bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multi-institutional study of immunosuppressed and immunocompetent patients with cutaneous squamous cell carcinoma of the head and neck treated with definitive surgery and radiotherapy: Outcomes after disease recurrence.
Authors: Koyfman Shlomo A. , Manyam Bindu V. , Garsa Adam Arebi , Chin Re-I , Reddy Chandana A. , Gastman Brian , Thorstad Wade , Yom Sue S. , Nussenbaum Brian , Wang Steven , Vidimos Allison T. 
Published: November 2019

63 Background: Our multi-institutional group previously demonstrated that immunosuppressed (IS) patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and adjuvant radiotherapy had inferior survival compared to immunocompetent (IC) patients. This study further examines those patients who experienced disease recurrence and compares the impact of immune status on overall survival after recurrence. Methods: Pts who received surgical resection and postoperative RT for primary or recurrent, stage I-IV (non-metastatic) cSCC-HN between 1995-2015 at Cleveland Clinic, Washington University St. Louis, and University of California San Francisco were included in this IRB approved study. Pts were categorized as IS if they were diagnosed with chronic hematologic malignancy, HIV/AIDS, or were treated with immunosuppressive therapy for organ transplantation ≥ 6 months prior to diagnosis. Pts with recurrence included those who experienced local, regional, or distant failure after completion of definitive surgery and radiation. Overall survival (OS) and progression free survival (PFS) were calculated using the Kaplan Meier method. Results: In the initial study of 205 pts, 138 (67.3%) were immunocompetent (IC) and 67 (32.7%) were IS, and were followed for a median of 25 months. PFS was significantly lower in IS pts compared to IC at 2 years (38.7% vs. 71.6%; p = 0.002), while 2yr OS demonstrated a similar but non-significant trend (60.9% vs. 78.1%; p = 0.135). A total of 72 patients (35%) recurred, including 31 with distant failure. 1yr post-recurrence OS was 42% with a median survival of 8.4 months. Median survival did not significantly differ between the IS and IC groups (8.0 vs. 12.9 months; p = 0.9). Conclusions: Pts with cSCC-HN who experience disease recurrence after definitive treatment with surgery and radiation have poor survival, irrespective of immune status. Clinical trials testing immunotherapies are needed for both IC and IS patients with this understudied disease.
Auto-antibody detection of ovarian cancer with paraneoplastic antigens.
Authors: Hurley Laura C. 
Published: November 2019

70 Background: The high mortality rate of ovarian cancer (OVCA) is due to late detection and high incidence of recurrence. Autoantibody diagnostic tests for early detection and prediction of recurrence have the potential to improve patient outcome. Paraneoplastic neurological syndromes (PNSs) are rare disorders due to remote effects of the immune response against a tumor, targeting both the tumor and healthy tissues such as muscle, brain, and nervous system. Symptoms of PNSs generally precede detection of a tumor; therefore paraneoplastic antibodies are a logical resource for the early detection of cancer. Two PNSs associated with OVCA are myositis and paraneoplastic cerebellar degeneration (PCD), which target muscle and purkinje cells, respectively. Our laboratory has detected the presence of several myositis and PCD associated paraneoplastic antibodies in the sera of patients with OVCA. Methods: Incubation of OVCA patient sera with commercially available paraneoplastic diagnostic line blots indicated presence of paraneoplastic antibodies. OVCA specific epitopes discovered previously in our laboratory by phage-display biopanning were evaluated for both homology to paraneoplastic antigens and for reactivity with PNS patient sera. Selected paraneoplastic antigens reactive with OVCA sera and OVCA specific epitopes homologous with paraneoplastic antigens or reactive with PNS patient sera were evaluated on western blot with OVCA sera, healthy control sera, and sera from patients with benign gynecological conditions. The sera screening will be replicated on ELISA. Recently identified paraneoplastic antigens associated with myositis and PCD that are expressed in OVCA tissue are being evaluated for reactivity with OVCA sera on western blot. Results: We have established a panel of four paraneoplastic antigens that in combination are able to discriminate OVCA sera from healthy patient sera and sera from patients with benign gynecological conditions. Conclusions: Although paraneoplastic syndromes are rare, paraneoplastic antibodies can be present in patients with ovarian cancer without PNS. A panel of paraneoplastic antigens for the autoantibody detection of ovarian cancer has the potential for development of a clinical test.
Clinical utility of clonality testing by next generation sequencing in the monitoring of B-cell and T-cell malignancies.
Authors: Syed Mustafa H. , Ho Caleb , Petrova-Drus Kseniya , Yao JinJuan , Yu Wayne , Zehir Ahmet , Nafa Khedoudja , Arcila Maria E. 
Published: November 2019

72 Background: Clonality testing is an integral part of the initial assessment of B and T cell malignancies. The further use of conventional clonality assays for monitoring of disease post treatment is limited by low assay sensitivity and inability to track clones based on their unique sequences. Clonality assessment by next generation sequencing (NGS) provides increased diagnostic capabilities, allowing the tracking of disease specific clones as well as the full spectrum of clonal sequences that arise in response to therapy. Here we describe our initial experience using an NGS based assay for monitoring and our comparison to conventional clonality assays and flow cytometry. Methods: DNA was extracted from hematologic samples received for routine clonality assessment including diagnostic (DS) and follow-up post therapy (PT) samples. Clonality testing was performed by conventional PCR-based assays using biomed II primers and by NGS utilizing Lymphotrack IGH FR1 and TRG kits (Invivoscribe). The amplified products were sequenced on Illumina MiSeq. For MRD assessment, we created dedicated laboratory protocols as well as in-house developed software, MSK-LymphoClone (LC), containing a data analysis pipeline, analytical tools for clonality assessment and a signout portal for easy search and retrieval of pertinent clones. Results: Samples from 48 patients were included (48 DS and 60 PT) encompassing 12 plasma cell neoplasms, 11 acute lymphoblastic leukemias, 16 mature B-cell and 9 T-cell lymphomas. All diagnostic samples showed clonal rearrangement with 100% concordance between conventional and NGS assays. Residual disease was detected in 27/60 (45%) PT samples using conventional fragment size based assays, 27/57 (47%) using flow and 38/60 (63%) using NGS. Diagnostic clonal sequences were detected in as low as 0.0019% of total reads in PT samples tested by NGS. 18/60 (30.0%) PT samples (17 patients) were disease negative by all assays; 16 patients remained disease-free (median follow-up - 2.4 months). Conclusions: NGS clonality testing is a valuable tool for monitoring patients with B and T cell neoplasms showing higher sensitivity and specificity than conventional assays.
CD38 as a novel immune checkpoint and a mechanism of resistance to the blockade of the PD-1/PD-L1 axis.
Authors: Chen Limo , Byers Lauren Averett , Ullrich Stephen , Wistuba Ignacio Ivan , Qin Xiao-Feng , Gibbons Don Lynn 
Published: November 2019

79 Background: Although immune checkpoint inhibitors including PD-L1 blockade provide significant clinical benefit for patients with lung cancer, barriers to immunotherapy clinical successes have been due to a high rate of resistance. The therapeutic improvement requires a thorough understanding of the biological process of resistance. Until recently, there have been only a few studies reporting the mechanisms of resistance to PD-L1 blockade. The mechanistic basis remains poorly defined. Methods: In multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the resistance mechanisms using pharmacological and genetic approaches (monoclonal antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. More importantly, to determine the applicability to patients with lung cancer, we analyzed 259 patients specimens with IHC staining and mined many immune markers in TCGA adeno and squamous datasets. Results: We identified the up-regulation of CD38 on tumor cells as well as enrichment of CD38highTregs and CD38highMDSCs in tumor as the markers of treatment resistance. We observed the same resistance mechanism caused by CD38 in PD-L1 KO mice bearing PD-L1 KO Lewis lung tumors edited with the CRISPR/Cas9 system. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines, in vitro and in vivo data demonstrates that CD38 inhibits CD8+ T cell proliferation, antitumor cytokine secretion, and tumor cell killing capability. To test whether CD38 blockade might be therapeutically efficacious to anti-PD-L1 resistance, we applied the combination therapy of anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in 259 lung patients, 18.5% of cases exhibited positive staining for CD38 on tumor cells, showing a great potential benefit for treating lung patients. Conclusions: CD38 is defined as a novel immune checkpoint and acts as a mechanism of resistance in the context of PD-L1 therapy. Targeting this novel immune checkpoint may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.
Characterization of a humanized PD-L1 blocking antibody with pH-dependent antigen binding in a humanized syngenic tumor model.
Authors: Qian Xueming , Teng Fei , Guo Huanhuan , Li Zhen , Qin Xiao-Feng 
Published: November 2019

81 Background: Checkpoint inhibition is a promising approach for cancer treatment with durable responses and survival benefits. Currently, immune-checkpoint inhibitors are delivered at maximally tolerated doses, resulting in significant toxicities and cost burden. There is significant need to develop more efficacious and safer immune checkpoint inhibitor. Towards this goal, we have developed a next-generation humanized PD-L1 antibody with pH-dependent antigen binding and evaluated its biological activities in vitro and in vivo. Methods: Hybridoma approach was employed to generate anti-PD-L1 antibodies. A cell-based receptor-ligand blocking assay was employed to identify neutralizing antibodies. Antibodies with pH-dependent antigen binding property were identified and characterized further with those without using PD-L1/PD-1 binding assay, mixed lymphocyte reaction assay, and in vivo tumor growth inhibition assay in syngeneic MC38 tumor model expressing human PD-L1 protein. Results: A panel of neutralizing antibodies blocking PD-L1/PD-L1 binding was isolated. Among them we identified antibodies with or without pH-dependent binding property. While the in vitro activities of these antibodies are similar, their tumor growth inhibition activities differ significantly. The in vivo activity of 23F11, an antibody with ph-dependent binding, is maximized at 1mg/kg in MC38/hPD-L1 model. At 1 mg/kg, 23F11 induced complete tumor regression in 7/12 of the mice treated, more potent than antibodies without pH-dependent binding. Imaging study revealed that significantly higher drug concentration in the tumor for 23F11 and correlated with extended period of target occupancy. Furthermore 23F11 treatment is correlated with sustained up-regulation of plasma mIL-18, a potential pharmacodynamics response marker. Conclusions: We have identified antibodies with pH-dependent PD-L1 binding property. These antibodies can maintain high antibody level in PD-L1 expressing tumor and have potent tumor inhibition activity at low dose. Current work will evaluate whether humanized 23F11 can be at least as efficacious as benchmark antibodies yet with improved safety profile in patients.
Retrospective study comparing survival when ipilimimab used with and without radiotherapy in patients with advanced melanoma.
Authors: Parslow Dominique Siobhan , Talbot Toby Laurence James 
Published: November 2019

83 Background: Ipilimumab, a monoclonal antibody targeting CTLA-4, has increased median survival in patients with advanced melanoma from 6.4 to 10 months, with 20% of patients showing a sustained response. Preclinical and clinical studies have shown possible synergistic and abscopal effects between ipilimumab and radiotherapy. The aim of this study was to compare survival curves of patients who have received ipilimumab with and without radiotherapy, and also look at other potential prognostic indicators for patients with advanced melanoma. Methods: Data was collected retrospectively from patients with advanced melanoma treated with ipilimumab at Royal Cornwall Hospital (RCH), United Kingdom. The data collection proforma included: demographic details, BRAF status, treatments prior to and since ipilimumab, whether and when radiotherapy given, response, autoimmune phenomena documented, overall survival, and survival time since ipilimumab. Results: 43 patients (20 men and 23 women) have received ipilimumab for metastatic melanoma at RCH between 2011 and 2015. Age range 27-88 years, with a median age of 60 years. 13 were BRAF mutated, 28 were BRAF wild-type and 2 were unknown. 33% of patients who received ipilimumab had some response to it, with 21% achieving a complete response. 25% of patient who displayed autoimmune phenomena clinically responded to ipilimumab; only 15% of those who did not display autoimmune phenomena clinically responded. 20 patients received radiotherapy and 23 did not; there was no significant survival difference related to radiotherapy usage. Patients with the BRAF mutation had a shorter median survival than those who were BRAF wild-type. Conclusions: Although this study was retrospective and not randomised, it appears to show an increased likelihood of a response to ipilimumab in patients who also had autoimmune side effects from treatment. Patients with a BRAF mutation had a shorter median survival than those who were BRAF wild type. The addition of radiotherapy to ipilimumab did not appear to impact on survival or response, although, as the patients were not randomised as to whether they received radiotherapy it is difficult to draw firm conclusions from this.
Incidence and average cost per toxicity in patients treated with nivolumab.
Authors: Mason Neil Thomas , Khushalani Nikhil I. , Antonia Scott Joseph , McLeod Howard L. 
Published: November 2019

93 Background: Recently approved PD-1 inhibitors such as nivolumab have demonstrated clear efficacy in metastatic melanoma and other cancers, but also come at a high cost and with the potential for severe side effects. However, most of the data available comes from clinical trials rather than patients treated in clinical practice as standard-of-care. This study reports the incidence of severe toxicities in a number of cancer types and estimates the per patient cost of managing these toxicities. Methods: Patients with metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma treated with nivolumab between January 1, 2014 through April 30, 2016 were identified at Moffitt Cancer Center (N=74). Toxicities occurring during treatment or within 2 months of stopping treatment were identified by a chart review and each toxicity graded using the CTCAE 4.0 criteria. A cost of care analysis was performed to estimate the cost of serious toxicities (Grade 3-5) compared to a control group who experienced no or minor adverse events (Grade 0-2). Billing data was used to estimate the mean cost of care for each group. Costs were subcategorized by service line, e.g., pharmacy costs, radiology, laboratory services. Results: The most common severe toxicities were anemia, dyspnea, renal failure, colitis, fatigue, and pneumonitis (Table 1). The average cost of care for patients experiencing grade 3-5 toxicities was $2,036 higher than those without toxicity. Conclusions: The incidence of toxicity in our population was similar to that reported in clinical trials. Costs were higher for patients with toxicities, driven by additional outpatient care (19% higher cost per patient) as well as additional pharmacy costs (22% higher per patient). Though small in comparison to the cost of nivolumab, over $6,000 per dose, these costs should not be dismissed, particularly when performing cost effectiveness and value research. [Table: see text]
Preliminary results from a single-arm, phase II study assessing the efficacy of pembrolizumab plus radiotherapy in metastatic triple negative breast cancer.
Authors: Ho Alice , Barker Christopher Andrew , Gucalp Ayca , Lebron-Zapata Lizza , Wen Yong Hannah , Phung Anh , Wilgucki Molly , Henrich Micaela , Arnold Brittany , Patil Sujata , McArthur Heather L. 
Published: November 2019

95 Background: Two trials have demonstrated overall response rates of 19% with immune checkpoint inhibitors alone in chemotherapy-resistant triple negative breast cancer (TNBC). Radiation therapy (RT) is frequently used to enhance local control in TNBC and has been reported to induce distant (abscopal) tumor responses when combined with immunotherapy. We evaluate the safety and efficacy of the combination of RT and pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, in a single-arm, two-stage, phase II study in metastatic TNBC. Results from the first stage are reported. Methods: Eligibility criteria includes women with biopsy-proven TNBC, ECOG performance status 0-2, ≥ 2 measurable sites of metastatic disease with at least one site requiring RT. A total RT dose of 3000 cGy is delivered in one week in 5 fractions. Pembrolizumab is given intravenously at 200 mg/kg D1+/- 3 days and then every 3 weeks until disease progression as defined by RECIST v 1.1. The primary endpoint is overall response rate at week 13 in the non-targeted, non-irradiated lesions. Secondary endpoints include safety and overall survival. Tumor biopsies are obtained at baseline and at week 7. PD-L1 expression was not required for study entry. Results: Nine patients were enrolled in the first phase and assessed for antitumor activity and safety. Median age was 52 years (range 37-73). Three patients died secondary to disease-related complications (at weeks 2, 6 and 8) and 1 came off study due to disease progression prior to week 13. Of the 5 patients evaluable at week 13, 2 had a partial response, 1 had stable disease and 2 had disease progression. Common toxicities were mild and included fatigue, myalgia and nausea. One grade 3 event was reported - hyperbilirubinemia not attributable to study therapy after one dose of pembrolizumab. Conclusions: The combination of pembrolizumab and RT was well-tolerated in the first stage of a phase II study. Responses were observed outside of the RT fields in 2 of 5 patients who were evaluable at 13 weeks. The contribution of RT to pembrolizumab is unknown and will be investigated in the second stage of the study, which is ongoing. Correlative studies are planned. Clinical trial information: NCT02730130.
Sample Timing, Diagnosis of Subclinical Thyroid Dysfunction and Mortality in Acute Myocardial Infarction: ThyrAMI1 Study
Authors: Razvi Salman , Leng Owain , Jabbar Avais , Bano Arjola , Ingoe Lorna , Addison Caroline , Thomas Honey , Carey Peter , Junejo Shahid , Austin David , Greenwood John P , Zaman Azfar 
Published: November 2019

Abstract

Objective
The objective of this study was to determine the impact of blood sample timing on the diagnosis of subclinical thyroid dysfunction (SCTD) and mortality in patients with acute myocardial infarction (AMI).

Patients, Design, and Main Outcome Measures
Patients with AMI had thyroid function evaluated on admission between December 2014 and December 2016 and those with abnormal serum thyrotropin (TSH) had repeat thyroid function assessed at least a week later. The association between sample timing and SCTD was evaluated by logistic regression analysis. Secondary outcomes were confirmation of SCTD on repeat testing and all-cause mortality up to June 2018.

Results
Of the 1806 patients [29.2% women, mean (± standard deviation) age of 64.2 (±12.1) years] analyzed, the prevalence of subclinical hypothyroidism (SCH) was 17.2% (n = 311) and subclinical hyperthyroidism (SHyper) was 1.2% (n = 22) using a uniform TSH reference interval. The risk of being diagnosed with SCTD varied by sample timing in fully-adjusted models. The risk of SCH was highest between 00.01 and 06.00 hours and lowest between 12.01 and 18.00 hours, P for trend &lt;.001, and risk of SHyper was highest between 12.01 hours and 18.00 hours and lowest between 00.01 hours and 06.00 hours. Furthermore, time of the initial sample was associated with the risk of remaining in a SCH state subsequently. Mortality in SCH patients was not elevated when a uniform TSH reference interval was utilized. However, when time period–specific TSH reference ranges were utilized, the mortality risk was significantly higher in SCH patients with HR (95% CI) of 2.26 (1.01–5.19), P = .04.

Conclusions
Sample timing impacts on the diagnosis and prognosis of SCH in AMI patients. If sample timing is not accounted for, SCH is systemically misclassified, and its measurable influence on mortality is lost.
On Displacement
Authors: Klosterwill Kevan 
Published: November 2019

AbstractDo urban open spaces, whether comprised of small planting beds and gardens or larger parks and reserves, signal the juxtaposition of two worlds, two forms of life, one human and one natural and nonhuman? Or are those spaces necessarily embedded within the logics of real estate capital that shape cities? And if so, can this be avoided? This article explores the operation of three large-scale site-specific artworks in New York City that suggest other logics by which botanically dominated spaces might operate in the city: a recent work by Mary Mattingly entitled Swale, as well as two more well-known works, Alan Sonfist’s Time Landscape and Agnes Denes’s Wheatfield—A Confrontation. These works share similar form, scale, and media but most significantly function as social practice artworks that enact multispecies performances. Drawing on notions of urban cosmopolitics, the article considers how these works illustrate and perform alternative worlds and forms of life in an environment that is perceived as hostile to those ways of being. These works resist a totalizing impulse in the production of urban architectures and landscapes that would prematurely foreclose the world to nonhuman agency through a project of human control of all environmental variables. Theories of heterotopias as counter-spaces facilitate exploration of “displacement” as a metaphor that accounts for both the attempted eviction of alternative environmental practices and the works’ ongoing strategies of resistance. Through tactics such as orderly frames, sustained interactions, and cleverly attenuated performative practices, these works resist co-option within capitalist logics, which would prematurely close off the worlds they call into being. My discussion of these art-activist efforts brings authors on multispecies relations into conversation with landscape and urban theorists, raising possibilities for more-than-human modes of understanding urban and environmental design practice, with these activist artworks providing inspiration for and interpretation of alternative urban spatial practices.