bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased risk of hypothyroidism in patients with primary head and neck cancer compared to non-head and neck primary malignancies.
Authors: Alaber Omar A. , Chander Apoorva K. , Jain Prantesh , Rajpal Aman , Patel Monaliben , Hoimes Christopher J. , Mendiratta Prateek , Lavertu Pierre , Mangla Ankit
Published: February 2020

37

Background: Immune related thyroiditis is a common adverse effect of Immune checkpoint inhibitors (ICI). We sought to determine if the incidence of hypothyroidism (HT) in patients with primary head and neck cancers (pHNC) who received ICI, is increased compared to other primary cancers (lung, gastrointestinal (GI), skin melanoma or urinary system(GU). Methods: Data were obtained from a commercial de-identified database (IBM Explorys Solutions, IBM, Inc.). Cases included patients ≥ 18 years with a diagnosis of pHNC and controls included patients with a diagnosis of lung, GI, skin melanoma or GU cancer. All patients received one of 5 ICI (Avelumab, Atezolizumab, Durvalumab, Nivolumab or Pembrolizumab). Incidence of HT was defined as patient with a new diagnosis of HT at least 1 day following initiation of ICI. All patients with diagnosed HT, thyroid cancer (previous/concurrent), lymphomas were excluded. Odds ratios (OR) and confidence intervals (CI) were calculated using chi-square test. Results: There were 238,490 patients with a diagnosis of pHNC, and 616,850 patients with a diagnosis of other cancers in the database. Out of 710 pHNC patients, 80 patients (18.6%) and out of 7420 patients with other primary cancers, 850 (12.57%) had a new diagnosis of HT. When compared to non-HNC patients, HNC cases had a 1.6 (CI = 1.23 - 2.05) times higher odds of developing HT. In subgroup analyses, HNC cases were significantly more likely to develop HT compared to patients with GI or lung cancer, but not with skin melanomas or GU cancers. Overall, male cases and adults aged 18 - 65 years were significantly more likely to develop HT. (Table). Conclusions: The risk of developing HT after ICI is higher in patients with HNC compared to other primary cancers. Men and patients between the ages 18-65 years with pHNC were more likely to become HT. [Table: see text]
Human leukocyte antigen expression in paired primary lung lesions and brain metastases in non-small cell lung cancer.
Authors: Failing Jarrett , Aubry Marie-Christine , Mansfield Aaron Scott
Published: February 2020

43

Background: Human leukocyte antigens (HLA) are crucial for cytotoxic T cell responses to cancer. Loss of HLA expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors we have observed discordant responses between brain metastases and extracranial disease and reported on differential PD-L1 expression and clonal T cell infiltration between paired primary lung lesions and brain metastases. In this project we sought to evaluate whether HLA expression was retained in metastatic NSCLC. Methods: Adult patients with paired primary NSCLC and brain metastases were identified from our institution’s tissue registry. HLA-A cell membrane expression on tumor cells was determined by immunohistochemistry with an anti-HLA-A antibody. Tumors with greater than 10% HLA expression were considered positive. Agreement statistics (κ) and Fisher’s exact test were used for analysis. Results: 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%)(κ = 0.57, 95% CI 0.35-0.79)(p = 0.0001). There was no significant difference in the time between the primary tumor and brain metastasis resections in patients with HLA expression disagreement compared to those with HLA expression agreement. None of the patients received immune checkpoint inhibitors for treatment of these lesions. Conclusions: We found significant differences in HLA-A expression on tumor cells in nearly one quarter of paired primary lung cancers and brain metastases. Differences in HLA expression may help explain the discrepancies in response to immune checkpoint inhibitors at different sites of disease and warrants further study.
Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018.
Authors: Corrie Philippa Gail , Chao David , Board Ruth , Sarah Lawton , Smittenaar Rebecca
Published: February 2020

55

Background: Population-based research provides real world information about prescribing trends, as well as benefits and harms associated with new interventions first evaluated in randomized clinical trials (RCTs). The national health service in England has comprehensive databases which we used to track prescribing of checkpoint inhibitors (CPIs) approved for 1st line use in metastatic melanoma and determine patient outcomes associated with survival and treatment toxicity. Methods: National Cancer Registration and Analysis Services (NCRAS) datasets were used to identify metastatic melanoma patients (pts) prescribed 1st line CPIs and calculate survival outcomes. The HES (Hospital Episode Statistics) database was used to identify emergency attendances and emergency hospital admissions. Results: 5465 melanoma pts were registered between April ‘14 and March ‘18. 2322 pts received 1st line CPIs: 1174 pembrolizumab (pem), 724 ipilimumab (ipi), 52 nivolumab (nivo), 372 ipinivo. Prescribing reflected national access, with ipi starting in July ‘14 and dropping rapidly on approval of pem in Nov ’15. Ipinivo prescriptions increased annually since July ’16. There was good 3yr OS concordance with RCT outcomes for ipinivo (56%), nivo (51%), pembro (40%) and ipi (32%). Pts treated with ipinivo were significantly younger (88% vs 49% <70 years, P<0.001) and fitter (60% vs 38% ECOG PS 0, P<0.0001) than pts treated with antiPD1. 30-day mortality from last SACT was 3.8% for ipinivo, 9.1% for antiPD1 and 9.4% for ipi. 30-day rates of emergency hospital admissions/A&E emergency attendances from the earliest SACT and last SACT treatment dates were significantly higher for ipinivo (37%/16% and 55%/19%) compared with antiPD1 (17%/8% and 29%/14%) and ipi (24%/9% and 40%/15%), P<0.01. 25% of ipinivo-, 4% of antiPD1- and 15% of ipi-treated pts had a hospital admission for colitis. Conclusions: This largest real world dataset demonstrated rapid uptake of CPIs and survival outcomes similar to RCTs. Use of emergency services varied by regimen, with colitis dominating hospitalization after ipi+/-nivo. Pt selection appeared to differ for different regimens, the consequences of which warrant further research.
Association of antibiotic exposure with overall survival and colitis in patients with stage III and IV melanoma receiving immune checkpoint inhibitors.
Authors: Chu Brian , Mohiuddin Jahan J. , Facciabene Andrea , Wang Xingmei , Doucette Abigail , Zheng Cathy , Xu Wei , Amaravadi Ravi K. , Karakousis Giorgos C. , Mitchell Tara C. , Maity Amit , Schuchter Lynn Mara , Lukens John Nicholas
Published: February 2020

56

Background: Recent studies suggest that changes in the gut microbiome modulate response to cancer treatment, including immune checkpoint inhibitors (ICI). Broad-spectrum antibiotics (Abx) are known to cause significant dysbiosis. We hypothesize that recent Abx exposure worsens outcomes in patients (pts) with stage III/IV melanoma (MM) receiving ICI. Methods: We identified MM pts treated with ICI from our institutional database. All received their first ICI between 2004-2019. Antibiotic exposure was defined as receipt of Abx within 3 months prior to the first infusion of ICI. The primary outcome was overall survival (OS) and the secondary outcome was immune-mediated colitis requiring intravenous (IV) steroids. Stage III and IV pts were analyzed separately for the primary analysis. Results: Of 568 pts in our database, 20% received Abx within the 3 months prior to ICI. 36% of pts had stage III disease and 26% of pts were treated with either adjuvant or neoadjuvant ICI. 1.6% of pts died of causes other than MM. The Abx+ and Abx- groups were balanced in terms of stage, race, age, sex, BRAF status, LDH, prior systemic therapies, and class of ICI received. Only 4 pts were hospitalized due to the infection prompting the Abx, and no pts died due to the infection. In the Stage IV group, Abx+ pts had worse OS on MV analysis (HR 1.6, 95% CI 1.1-2.2). Stage III Abx+ also had worse OS (HR 2.8, 95% CI 1.3-5.9). In a sensitivity analysis excluding pts who received IV Abx or were admitted due to infection, survival was still worse for Abx+ pts (HR 1.7, 95% CI 1.2-2.4). In a Fine-Grey competing risk MV model, Abx+ had a higher rate of immune-mediated colitis requiring IV steroids (HR 2.1, 95% CI 1.02-4.5). Conclusions: In MM pts treated with ICI, receipt of Abx within 3 months prior to ICI initiation was associated with decreased OS and increased colitis. Future research should include prospective studies to better define the risk/benefit profile of antibiotics in close proximity to ICI. [Table: see text]
Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of hormone replacement and immunosuppressants, and association with outcome: E1609 study analysis.
Authors: Tarhini Ahmad A. , Lee Sandra J. , Kang Ni , Hodi F. Stephen , Rao Uma N. M. , Cohen Gary Irvin , Flaherty Lawrence E. , Petrella Teresa M. , Sondak Vernon K. , Kirkwood John M.
Published: February 2020

60

Background: E1609 evaluated adjuvant ipilimumab at 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). In-depth analysis of irAEs and the use of immunosuppressants and hormone replacement may provide important lessons for management and future research. Methods: E1609 enrolled 1670 adult pts with resected cutaneous melanoma (AJCC7 IIIB, IIIC, M1a, M1b); Table. We investigated the characteristics of irAEs, corticosteroid, immunosuppressant and hormone use on the ipi arms and association with outcome. Stratified log-rank test was used and since most irAEs were observed within 3 months of initiating ipi, a 3-month landmark adjustment analysis was conducted. Results: The rates of corticosteroid, immunosuppressant and hormone use by treatment are summarized in Table and none had a significant association with RFS or OS. Significant association between occurrence of grade 1-4 irAEs (vs. no AE) and RFS was observed [5-year RFS: 0.49, 95% CI: (0.45, 0.52) compared to 0.41, 95% CI: (0.31, 0.50); landmark p=0.010]. Occurrence of grade 1-2 irAEs appeared to have a stronger association with RFS [5-years RFS: 0.52, 95% CI: (0.47, 0.56) compared to 0.41, 95% CI: (0.31,0.50) with no AE; p=0.006] and a trend towards improved OS [5-year OS: 0.75, 95%CI:( 0.71, 0.79) compared to 0.67, 95% CI: (0.56, 0.75) with no AE; p=0.064]. Among specific irAEs, rash was most significantly associated with RFS (p = 0.004 and 0.002) and OS (p = 0.007 and 0.003) for grade 1-4 and grade 1-2, respectively, followed by endocrinopathies, and weaker associations seen with other AEs. Conclusions: Adjuvant therapy with ipi is associated with significant irAEs that appear to be related to the immune mechanism of action. Corticosteroids and immunosuppressants were not shown to negatively affect the clinical outcomes. Predictors of irAE risk and understanding the underlying mechanisms are a major gap and are currently actively being investigated. Clinical trial information: NCT01274338. [Table: see text]
Interim results from a phase Ib/II study of pepinemab in combination with avelumab in advanced NSCLC patients following progression on prior systemic and/or anti-PDx therapies.
Authors: Shafique Michael Rahman , Fisher Terrence Lee , Evans Elizabeth E. , Leonard John E. , Pastore Desa Rae Electa , Mallow Crystal L. , Smith Ernest , Schröder Andreas , Chin Kevin M. , Beck J. Thaddeus , Baumgart Megan Ann , Govindan Ramaswamy , Gabrail Nashat Y. , Sanborn Rachel E. , Spira Alexander I. , Seetharamu Nagashree , Lou Yanyan , Mansfield Aaron Scott , Goldman Jonathan Wade , Zauderer Maurice
Published: February 2020

75

Background: Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, as well as durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. Methods: The CLASSICAL-Lung clinical trial (NCT03268057) evaluates the combination of pepinemab with anti-PD-L1 antibody avelumab to couple beneficial modifications of the immune microenvironment via pepinemab with immune activation via checkpoint inhibition. This ongoing study evaluates the safety, tolerability and efficacy of the combination in patients with advanced (stage IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Results: The combination was well tolerated with no major safety signals identified. Among 29 evaluable IOF patients, two experienced confirmed partial response (PR) with 63% and 52% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease, and at least 5 patients with durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, clinical benefit ≥ 1 year was observed in 3 patients, and Disease Control Rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, reduction or elimination of tumor in 11/13 biopsies from subjects with PR or SD. Conclusions: Interim analysis suggests the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data (minimum of 6 mo. follow-up), as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Clinical trial information: NCT03268057.
Intratumoral administration of DNA-damaging chemotherapy-treated tumor cells to enhance therapeutic benefit of systemic immune checkpoint blockade in mouse cancer models.
Authors: Sriram Ganapathy , Milling Lauren , Chen Jung-Kuei , Abraham Wuhbet , Irvine Darrell J. , Yaffe Michael B.
Published: February 2020

77

Background: Immune checkpoint inhibition or ICI (antibodies to PD-1 and CTLA4), has shown promise in the treatment of some tumor types, especially in inducing durable remissions in advanced stage cancer patients. However, the majority of patients do not respond to ICI. Identifying combinations to enhance response to ICI is an urgent medical need. Methods: Murine tumor cell lines B16-Ova and MC-38-Ova were treated with DNA-damaging chemotherapeutic drugs, co-cultured with primary murine bone marrow derived dendritic cells (BMDC) followed by addition of OT-1 CD8+ T-cells and flow cytometric analysis of IFN-γ+ CD8+ T-cells. Mice bearing B16-Ova or MC-38 flank tumors were injected intra-tumorally with ex vivo chemotherapy-treated B16-Ova cells with or without systemic ICI. Tumor cross-sectional area was measured using calipers. Intra-tumoral DC and circulating H2-Kb/SIINFEKL-specific CD8+ T-cells were analyzed by flow cytometry. Results: Etoposide and mitoxantrone-treated B16-Ova and MC-38-Ova tumor cells, when co-cultured with BMDC, efficiently promote IFN- γ induction in OT-1 CD8+ T-cells. This was abrogated by co-treatment of tumor cells with Necrostatin-1 but not ZVAD-FMK. Intra-tumoral injection of ex vivo etoposide-treated tumor cells, with systemic ICI, increases the numbers of intra-tumoral CD103+ DC, the frequency of circulating H2-Kb/SIINFEKL-specific CD8+ T-cells and significantly improves survival. The tumor cell vaccine/systemic ICI combination, but not ICI alone, induced complete tumor regressions in a subset of mice. This is abrogated in BATF3-deficient mice. Conclusions: Etoposide and mitoxantrone-treated tumor cells efficiently promote BMDC-mediated CD8+ T-cell priming, in a tumor cell RIPK1 activity-dependent but caspase-independent manner. Intra-tumoral administration of the DNA-damage induced tumor cell vaccine in vivo, in combination with systemic ICI, enhances anti-tumor CD8+ T-cell responses, tumor-free and overall survival, and anti-tumor immunological memory. This enhancement in therapeutic efficacy is dependent on BATF3+ DC in vivo.
Phase I results of the phase I/II study of pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer.
Authors: Chumsri Saranya , Polley Mei-Yin , Mathur Pulkit , Reis Aline , Tenner Kathleen S. , Weidner Morgan , Advani Pooja , Moreno-Aspitia Alvaro , Perez Edith A. , Knutson Keith L.
Published: February 2020

78

Background: Previous study demonstrated that activation of RAS/MAPK pathway is associated with reduced tumor infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple negative breast cancer (TNBC). Further study showed that inhibition of MAPK pathway with a MEK inhibitor is synergistic with anti-PD1/PD-L1 therapies. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy without prior anti-PD-1/PD-L1/PD-L2 therapies were enrolled. Treatment was started with a 2-week run in period with single agent binimetinib. Dose level 0 was binimetinib at 45 mg oral twice daily continuously and dose level -1 was 30 mg twice daily. Pembrolizumab was given at a fixed dose of 200 mg every 3 weeks at both dose levels. Phase I study was based on the standard 3+3 design. Results: A total of 12 patients were enrolled and treated in the phase 1. Five patients were enrolled at dose level 0, 1 patient withdrew prior to treatment and 1 patient was not evaluable for dose limiting toxicity (DLT). Among 3 evaluable patients, 2 patients experienced DLT with grade 3 flank pain and ALT abnormality. Additional 8 patients were enrolled at dose level -1. Out of 6 evaluable patients for DLT, there was 1 DLT observed with grade 3 AST and ALT abnormality. However, this particular patient had liver metastasis with grade 1 AST and ALT abnormality at baseline and her liver function test (LFT) normalized in 3 weeks after treatment discontinuation and oral prednisone. Other grade 1-2 common AEs included rash, LFT increase, abdominal pain, mucositis, nausea, cardiac troponin T increase without EKG change. The efficacy data will be presented at the meeting after the phase II interim analysis. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe based on the initial cohort. Phase II part is currently ongoing with binimetinib 30 mg twice daily and pembrolizumab 200 mg every 3 weeks with a total of 23 patients planned where the safety and efficacy of this combination will be further evaluated. Clinical trial information: NCT03106415.
Quantification of dose dependence and frequency of checkpoint inhibitor immune-mediated adverse events: A Bayesian model-based meta-analysis.
Authors: Shulgin Boris , Kosinsky Yuri , Smirnova Alexandra , Helmlinger Gabriel , Peskov Kirill
Published: February 2020

83

Background: Immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis to quantify dose dependence and compare imAE frequencies for PD-1, PD-L1 and CTLA-4 inhibitor monotherapies and their combinations. Methods: We searched PubMed, TrialTrove, ASCO and ESMO databases and retrieved relevant ICI safety data. In order to quantitatively compare safety across doses and drugs against a given target, we converted the various dose regimens used into drug exposures derived from pharmacokinetic models; we also normalized exposures by the corresponding drug potency. We performed a Bayesian meta-analysis for Grades 3&4 of treatment related (trAE) and immune-mediated (imAE) adverse events. Results: A total of 149 articles were identified, covering 35,559 patients in 197 dosing cohorts treated with ICI therapies. For PD-1 and PD-L1 inhibitor monotherapies, no dose dependence of AEs was found; Grades 3&4 trAE rates for anti PD-L1 vs. anti PD-1 were, respectively, 12% and 15%. The AE rates for the different ICI drugs and organ classes were estimated. Dose dependence was found for anti CTLA-4 monotherapies, for total trAEs of Grades 3/4, gastrointestinal and hepatic imAEs. Dose dependence was found and quantified for anti CTLA-4 in combination with anti PD-1 with respect to total trAEs of Grades 3/4 trAEs and imAEs per gastrointestinal and hepatic organ groups. We found that combination of anti PD-L1 agents with anti CTLA-4 exhibited lower AE rates, as compared to anti PD-1 combined with anti CTLA-4. Conclusions: We introduced a novel meta-analysis methodology and used it to quantify and compare AE rates across ICI agents. Significant AE rate dose dependencies were observed for CTLA-4 inhibitors, either as monotherapy or used in combinations. Patients naive to anti-cancer therapies exhibited higher AE rates vs. previously treated patients. AE rates for CTLA-4 + PD-1 inhibitor combination regimens were supra-additive vs. the respective monotherapies. AE rates for anti PD-L1 agents were lower vs. anti PD-1, both in monotherapy and combinations with CTLA-4.
Interferons alpha and gamma with monocytes as a therapeutic strategy for ovarian cancer.
Authors: Annunziata Christina M. , Duemler Anna , Ning Franklin
Published: February 2020

9

Background: In the presence of pro-inflammatory cytokines, monocytes are cytotoxic to tumor cells. We previously showed that monocytes stimulated with interferon alpha and gamma result in synergistic killing of ovarian cancer cells in vitro. Here we better characterize monocyte differentiation and their ability to induce cell death through co-culture experiments with spheroids and in mouse xenografts. Methods: OVCAR8 cells were grown in ultra-low attachment conditions for three days before being co-cultured with human monocytes as well as interferon gamma and interferon alpha. Monocytes and OVCAR8s were assayed by flow cytometry for markers of differentiation and viability, respectively. Mouse studies were performed to confirm the viability of human monocytes stimulated with interferon alpha and gamma within the peritoneal cavity seventy-two hours after injection. Subsequent mouse experiments analyzed monocyte differentiation towards M1 or M2 phenotypes by flow cytometry with or without exposure to tumor cells and/or interferons. Results: OVCAR8 spheroids showed decreased viability in the presence of monocytes combined with interferon. We show that monocytes also express a hybrid M1/M2 phenotype when stimulated to IFN and exposed to tumor cells. In mice, monocytes demonstrated a unique differentiation towards both M1 and M2 macrophages as well as plasmacytoid and classic DCs. Various immune cell subsets also differed when comparing peritoneal washes versus tissue digests. Mouse survival studies are ongoing. Conclusions: Monocytes with the combination of interferons alpha and gamma are effective at killing ovarian cancer cells in laboratory models. Phenotypic analyses show a novel pattern of differentiation markers. Our ongoing clinical trial with these agents will incorporate similar studies to correlate monocyte differentiation with anti-tumor activity.
Identifying strategies to address obstacles to optimal integration of cancer immunotherapies in the community.
Authors: Shivakumar Latha , Weldon Christine B. , McBride Ali , Puzanov Igor , Riemer Joanne , Zibelman Matthew R. , Boehmer Leigh
Published: February 2020

96

Background: Evolving indications for immuno-oncology (IO) therapies in cancer pose a significant challenge to community clinicians around the practical issues that must be addressed to implement these therapies safely and effectively. The Association of Community Cancer Centers (ACCC) initiated a quality improvement (QI) research study to assess the impact of educational interventions targeting the multidisciplinary cancer care team on evidence-based integration of IO therapy. Methods: The QI study collected baseline data from 100 patients initiating IO therapy between Dec 2017-Apr 2018 at two community cancer centers on co-morbidities, immune-related adverse events (irAEs), laboratory tests, ER visits and hospitalizations, patient education, and adherence. The advisory committee analyzed this data to identify practice gaps and designed educational interventions to address these gaps. After clinicians at both centers completed the educational interventions, data was collected from 100 patients initiating IO therapy between Jan 2019-Apr2019 and compared using Fisher’s exact test. We also conducted staff surveys before and after participating in the interventions. Results: Offering ACCC-created IO wallet cards to patients was a recommended intervention but only one site adopted this. The site that used the wallet cards had a statistically significant reduction in hospitalization rates compared to the other site (38% vs 70%, p = 0.0024). Respondents to the practice surveys reported an increase in handing out patient education materials following participation in the interventions. They also reported an improved understanding of strategies to manage patients with co-morbidities, management of irAEs, patient education and engagement, interprofessional communication, and coordination with non-oncology specialists. Conclusions: Community cancer center directed educational interventions are feasible and may improve clinician understanding, comfort, and attitudes with the integration of emerging IO agents. Administering wallet cards to patients at the beginning of IO therapy may decrease the risk of hospitalization and warrants further investigation in larger studies.
A phase II trial with safety lead-in to evaluate the addition of APX005M, a CD40 agonistic monoclonal antibody, to standard-of-care doxorubicin chemotherapy for the treatment of advanced soft tissue sarcoma.
Authors: Ingham Matthew , Lee Shing Mirn , Doshi Sahil , Hernandez Susana , Singh-Kandah Shahnaz V. , Singer Zoe , Trifan Ovidiu C. , Schwartz Gary K.
Published: February 2020

TPS85

Background: Soft tissue sarcoma (STS) is a biologically heterogeneous disease for which existing immunotherapy approaches (e.g. anti-PD-1) have shown limited clinical activity. Cytotoxic chemotherapy with doxorubicin (D), an anthracycline, remains standard-of-care treatment for most advanced STS. Combining chemotherapy with immunomodulatory treatments may enhance antigen presentation and favorably impact the immune microenvironment (iME). APX005M (Apexigen; San Carlos, CA) is a novel CD40 agonistic antibody. Preclinically, CD40 ligation plus chemotherapy induced expression of costimulatory and major histocompatibility complex molecules on antigen presenting cells (APCs), shifted the myeloid compartment towards an M1 phenotype and expanded T-cell receptor clonality, which are characteristics in which the sarcoma iME is deficient (2,3). In phase 1, APX005M showed dose-dependent activation of APCs in peripheral blood and favorable tolerability. We designed a phase II study evaluating D+A as a novel combination for STS. Methods: This is a single-arm, open-label, Simon 2 stage phase II study with safety lead-in evaluating D+A among 27 patients with STS. Pts have advanced STS (excluding GIST and Kaposi sarcoma) for which doxorubicin is appropriate and any prior lines of therapy, including none. Pts receive D 75 mg/m2 and A 0.3 mg/m2 IV day 1 in 21 day cycles. Doxorubicin is stopped after cycle 8 but APX005M may continue. The primary endpoint is the objective response rate (ORR). The study design has power of 85% to show an improvement in ORR from 10% (inactive) to 30% (active) with α = 0.04. Secondary endpoints include PFS and safety. Pts undergo collection of stool specimens at baseline and cycle 3 to evaluate composition of the gut microbiome including effects on clinical outcomes and modulation of microbiome by treatment. Pts undergo paired tumor biopsies at baseline and cycle 2 which are evaluated with gene expression and multiplex immunohistochemistry to evaluate effects of D+A on iME. The study opened in 1/2019. Clinical trial information: NCT03719430.
NANORAY-1100: A phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with anti-PD-1 therapy.
Authors: Shen Colette J. , Jameson Katherine LaRoque , Weiss Jared , Hackman Trevor , Dixon Robert , Akulian Jason A. , Pearson Alexander T. , Frakes Jessica , Said Patricia , Seiwert Tanguy Y.
Published: February 2020

TPS86

Background: Most cancer patients present resistance to immune therapy; only approximately 15% of patients respond to immune checkpoint inhibitors (ICI). Strategies able to increase ICI response are thus of great interest. Radiotherapy (RT), by acting as an immunomodulator is a good candidate to increase the proportion of ICI responders. However, RT dose and ultimate efficacy are limited by potential toxicity to healthy tissues. NBTXR3, a first in class radioenhancer administered by intratumoral injection, has been designed at the nanoscale to increase RT energy dose deposition within the tumor. The result is increased radiation-dependent tumor cell killing, without increasing radiation exposure of healthy tissues. Preclinical and early clinical data suggest NBTXR3 activated by RT can increase the anti-tumor response yielding both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect while also producing a systemic effect sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: NANORAY-1100 [NCT03589339] is a multicenter, open-label, phase 1 study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregionally recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases from any primary cancer eligible for anti-PD-1, or (3) Liver metastases from any primary cancer eligible for anti-PD-1. Approximately two-thirds of each cohort will be composed of anti-PD-1 non-responders. NBTXR3 injection volume is based on a percentage of gross tumor volume (GTV) determined by central review. The primary objective is to determine R3/RT/PD-1 RP2D. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR) of R3/RT/PD-1, safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, mRNA and cytokine immune marker profiling. Clinical trial information: NCT03589339.
The Association Between Heart Rate and Glycemic Status in the National Health and Nutrition Examination Surveys
Authors: Casagrande Sarah S , Cowie Catherine C , Sosenko Jay M , Mizokami-Stout Kara , Boulton Andrew J M , Pop-Busui Rodica
Published: February 2020

Context

Evidence suggests that heart rate (HR) is a prognostic factor for cardiovascular disease (CVD), for which persons with diabetes are at increased risk.

Objective

The objective of this article is to determine the association between HR and glycemic status in a nationally representative sample of US adults, and, among adults with diagnosed diabetes, the association between HR and hemoglobin A1c (HbA1c) level.

Design

A cross-sectional study was conducted.

Setting

The setting of this study is the National Health and Nutrition Examination Surveys, 2011 to 2016.

Participants

US general adult (age ≥ 20 years) population who had information on glycemic status based on self-report, HbA1c, and fasting plasma glucose (N = 8562).

Intervention

There was no intervention.

Main outcome measure

The main outcome measure of this study was mean HR (beats per minute).

Results

After adjustment for examination time, age, other demographic characteristics, health insurance, health behaviors, body mass index, CVD and kidney disease, and taking antihypertensive medications, mean HR was significantly higher for those with diagnosed (75 bpm), undiagnosed diabetes (75 bpm), and prediabetes (73 bpm) compared to those with normoglycemia (71 bpm, P < .05 for all); this association was robust both for men and women. Mean HR increased with increasing HbA1c level among individuals with diagnosed diabetes independent of other risk factors (HbA1c < 7.0% [< 53 mmol/mol], 73 bpm vs A1c ≥ 11.0% [≥ 97mmol/mol], 79 bpm, P < .001); this association was most pronounced for women.

Conclusions

Adjusted mean HR was higher among individuals with diabetes and increased glycemia, which may reflect underlying autonomic and/or myocardial dysfunction among those with diabetes.
Parathyroidectomy in First Trimester of Pregnancy
Authors: Sharma Sonia G , Levine Steven N , Yatavelli Rajini K , Shaha Manish A , Nathan Cherie Ann O
Published: February 2020

Primary hyperparathyroidism is not commonly diagnosed during pregnancy. For pregnant women with mild, asymptomatic disease, surgery can be avoided unless the degree of hypercalcemia becomes more severe or they develop complications. However, there are no evidence-based guidelines to assist clinicians regarding the management of primary hyperparathyroidism during pregnancy. When surgery is deemed necessary during pregnancy, the second trimester is generally considered to be the optimal time. We report the case of a 31-year-old female G1P0 who presented at 6 weeks gestation with symptoms of nausea, vomiting, polyuria, and corrected calcium of 14.8 mg/dL. Due to the extreme degree of hypercalcemia and refractory to medical treatment, it was decided that surgery could not be delayed until the second trimester. At 7w3d gestational age the patient had resection of a 37 gram, 5 × 4 × 3 cm right inferior parathyroid adenoma.
The Quarrel of Policy Advisers That Became Development Experts: Currie and Hirschman in Colombia
Authors: Álvarez Andrés , Guiot-Isaac Andrés M. , Hurtado Jimena
Published: February 2020

Lauchlin Currie and Albert O. Hirschman worked together as advisers to the National Planning Council in Colombia in the 1950s. Both had little experience in development economics when they arrived, and did not see eye to eye about the functioning and policy recommendations of the council. Retracing their debates on internal and public issues using archival sources shows how the Colombian experience marked their views on the role of policy advisers, development policy, and the obstacles to development processes. Our main contribution is to show how this experience contributed to form their theories of development, which evolved from technical discussions on growth mechanics to the necessity of adopting a development strategy dealing with issues of political economy.
Tendências inovadoras de gestão nos governos subnacionais brasileiros
Authors: Costa Cavalcante Pedro Luiz
Published: February 2020

O propósito deste trabalho é analisar em que medida as políticas públicas e de gestão dos governos subnacionais brasileiros estão alinhadas com as tendências de inovação na atual era pós-nova gestão pública. Para tanto, o artigo desenvolve uma abrangente análise de conteúdo dos trabalhos apresentados nas nove edições do congresso do Consad focados em iniciativas dos Estados e municípios, a partir da análise de um protocolo de tendências de gestão identificadas na literatura. Os resultados da pesquisa, em geral, também complementados com referências a casos de sucesso, sinalizam que os governos subnacionais no Brasil estão convergentes com as práticas mais contemporâneas. Além disso, a maioria das iniciativas incorpora mais de uma tendência, o que confirma a perspectiva de que as políticas inovadoras advêm da implementação de diferentes princípios e diretrizes.
Intersetorialidade e redes: a trajetória de Luciano Antonio Prates Junqueira na gestão social
Authors: Cora Maria Amelia Jundurian , Motta Rodrigo Guimarães
Published: February 2020

Por ocasião dos 80 anos do intelectual Luciano Antonio Prates Junqueira, professor e pesquisador na Pontifícia Universidade Católica de São Paulo (PUC-SP), este artigo tem por objetivo analisar sua trajetória como intelectual e a construção de um novo campo de estudos, que é gestão social. Como metodologia, para narrar sua trajetória, foram feitas entrevistas com o próprio pesquisado, além de seis pesquisadores reconhecidos do campo de gestão social e integrantes da Rede de Pesquisadores de Gestão Social. Na sustentação deste estudo, realizou-se, ainda, uma análise das citações dos artigos de Luciano Junqueira referenciados pelo Spell. Entre as contribuições do presente trabalho, a principal foi compreender o papel do intelectual como agente social, quando a sua presença e participação garantem legitimidade e fortalecem o campo do conhecimento. Além disso, observou-se que as suas características pessoais e as suas práticas de trabalho são aderentes e compartilham dos seus objetos de estudo, o que demonstra que Luciano atua de modo intersetorial, promovendo redes de compartilhamento do saber, marcadas pela confiança e afetividade.
Concentração e dependência das transferências constitucionais nos municípios do Pará
Authors: Rodrigues Marcos , Silva David Costa Correia
Published: February 2020

Esta pesquisa aborda o tema transferências de receitas intergovernamentais e orienta-se pelo seguinte: em que medida as transferências de recursos entre os entes federados cumpre o seu objetivo de equalização de disparidades regionais? O objetivo deste artigo foi investigar a desigualdade na distribuição de recursos por meio das transferências constitucionais aos municípios do Pará, Brasil. A pesquisa está sustentada na teoria das finanças públicas, notadamente na teoria da repartição de receitas tributárias entre entes federados. Parte-se da hipótese de existência de concentração das transferências intergovernamentais nos municípios paraenses, especificamente do Fundo de Participação dos Municípios (FPM) e a distribuição das cotas-partes do Imposto sobre Circulação de Mercadorias e Serviços (cota-parte do ICMS). Para testar a hipótese, foram usados índice T de Theil e coeficiente de Gini para os municípios do Estado entre 2010 e 2016. Os resultados demonstraram que há concentração de recursos em um grupo restrito de municípios com as cotas-parte do ICMS. Por outro lado, existe maior dispersão na distribuição do FPM. Tal situação deve-se pelo fato de o ICMS ter grande peso sobre municípios com maior valor adicionado fiscal, enquanto que o FPM possui critérios que favorecem melhor distribuição. Entretanto existe ainda uma forte dependência dos municípios paraenses em relação à distribuição destes recursos, o que requer uma gestão mais eficiente dos governos municipais para melhor utilizar os recursos disponíveis.
Study of the 193Ir(n,2n)192Ir Reaction Cross Section
Authors: Patronis N. , Kalamara A. , Harissopulos S. , Kokkoris M. , Lagoyannis A. , Vlastou R.
Published: February 2020

The 193Ir(n,2n)192Ir reaction cross section was measured relative to the 27Al(n,a)24Na and 197Au(n,2n)196Au reactions by means of the activation technique at two neutron beam energies: 10.0 and 10.5 MeV. The neutron beam was produced via the 2H(d,n)3Ηe reaction. The deuteron beam was provided by the 5.5 MV Tandem Van de Graaff accelerator of the N.C.S.R. “Demokritos”. After the irradiations the induced activity of the samples was measured through a 56% relative efficiency HPGe detector. The total reaction cross section for the population of the ground state (4+) and the first isomeric state (1-) was determined. The adopted method for the correction concerning the population of the product nucleus 192Ir through the 191Ir(n,γ)192Ir reaction is also presented.
Interactions between carbon impurities and defects produced by proton irradiation in α-iron
Authors: Apostolopoulos G. , Lukianova V. , Kotsina Z. , Lagoyannis A. , Mergia K. , Harissopulos S. , Messoloras S.
Published: February 2020

Resistivity recovery experiments are performed on α-Fe and an Fe - 220 at. ppm C alloy after 5 MeV proton irradiation at cryogenic temperature of 50 K. By comparing the recovery spectra of pure Fe and the Fe-C alloy we are able to resolve the effect of carbon atoms on the point defect kinetics. It is observed that carbon interacts with both interstitial and vacancy type of defects and delays their annihilation. At temperatures above 500 K the formation of carbides reduces the resistivity of the alloy.
Activities and prospects of the Radioactive Materials Management Laboratory at the NCSR “Demokritos”
Authors: Savidou A. , Ntalla E. , Chanousis A.
Published: February 2020

The Radioactive Materials Management Laboratory (RMML) was established in July 2013. The RMML is the sole laboratory in the country that holds the know-how in all the fields of radioactive waste management and decommissioning of nuclear facilities.The challenge for the Laboratory is the prospect of development of the Centralized Infrastructure of the country for Radioactive Waste at the NCSR D.
Preparation of activation experiments for ITER material characterization and data validation in the Deuterium–Tritium JET campaign
Authors: Vasilopoulou T. , Stamatelatos I. E. , Packer L. W. , Lilley S. , Batistoni P. , JET contributors And
Published: February 2020

The levels of induced activity in samples of ITER materials and dosimetry foils to be irradiated during the planned JET campaign with deuterium-tritium (D-T) plasma were predicted. Calculations were performed for the neutron energy spectrum of the JET internal Long Term Irradiation Station (LTIS). The European Activation System (EASY-II) and the EAF-2010 nuclear data library were used in order to estimate specific activity and dose rates as a function of time after the end of irradiation. The results of the study provide important data for comparison against activation measurements and support the planning of the irradiation, measurement and radiation protection procedures to be implemented in the planned JET activation experiment.
Activity size distribution of radioactive nuclide 7Be at different locations and under different meteorological conditions
Authors: Ioannidou A. , Groppi F. , Bonardi M. L. , Manenti S. , Gini L.
Published: February 2020

The activity size distributions of the natural radionuclide tracer 7Be in different size fractions (<0.4 μm, 0.4-0.7 μm, 0.7-1.1 μm, 1.1-2.1 μm, 2.1-3.1 μm, 3.1-4.2 μm, 4.2-5.8 μm, 5.8-9.0 μm >9.0 μm) were determined at different site places in Northern Italy. Samplings were carried out during the four different seasons of the year 2011. The aim of this work was to define any differences due to the different environments and different meteorological conditions and clarify the main parameters influencing the activity size distribution of radioactive aerosols.
Rare Isotope Production in peripheral heavy-ion collisions in the energy range 15-25 MeV/nucleon
Authors: Papageorgiou A. , Souliotis G. A. , Kwon Y. K. , Tshoo K. , Jeong S. C. , Veselsky M. , Bonasera A.
Published: February 2020

In this contribution we summarize recent efforts to describe the production of rare isotopes with beams of 15–25 MeV/nucleon expected from low-energy facilities. We first present calculated production cross sections of proton-rich nuclides from collisions of stable beams of mass A∼60–80. Our calculations are performed with the phenomenological deep-inelastic transfer (DIT) model and the microscopic con- strained molecular dynamics model (CoMD). De-excitation of the excited quasipro- jectiles from the dynamical stage of the reaction is performed with the statistical multifragmentation model (SMM). In addition to the efforts on proton-rich nuclides, we investigated the possibility of producing neutron-rich rare isotopes in the mass range A∼180–200, i.e. near the third r-process peak of A=195. We performed calcu- lations for a 208Pb (15MeV/nucleon) beam and find that the multinucleon transfer mechanism leads to very neutron-rich nuclides in this mass range. We believe that our continued progress on the study of multinucleon transfer reactions using heavy- ion beams of 15–25 MeV/nucleon, can provide new opportunities in rare isotope research in the near future, as planned at the KOBRA facility of RISP in Korea.
Investigation of the dependence of the activity concentration of natural and artificial radionuclides on particle size in surface soil
Authors: Mitsios I. K. , Karangelos D. J. , Anagnostakis M. J.
Published: February 2020

Surface soil radioactivity is being studied at NED-NTUA since almost thirty years. The last few years this research has expanded to the study of soil particle size fractionation of radionuclides. The purpose of the present work was to study the tendency of many radionuclides to accumulate in the smaller particle size fractions. To this end, soil samples were collected from an area in the NTUA Campus where 241Am contamination, due to a failed 241Am-tipped lightning rod, had been previously detected. The samples were separated into size fractions using a sieving machine and analyzed by gamma spectrometry to determine 210Pb, 241Am, 234Th, 228Ra, 228Th, 226Ra, 7Be, 137Cs and 40K. The activity concentrations of these nuclides were found to significantly differ among the size fractions examined.
Microscopic description of neutron-induced fission with the CoMD Model: Preliminary Results
Authors: Papadimitriou S. , Souliotis G. A. , Assimakopoulou A. , Bonasera A. , Veselsky M.
Published: February 2020

In the present work, we initiated a systematic study of neutron-induced fission reactions using the code CoMD (Constrained Molecular Dynamics) of A. Bonasera and M. Papa [1,2]. The code implements an effective interaction with a nuclear-matter compressibility of K=200 (soft EOS) with several forms of the density-dependence of the nucleon symmetry potential. In addition, CoMD imposes a constraint in the phase space occupation for each nucleon restoring the Pauli principle at each time step of the collision). Proper choice of the surface parameter of the effective interaction has been made to describe fission. In this poster, we presented preliminary results of neutron-indued fission on 235U at neutron energies 5, 10, 15, 25, 50 and 100 MeV. Calculated mass and energy distributions are shown and compared with the recent experimental data of Loveland et al. [3]. It appears that the microscopic code CoMD is able to describe the complicated many-body dynamics of the n-induced fission process. Proper adjustment of the parameters of the effective interaction and further improvements of the code will be implemented to achieve a satisfactory description of the experiment data.
Determination of the Neutron Beam Spatial Profile at n_TOF EAR-2 using the CR-39 Track Detectors
Authors: Eleme Z. , Alexandropoulou M. , Georgiadou A. , Ioannides K. G. , Kokkoris M. , Patronis N. , Stamatopoulos A. , Stamoulis K. C. , Tsinganis A. , Vlastou R. , N_TOF Collaboration And the
Published: February 2020

Within the present work the neutron beam spatial profile was determined at the sample position in EAR-2 at the n_TOF facility at CERN. The CR-39 detectors were coupled with a 2mm PE foil serving as neutron-to-proton converter. Two irradiations were performed in the 10x5 cm surface of CR-39 detectors. Proton tracks were revealed in the CR-39 detectors resulting from the elastic scattering of fast neutrons on the hydrogen atoms in the PE converter. Afterwards, the CR-39 detectors were chemically etched in aqueous NaOH solution and latent tracks were considerably enlarged to become visible under an optical microscope. After the scanning of the detectors surface, the acquired images were analyzed using the ImageJ program. In the present work, the experimental setup and procedure will be presented along with the results concerning the characterization of the neutron beam spatial profile at the sample position in the n_TOF EAR-2.