bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThis 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

Abstract
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 &lt; 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 &lt; 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 &lt; 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 &lt; 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.