bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I trial evaluating safety and efficacy of intratumorally administered allogeneic monocyte-derived cells (ilixadencel) in advanced gastrointestinal stromal tumors.
Authors: Karlsson-Parra Alex , Fröbom Robin , Berglund Erik , Berglund David , Nilsson Inga-Lena , Linder-Stragliotto Christina , Suenaert Peter , Branstrom Robert
Published: February 2020

15

Background: Ilixadencel is a cell-based, off-the-shelf product based on allogeneic monocyte-derived inflammatory cells aimed to prime an anti-cancer immune response when injected intratumorally. The present single arm Phase I trial (ClinicalTrials.gov Identifier: NCT02686944) assessed the safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Methods: Three GIST patients were progressing while on sunitinib (second-line), one on regorafenib (third-line), and two on pazopanib (fifth-line). Treatment consisted of two intratumoral injections of ilixadencel two weeks apart. If further tumor progression was observed at the 3-month follow up, the TKI was withdrawn and the subject performed an end of study visit. If stable disease or objective response was observed, the subject continued with the TKI until progression of disease. Results: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. Two patients had stable disease as best response; one of these patients (on third-line regorafenib) progressed at 12 months and the other (a patient on second-line sunitinib) showed continued stable disease at end of study (12 months) as per RECIST 1.1. These two patients also developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. No serious adverse events were found to be possibly or probably related to ilixadencel administrtion. Conclusions: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial information: 02686944.
CXCR1/2 blockade to enhance response to immune checkpoint inhibition in an aggressive orthotopic pancreatic adenocarcinoma model.
Authors: Ullman Nicholas A. , Ruffolo Luis I. , Jackson Katherine M. , Chacon Alexander , Georger Mary , Jewell Rachel , Belt Brian A. , Maeda Dean , Zebala John , Linehan David
Published: February 2020

19

Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths, with the incidence expected to rise in the coming years. Despite conventional chemotherapy and advances in immune checkpoint blockade, 5 year survival remains a dismal 8%. Intratumoral accumulation of granulocytic myeloid derived suppressor cells (G-MDSC) pose a significant barrier to treatment as they contribute to immune evasion by PDAC and correlate with poor prognosis. The ELR+ CXC chemokine receptors CXCR1 and CXCR2 (CXCR1/2) contribute to peripheral neutrophil migration into tissues and have been implicated in tumor mediated G-MDSC recruitment to the tumor microenvironment. Here we present our findings using an orally dosed CXCR1/2 inhibitor, SX-682, in an orthotopic PDAC model. Methods: C57BL/6 mice underwent orthotopic injections with KP2 cells. Mice were randomized into five groups (Table) receiving three weeks of FOLFIRINOX with combinations of SX-682 and/or checkpoint inhibition (anti-PD1/anti-CTLA4). FOLFIRINOX was dosed weekly for three weeks. Checkpoint inhibition was administered twice weekly. Chow weights were monitored for consumption of SX-682. Results: The simultaneous administration of FOLFIRINOX with SX-682 combined with checkpoint inhibition (triple therapy) resulted in a significant increase in survival compared to other groups (p = 0.0001). Notably, there was a significant increase in survival with triple therapy versus FOLFIRINOX plus checkpoint alone (p = 0.0259). Median survival of the triple therapy group was 42.5 days, compared to 37 days with checkpoint inhibition (p = <0.05). There were no differences in chow consumption between the control and medicated chow groups. Conclusions: CXCR1/2 blockade combined with immune checkpoint inhibition and first line chemotherapy significantly enhanced survival in our PDAC mouse model. Thus, CXCR1/2 inhibition with SX-682 represents a promising target for clinical intervention in PDAC. [Table: see text]
Antibody blockade of semaphorin 4D to sensitize pancreatic cancer to immune checkpoint blockade.
Authors: Ruffolo Luis I. , Ullman Nicholas A. , Dale Benjamin , Jackson Katherine M. , Burchard Paul , Georger Mary , Jewell Rachel , Belt Brian A. , Galka Eva , Schoeniger Luke O. , Mallow Crystal L. , Evans Elizabeth E. , Fisher Terrence Lee , Zauderer Maurice , Linehan David
Published: February 2020

26

Background: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, and will soon become the second leading cause of cancer mortality. Unfortunately, T-cell directed immunotherapies have failed to demonstrate efficacy in PDAC. These failures may in part be mediated by an immunosuppressive tumor microenvironment (TME). Semaphorin 4D (Sema4D) is a glycoprotein which binds its cognate receptors Plexin B1/B2. Here we present our work in blocking Sema4D in a murine model of PDAC. Methods: C57b/6 mice were orthotopically injected with PDAC line (KP2) derived from KRASG12D,TP53Flox/Wt;P48-Cre autochthonous tumors and confirmed for disease by ultrasound. Mice were treated with FOLFIRINOX (5-FU, Irinotecan, Oxaliplatin, weekly), immune checkpoint blockade (ICB) (anti-PD1, anti-CTLA-4 mAbs bi-weekly), and anti-Sema4D mAB (bi-weekly). Human and mouse circulating and tumor infiltrating leukocytes were interrogated through flow cytometry (FACS) for immune subset and expression of Sema4D and Plexin receptors. Archived human PDAC tissues were assessed through quantitative immunohistochemistry (IHC) for presence of Sema4D positive infiltrate. Results: Both FACS and IHC analysis of human PDAC specimens confirm the presence and increased prevalence over normal pancreata of Sema4D lymphocytes and Plexin B1/B2 expressing tumor associated macrophages (TAMs). KP2 orthotopically injected mice exhibited longer survival when treated with the triple combination of FOLFIRINOX, ICB, and anti-Sema4D antibody, compared to FOLFIRINOX alone, FOLFIRINOX plus ICB, or FOLFIRINOX plus anti-Sema4D antibody (P < 0.02). Flow cytometric analysis of anti-Sema4D and ICB treated murine tumors show a doubling of penetration by CD 8+ effector T cells within tumors compared to control groups (P = 0.03). A loss in Sema4D fluorescence signal via FACS in tumor-infiltrating CD3+ leukocytes was observed in mice treated with anti-SEMA4D, confirming penetration and target blockade within the TME. Conclusions: Sema4D and Plexin B1/B2 leukocytes penetrate human PDAC tumors, and treatment with Sema4D blocking antibody improved response to ICB in combination with standard of care FOLFIRINOX in preclinical murine studies.
Network analysis to reveal BTK as a link between myeloid and T cells in TLR signaling in colorectal cancer.
Authors: Hummel Justin , Shen Yuanyuan , Innokenteva Iiulia , Papageorgiou Christos , Shyu Chi-Ren , Mitchem Jonathan B.
Published: February 2020

30

Background: Colorectal cancer (CRC) is the second-leading cause of cancer mortality in the US today. Recent advances in immunotherapy have only been shown to benefit a limited subgroup of patients with CRC. In other malignancies, activation of Toll-like receptors (TLRs) has been shown to overcome resistance to immunotherapy, such as immune checkpoint inhibition (ICI). In this study, using publicly available data and informatics-based analysis, we identified BTK as a critical link between TLR signaling and T cells in the CRC tumor microenvironment. Methods: Using RNA-seq data from The Cancer Genome Atlas (TCGA) and the Microenvironment Cell Populations (MCP)-Counter, abundance scores were generated for the tumor microenvironment of each patient. A curated TLR gene panel was generated using Reactome and GO. Pearson analysis was used to evaluate each pairwise combination of genes and cell-types. Significance was determined by the correlation coefficient, r ≥ | 0.7 | with a p-value < 0.05. Network analysis was performed using the Girvan–Newman algorithm to establish critical connections across these features. Results: After establishing a 453 gene TLR panel and creating MCP-Counter scores, correlation analysis demonstrated strong correlations between 54 different genes and 7 cell-types. As expected the most genes were associated with monocytic lineage cells' (30) and 'myeloid dendritic cells' (7). Only 5 genes were significantly associated with 'T cells'. Genes and cell-types that were highly correlated were then further analyzed for network association. From this analysis, BTK was identified as a critical edge acting as the primary link between ‘myeloid cells’ and ‘T cells’. Conclusions: Developing novel strategies for the treatment of CRC is critical and immunotherapy represents an area ripe for advancement. Informatics based analysis combined with publicly available data provides us with an opportunity to shape pre-clinical and translational studies. Using this approach, we have identified BTK as a critical link between myeloid cells and T cells in the tumor microenvironment in CRC. Further studies in our laboratory will focus confirming these findings for translation into patients.
Avelumab flat dose regimen: Justification for use in advanced renal cell carcinoma (aRCC).
Authors: Haanen John B. A. G. , Masters Joanna C. , Huang Bo , Choueiri Toni K. , Motzer Robert J. , Khandelwal Akash , Dai Haiqing (Isaac) , di Pietro Alessandra , Brar Satjit , Rini Brian I. , Albiges Laurence , Larkin James M. G.
Published: February 2020

32

Background: Avelumab, an anti–PD-L1 monoclonal antibody, was recently approved for the treatment of aRCC in combination with axitinib and was previously indicated for the treatment of metastatic Merkel cell carcinoma (MCC) and platinum-treated advanced/metastatic urothelial carcinoma (UC). Although avelumab was approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), it was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (popPK), exposure-efficacy and exposure-safety modeling and simulations in MCC and UC (Novakovic AM, et al. Clin Pharmacol Ther. 2019). The justification for the recommended flat-dose regimen for avelumab as combination therapy with axitinib in aRCC is presented. Methods: Simulated exposure metrics (eg, area under the curve) from the previous popPK model (data from 1,827 patients with solid tumors across 3 clinical trials) for both weight-based and flat-dose regimens were compared with the exposure metrics obtained from treatment-naive patients with aRCC enrolled in 2 clinical studies (N = 488 from NCT02493751 and NCT02684006) who received avelumab (10 mg/kg Q2W) + axitinib (5 mg orally twice daily). Avelumab exposure-response relationships for safety and efficacy were also analyzed. Endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs) and immune-related (ir)AEs, and progression-free survival (PFS) by independent review. Results: The administration of weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to simulated reference exposures of the flat-dose regimen in the solid tumor population. Avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or IRRs, although there was a weak association with an increased probability of any-grade irAEs. Conclusions: The similar exposures observed for both avelumab dosing regimens in aRCC, and in prior studies in the MCC and UC populations, suggest that the 800 mg Q2W flat-dose regimen will maintain the benefit-risk ratio for avelumab + axitinib for treatment-naive patients with aRCC. Clinical trial information: NCT02493751 . Clinical trial information: NCT02684006.
Lentiviral interferon with immune checkpoint blockade: A novel method for gene therapy in bladder cancer.
Authors: Mokkapati Sharada , Kokorovic Andrea , Duplisea Jonathan J. , Plote Devin , Lim Amy , Narayan Vikram M. , Metcalfe Michael J. , Dunner Kenneth , Czerniak Bogdan , Nieminen Tiina , Heikura Tommi , Yla-Herttuala Seppo , Parker Nigel , McConkey David James , Dinney Colin P.N.
Published: February 2020

33

Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. LV can infect non-dividing cells and integrate into the host’s genome, making it more efficient gene delivery vectors. As treatment with IFN upregulates checkpoint inhibitors, we also wanted to investigate the role of checkpoint inhibitors with and without IFN gene therapy. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα (MOI 2:1). IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, the MB49 intravesical tumor model and p53+/- C57/B6 mouse model were employed. We also assessed the role of combination therapy with immune checkpoint blockade using PD1 antibody using our MB49 intravesical model. Results: Efficient LV-IFNα transduction of BLCA cells resulted in increased expression of IFNα and its target genes and reduced cell viability vs. controls (p<0.001). Mechanistically, TRAIL dependent cytotoxicity in the LV-IFNα cells was rescued by Caspase8 inhibition. Urinary IFNα levels were elevated in mice receiving LV-IFNα compared with control virus. Overall survival improved in the MB49 model and BBN model in treated mice. LV-IFN induced intratumoral CD8+ T cell infiltration, high expression of PD-L1, and inhibited angiogenesis in BBN model whereas in the MB49 tumor response was mediated by TRAIL. Combination therapy with PD1 resulted in further improved survival. Conclusions: LV-IFNα effectively upregulated IFNα target genes, was cytotoxic to murine BLCA cells, and improved the survival in mouse models. Combining it with PD1 therapy appears to further improve survival.
PD-L1 profiling of circulating tumor cells for immune checkpoint inhibitor therapy in head and neck cancers.
Authors: Patil Revati , Akolkar Dadasaheb B. , Patil Darshana , Devhare Pradip , Srivastava Navin , Fulmali Pooja , Patel Shoeb , Shejwalkar Pradyumna , Datta Vineet , Sims Cynthe , Srinivasan Ajay , Datar Rajan
Published: February 2020

36

Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Head and Neck cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have been constrained by low CTC yields. We employed a novel approach for harvesting sufficient CTCs from Head and Neck cancers that permit PD-L1 profiling by Immunocytochemistry (ICC). Methods: 15 ml peripheral blood was collected from 95 patients with head and neck squamous cell carcinomas (HNSCC). CTCs were enriched from PBMCs via an epigenetically acting stabilization process which induced apoptosis in non-malignant cells and conferred survival privilege on apoptosis-resistant CTCs, which were harvested and confirmed by immunostaining for EpCAM and pan-CK. Deep ICC profiling of CTCs was performed with organ-specific markers as well as PD-L1:22c3 and PD-L1:28-8 clones. Results: Viable CTCs could be enriched and harvested in 90 out of 95 samples (95.3%) regardless of metastatic or treatment status. Deep ICC and PD-L1 profiling could be performed in all 90 samples (100%). PD-L1 expression was quantitatively assigned as ‘Low’, ‘Moderate’ or ‘High’. 28 (31.1%) samples were positive for PD-L1:28-8 (27 Low + 1 Moderate) and 26 (28.9%) samples were positive for PD-L1:22c3 (24 Low + 2 Moderate). 15 samples were positive for both PD-L1 clones. Conclusions: CTCs in Head and Neck squamous cell carcinomas can be considered for evaluating PD-L1 expression in patients where ICI therapies are otherwise viable.
Can immunologically hot lung cancer be distinguished from cold tumor by peripheral blood?
Authors: Muto Satoshi , Mine Hayato , Takagi Hironori , Watanabe Masayuki , Ozaki Yuki , Okabe Naoyuki , Matsumura Yuki , Hasegawa Takeo , Shio Yutaka , Suzuki Hiroyuki
Published: February 2020

48

Background: Depending on the number of tumor infiltrating lymphocytes, immunological cold to hot conditions vary. There are several clinical trials of administering immune checkpoint inhibitors as perioperative adjuvant therapy. Immune checkpoint inhibitors are generally effective in immunologically hot conditions. However, biopsy specimens are not enough to determine the amount of tumor infiltrating lymphocytes. Therefore, we focused on effector T lymphocytes in peripheral blood, and tried to understand the tumor microenvironment by looking at peripheral blood. Methods: Twenty-four patients with lung cancer who underwent surgery at Fukushima Medical University Hospital from December 2018 to June 2019 were able to separate and collect tumor infiltrating lymphocytes by magnetic cell sorting. Flow cytometry was used to analyze infiltrating lymphocytes and preoperative peripheral blood lymphocytes. Those not expressing CD62L, a marker of Naïve T lymphocytes, were designated as effector T lymphocytes. Results: In the group with a high proportion of cytotoxic T lymphocytes in tumor infiltrating lymphocytes, the proportion of CD62L-negative effector CD4 T lymphocytes in peripheral blood was high (p < 0.05). The percentage of lymphocytes in peripheral blood was also high (p < 0.05). Furthermore, tumor infiltrating lymphocytes had a high proportion of effector CD4 T lymphocytes (p < 0.05). There was a similar trend in the proportion of CD8 T lymphocytes, but there was no statistically significant difference. Conclusions: These results showed that immunologically hot cases could be identified by measuring effector CD4 T lymphocytes in peripheral blood. In the future, we will continue to verify the results and examine antigen specificity of these T lymphocytes.
Biological characteristics and prognostic value of Tfh-like cells in the tumor tissue of breast cancer.
Authors: Ma Linxiaoxi , Guo Liang , Goswami Shyamal , Zhang Xiaoming , Wu Jiong
Published: February 2020

5

Background: T follicular helper (Tfh) cells formed in germinal center are CXCR5+ICOS+PD-1hiBcl-6+CXCL13+IL-21+CD4+ T cells. They have been identified in different types of tumors. However, it still remains unclear in breast cancer, with one indicating the positive prognostic value of 8-gene Tfh signature. Methods: Freshly resected invasive breast cancer tissues from Fudan University Shanghai Cancer Center of all 386 patients were collected during 03/2015 to 05/2017. Data was analyzed based on the result from Multiparameter Flow Cytometry and IHC. The correlation between Tfh-like cells and clinicopathological characteristics in breast cancer was examined with t test or one way ANOVA with Tukey’s multiple comparisons test. Results: A subpopulation of PD1hiCD4+ T cells in the tumor tissues of breast cancer was identified as Tfh-like cells, with the specific expression of Bcl-6 and CXCL13. Tfh-like cells were of a high level of ICOS but negative for CXCR5. They had high levels of activated molecules such as CD38, CD71, CD95 and HLADR, high levels of suppressive markers as Tim3, TIGIT, and LAG3 and high level of proliferation marker Ki-67, specifically secreting cytokine IL-21 with stimulation. Data showed that high grade (N = 166; mean±SEM, 17.62±0.87) compared with low grade (N = 220; mean±SEM, 12.41±0.46) or high Ki-67 level (N = 300; mean±SEM, 15.38±0.58) with low Ki-67 level (N = 86; mean±SEM, 12.10±0.67), and negative ER expression (N = 115; mean±SEM, 17.47±1.05) compared with positive ER expression (N = 271; mean±SEM, 13.46±0.50) or negative PR expression (N = 177; mean±SEM, 16.87±0.83) compared with positive PR expression (N = 209; mean±SEM, 12.77±0.50) was associated with higher frequency of Tfh-like cells (P < 0.01 to all). Patients with triple negative had higher frequency of Tfh-like cells than those with Luminal A (difference, 6.83; P = 0.0006) and Luminal B (HER2-) (difference, 4.61; P = 0.0124). These results indicate that higher frequency of Tfh-like cells could have negative prognostic influence. Conclusions: Our study defined a PD1hiBcl6+CXCL13+CD4+IL-21+ T cell subpopulation. Higher frequency of Tfh-like cells is more likely to be seen in patients with poor prognosis.
The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-I.
Authors: Long Georgina V. , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Ana , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Lee Dung-Yang , Masood Aisha , Gasal Eduard , Dummer Reinhard
Published: February 2020

57

Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with BRAF V600–mutant advanced melanoma; however, many pts progress and new treatment (tx) strategies are needed. BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and PD-1/PD-L1 expression, which may lead to synergistic activity with anti–PD-1 therapy. Methods: COMBI-i is investigating first-line S 400 mg Q4W + D 150 mg BID + T 2 mg QD in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). Here we report pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort). Response was assessed per RECIST v1.1. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 18 (50%) had stage IV M1c and 15 (42%) had elevated LDH levels. At the data cutoff (median follow-up, 15.2 mo), tx was ongoing in 17 pts (47%). The confirmed objective response rate (ORR) by investigator assessment was 75% (n = 27), with 33% complete responses (CRs; n = 12). Medians for duration of response (DOR; 7/27 pts with events), progression-free survival (PFS; 13/36 pts with events), and overall survival (OS; 7/36 pts with events) were not reached. 12-mo DOR rate was 71.4% (95% CI, 49%-85%). 12-mo PFS and OS rates were 65.3% (95% CI, 47%-79%) and 85.9% (95% CI, 69%-94%), respectively. In pts with high baseline LDH: ORR was 67%, with 3 CRs (20%), median PFS was 10.7 mo (events in 10/15 pts [67%]), and median OS was not reached, with events in 6/15 pts (40%). All pts had ≥ 1 AE; 27 (75%) had grade ≥ 3 AEs. 6 pts (17%) had AEs leading to discontinuation of all 3 study drugs. Any-grade AEs in ≥ 40% of pts included pyrexia, chills, fatigue, cough, and arthralgia. Grade ≥ 3 AEs in > 3 pts were neutropenia, pyrexia, and increased lipase. One pt died of cardiac arrest that was not considered related to study tx. Conclusions: S+D+T showed promising and durable ORR (75%) with CR in 33% of pts. With > 15 mo of follow-up, median PFS was not reached. The safety profile was manageable reflecting individual toxicities of D, T, and S. The global, placebo-controlled, randomized phase 3 (part 3) of COMBI-i is ongoing. Clinical trial information: NCT02967692.
Review of neurological side effects associated with checkpoint inhibitor therapy in cancer patients.
Authors: Chintalacheruvu Lakshmi Manogna , Naha Kushal , Chilluru Vamsi Krishna , Doll Donald C.
Published: February 2020

72

Background: Checkpoint inhibitors have demonstrated efficacy in many cancer types. Neurological side effects are not well studied with check point inhibitors therapy. We conducted systematic review and meta analysis to evaluate the incidence of neurological side effects among various check point inhibitors. Methods: Eligible studies were searched for in PubMed and Google scholar. We searched for randomized controlled trials with cancer patients treated with check point inhibitors with neurological adverse effects. A total of 26 randomized controlled trials involving 6110 patients met eligibility criteria for the study. Results: Incidence rate of all grade neurological side effects include 5.6%(95% confidence interval [CI], 5.4-6.7%). Most common side effects include Headache (4.6%) (95% confidence interval [CI] 3.7-4.7%) followed by peripheral neuropathy (0.3%) (95% confidence interval [CI] 0.1-0.5%). Ipilimumab plus Nivolumab is associated with higher risk of headache and serious neurological side effects including myasthenia gravis, encephalitis, toxic encephalopathy and seizures. Conclusions: The incidence of neurological side effects associated with immune checkpoint inhibitors is low but not negligable. Patients on combination immunotherapy need more close monitoring for serious neurological side effects.
Exploring online access of an immuno-oncology wallet card among oncology providers.
Authors: Schrag Janelle , Shivakumar Latha , Dawkins Monique , Boehmer Leigh , Lucas Lorna
Published: February 2020

93

Background: In 2019, the Association of Community Cancer Centers (ACCC) developed an immuno-oncology (IO) wallet card to address the continuous need for immune-related adverse event education and resources, particularly for IO patients and the non-oncology providers from whom they receive care. The wallet card was distributed to ACCC’s membership of cancer programs via mailings and online, which included a short survey for users to complete at time of download. Methods: To better understand the demographics and motivations of individuals who access the IO wallet card, an exploratory analysis was performed on data collected through the download survey. Data included the survey responses from all downloads between March and September 2019 (n = 141), which was then cleaned to remove duplicates, incomplete responses, and responses from ACCC staff, international users, pharmaceutical representatives, consultants, and patients. Analysis was then performed on the resulting data set of downloads from US-based health care providers (n = 86). Results: Cancer program administrators and nurses accounted for the majority of downloads (30% and 20%, respectively), as well as individuals from comprehensive community cancer programs (44%) and NCI-designated comprehensive cancer programs (16%). Fewer downloads came from other oncology disciplines (2-9%) and small practices (2-6%). Survey responses indicated that the majority of downloads were due to the cancer program not already having the resource (47%), or for comparison with a wallet card developed by the cancer program (15%) or another organization (10%). Patient education materials provided by these institutions included wallet cards (45%), as well as print materials developed by the cancer program (16%), another professional organization (7%), or distributed by drug companies (5%). Conclusions: These finding shed light on the primary audiences accessing the IO wallet card, how this resource may complement other IO patient education materials, and areas where additional education may be needed. Specifically, IO wallet card dissemination or related education may need to be tailored to better reach specific oncology disciplines as well as those practicing in smaller clinics.
A phase I study evaluating COM701 monotherapy and in combination with nivolumab in patients with advanced solid malignancies.
Authors: Sullivan Ryan J. , Lim Emerson A. , Sharma Manish , Shepard Dale Randall , Patnaik Amita , Hamilton Erika Paige , Fleming Gini F. , Papadopoulos Kyriakos P. , ElNaggar Adam , Adewoye Adeboye H. , Hunter John , Ileana Dumbrava Ecaterina Elena , Chmielowski Bartosz , Rasco Drew W. , Vaena Daniel A.
Published: February 2020

TPS23

Background: COM701 is a novel 1st-in-class monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with its ligand, PVRL2. In preclinical experiments inhibition of PVRIG alone and in combination with a PD-1 inhibitor leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. Novel checkpoint therapies are needed for the treatment of patients with advanced malignancies. We hypothesized that COM701 monotherapy and in combination with nivolumab will be safe and tolerable and demonstrate preliminary antitumor activity in pts with advanced solid malignancies. Methods: This ongoing phase 1 study (NCT03667716) is evaluating the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 or Q4 weekly and in combination with nivolumab 360 mg IV Q3 weekly or 480 mg IV Q4 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed advanced solid malignancy and has exhausted all available standard therapy, ECOG performance status 0-1, prior ICI permissible. Key Exclusion Criteria: Symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day or 28-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Key secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701 as monotherapy and in combination with nivolumab. Study Design: Hybrid accelerated titration and 3+3 study design. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. Analyses of all study objectives are descriptive and hypothesis generating. As of the date of this submission dose level 8 of COM701 monotherapy and dose level 3 of the combination arm are open to enrollment. Updated data will be presented at the conference. Clinical trial information: NCT03667716.
Internationalizing the Revolutionary Family
Authors: Snyder Emily
Published: February 2020

This article argues that Cuban ideas about gender, sexuality, and the family shaped Cuban internationalist collaboration with Nicaragua in the 1970s and 1980s. It demonstrates that collaboration sprang from a gendered political discourse, and in turn the dynamics of gendered relationships between Cubans and Nicaraguans affected the internationalist campaigns. First, the essay argues that state discourse expanded the idea of the New Man to include volunteering abroad, and cast female participants as moral agents of internationalism. Second, it analyzes the idea of revolutionary love and how it related to internationalism. Then, the article demonstrates how internationalism created transnational relationships. Finally, it examines the experiences of Nicaraguan students who went to boarding schools on the Isla de la Juventud. Throughout, the article centers the notion of family and shows how internationalist mobility created space for personal experiences, love within revolution, and new family dynamics.
Ab Initio Fragment Molecular Orbital-Based Molecular Dynamics (FMO-MD) Simulations of (NH3)32 Cluster: Effects of Electron Correlation
Authors: Ninomiya Moeko , Doi Hideo , Matsumoto Yoshiteru , Mochizuki Yuji , Komeiji Yuto
Published: February 2020

An isolated cluster of 32 ammonia (NH3) molecules was simulated at 50 and 100 K by the ab initio fragment molecular orbital based molecular dynamics (FMO-MD) method to analyze the effect of electron correlation via second-order Møller–Plesset perturbation (MP2). Both the energy and force of the system were calculated at the MP2 and Hartree-Fock (HF) levels with the 6-31G** basis set. The radial distribution and angular distribution functions were obtained from the trajectories. A comparison of MP2 and HF suggested that the electron-correlation effect via MP2 leads to relative condensation through electron delocalization, similar to the case of water. Vibrational spectra were also calculated at both the MP2 and HF levels, and the former gave a more minute split of the higher modes. This again suggested that MP2 better describes the electron delocalization.
Impact of CT Injector Technology and Contrast Media Viscosity on Vascular Enhancement: Evaluation in a Circulation Phantom
Authors: McDermott Michael , Kemper Corey , Barone William , Jost Gregor , Endrikat Jan
Published: February 2020

Objective:

To assess the impact of piston-based vs peristaltic injection system technology and contrast media viscosity on achievable iodine delivery rates (IDRs) and vascular enhancement in a pre-clinical study.

Methods:

Four injectors were tested: MEDRAD® Centargo, MEDRAD® Stellant, CT Exprès®, and CT motion™ using five contrast media [iopromide (300 and 370 mgI ml−1), iodixanol 320 mgI ml−1, iohexol 350 mgI ml−1, iomeprol 400 mgI ml−1]. Three experiments were performed evaluating achievable IDR and corresponding enhancement in a circulation phantom.

Results:

Experiment I: Centargo provided the highest achievable IDRs with all tested contrast media (p < 0.05). Iopromide 370 yielded the highest IDR with an 18G catheter (3.15 gI/s); iopromide 300 yielded the highest IDR with 20G (2.70 gI/s) and 22G (1.65 gI/s) catheters (p < 0.05).

Experiment II: with higher achievable IDRs, piston-based injectors provided significantly higher peak vascular enhancement (up to 48% increase) than the peristaltic injectors with programmed IDRs from 1.8 to 2.4 gI/s (p < 0.05).

Experiment III: with programmed IDRs (e.g. 1.5 gI/s) achievable by all injection systems, Centargo, with sharper measured bolus shape, provided significant increases in enhancement of 34–73 HU in the pulmonary artery with iopromide 370 (p < 0.05).

Conclusion:

The tested piston-based injection systems combined with low viscosity contrast media provide higher achievable IDRs and higher peak vascular enhancement than the tested peristaltic-based injectors. With equivalent IDRs, Centargo provides higher peak vascular enhancement due to improved bolus shape.

Advances in knowledge:

This paper introduces a new parameter to compare expected performance among contrast media: the concentration/viscosity ratio. Additionally, it demonstrates previously unexplored impacts of bolus shape on vascular enhancement.
Aprendizado político no Conselho do Orçamento Participativo em Cachoeiro de Itapemirim – Espírito Santo – Brasil
Authors: Souza Leandro Vianna Silva , Palassi Marcia Prezotti , Da Silveira Rogério Zanon , Leite da Silva Alfredo Rodrigues
Published: February 2020

Analisa as crenças, valores e expectativas presentes na cultura política local e no aprendizado político dos membros do Conselho do Orçamento Participativo (OP) de Cachoeiro de Itapemirim, no Espírito Santo – Brasil. A base teórica articula aspectos do OP com o conceito de aprendizado político e cultura política onde se inserem as crenças, os valores e as expectativas. Utiliza a pesquisa qualitativa, entrevistas e documentos da prefeitura, submetidos à análise de conteúdo. Inicialmente o OP associava-se ao poder político municipal. Após os ciclos do OP, novos valores ligados à noção de participação e autonomia desenvolveram-se, valorizando o OP como prática legal e social.
True ternary fission in high energy proton reactions with 238U and 207Pb
Authors: Zamani M. , Debeauvais M.
Published: February 2020

A re-evaluation of ternary fission data collected in previous experiments of high energy proton reactions with 238U and 207Pb targets was made. The analysis of fragment mass distributions, fission fragment relative velocities and the kinetic energies of fragments permit to classify most of them as almost true ternary fission events. At the higher energies studied a percentage of 5% and about 2% for 238U and 207Pb respectively, present three equal masses and are events which belong to true ternary fission.
Engineering Design Integration & Non-Destructive Testing for the ESS accelerator
Authors: Gazis N. , Molloy S. , Solbrekken G. , Tanke E. , McGinnis D.
Published: February 2020

The ESS linac is under construction by the ESS partner institutes (so- called In-Kind Contributors - IKC) and will operate the most powerful proton beam ever for neutron spallation source. The linac delivers 5 MW via 2 GeV protons at a repetition rate of 14 Hz at the He-cooled solid tungsten target. The pulsed neutrons, result of the spallation, will reach the science instruments after having been moderated. The engineering effort needed to assemble the linac and its RF sources (klystrons), commenced with the design integration and currently is undergoing installation planning. In addition, the first dedicated engineering properties experiments, so-called Non-Destructive Testing for Accelerators (NDTA), take place to map and pilot the innovative testing strategy for the ESS linac structural materials. The Engineering Resources Group (ERG) of the Accelerator Division (AD) has been created to provide services of design integration, mechanical engineering and system engineering to ESS Accelerator Systems (ACCSYS) that are applicable across work package boundaries and principles of the linac systems. In parallel, part of the machine integration is the physical plant coordination and supervision. At last, in order to fulfill the missions of feasibility and planning, the ERG designs and leads the development of the technical laboratories for the accelerator systems. The current citation describes the engineering proposal for the mechanical design study and integration of the linac machine, its non- destructive testing and the essential development of the technical areas to service the long-term operational needs.
Experimental study of the flux trap effect in a sub-critical assembly
Authors: Routsonis K. , Stoulos S. , Clouvas A. , Varvayanni M. , Catsaros N. , Manolopoulou M.
Published: February 2020

The neutron flux trap effect was experimentally studied in the sub-critical assembly of the Atomic and Nuclear Physics Laboratory of the Aristotle University of Thessaloniki, using delayed gamma neutron activation analysis (DGNAA). Measurements were taken within the fuel grid, in vertical levels symmetrical to the Am-Be neutron source, before and after the removal of fuel elements, also permitting a basic study of the vertical flux profile. Three identical flux traps of diamond shape and an area of 96 cm2 were created by removing four fuel rods for each one. Two (n,γ) reactions and one (n,p) threshold reaction were selected for thermal, epithermal and fast flux study. For the thermal and epithermal flux, results obtained through the 197Au(n,γ)198Au, and 186W(n,γ)187W reactions were used, with and without Cd covers, to differentiate between the two flux regions. For the fast flux, the 58Ni(n,p)58Co reaction was used.All measurements were taken in a HPGe detector of 42% relative efficiency, with a resolution of 1.8 keV at 1332 keV and analyzed in the SPECTRW software package, developed at NCSR Demokritos.An interpolation technique based on local procedures is used to fit the cross sections and the flux spectra.End results show a thermal flux increase of 105% at the source level, and 90% across all levels, pointing to a high potential to increase the available thermal flux for future experiments. Furthermore, the vertical flux profile was found to be slightly asymmetric, with higher flux values at the top part of the assembly.
Assessing chelators’ efficiency in removing iron stains from textiles using X-ray fluorescence: Preliminary results
Authors: Kolovi S. , Tsompopoulou E. , Mergia K. , Stamatelatos I. E.
Published: February 2020

The removal of iron corrosion products is considered necessary in textile conservation and it is usually undertaken by the application of chelating agents. The efficacy of the various chelating agents is not always known and therefore, non-destructive analytical methods are often used to assess their performance. In the present work, Energy Dispersive X-ray fluorescence (EDXRF) spectroscopy was used to determine iron in textile samples before and after cleaning. It was shown that EDXRF provides a simple, rapid, non-destructive technique to determine the efficiency of iron removal after conservation treatment in textiles.
Construction and Ion-Beam Characterization of Nuclear Targets
Authors: Lykiardopoulou M. , Tsampa K. , Mertzimekis T. J.
Published: February 2020

We report on the construction and ion-beam characterization of nuclear targets and thin films as part of the ongoing NuSTRAP group research program at the University of Athens. Two different techniques were used for the preparation of new targets, depending on the desired material and thickness. Self-supported, natural silver targets were manufactured by Physical Evaporation Deposition (PVD) through electrical resistance heating, using the evaporation apparatus at the INPP (NCSR “Demokritos”). Thick iron targets were constructed using the rolling technique at the INRASTES (NCSR “Demokritos”) facilities. The Rutherford Backscattering Spectrometry (RBS) was employed to characterize the newly manufactured and existing targets using proton and deuteron beams accelerated by the Tandem Van de Graff Accelerator (at INPP) at several energies. The results from the analysis of experimental spectra and corresponding simulations carried out with the simNRA software package are presented.
Exploring the feasibility of magnetic moment measurements in the exotic 20C nucleus using LISE++ calculations
Authors: Papaioannou D. , Peroulis S. K. , Mertzimekis T. J.
Published: February 2020

Nuclear magnetic moment measurements in neutron-rich isotopes require special techniques that have to be applied in the latest generation of RIB factories. Fragmentation reactions used in these labs can produce exotic species as secondary beams. Specialized fragment separators are used to optimize the production of secondary beams. In this work, a simulation code, LISE++, is used to explore the feasibility of a magnetic moment measurement in the exotic 20C nucleus, produced as a secondary beam in NSCL A1900 and RIKEN RIPS fragment separators, by optimizing the settings of operations in both.
Bremsstrahlung Spectra Characterization by Photo-Activation: Preliminary Results
Authors: Ntalla E. , Vasilopoulou T. , Georgolopoulou P. , Stamatelatos I. E.
Published: February 2020

A method for the determination of the bremsstrahlung spectra of medical linear accelerators by photo-activation measurements is discussed. A set of activation foils with different photonuclear reaction energy thresholds was irradiated at two linear accelerators of 15 and 23 MV. The activity induced was determined using a germanium detector based gamma spectrometry system. The spectrum was reconstructed using theoretical expressions for photons emitted by electron interactions in thick targets and cross- sections from the IAEA Photonuclear Data Library. The results of this study enable experimental validation of the functional forms of bremsstrahlung spectra commonly used in radiotherapy treatment planning in the clinical environment.
Analysis of uncertainties associated with different factors used to determine the age of sediments with the Optically Stimulated Luminescence method
Authors: Tsodoulos I. M. , Stamoulis K. , Papachristodoulou C. A. , Ioannides K. G.
Published: February 2020

In this work, a sediment sample from an excavated paleoseismological trench was collected and dated following the Optically Stimulated Luminescence (OSL) dating method, using the Riso TL/OSL DA-20 reader. Chemically purified quartz, from the sample, was analysed following a single-aliquot regenerative-dose (SAR) protocol for the equivalent dose (De) determination. Also, to estimate dose rates, the natural radioactivity of soil from the surroundings of the original sample location was measured, using gamma spectrometry. Since the application of the OSL dating method involves a number of intermediary factors and processes, all being the sources of uncertainties propagating to the total uncertainty, an exhaustive analysis of the involved uncertainties is presented and the implications to the derivation of the final ages are discussed.
RICOCHET: A quick-and-dirty approach to analyze μ-XRF synchrotron data using open-source utilities
Authors: Mitsi E. , Mertzimekis T. J.
Published: February 2020

A semi-automated procedure based on open-source utilities was designed and built to analyze spectra collected at a synchrotron accelerator using the μ-XRF technique. The software (RICOCHET) has a fast, efficient and user-friendly design aimed at performing online analysis. A few examples of its application using recent μ-XRF data from the SUL-X beamline at ANKA Synchrotron Facility (KIT) are presented.
Neutron induced fission cross-section of 240Pu(n,f): first results from n_TOF (CERN) Experimental Area II
Authors: Tsinganis A. , Stamatopoulos A. , Colonna N. , Vlastou R. , Schillebeeckx P. , Plompen A. , Heyse J. , Kokkoris M. , Barbagallo M. , Berthoumieux E. , Calviani M. , Chiaveri E. , N_TOF Collaboration And the
Published: February 2020

The accurate knowledge of neutron cross-sections of a variety of plutonium isotopes and other minor actinides, such as neptunium, americium and curium, is crucial for feasibility and performance studies of advanced nuclear systems (Generation-IV reactors, Accelerator Driven Systems). In this context, the 240Pu(n,f) cross-section was measured with the time-of-flight technique at the CERN n_TOF facility at incident neutron energies ranging from thermal to several MeV. The present measurement is the first to have been performed at n_TOF's newly commissioned Experimental Area II (EAR-2), which is located at the end of an 18m neutron beam-line and features a neutron fluence that is 25-30 times higher with respect to the existing 185m flight-path (EAR-1), as well as stronger suppression of sample-induced backgrounds, due to the shorter times-of-flight involved. Preliminary results are presented.
CONY - Computer code for Neutron Yield calculations: The 7Li(p,n)7Be and 3H(d,n)4He reactions.
Authors: Grigoriadou M. , Kokkoris M. , Patronis N. , Vlastou R.
Published: February 2020

The neutron beam facility at NCSR “Demokritos” is driven by a 5.5 MV tandem T11/25 Van De Graff accelerator that provides continuous, high intensity ion beams. Depending on the neutron production reaction, different energy regions of neutron beams are available. Neutron fields with well defined energies are produced by means of nuclear reactions such as: 7Li(p,n)7Be, 3H(p,n)3He, 2H(d,n)3He and 3H(d,n)4He, delivering neutrons up to the energy of ~28 MeV. In order to fully characterize the neutron beam at NCSR “Demokritos”, in the framework of the present work, the CONY C++ computer code has been developed. The implementation of the code for the 7Li(p,n)7Be and 3H(d,n)4He reactions is discussed. The method of calculation of differential neutron yields by thin and thick targets is described. Specifically, for the reaction 7Li(p,n)7Be the mathematical singularity at near threshold energies is discussed along with the method that was used as to overcome this issue. Finally, the results of the code including the double differential neutron yields, the neutron beam energy distribution at the sample position and the total neutron yields have been compared with experimental data as well as with the results of the NeuSDesc software (JRC-IRMM: Neutron Source Description).