bluuebunny/crossref_metadata_2025 huggingface dataset:
Vertebral Osteomyelitis: A Mortality Analysis Comparing Surgical and Conservative Management
Authors: Zadran Spogmai , Pedersen Peter Heide , Eiskjær Søren
Published: July 2019

Study Design:

Retrospective cohort study.

Objectives:

To compare the mortality between patients treated for vertebral osteomyelitis (VO) with either surgical or conservative management and to construct a predictive model for mortality after VO.

Methods:

All patients with a diagnosis of VO in Region North Denmark from 2004 to 2014 were followed for at least 2 years or until death. They were all treated according to a standardized guideline for the choice of treatment modality. Nineteen dichotomized variables with possible influence on the mortality were registered for all patients in the study. LASSO (least absolute shrinkage and selection operator) penalized Cox regression analysis was used to build a predictive model for 2-year survival after VO.

Results:

A total of 125 patients were eligible for inclusion, mean age 67 years, 36 women. 75 were treated surgically. Twenty-one patients were dead 2 years after the diagnosis. Kaplan-Meier estimate of 2-year survival was 0.82 [0.75, 0.88]. Any difference in mortality between surgically and conservatively treated patients was nonsignificant at 1 and 2 years (univariate Cox regression analysis). Significant factors included in the predictive model after LASSO penalized Cox regression analysis was Charlson Comorbidity Index (CCI), cardiovascular disease, C-reactive protein (CRP) normalization, thoracic infection, and Karnofsky score. The area under the curve (AUC) for the predictive model ranged from 0.74 to 0.77.

Conclusion:

Patients undergoing surgical management for vertebral osteomyelitis according to standardized and agreed-upon guidelines had no higher mortality than those allocated to conservative treatment. The predictive model included 5 variables associated with an increased mortality: CCI, CRP normalization, cardiovascular disease, thoracic infection, and Karnofsky score.
Towards Clinical Sustainability from Evolution to Revolution: A Study of Sustainable Factors for Law Clinics
Authors: Nwedu Cosmos Nike
Published: July 2019

Clinical legal education (CLE) has grown from country-specific concept to a widely feted global practice with a high degree of momentum and acceptability. There is an increasing profound interest from universities, law schools, law academics and researchers, non-governmental organizations and students alike towards mainstreaming this concept. A growing body of literature designed around different creativities, ideas and methodologies aimed at expanding its scope of operability, values and rationales has sufficed. Nonetheless, there is a little strand of academic literature on the sustainability of CLE in all respects. While the question of whether CLE has come to stay may seem axiomatic, it however depends on certain critical sustainable factors. Thus, it makes sense to consider in what ways law clinics can bring a sustained clinical legal practice. This article takes a forward-looking approach by exploring critical sustainable factors considered as crucial accelerators for wheeling clinical pedagogy in growth motion and driving the effectiveness of law clinics and clinical activities. The study provides a framework for ensuring not only that the rationalistic status quo of CLE is maintained but also offers a futuristic context in fostering clinical movement and activities and ensuring inclusiveness.
Poverty Simulations With Health Professional Students: Evidence of Impact
Authors: Thompson Jessica R. , Goldberger Rachel B. , Elias Thistle I.
Published: July 2019

Poverty is one of the most significant determinants of health inequity in the United States, yet students of the health professions are more likely to come from higher rather than from lower income families, separating them economically from many of the individuals they will serve. Poverty simulations can expose health professional students to experiences of those living in poverty and provide a more holistic, structural perspective of poverty that informs their later practice. We sought to understand the current state of poverty simulations being utilized throughout the United States. Through a review of abstracts via Ovid and Google Scholar, we identified nine articles that focus directly on describing poverty simulations in university-based programs with health or social work university students and that incorporate some form of pre- and postevaluation methods. After a careful review of these articles, we describe the distinct differences in components and contexts between the simulations, including Bridging the Gaps–Pittsburgh’s Experiential Poverty Exercise, and how effects on students is determined across the various simulations. Additionally, we review how unique aspects of the Bridging the Gaps–Pittsburgh’s Experiential Poverty Exercise can serve as a model for providing multidisciplinary graduate students the opportunity to increase their knowledge and shift attitudes about people experiencing poverty before working with them as health professionals. In presenting the current status of these simulations, we seek to develop recommendations regarding the components and context of poverty simulations as well as approaches to assessing effects.
How Far From Meritocracy? A Cross-National Longitudinal Analysis of European Countries
Authors: Kołczyńska Marta
Published: July 2019

This figure describes the distance from meritocracy in 36 European countries between 2002 and 2017. Following Krauze and Slomczynski, the author defines meritocratic allocation of individuals by education to occupational status groups as a situation when more educated persons do not have jobs with lower status than less educated persons. Using data from the European Social Survey rounds 1 to 8, for each country-round, the author identifies the theoretical meritocratic joint distribution of education and occupational status, as well as the theoretical distribution under statistical independence, and measures the distance of empirical distributions to these two ideal situations. The author finds that the distance to meritocracy varies substantially across European countries, with some countries being closer to allocation under independence than to meritocratic allocation. In terms of cross-country differences, the distance to meritocracy is smaller in postcommunist countries than in Western Europe, with some convergence observable over time.
Treatment of Facial Dog Bite Injuries in the Emergency Department Compared to the Operating Room
Authors: Essig Garth F. , Sheehan Cameron C. , Niermeyer Weston L. , Lopez Joseph J. , Elmaraghy Charles A.
Published: July 2019

Objective

To assess factors associated with repair of facial dog bites in the emergency department (ED) versus the operating room (OR) and to compare rates of surgical site infection and reoperation for each venue.

Study Design

Case series with chart review.

Setting

Single institution.

Subjects and Methods

All patients younger than 18 years of age who underwent surgical repair by a consulting surgical service within 24 hours of presentation for facial dog bites between 2010 and 2013 were included. Demographics, site of injury, associated evidence of complex injury, surgical site infections within 30 days, and reoperation within 2 years were compared between patients undergoing surgical repair in the ED versus the OR.

Results

One hundred sixty‐five patients were evaluated; 75 patients underwent repair in the ED, and 90 patients were treated in the OR. Patients treated in the ED underwent surgery more promptly than patients treated in the OR (median time from arrival to procedure start 3.3 vs 6.8 hours, P <. 001). Patients treated in the OR were more likely to have longer lacerations (3.0 cm vs 7.8 cm, P <. 001), lacerations of the eyelid (17% vs 42%, P =. 001), involvement of multiple regions of the face (11% vs 22%, P =. 039), and multiple indicators of severe injury (3% vs 12%, P =. 024). There were no differences in surgical site infections (1% vs 1%, P =. 721) or reoperation rates (5% vs 13%, P =. 071).

Conclusions

Surgical management of pediatric facial dog bites may be successfully performed in both the ED and OR settings. Severity of the injury should dictate the choice for management.
Sexual Transference Towards a Therapist in the Mid-phase of Short-term Psychodynamic Psychotherapy: A Case Report
Authors: Kakar Sona
Published: July 2019

Transference has been described as unconscious feelings that are transposed onto another significant individual ( Bloom. J Am Psychoanal Assoc. 1973 ;21:61-76). In the strictest sense, this occurs only in therapy settings, but in a more general sense, it occurs throughout life. Transference can be negative, positive, or sexualized. If unresolved it can create a sticky transference neurosis and impediments to progress (Koo. J Psychother Pract Res. 2001;10(1):28-36). Short-term dynamic therapy, as propounded by Dr Habib Davanloo, is structured to prevent the development of a transference neurosis and addresses the transference from the very beginning, including the first session itself. Following is a case of sexual transference which was addressed in the mid-phase of short-term psychodynamic psychotherapy.
Correction to: Clinically relevant phenotypes in chronic rhinosinusitis
Authors: Grayson Jessica W. , Cavada Marina , Harvey Richard J.
Published: July 2019

Following publication of the original article [1], the authors reported an error in Table 1. In the second columns of the ‘Radiology’ row, ‘Normal anterolateral sinus mucosa’ should read ‘Normal superolateral sinus mucosa’. A corrected version of Table 1 is included in this Correction.
Characterizing the T cell repertoire in lung squamous cell premalignancy and its association with lesion outcome.
Authors: Maoz Asaf , Merenstein Carter , Mazzilli Sarah , Campbell Joshua , Liu Gang , Zhang Sherry , Dhillon Samjot S. , Stevenson Christopher , Reid Mary E. , Lenburg Marc , Avi Spira , Beane Jennifer
Published: July 2019

102

Background: The immune response to frank malignancy has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological and molecular features. Methods: Endobronchial biopsies (n=294) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via auto fluorescence bronchoscopy and CT, were profiled by RNA-Seq as part of the Pre-Cancer Genome Atlas (PCGA). We applied the TCR Repertoire Utilities for Solid Tissue/Tumor (TRUST) tool to identify TCR CDR3 sequences in the RNA-Seq data. We quantified the ratio of private (i.e., found in one patient only) and public (i.e. found in two or more patients) TCRs that are found in curated databases with known antigen specificities. We measured the correlation of TCR diversity with previously derived PML transcriptional signatures and molecular subtypes; and with mutational burden among a subset of biopsies (n=115) also profiled with whole exome sequencing. Results: We detected 40,421 unique TCR sequences, of which 3,396 (8.4%) were found in more than one sample and 1,057 (2.6%) were found in two or more patients (i.e. Public). TCRs with known antigen specificities were enriched among public TCRs (p < 0.001). In PMLs with a proliferative molecular subtype reflective of dysplasia (n=80), TCR diversity was decreased in PMLs that regressed versus PMLs that progressed (p=0.045). TCR diversity was negatively associated with a transcriptional signature of T-cell mediated immune activation (Spearman’s rho -0.26, p < 0.001) but was not associated with mutational burden. Conclusions: To our knowledge, this is the first characterization of the TCR repertoire associated with bronchial premalignant lesions. TCR diversity may help predict the efficacy of the host immune response to PMLs but it is not associated with mutational burden. Further studies are needed to leverage these findings and explore the potential for immunoprevention of PMLs.
Cancer-immune checkpoint inhibition and autoimmune-related adverse events.
Authors: Rathmann Joerg , Vredenburgh James J. , Demesropian Racha , Wakefield Dorothy , Williams Kendra , Purushothaman Archana , Bello Jessica , Dulipsingh Latha
Published: July 2019

107

Background: Immunotherapies effect adaptive or innate immune responses. Programmed-death 1 (PD-1), a cell surface protein on activated T cells, which, when bound to its ligands PD-L1 and PD-L2, inhibits T-cell activation. Inhibition can be associated with complicating immune-related adverse events (IRAEs). Immune checkpoint inhibitors (ICIs) are FDA approved for advanced NSCLC. Study aims: (1) determine if the use of ICIs nivolumab (N) and pembrolizumab (P) is associated with development of autoimmune diabetes and thyroid disease and (2) determine the impact of (N) and (P) on pre-existing autoimmunity. Methods: Prospective, biological and clinical end-point-driven study in subjects with NSCLC considered for 1st or 2nd-line treatment with N or P. Subjects were assessed for thyroid stimulation hormone (TSH), hemoglobin A1c (HbA1c), thyroid peroxidase antibodies (TPO), glutamic acid decarboxylase (GAD) antibodies and islet cell antibodies (IC) at time of treatment start and wk 16 end point. Results: 29 subjects enrolled with base-line laboratory testing of which 14 subjects could be assessed at wk 16. At baseline, 1/14 subject had abnl TSH but at week 16 all subjects had a nl TSH (p 0.0687). Subjects had nl TPO at baseline and only 1/14 had an abnl TPO at 16 weeks (p 0.1634 ) but TSH remained nl. All 14 subjects had nl GAD and IC antibodies at baseline and at 16 wks; however, 2/14 of subjects had abnl IC antibodies at 16 wks but had nl HbA1c. 6/14 had nl HbA1c at baseline and 1/6 went on to develop pre-diabetes and 1/6 developed diabetes at the 16 wks. 5/14 subjects had pre-diabetes at baseline: 1/5 had nl HbA1c while 1/5 developed diabetes at 16 wks. 2 subjects developing diabetes had no positive GAD or IC antibodies. 3/14 had diabetes at study start with no worsening of the HbA1c or diabetes-related complications at wk 16. Conclusions: ICIs can cause IRAEs. Study result suggests that treatments with N and P can cause new onset of non-immune diabetes mellitus. Clinical awareness is important while managing NSCLC patients on ICIs. Patient should be screened for diabetes and thyroid disease prior to therapy and with repeat testing so as to avoid treatment complications. Longer follow-up and further study of ICI-mediated auto-immune endocrinopathies is needed.
Correlation of circulating tumor enumeration and immune checkpoint marker expression on CD103+, CD4+ T cells in non-small cell lung cancer tissue.
Authors: WANG Xiaoyang , Chen Pin-I , Jaimes Maria , Gu Humin , Shults Keith , Putta Santosh , Fazeli Fariba , Fernandez Janine , Sharma Vishal , Chow Will , Gogoi Priya , Handique Kalyan , Patterson Bruce Kendrick
Published: July 2019

109

Background: Non-small cell lung cancer (NSCLC) has a poor prognosis as most patients are at advanced stage when diagnosed. Targeted therapy and immunotherapy in recent years has significantly improved NSCLC patient outcome. In this study, we employed cell-by-cell immune and cancer marker profiling of the primary tumor cells to investigate possible signatures that might predict the presence or absence of circulating tumor cells (CTCs). Methods: We performed a comprehensive study on 10 NSCLC patient tissue samples with paired blood samples. The solid tissue biopsy samples were dissociated into single cells by non-enzymatic tissue homogenization. The single cell suspensions were stained with a total 25 immune, cancer markers and a DNA content dye and analyzed with advanced, high-parameter flow cytometry. CTCs were isolated and analyzed from the paired peripheral blood. Results: Out of the 26 unique cell markers stained, we investigated a total of 72 biomarkers for their correlation with CTC number. Strong correlations were observed between CTC number and the frequency of immune checkpoint marker expressing lymphocytes, especially with the immune checkpoint marker expressing CD103+CD4+ T lymphocytes. CTC number is also correlated with the frequency of PD-L1 expressing cancer cells and cancer cell DNA content. In contrast, CTC number inversely correlated to the frequency of CD44+E-cadherin- cancer cells. Unsupervised clustering analysis based on the biomarker analysis separated the CTC negative patients from the CTC positive patients. Conclusions: Profiling multiple immune and cancer markers on cancer samples with multi-parametric flow cytometry allowed us to obtain protein expression information at the single cell level. Clustering analysis of the proteomic data revealed a signature driven by checkpoint marker expression on CD103+CD4+ T cells that could potentially be predictive of CTCs.
Healthcare provider awareness and integration of immunotherapy for stage III NSCLC.
Authors: Andrie Rachael , Quill Timothy A. , Vinther Angelique , Stacy Tina B. , Obholz Kevin
Published: July 2019

123

Background: In February 2018, immunotherapy was approved for patients with unresectable stage III NSCLC without progression after concurrent chemoradiotherapy (cCRT). The anti–PD-L1 inhibitor durvalumab is now considered by most experts to be the standard of care (SoC) in this setting based on improved survival outcomes. Methods: We conducted a series of 5 CME-certified symposia to provide healthcare providers (HCPs) with education that included expert and guideline recommendations on the optimal use of durvalumab therapy for patients with unresectable stage III NSCLC. These symposia were conducted at 3 major oncology conferences (NCCN Annual, AACR, ASCO Annual) and 2 managed care pharmacy (MCP) conferences (AMCP Annual, AMCP Nexus) over an 8-month period after durvalumab was approved (Table). Polling questions designed to assess key aspects of HCP knowledge and practice patterns were repeated at each symposium and responses were collected through an audience response system. Results: Across the 5 symposia, on average fewer than 45% of responding HCPs recommended durvalumab consolidation therapy for an ideal patient candidate with stage III NSCLC after cCRT (Table). Among responding HCPs across 4 symposia, on average fewer than 30% identified the optimal recommended duration of 1 year of durvalumab therapy based on current clinical evidence. Physicians did identify the optimal management of immune-related pulmonary toxicity associated with durvalumab treatment more often than other HCPs (Table). Conclusions: These pre-education data suggest that a large percentage of HCPs are not fully aware of the available clinical evidence and are delayed in the implementation of immunotherapy for unresectable stage III NSCLC. [Table: see text]
Phase I study of CpG ODN(K3), a novel toll-like receptor 9 agonist, for advanced lung cancer: Interim analyses of safety and immunity in subcutaneous injection cohort.
Authors: Otsuka Tomoyuki , Nishida Sumiyuki , Hamaguchi Masanari , Shibahara Takayuki , Shiroyama Takayuki , Kimura Keiko , Hirata Haruhiko , Kida Hiroshi , Ishii Ken J. , Kumanogoh Atsushi
Published: July 2019

126

Background: CpG oligodeoxynucleotide (CpG ODN) (K3), a toll-like receptor 9 agonist, is a novel synthetic single-strand DNA immune adjuvant for cancer immunotherapy. CpG ODN(K3) induces the production of type 1 IFNs and pro-inflammatory cytokines in innate immune cells, leading to a potential Th1-type adaptive immune response against cancer cells, leading to an immunogenic tumor microenvironment. To determine the recommended dose (RD) of CpG ODN(K3) via subcutaneous injection (sc) or intravenous administration (iv) and to investigate the immune response induced by CpG ODN(K3) in advanced lung cancer patients, we designed an open-labeled, dose-escalation phase I study. Methods: Pts with advanced lung cancer who had achieved CR, PR or SD after the prior Pt-based chemotherapy were enrolled. The primary endpoint was the proportion of DLTs at each dose level. Secondary endpoints included safety profile, immune response including dynamic changes of immune cell and cytokine production, and PFS. In a 3+3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body sc and 0.2 or 0.6 mg/kg iv on day1, 8, 15 and 29. Pts without PD or unacceptable toxicity were allowed to receive CpG ODN(K3) up to a maximum of 6 months. Results: 6 pts were treated in sc part. 5 had NSCLC (3 had adenocarcinoma, 1 squamous cell carcinoma, and 1 mucoepidermoid carcinoma) and 1 had SCLC. There were no DLTs at any dose levels. Treatment-related toxicities were limited to G1 and G2 including local skin reactions. No pts experienced serious AEs including immune-related AEs. Some pts exhibited the dynamic change of immune-related cells and the immediate production of inflammatory cytokines and chemokines, such as IL1-beta, CCL2, and CXCL10, and Th1 cytokines including IFN-gamma, in response to CpG ODN(K3), suggesting that CpG ODN(K3) elicited innate immunity followed by Th1 adaptive immune response. Conclusions: This was the first clinical application of CpG ODN(K3) for cancer pts. CpG ODN(K3) sc was well-tolerated and was expected to activate innate immunity followed by Th1 adaptive immune response. Clinical trial information: UMIN000023276.
The role of high-dimensional profiling of the systemic immune response on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB).
Authors: Chua Kevin Lee Min , Fehlings Michael , Chu Pek Lim , Lin Xiao-Tian , Yeo Eugenia , Low Kar Perng , Poon Dennis , Ong Enya , Woo Wai Yee , Wee Joseph , Nardin Alessandra , Iyer N Gopalakrishna , Tan Daniel Shao-Weng , Soo Khee Chee , Newell Evan , Chua Melvin Lee Kiang
Published: July 2019

13

Background: Combinatorial RT-ICB potentiates anti-tumour reactivity by modulating the immune response. We therefore performed in-depth phenotypic profiling of the systemic T cell compartment following treatment with RT-ICB. Methods: We recruited 20 patients with biopsy-proven metastatic renal cell and non-small cell lung carcinoma, who were treated with a sandwich regime of ICB-RT-ICB under a prospective observational study protocol, and compared against a RT alone-treated cohort (N = 10). All patients received ablative RT (8-50 Gy/1-5 fr) for oligoprogression and/or local palliation. Blood samples were longitudinally collected at pre-RT, 14 d post-RT and cycle 2 ICB post-RT. Deep T cell profiling was performed by mass cytometry using a customised 41 parameter panel, together with high dimensional analysis tools. Results: Median follow-up of the overall cohort was 18 mo; median duration of ICB received in the ICB-RT-ICB arm was 15 mo. We observed significant diversity of the systemic T cell repertoire between patients at baseline, and this corresponded to significant interpatient heterogeneity in T cell responses specific to the central/effector memory, EMRA and Treg subsets post-RT. Dramatic local response (complete response at 1 mo post-RT) was significantly higher in the ICB-RT-ICB cohort compared to the RT alone cohort (12/20 vs 1/10, P <0.01). This clinical phenomenon corresponded to an increased % Ki67highCD8 and CD4 T cells post-RT exclusively in the combinatorial treated cohort, which was further enhanced upon resumption of ICB (mean = 10% vs 3% [CD8]; 13% vs 2% [CD4]; P <0.01). Deeper immunophenotyping of the Ki67high subsets revealed associated high expression of GranzymeB and Eomes. Conclusions: Here, we observed changes in the T cell phenotypes that varied remarkably across all patients following RT. We further highlight a RT-dependent T cell proliferation amongst all RT-ICB-treated patients that was further enhanced by ICB in prior responders. This immune phenomenon may account for the dramatic responses to combinatorial treatment, and informs on optimal sequencing strategies for combining RT and ICB.
Response rate and safety of standard-dose nivolumab with reduced-dose ipilimumab in metastatic melanoma.
Authors: Mehmi Inderjit , Hill Jordan
Published: July 2019

140

Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab was shown to improve overall response rate (58%), progression free survival (11.5 months), and overall survival compared to ipilimumab alone in Checkmate 067. Improved outcomes were accompanied by an increased risk of toxicities with a 59% rate of grade 3-4 toxicities for the combination. Keynote 029 evaluated standard-dose pembrolizumab with reduced-dose ipilimumab with a slightly lower risk of grade 3-4 toxicities at 45%. Here we report outcomes for standard-dose nivolumab combined with reduced-dose ipilimumab in metastatic melanoma. Methods: We conducted a retrospective review of metastatic melanoma patients that received standard-dose nivolumab with reduced-dose ipilimumab at West Virginia University Cancer Institute. Response to therapy and incidence of immune-related adverse events were assessed. Results: From February 2017 to October 2018, 11 patients received the alternative dosing regimen. Only 1 (9%) patient experienced a grade 3-4 toxicity, and 3 (27%) additional patients experienced a grade 1-2 toxicity. The overall response rate was 54%. Conclusions: Standard-dose nivolumab in combination with reduced-dose ipilimumab is better tolerated than reduced-dose nivolumab with standard-dose ipilimumab without a loss in overall response rate.
Autoimmune toxicities with anti-PD-1 treatment of metastatic melanoma in predominantly older patients: A single institutional experience.
Authors: Parmar Harsh V , Kerr Phil , Stevenson Christina Elizabeth , Masternak Sophie , Hegde Upendra P.
Published: July 2019

144

Background: Anti-PD-1 therapy has become an effective method of treating patients including elderly subjects diagnosed with un-resectable or metastatic melanoma. While effective, toxicity reports in elderly are conflicting. Some reports indicate no added autoimmunity with older melanoma patients, while we had previously reported our concerns of heightened autoimmune toxicity with anti-PD-1 treatment of melanoma in elderly subjects. This report includes updated results in 36 patients receiving anti-PD-1 treatment for melanoma with an increased proportion of older subjects from a single institute. Methods: Between 2014-2018, we performed retrospective review of charts of patients treated with anti-PD-1 agents for stage III and IV melanoma following IRB approval. Data for treatment outcomes and grade III and IV immune related adverse events were collected. Results: 36 patients were treated with either Pembrolizumab or Nivolumab that included stage IV melanoma (28 pts), un-resectable stage III (5 pts) and stage III melanoma in adjuvant setting (3 pts). 30 out of 36 patients were over 60 years of age (median age 77, range 62-90) and 6 patients were younger than 60 years (median age 48, range 24-56). 16 out of 30 patients over age of 60 years (53%) experienced grade III or IV toxicities following anti-PD-1 therapy compared to none (0%) in age below 60 years. Overall, 19 patients are alive either with disease or on treatment with stable, partial or complete responses. 17 patients have died, out of which 12 died of progressive disease, 2 elderly patients died suddenly and 3 elderly patients died of autoimmune toxicity (myasthenia gravis like syndrome, acute inflammatory demyelinating polyneuropathy, pneumonitis). Some unusual autoimmune toxicity seen in elderly subjects included diabetes mellitus, Behcet disease, acute inflammatory demyelinating polyneuropathy, retinitis, Bell's palsy and bullous pemphigoid). Conclusions: Our data continue to indicate that increased risk of severe autoimmune toxicity following anti-PD-1 treatment involved older patients over 60 years of age. This finding may highlight the increased susceptibility of autoimmunity with aging.
MHC-1 genotype as a predictor of response to immunotherapy.
Authors: Goodman Aaron , Pyke Rachel , Kato Shumei , Okamura Ryosuke , Sokol Ethan , Frampton Garrett Michael , Miller Vincent A. , Carter Hannah , Kurzrock Razelle
Published: July 2019

149

Background: MHC-1 molecules present intracellular peptides on the surface of tumor cells for recognition by CD8+ cytotoxic T-cells. Cancers with a high tumor mutational burden (TMB) are more likely to respond to immune checkpoint blockade (ICB) due to the increased chance of having a mutated peptide presented by MHC-1. However, the interaction between TMB and patient-specific MHC-1 and ICB response is unknown. Methods: We analyzed 83 patients with diverse solid tumors treated with ICB for TMB and MHC-1 (tissue next generation sequencing (NGS) (Foundation Medicine)). TMB low vs high were defined as <20 vs ≥20 mut/mb, respectively. Patient Harmonic-mean Best Rank (PHBR) (Marty et al. 2018) scores the ability of the MHC-I of an individual to bind and present a specific missense mutation. Patients were assigned the PHBR of their best presented missense driver mutation. PHBR low (strong presentation) vs high (weak presentation) were defined as <1.01 vs ≥1.01 respectively (cutoff per a receiver operator curve). Overall response rate (ORR) (includes stable disease for ≥6 months) was determined (RECIST criteria). Results: The ORR, PFS, and OS for patients treated with ICB with PHBR low vs. high tumors was 72% vs 28% (P = 0.01), 6.3 vs 4.1 months (P = 0.03), and 37.1 vs 13.9 months (P = 0.25), respectively. The ORR, PFS, and OS for TMB low vs high was 36% vs 67% (P = 0.02), 4.3 vs 14.1 months (P = 0.01), and 12.0 months vs not reached (P = 0.03), respectively. The ORR, PFS, and OS for TMB high/PHBR high vs TMB high/PHBR low was 38% vs 85% (P < 0.01), 3.9 vs 26.8 months (P <0.01), and 17.1 vs not reached (P = 0.02), respectively Conclusions: MHC-1 genotype and the ability to present driver neo-antigens predicts which patients with TMB high will respond to ICB.[Table: see text]
Analysis of real-world PD-L1 IHC testing for clinical use in patients across multiple tumor types.
Authors: Krigsfeld Gabriel S , Prince Emily , Zerba Kim , Chizhevsky Vladislav , Ragheb Josette William , White James William
Published: July 2019

151

Background: A number of programmed death ligand 1 (PD-L1) IHC diagnostic tests have been approved by the FDA to guide treatment with programmed death-1/PD-L1 inhibitors. We evaluated PD-L1 assay utilization and concordance across all tumor types, including melanoma (MEL) and squamous cell carcinoma of the head and neck (SCCHN), using real-world cancer samples tested at a single reference laboratory in the United States. Methods: 55,652 samples with clinical characteristics were provided by Symphony Health Solutions. NeoGenomics Laboratories, Inc assessed PD-L1 expression using the Dako PD-L1 IHC 28-8 or 22C3 pharmDx, or Ventana PD-L1 SP142 assay tests between October 2015 and April 2018, according to the manufacturers’ protocols at the time of the study. Clinical characteristics were matched to PD-L1 test results using unique identifiers. Data were analyzed by BioStat Solutions, Inc. Results: 61,568 tests from 55,652 patients were included. Across all 61,568 tests, 88.8% were carried out with 22C3, 9.8% with 28-8, and 1.4% with SP142. The 28-8 and 22C3 pharmDx assays showed high analytical concordance in all 3113 matched samples with PD-L1 expression data for both assays (OPA = 96.2%, Spearman’s r = 0.96; Table). The failure rate across all tests was 3.5%, and 96.6% of patients had a quantifiable test result. Average test turnaround time was 3.1 days, with a 9.1-fold increase in total number of tests performed between Q4 2015 and Q1 2018 (from 1163 to 10,544). Subgroup analyses for 678 patients (1.2%) with MEL and 270 patients (0.5%) with SCCHN will be presented. Conclusions: Despite an increased demand for PD-L1 testing in the US, most patients received a result in 2–4 days. These real-world analytical data support the potential interchangeability of the Dako PD-L1 IHC 28-8 and 22C3 pharmDx assays in clinical practice for assessing tumor cell membrane PD-L1 expression across tumor types, and provide context on the evolution and adoption of PD-L1 testing for patients with cancer. [Table: see text]
Isolation and characterization of exosomes from IDH mutant gliomas.
Authors: Ludwig Nils , Rao Aparna , Yerneni Saigopalakrishna Saileelaprasad , Amankulor Nduka , Whiteside Theresa
Published: July 2019

152

Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are found in > 70% of intermediate grade gliomas. Gain-of-function mutations in IDH1 promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Tumor-derived exosomes (TEX) accumulate in the tumor microenvironment (TME) and in body fluids of patients. TEX serve as a communication system between tumor and normal cells. Circulating TEX carry a complex molecular and genetic cargo and interfere with functions of immune cells. This study characterizes TEX produced by IDH mutant glioma spheres and TEX from plasma of patients with IDH mutant gliomas. Methods: TEX produced by patient-derived IDH1(mut) or IDH1(wt) glioma spheres or TEX in patient’s plasma were isolated by mini size exclusion chromatography (mini-SEC). TEX morphology, size, numbers and molecular profile were characterized and the crossing of the blood-brain barrier (BBB) and biodistribution was investigated by in vivo imaging of TEX. Interactions of TEX with endothelial cells, astrocytes and immune cells were demonstrated by confocal microscopy. Results: TEX isolated from supernatants of IDH1(mut) or IDH1(wt) glioma spheres by mini-SEC carried TSG101 and showed the typical size and vesicular morphology of exosomes. BCA protein assays and qNano analysis revealed an elevated exosome production by IDH mutant cells ( p< 0.01). TEX carried immunosuppressive proteins (FasL, CTLA-4 and TRAIL) and IDH mutant exosomes carried higher levels of these proteins and of adenosine pathway components CD39 and CD73. Labeled TEX injected in the white matter of mice crossed the BBB and were detectable in distant organs 24h after injection. TEX were rapidly internalized by endothelial cells and astrocytes, but not by T cells, which interacted with TEX by surface signaling. These results were confirmed by investigating TEX isolated from glioma patient’s plasma. Conclusions: The data suggest that TEX play an important role in IDH mutant gliomas and drive tumor progression in part by inducing suppression of immune cells. Future efforts will focus on characterizing immunosuppressive effects of TEX derived from IDH mutant cells vs gliomas without IDH mutations.
Phase I study to evaluate the safety and efficacy of rivoceranib (apatinib) and nivolumab in patients with unresectable or metastatic cancer.
Authors: Chawla Sant P. , Chua Victoria S. , Gordon Erlinda Maria , Moradkhani Ania , Kim Katherine , Quon Doris , Wong Steven , Sumner Robert , Mac Virginia , Huang Raymond , Wang Kelly , Kim Jiyeun , Kim Bumjin , McGinn Arlo N. , Park Cheol Hee , Houston Scott , Sankar Neil
Published: July 2019

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Background: Due to their immuno-modulatory effects, anti-angiogenic drugs have been clinically investigated in combination with anti-PD-1 therapies. The addition of rivoceranib (apatinib), a highly-selective VEGFR-2 tyrosine kinase inhibitor, is being evaluated in an ongoing 2-part Phase I trial in subjects with locally advanced unresectable/metastatic solid tumors who have received at least 3 doses of nivolumab. A classic 3+3 dose escalation has been completed (Part 1) and the study is currently ongoing with an extension period (Part 2). Herein, we present the safety and preliminary efficacy. Methods: To date, 10 subjects were enrolled in Part 1 while 3 subjects have been enrolled in Part 2. Median number of prior lines of therapy were 3 and 1, respectively, for the two study segments. The major inclusion criteria specified that patients must have received at least 3 doses of nivolumab and are continuing nivolumab therapy. Escalating doses of rivoceranib at 400, 600, and 700 mg po qd was proposed in combination with nivolumab at 240 mg iv q2w to determine the MTD. Best tumor response and time of progression was assessed using RECIST v1.1 and iRECIST. Results: 300 mg rivoceranib was determined as RP2D for Part 2. 5/13 patients had G2/3 hypertension. Common treatment-related AEs were hypertension, hand and foot syndrome, and nausea and immune-related AEs were hypothyroidism and diarrhea. Notably, in 10 evaluable patients, 3 patients had PD and 4 patients showed tumor shrinkage (5-29%). A patient with Malignant Spindled/Epitheloid Sarcoma, who had PD during previous nivolumab treatment has shown tumor reduction, so far, of 9%. A patient with Gastric Cancer, who had stable disease (a 4% increase) after 2 months of nivolumab showed a reduction of 29%, 2 months after introduction of rivoceranib. 2 patients have had stable disease for more than 8 months as of Oct 26, 2018. Conclusions: Preliminary results indicate the potential clinical benefit of a 300 mg starting dose in combination with 240 mg of nivolumab in unresectable/metastatic solid tumors with a tolerable safety profile. Efficacy of ongoing and future patients in Part 2 will be further evaluated. Clinical trial information: NCT03396211.
Managing combination immunotherapy trials from a contract research organization's (CRO's) perspective.
Authors: Balkissoon Jai , Nguyen Binh , Combest Austin J. , Stoitchkov Konstantin Yordanov , Stoyanov Nikolay , Hsu Judy , Reitsma Dirk J.
Published: July 2019

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Background: With the increased clinical activity that we are seeing with combination IO therapies, more sponsors are searching for contract research organizations (CROs) that have experience managing combination IO clinical trials which are often large, complex, multi-national, resource-intensive, competitive and highly specialized. Pharmaceutical Product Development (PPD), a contract research organization (CRO) has worked with sponsors in managing combination IO clinical trials. This includes early and late phase trials with many different classes of agents in multiple tumor types. We sought to review PPDs experience in combination immunotherapy trials and highlight key challenges, efficiencies, innovative modern trial designs, endpoints and enrollment strategies in a competitive market. Methods: We reviewed IO trials managed by PPD over the past 5 years, information from PPDs Immuno-Oncology Center of Excellence (IOCOE) and Immuno-Oncology Working Group (IOWG) and the current pace of development of IO therapies. Results: PPD has collaborated with multiple sponsors to manage innovative, complex IO trials that push the boundaries of clinical development. Comprehensive planning and risk management strategies steeped in a deep understanding of the trial environment are essential for successful IO protocols. Protocol and trial optimization have been useful to make trials more efficient and less expensive. Conclusions: IO approvals are increasing at a rapid pace and both sponsors and CROs will need to work together to continue to develop innovative trial designs, biomarkers and endpoints that will determine efficacy and tolerability of combination IO therapies. PPDs innovative tools, technology and resources have been useful to help sponsors with enrollment strategies to prevent increasing study timelines and delays in study results. The IO space is pushing the limitations of scientific, technological and operational advances, and we are happy to continue to share our learnings in this ever-evolving landscape.
Initial results of a phase III investigation of safety/efficacy of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma.
Authors: Chua-Alcala Victoria S. , Kim Katherine , Assudani Nupur , Al-Shihabi Ahmad , Quon Doris , Wong Steven , Chawla Sant P. , Gordon Erlinda Maria
Published: July 2019

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Background: Objectives: (1) To investigate the MTD of ABI-009 when given with nivolumab, a PD-1 inhibitor, in previously treated advanced undifferentiated pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of this combination therapy in the above mentioned patient group, and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: This is an IRB approved protocol with 2 parts. The Phase 1 part is a dose-finding study using the “cohort of three design”, wherein standard doses of nivolumab 240 mg is given iv every 3 weeks (Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75, and 100 mg/m2. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: The Phase 1 part of study is closed, after 9 patients were treated successfully at 3 dose levels. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1 (n=3): Grade 3 treatment-related adverse events (TRAEs) included hyperdyslipidemia (n=1), and hyperglycemia (n=1). At Dose 2 (n=3): Grade 3 TRAEs included increased ALT (n=1). At Dose 3 (n=3): Grade 3 TRAEs included hypophosphatemia (n=1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. Conclusions: The primary objective has been met with no DLTs, the MTD was not reached and Dose 3 has been designated as the phase 2 dose of ABI-009 which is on-going. Clinical trial information: NCT03190174.
A phase II single-arm study of CRS-207 with pembrolizumab (pembro) in previously treated malignant pleural mesothelioma (MPM).
Authors: Alley Evan W. , Tanvetyanon Tawee , Jahan Thierry Marie , Gandhi Leena , Peikert Tobias , Stevenson James , Schlienger Katia , Liu Weiqun , Nair Nitya , Honarmand Somayeh , Kindler Hedy L.
Published: July 2019

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Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) engineered to stimulate immune response to mesothelin. In a phase I trial of 60 MPM patients, 34% of subjects had tumor reduction (range -1 to -47%) following 2 doses of CRS-207 alone. In KEYNOTE-028 pembro showed activity in PDL1+ (≥1% by IHC) MPM, with an objective response rate (ORR) of 20% (5/25) and stable disease in 52% of subjects who had failed or did not receive chemotherapy. Subsequent studies of pembro have shown similar results in MPM. Results from a pre-clinical murine lung tumor model (CT26hMeso) showed anti-PD-1 enhanced LADD-induced tumor response. The study described here evaluated the efficacy of combination therapy of CRS-207/pembro. Methods: Adults with epithelial/biphasic MPM, ≤2 prior lines, progression on pemetrexed and platinum-based therapy, and no prior immunotherapies were enrolled. CRS-207/pembro were administered IV Q3W for 4 cycles, after which pembro continued Q3W and CRS-207 changed to Q6W. Response was assessed Q6W by modified RECIST for MPM (Byrne and Nowak, 2004). The primary endpoint was ORR; secondary endpoints included DOR, disease control rate (DCR), progression-free survival (PFS) and overall survival. Pre- and on-treatment blood and tumor samples were collected. Shedding and blood clearance of CRS-207 were evaluated. Results: 9/10 subjects were evaluable for response. No responses were observed; DCR was 11% (1/9 with SD) and PFS ranged from 3.4 to 8.9 weeks. Most common treatment related adverse events were chills, pyrexia and nausea. 3/10 subjects evaluated were PDL-1 negative by IHC. Of 6 subjects who underwent clearance and shedding evaluation, CRS-207 was detected in blood in 1 at 18-24 hrs after the first CRS-207 dose and cleared by the next evaluation at Day 4; shedding samples (urine, fecal, and saliva) tested negative. Conclusions: The toxicity profile of CRS-207/pembro combination was consistent with the safety profile of each component alone. No evidence of clinical activity was observed. Based on the results and an overall evaluation of the program, the clinical development of CRS-207 was discontinued. (NCT01675765) (NCT02054806). Clinical trial information: NCT03175172.
PTEN/PI3K signaling in cancer and the response to cytokines: From growth factors to immune actors.
Authors: Chandrasekaran Sanjay , Sasaki Maiko , Pollack Brian Paul
Published: July 2019

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Background: The PTEN/PIK3 pathway plays an important role in the cellular response to growth factors and aberrant activation of PI3K signaling is a hallmark of many forms of cancer. While the role of PI3K signaling has been well studied in the context of growth factor biology, its role in the cellular response to cytokines such as interferons (IFNs) is less well understood. We examined the impact of PI3K activation on interferon signaling pathways using an in vitro experimental model system. Methods: Cultured human HCT 116 colorectal carcinoma cells and isogenic PTEN (-/-) cells were treated with escalating doses of IFNg, IFNa2b, and IFNl. IFN response was evaluated by measuring MHC Class I and Class II mRNA levels and cell surface expression via RT-PCR and flow cytometry, respectively. Western blots for total AKT, phospho-AKT (pAKT), PTEN, STAT1, and pSTAT1 were performed. Corroborating pharmacologic studies were performed using cultured HPV-negative SqCC/Y1 oSCC cells treated with IFN and the PTEN inhibitor VO-OHpic and AKT activator SC79. Clinical correlates utilizing immunohistochemistry (IHC) on human head and neck cancers were conducted. Results: PTEN (-/-) cells expressed lower basal levels of MHC I and the induction by IFNs were likewise attenuated. Dramatically, PTEN knockout reduced IFN-g- induced surface expression of MHC II by > 50%. Corresponding reductions in MHC I/II mRNA were seen. IHC in patient biopsy samples showed an inverse relationship between phospho-AKT and MHC I expression. We identified a potential explanation of this effect wherein PTEN/PIK3 signaling implicates STAT1, a downstream target of IFN signaling. PTEN inhibition consistently modulated total and phosphorylated levels of STAT1 protein. Conclusions: Much remains unknown about the link between growth factor pathways and the tumor immune response. We demonstrate using an in vitro model that genetic and pharmacologic activation of the PI3K pathway attenuates the immune response to IFNs and represses MHC induction and expression. We present a novel mechanism for explaining this phenomenon linking the PTEN/PIK3 and STAT1 pathways. Further characterization of this interaction in in vitro models is necessary.