDSC and clinical parameters were determined retrospectively. Results: Patients presented significantly higher level of PMN-MDSCs. In order to confirm immune suppressive capacity of PMN-MDSCs in HCC patients, circulative PMN-MDSCs and T cells were purified using flow sorting and cocultured. T cell proliferation was abrogated by the addition of PMN-MDSC with a dosage dependent manner, as well as the production of IFN-γ. Besides, the suppression on T cell proliferation and IFN-γ production was partially reversed by reactive oxygen species (ROS) inhibitor and Arginase inhibitor. The ROS level were higher in PMN-MDSC than their normal controls. The mRNA level of NOX2, the key protein complex responsible for ROS productin in MDSC, and Arginase I were higher in PMN-MDSCs. Finally, the frequencies of PMN-MDSCs was positively associated with tumor volume. Conclusions: The present study found that Lox-1 + CD15 + were novel markers for PMN-MDSCs in whole blood and very easily to be standardized between institutions.
Combining prognostic value of nodal ratio and neutrophil to lymphocyte ratio in completely resected gastric cancer with D2 lymph node dissection.
Authors: Andres Guevara, Daniel Enriquez, Patricia Elizabeth Rioja, Christian Pacheco, Victor Castro, Paola Catherine Montenegro, Eduardo Payet
Journal: Journal of Clinical Oncology (2017)

e15565 Background: Outcomes in gastric cancer (GC) are still dismal even with complete D2 resection surgery and chemotherapy (CT), therefore identification of prognostic factors is critical to stratify patients at risk of recurrence or death. Nodal ratio (NR) has been recognized as a valuable prognostic factor and neutrophil to lymphocyte ratio (NLR) as systemic inflammation biomarker in some neoplasms. We evaluate overall survival (OS) combining NR and NLR among completely resected GC patients with D2 lymph node dissection in a Peruvian population. Methods: We reviewed retrospectively 791 medical records from GC pts with complete radical D2 resection between 2008 and 2012 at Instituto Nacional de Enfermedades Neoplasicas. We grouped according NR in &lt; 0.2(Low), 0.2-0.5(Intermediate) and &gt; 0.5(High), and NLR with cut-off &lt; 3 and ≥3. We evaluated overall survival combining NR and NLR, also univariate and multivariate cox analysis were performed. OS was based on national registry and cannot evaluate DFS as long most patients return to their primary hospitals to follow-up. Results: Mean age was 60y [rank: 19-89]. Most frequent characteristics were distal localization (52.4%), intestinal subtype (52.6%) and poor differentiated histology (53%). From 791 patients, 156, 194 and 441 were diagnosed at I, II and III CS, respectively. Most patients had nodal involvement (66.8%), 21% and 28.4% received RT and CT, respectively. NLR &lt; 3 was associated to early disease (p &lt; 0.05). In nodal ratio groups, 68.9% had low, 23% intermediate and 8.1% high ratio, no differences were observed with NLR. At 5years median follow up, patients with NLR &lt; 3 and low nodal ratio had better 5-year OS in this nodal group (71% vs 58% on NLR≥3; HR:0.75, 95%CI:0.49-0.94, p = 0.016]), and patients with intermediate and high nodal ratio had worse outcomes (25 and 15% 5year OS, respectively) without differences with NLR. Multivariate analysis showed higher nodal ratio had negative impact on OS. Conclusions: Neutrophil to lymphocyte ratio &lt; 3 was associated to better OS in patients with low nodal ratio ( &lt; 0.2), indeed this approach could be usefull to identify high risks patients with early disease in further studies.
Single-cell cytokine profiling of tumor-infiltrating T cells to measure patient responses to anti-PD-1 therapy.
Authors: Sean Mackay, Brianna Flynn, Kevin Morse, Patrick Paczkowski, Antonella Bacchiocchi, Rong Fan, Ruth Halaban, Jing Zhou
Journal: Journal of Clinical Oncology (2017)

49 Background: Functional alteration of tumor-infiltrating T lymphocytes (TILs) may serve as a predictor for clinical outcome in cancer patients receiving immunotherapy.To evaluate TILs function unleashed by anti-PD-1 blocking, we employed a single-cell technology integrated with automated bioinformatics to simultaneously measure 17 cytokines secreted by single TILs, permitting the full spectrum delineation of anti-tumor T cell functions in patients with metastatic melanoma. Methods: TILs were enriched from biopsied melanoma tissues digested with enzymes, stimulated with anti-CD3 at 37°C, 5% CO 2 for 24 hrs and loaded into a single-cell barcode chip (SCBC) containing ~12000 microchambers. Each chamber (~1.2 nl) was pre-patterned with a complete copy of a 17-plex antibody array. Cells on the SCBC were imaged and incubated for 16 hrs at 37°C, 5% CO 2 ; single-cell cytokine signals were captured with a microarray scanner. The polyfunctional expression (2+ cytokines per cell) of single TILs was evaluated across 4 groups: Effector (Granzyme B, IFN-γ, MIP-1α, Perforin, TNF-α), Stimulatory (GM-CSF, IL-2, IL-5, IL-8, IL-9), Regulatory (IL-4, IL-10, IL-13, IL-22), and Inflammatory (IL-6, IL-17A, MCP-1). Results: Single-cell TILs analysis revealed significant increase of polyfunctional cytokines in patients who responded to anti-PD-1 therapy, compared to those resistant to therapy or in the control group. It was further revealed that the major contributions to enhanced polyfunctional strength are dominated by effector and stimulatory cytokines – both associated with anti-tumor immunity. Notably, TILs of patients responding to therapy exhibited polyfunctional secretions containing a subset of cells co-secreting Granzyme B, IFN- γ, MIP-1 α, and IL-8, which upon further validation is potentially a biomarker to predict clinical outcome of melanoma patients treated by checkpoint immunotherapy. Conclusions: Single-cell multiplexed cytokine profiling is capable of dissecting the full spectrum of immune functions associated with anti-tumor T cell immunity and more accurately measuring the function of TILs for predicting the response of patients receiving anti-PD-1 blocking therapy.
Development of DDPCR blood-based diagnostic tests that simultaneously measure mRNA expression from immune and cancer cells.
Authors: Hestia S. Mellert, Leisa Jackson, Chris Tompkins, Anne Lodge, Gary Anthony Pestano
Journal: Journal of Clinical Oncology (2017)

22 Background: Therapeutic options for patients with non-small cell lung cancer (NSCLC) continue to expand with the advent of immunotherapies. Lack of tissue and drawbacks with available IHC tests have increased the need for blood-based diagnostics. Thus, the detection of circulating nucleic acids has become highly relevant to clinical testing. Methods: We focused on extending the utility of blood-based testing for measurement of intra-cellular transcripts to multiplexed detection of gene expression. Specifically, we addressed maximizing the yield of quality circulating RNA for use in multiplexed droplet digital PCR (ddPCR) assays. Evaluation criteria included droplet counts for biomarkers of cancer and immunotherapy response. The markers evaluated were CD45, CD3, CK8, CK18, CK19, and PD-L1. Specimens included cell lines and prospectively collected samples from normal, healthy donors and donors with NSCLC. Results: Cell lines expressing variable levels of cytokeratins and PD-L1 were used to establish assay sensitivity. In these experiments, the test system could detect these markers in the equivalent of a single cell. We evaluated specificity using RNA from these same cell lines, resting and activated lymphocytes, and monocytes. With the exception of CK8, all assays demonstrated the expected specificities. Given the complexity of assessing PD-L1 in circulation because of its expression on immune cells, a threshold of 30 copies of PD-L1 was established using normal healthy donors (n = 9). Using this cut-off we then measured PD-L1 in circulating RNA from donors with NSCLC (n = 20). By these criteria, PD-L1 expression of sufficient copy number was restricted to a single EGFR wild-type donor (1/10). Previous reports have indicated that for EGFR wild-type patients, PD-L1 over expression may be considered a poor prognostic indicator of OS. Conclusions: We are developing sensitive and specific methods that can be applied to gene expression studies in blood. We have shown feasibility of these methods by evaluating key immune and cancer-specific RNAs. Evaluations are on-going with prospective sample collections to validate thresholds for this assay that may lead to its clinical utility.
Prognostic significance of professional antigen presenting cells according to morphological subtype of periampullary adenocarcinoma.
Authors: Sebastian Lundgren, Carl Fredrik Warfvinge, Jacob Elebro, Bjorn Nodin, Agnieszka Krzyzanowska, Anders Bjartell, Emelie Karnevi, Jakob Eberhard, Karin Leandersson, Karin Jirstrom
Journal: Journal of Clinical Oncology (2017)

121 Background: Dendritic cells (DCs) and macrophages play vital roles in tumorigenesis and may, depending on the context, promote or inhibit tumor progression. In this study, we examined the prognostic significance of DCs and macrophages in periampullary adenocarcinoma, with particular reference to morphological type. Methods: Immune cell-specific expression of CD68, CD163 and CD1a was analysed by immunohistochemistry on tissue microarrays with tumours from 175 consecutive cases of periampullary adenocarcinoma, 110 of pancreatobiliary type (PB-type) and 65 of intestinal type (I-type) morphology. Kaplan-Meier and Cox regression analysis were applied to determine the impact of the investigated cells on 5-year overall survival (OS). Results: Low density of CD68+ cells or CD163 + cells was significantly associated with an improved 5-year OS in unadjusted Cox regression analysis in the entire cohort (HR = 1.66; 95% CI 1.05-2.63 and HR = 1.84; 95 % CI 1.09-3.09, respectively), but not in adjusted analysis or in strata according to subtype. CD1a+ cell density was not prognostic in entire cohort or in I-type tumours. However, in PB-type tumors, high CD1a+ cell density was significantly associated with a reduced OS in unadjusted as well as in adjusted analysis (HR = 2.09; 95% CI 1.07-4.09 and HR = 2.35; 95% CI 1.13-4.87). The prognostic value of the investigated markers did not differ in strata according to adjuvant chemotherapy, neither in the entire cohort nor according to morphological type. Conclusions: The results from study demonstrate that the prognostic significance of dendritic cells, but not macrophages, differs by morphological subtype in periampullary adenocarcinoma. Hence, morphological subtype is an important factor to consider in studies on the prognostic and predictive role of the immune microenvironment in these types of cancer.
RXÂ 3117: Activity of an oral antimetabolite nucleoside in subjects with pancreatic cancerâ€“Preliminary results of stage II of the phase Ia/IIb study.
Authors: Vincent M. Chung, Jaime R. Merchan, Allyson J. Ocean, Drew W. Rasco, Hani M. Babiker, Ira Oliff, Ravi Kumar Paluri, Eloy Roman, Julie Poore, Ely Benaim
Journal: Journal of Clinical Oncology (2018)

396 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 2 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 2 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% of evaluable subjects with a partial response rate or better. Results: As of Sep 2017, 44 subjects have been enrolled (22 females, 22 males). The median age was 68 years, ECOG performance statuses were 0 (13 subjects) and 1 (31 subjects) and 6 subjects had received 4 or more prior therapies. One subject had an unconfirmed partial response and 21 subjects met the primary endpoint of stable disease with a duration of 30-224 days. The most frequent adverse events were mild to moderate anemia (19%), mild to moderate fatigue (15%), mild to moderate diarrhea (11%), and severe anemia (9%). Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. The study continues to enroll subjects with advanced pancreatic cancer into stage 2. A phase 2 study with nab-paclitaxel in first-line patients with advanced pancreatic cancer has been started. Clinical trial information: NCT02030067.
Latest waiting time figures for emergency departments in England are worst on record
Authors: Ingrid Torjesen
Journal: BMJ (2018)

More patients are waiting more than four hours in emergency departments in England than ever before, the latest official waiting time figures from NHS England show. 

The figures for both March this year and for the whole of 2017-18 represent new performance lows. Just 84.6% of patients were seen within four hours in March—well below the 95% target.

The previous records for poor performance were in February, when 85% of patients were seen within four hours, and in December 2017, when 85.1% of patients were seen, equalling the previous low of January 2017.

Looking at performance at only major (type 1) emergency …
An Interleukin-25-Mediated Autoregulatory Circuit in Keratinocytes Plays a Pivotal Role in Psoriatic Skin Inflammation
Authors: Miao Xu, Huiping Lu, Young-Hee Lee, Yelin Wu, Kewei Liu, Yuling Shi, Haoran An, Jingren Zhang, Xiaohu Wang, Yuping Lai, Chen Dong
Journal: Immunity (2018)
Association between Pulmonary Hypertension and Clinical Outcomes in Hospitalized Patients with Sickle Cell Disease
Authors: Manyoo A. Agarwal, Mahek Shah, Brijesh Patel, Vikki G. Nolan, Guy L. Reed, Ronald J. Oudiz, Gaurav Choudhary, Bradley A. Maron
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
A hypothalamic circuit for the circadian control of aggression
Authors: William D. Todd, Henning Fenselau, Joshua L. Wang, Rong Zhang, Natalia L. Machado, Anne Venner, Rebecca Y. Broadhurst, Satvinder Kaur, Timothy Lynagh, David P. Olson, Bradford B. Lowell, Patrick M. Fuller, Clifford B. Saper
Journal: Nature Neuroscience (2018)
Intratumoral (i.t.) IMO-2125 (IMO), a TLR9 agonist, in combination with ipilimumab (ipi) in PD-(L)1 refractory melanoma (RM).
Authors: Marc Isamu Uemura, Cara L. Haymaker, Ravi Murthy, Marihella James, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer A. Wargo, Rodabe Navroze Amaria, Sapna Pradyuman Patel, Hussein Abdul-Hassan Tawbi, Isabella Claudia Glitza, Scott Eric Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W Overwijk, Chantale Bernatchez, Adi Diab
Journal: Journal of Clinical Oncology (2017)

136 Background: Checkpoint inhibitors (CPI) have transformed melanoma treatment but many patients remain refractory. CPI plus i.t. IMO may improve response by activating innate immune function. Based on this we initiated a trial of IMO in combination with ipi or pembrolizumab (pem) in RM. Methods: Adults with RM that progressed during or after ≥ 12 weeks of PD-1 therapy are eligible. IMO, 4 – 32 mg, is given i.t. for 6 doses, along with either ipi or pem. Endpoints are safety, response, biomarkers, and PK. Injected and distant tumors are biopsied pre-treatment and again at 24 hrs (injected tumor), weeks 8 and 13 for immune analyses. Results: As of October 7, 2016, 10 pts have been treated; median age 55 (range: 39-76), 8 with visceral and 1 with brain metastases. Two pts have mucosal histology. 60% have BRAF mutations. Prior duration of anti-PD-(L)1 therapy ranges from 8 to 63 weeks and median time from last PD-1 therapy to onset of study treatment is 6 (4,57) weeks. IMO has been administered at 4, 8, and 16 mg. No DLTs have been observed and there have been no treatment-related discontinuations or deaths. Ipi was discontinued after the second dose in one subject with previous ipi-related hepatitis for recurrent transaminase elevations (grade 4). Grade 3 hypophysitis is the only other immune-related AE (2 pts). Most frequent TEAE (N &gt; 2) are nausea, vomiting, anemia, diarrhea, increases in ALT/AST/GGT/triglycerides, chills, fatigue, pyrexia, and leukopenia; the majority are low-grade. 6 patients are evaluable for response - CR (1), PR (2), SD (2), PD (1) by RECIST1.1. Tumor biopsies show consistent maturation of the myeloid DC1 subset in IMO injected tumors at 24 hrs. Week 8 results are consistent with a higher rate of proliferative (Ki67) effector CD4+ and CD8+ T-cells in responders. Circulating IFNγ shows 2-3 fold increase in responders. Conclusions: The combination of IMO and ipi is tolerable and has activity in PD-1 refractory melanoma. Dose escalation is ongoing and a Phase 2 expansion with both combinations is planned. Updated safety, antitumor activity, PK, and biomarker data will be presented at the meeting. Clinical trial information: NCT02644967.
189P Are pretreatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and advanced lung cancer inflamation index (ALI) levels useful in predicting the outcomes of patients with advanced non-small cell lung cancer?
Authors: B. Komurcuoglu, A. Evkan, G. Karakurt
Journal: Journal of Thoracic Oncology (2018)
Blood eosinophil count and risk of pneumonia hospitalisations in individuals with COPD
Authors: Signe Vedel-Krogh, Børge G. Nordestgaard, Peter Lange, Jørgen Vestbo, Sune F. Nielsen
Journal: European Respiratory Journal (2018)

Blood eosinophil count in chronic obstructive pulmonary disease (COPD) is associated with higher exacerbation rate and favourable response to corticosteroids; however, frequent exacerbations and use of inhaled corticosteroids could elevate pneumonia risk. We tested the hypothesis that high blood eosinophil counts are associated with high risk of pneumonia in individuals with severe COPD from the general population. We included 7180 individuals with COPD from the Copenhagen General Population Study, including 643 with forced expiratory volume in 1 s (FEV 1 ) &lt;50% predicted between 2003 and 2011. All primary discharge diagnoses of pneumonia during follow-up were recorded. Among individuals with COPD and FEV 1 &lt;50% pred, the multivariable adjusted incidence rate ratio was 2.17 (95% CI 1.31–3.58) for pneumonia comparing individuals with blood eosinophil counts ≥0.34×10 9 cells·L −1 versus &lt;0.34×10 9 cells·L −1 . In individuals with clinical COPD, defined by recent exacerbation, ≥10 pack-years of smoking and FEV 1 &lt;70% pred, the corresponding risk was 4.52 (2.11–9.72). Risk of pneumonia did not differ by blood eosinophil count in individuals with COPD and FEV 1 ≥50% pred. In individuals with COPD and FEV 1 &lt;50% pred, blood eosinophil count ≥0.34×10 9 cells·L −1 was associated with high risk of hospitalisation due to pneumonia.
Abstract 11715: A Brief High-Fat Diet Induces Leukocyte Recruitment to Femoral Artery in Mice with Normal Arterial Shear Flow
Authors: Mizuko Osaka, Sumihiko Hagita, Masayuki Yoshida
Journal: Circulation (2011)

[Objective]  Though high-fat diet (HFD)-induced metabolic disorders are closely related to atherosclerosis, their causative role in vascular inflammation is not fully understood unless using genetically-modified animals. We thus decided to precisely document the onset of vascular inflammation and atherosclerosis by HFD in wild type C57BL/6 mice (wt) using intravital microscopic analysis (IVM).   [Methods and Results]  wt mice (male, 7weeks) were fed HFD (20%fat, 1.25%cholesterol) for 1, 2, 4 and 8 weeks. The interaction of leukocytes and the non-injured femoral artery was monitored by IVM. We discovered leukocyte recruitment as early as 2 weeks after HFD compared to normal chow diet (NC). The leukocyte adhesion was gradually increased at 4 weeks after HFD (HFD, 4.67+/−2.68/10 4 um 2  vessel surface; NC, 0.13+/−0.13; p   [Conclusion]  Current data discovered unexpectedly rapid onset of vascular inflammation that initiates atherosclerosis and shed a light on the importance of machinery which translates dietary nutrients to the macrovascular inflammation.