bluuebunny/crossref_metadata_2025_split huggingface dataset:
Introduction of a variable electrostatic field for targeted drug application following intraperitoneal aerosol chemotherapy (PIPAC).
Authors: Khosrawipour Veria , Chaudhry Haris , Mikolajczyk Agata , Schubert Justyna , Pigazzi Alessio , Khosrawipour Tanja 
Published: May 2019

e14211 Background: In the treatment of Peritoneal Metastasis, the delivery of pressurized chemo-aerosols into the capnoperitoneum has been reported to show superior qualities to the application of conventional liquid chemotherapy. However, there is little basic knowledge on how aerosol particle motion within the abdominal cavity may be influenced and directed by means of an electrostatic field. This study aims to investigate aerosol motion within the abdominal cavity using an ex-vivo model. Material and Methods: All experiments were performed in an ex-vivo box as well as on postmortem swine abdomen, both established ex-vivo PIPAC models previously introduced by our research team. Extra-abdominally created, unipolar charged aerosols are introduced to the abdominal cavity. A modulated electrostatic field within the abdominal cavity is established to examine aerosol particle collision via fluorescence microscopy and photography. Results: Aerosol particle collision was observed on the peritoneum in the varying electric field. Preliminary data suggests that tissue penetration rates change with a varying electric field (p < 0.05). Drug distribution pattern showed a significant improvement with a varying electric field vs. without (p < 0.05). Conclusions: Our data suggest that extra-abdominally created, highly drug concentrated aerosol particles have the capacity to achieve high drug penetration rates in the peritoneum. The addition of a varying electric field enhances particle collision as well as significantly improves drug distribution patterns. Further studies are required to investigate the in-vivo safety and efficacy of a varying electric field and the significance of extra-abdominally created chemo-aerosols with regards to possible clinical applications.
Some characteristics of cancer-testis gene expression regulation in colorectal cancer.
Authors: Soldatova Kristina I. , Kit Oleg Ivanovich , Tolmakh Roman E. , Kutilin Denis S. 
Published: May 2019

e14233 Background: Cancer-testis antigens (CTA) can be used in immunotherapy and for early detection of cancer. Despite numerous studies of the CTA expression in different tumors, their transcriptional activity and its regulation in colorectal cancer (CRC) remain poorly understood. The purpose of the study was to analyze the expression of cancer-testis genes (CT-genes) and mechanisms of its regulation in CRC. Methods: Tumor and intact tissues of the colon were studied in 60 patients. RNAs were isolated using the method described by Chomczynski and Sacchi (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Expression of 16 CT-genes (MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) and expression and copy number of 3 DNA methyltransferase genes (DNMT1, DNMT3A, DNMT3B) were determined by Real-Time qPCR (GAPDH and GUSB - reference genes). For the cluster analysis, we used our R scripts. Differences were assessed by the Mann-Whitney test, and correlations – by the Spearman's rank correlation coefficient (r). Results: The expression of 2 CT genes, SSX2 and PRAME1, was increased (p < 0.05) by 1.8 and 2.9 times, respectively, and the BAGE expression was decreased by 2.4 times in tumor tissues, compared to the normal tissues. The expression and copy number of DNMT3A in tumor tissues was 1.5 and 2 times higher (p < 0.05), and that of DNMT3B – 2 times lower (p < 0.005), compared to normal tissues. The copy number and expression of the DNMT1 gene did not change. A strong positive correlation (r = 0.996) between the expression and copy number of DNA methyltransferase genes was observed. Using cluster analysis (Hierarchical Clustering, Euclidean distance), we detected two clusters of CRC samples different in the expression of CT-genes and methyltransferases. Cluster 1 showed increased expression of DNMT1, DNMT3A and DNMT3B and decreased expression of BAGE, SSX2 and PRAME1; cluster 2 – decreased expression of DNMT1, DNMT3A and DNMT3B and increased expression of BAGE, SSX2 and PRAME1. Conclusions: The detected aberrant expression of the CT-genes BAGE, SSX2, PRAME1 in CRC depends on the expression of DNMT1, DNMT3A, DNMT3B, which in its turn depends on the copy number of the corresponding DNA methyltransferase genes.
Interleukin-2 boosts local and abscopal antitumor effect of radiotherapy combined with anti-PD-1: A translational research from clinical radio-memory effect.
Authors: Chen Dawei , Song Xinyu , Yue Jinbo , Xing Ligang , Yu Jinming 
Published: May 2019

e14244 Background: Preclinical and clinical studies have shown that prior receipt of radiotherapy enhances antitumor immune responses, a phenomenon we call the “radio-memory effect.” However, all of the evidence regarding this effect to date comes from work with anti-PD-1 or anti-PD-L1 inhibitors. Here we explore whether this effect also occurs with other forms of immune therapy, specifically interleukin-2 (IL-2). If so, whether this triple combination therapy could produce synergetic anti-tumor effect. Methods: 1. Clinical work: we retrospectively assessed outcomes in patients with malignant peritoneal effusion (MPE) who had previously received radiotherapy for colon or rectum cancer within 18 months before the intrapleural infusion of IL-2 or cisplatin. All patients received intrapleural infusion of IL-2 or cisplatin, and most had had several cycles of standard chemotherapy for colon or rectum cancer. 2. Translational work: MC38 cell line (5×106) was subcutaneously inoculated into the right lower extremity of C57/BL mice to construct a primary tumor model. Six days later, MC38 cell line (1×106) was subcutaneously inoculated into the left lower limb to construct a second tumor model. The main research is as follows: To explore the optimal radiation dose and fraction for radiotherapy; Whether the addition of IL-2 will further enhance the efficacy of radiotherapy combined with anti-PD-1; To explore the optimal combination model of radiation, anti-PD-1 and IL-2; Whether the addition of IL-2 will increase the abscopal effect produced by radiotherapy and anti-PD-1. Results: 1. We identified 3,747 patients with MPE (median age 66 years [range 24–81)) treated at one of several institutions from August 2009 through May 2016; 412 patients had been treated with IL-2 and 592 with cisplatin and had survived for at least 3 months afterward. 2. Hypofractionated radiotherapy (12Gy × 2) combined with IL-2 is better; IL-2 will enhance the efficacy of radiotherapy combined with anti-PD-1; IL-2 and anti-PD-1 followed by radiotherapy might maximize the anti-tumor effect; IL-2 might increase the abscopal effect produced by radiotherapy combined with anti-PD-1. Conclusions: We speculate that previous radiotherapy could enhance the efficacy of IL-2 and the anti-tumor effect produced by radiotherapy combined with anti-PD-1 could be enhanced by IL-2. The “radio-memory” effect could be beneficial in future studies.
Early response assessment through multiparametric MRI based endpoints in a phase II multicenter study evaluating the efficacy of DPX-Survivac, intermittent low dose cyclophosphamide (CPA) and pembrolizumab combination study in subjects with solid tumors.
Authors: Roettger Diana , Shaikh Faiq , Bisdas Sotirios , MacDonald Lisa Diana , Fiset Stephan , Rosu Gabriela Nicola 
Published: May 2019

e14245 Background: Accurate assessment of tumor response to immunotherapy is challenged by pseudoprogression that mimics true progression. Conventional imaging and RECIST assessment do not adequately distinguish between them given their inability to account for changes in the tumor microenvironment. DPX-Survivac is a novel T cell activating therapy that triggers immune responses against tumors expressing survivin and is being studied in this trial in combination with CPA and pembrolizumab in several solid tumors. Multiparametric MRI approaches - dynamic contrast-enhanced MRI and diffusion-weighted imaging MRI are useful for accurate assessment of structural, perfusion and vascular assessment of the lesion and may identify pseudoprogression and compare to the RECIST-based assessment. Methods: The study will enroll up to 226 evaluable subjects in 5 different cohorts: ovarian cancer, HCC, NSCLC, bladder cancer and MSI-H cancer. These subjects will undergo initial imaging 28 days prior to treatment, to be assessed based on RECIST 1.1, and a pre-treatment tumor biopsy for quantitation of survivin and PD-L1 expression and MSI analyses. Treatment for 35 cycles or until disease progression. All patients will have CT images for RECIST 1.1 and iRECIST assessment. A subset of subjects will undergo mpMRI to calculate advanced imaging biomarkers. Results: MRI, clinical and patient-reported outcomes will be analyzed. Conclusions: This study will provide important evidence on the utility of mpMRI + CT-based assessment of response to immunotherapy and use it as an adjunct to the CT-based RECIST criteria by providing insight on how tumor lesions are impacted by treatment.
Personalized multimodality therapy with immune checkpoint inhibitors (ICI), chemotherapy (CT), and targeted treatment (TT) in advanced refractory cancer.
Authors: Salem Philip A. , Jabboury Khaled W. , Stenoien Randall , Wheeler Thomas M. , Valerio Maria Rosaria 
Published: May 2019

e14254 Background: Therapy for advanced refractory malignancies remains a major challenge. As the combination of ICI and CT has been shown in some cancers to be superior to CT alone, and as ICI, CT, and TT have efficacy, but divergent toxicity; this combination was chosen for treating patients with such diseases. Methods: Treatment was highly personalized and was designed based on diagnosis, prior therapy and eligibility for TT. ICI included pembrolizumab in 7 (2 in combination with ipilimumab), nivolumab in 10, and atezolizumab in 2. Chemotherapy was given in 28-day cycles. Multiagent CT cycles were given in 17, and single-agent in 2.13 received platinum and 10 taxanes. TT included erlotinib 4, cituxumab 2, bevacizumab 2, dabrafenib/trametinib 3, crizotinib 1, alectinib 1, sorafenib 1, everolimus 1. 4 were not eligible for TT. Results: From 04/2016 to 10/2018 19 consecutive patients (PT) were treated; median (M), age 62 (27-82), ECOG PS 2 (0-4), female 15/male 4. Tumor type; lung 8, pancreas 3, lymphoma 2, melanoma 2, cholangioCA 1, ureter 1, cervix 1, Glioblastoma Multiforme 1. 13 PT had prior therapy, M2(1-11). 7 had prior ICI, 3 prior TT. Disease was bulky in 6. Response was based on PET evaluation with tumor regression depicted after cycle #1. 11 achieved CR (57%), M 6+ months (1+-15+), 7 PR (37%), M 4 months (1+-7) and 1 SD 7 months. 3 intracranial metastases; 2 CR, 1 PR. Response was seen in extensive prior therapy, bulky disease, poor performance, and prior ICI. No unexpected side effects were observed. Grade 3-4 adverse events; 12.7%, primarily hematologic. Conclusions: The personalized combination of ICI, CT, and TT in advanced refractory diverse cancer diseases is associated with high clinical activity. Further evaluation in clinical trials is strongly indicated.
The role of different TGFβ signatures in predicting outcome in high grade serous ovarian carcinoma.
Authors: Mahdi Haider , Rose Peter Graham , Abdul-Karim Fadi W , Monk Bradley J. , Ni Ying 
Published: May 2019

e14262 Background: Ovarian cancer (OV) is the most lethal gynecologic cancer in the US. Despite initial responsiveness to chemotherapy, > 50% experience recurrence. Recurrent disease is characterized by low response to chemotherapy and poor prognosis, especially platinum-resistant disease. Thus, there is an urgent need to identify new targeted therapy to improve the outcome of this aggressive cancer. The Transforming Growth Factor (TGFβ) family controls different cellular responses in development and cell homeostasis. Disruption of TGFβ signaling has been implicated in many cancers, including OV, but with paradox effects. It is unclear if TGFβ family genes can serve as a predictive marker and be selected for future therapy target in OV. Methods: We used quantified RNAseq data from 374 OV samples in The Cancer Genomic Atlas (TCGA) to extract 4 different sets of TGFβ pathway genes including: 3-gene ( TGFB1, TGFB2, TGFB3), 6-gene ( TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR3), 43-genes from cBioPortal, or 173-genes from Calon et al, 2012 to predict colorectal cancer relapse. Expression counts for these genes were normalized and log transformed to generate a TGFβ score based on the quartiles of the average. Samples were categorized in to low (lowest quartile), medium (middle 2 quartiles), and high (highest quartile) expression groups. Overall (OS) and progression-free (PFS) survivals were compared among groups using Kaplan-Meier method. Results: Interestingly, the minimum TGFβ 6-gene set can predict high grade serous ovarian cancer patient survival among all 4 gene panels using TCGA data, with average age of 60 years (range: 38 –81). Majority of the patients were stage IIIIV. OV patients with highest quartile, TGFβ signature expression have in general less somatic mutations and copy number alterations (average mutation count = 41, average CNA fraction = 0.5) compared to lowest quartile TGFβ expression group (average mutation count = 52, average CNA fraction = 0.6). Patients with TGFB 6-gene expression scored high showed worse OS (36.2 months vs 63.5 months, log-rank p = 0.001) and worse PFS (18.6 months vs 31.4 months, log-rank p = 0.09). Details of outcome by each specified gene signature will be outlined later. Conclusions: Our analysis suggested that the narrowed 6-gene TGFβ family expression profile could potential serve as a prognosis biomarker for OV. With proper validation and mechanistic investigation, existing TGFβ inhibitors may hold promise for targeted or combination therapies for OV. Targeting both TGFβ and PD1 might be of therapeutic value.
Tumor mutational burden assessed by a targeted NGS assay to predict clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer.
Authors: Rothschild Sacha , Alborelli Ilaria , Leonards Katharina , Leuenberger Laura P , Savic Prince Spasenija , Mertz Kirsten D , Poechtrager Severin , Zippelius Alfred , Laubli Heinz Philipp , Haegele Jasmin , Tolnay Markus , Bubendorf Lukas , Quagliata Luca , Jermann Philip 
Published: May 2019

e14266 Background: In non-small cell lung cancer (NSCLC) immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here we evaluated the predictive power of TMB measured through / by the Oncomine Tumor Mutational Load (TML - Thermo Fisher Scientific) targeted sequencing assay in 71 NSCLC patients treated with ICIs. Methods: TMB was assessed retrospectively in 71 metastatic NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were characterized as either having durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. Results: TMB was significantly higher in patients with DCB compared to patients with NDB (median TMB = 9.2 versus 5.3 mutations/Mb, Mann-Whitney p = 0.014). 70% of patients with high TMB (cutoff = 3rd tertile, TMB ≥ 9.2) were responders (DCB) compared to 29% of patients with low TMB (cutoff = 1st tertile, TMB ≤ 4.5). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log rank test, p = .0030 for PFS and 0 .0375 for OS, respectively). Combining PD-L1 expression and TMB value increased the predictive power of TMB. Conclusions: Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. We believe that a combination of biomarkers will maximize the precision of patient selection.
Comparison of biomarkers among 34,855 GI cancer samples show heterogeneity of tumor types.
Authors: Dawood Shaheenah S. 
Published: May 2019

e14287 Background: Recent data indicate that biomarker driven use of targeted therapy and I/O-therapy among patients with GI cancer is associated with improved outcome. The presence of biomarkers varies broadly between different GI tumor types, highlighting the importance of comprehensive molecular profiling.To analyze the presence of various alterations in GI cancer samples of a large database, comparing congruency between various tumor types. Methods: A retrospective data analysis of 34855 GI cancer patients profiled at CARIS Life Sciences obtained from Jan 1st2010 till Sep 14th2018 was performed. GI tumors were classified as : CRC, esophageal/gastric/GIST, small intestine, pancreatic/hepatobiliary/liver. Technologies used to analyze the biomarkers: IHC for PD-L1, MMR and Her2, and DNA-NGS for EGFR, BRAF, KRAS, NRAS, MET-CNV, TMB, MSI, POLE and BRCA1/2. Results: Median age was 61 (range 18-89 years). 51.5% was CRC (n = 18047), 15.5 % was esophageal /Gastric/GIST (n = 5470), 3% was small intestinal cancer (n = 886) and 30% was pancreatic/hepatobiliary/liver cancer (n = 10452). Information on biomarkers was available from 2931 cases for MET amplification to 28536 for RAS information. Overall, the most common finding was a pathogenic RAS-mutation (either KRAS or NRAS) in 7650 cases (26.81%), the rarest one was a mutation in EGFR in 12 cases (0.06%). Higher rate of HER2 amplification was observed among pts with esophageal/gastric/GIST tumors (6.5%) in comparison to tumors at other GI sites ( ~1.5%). High TMB was seen among patient with CRC and small intestine tumors (~7%) while it was lowest among pancreatic cancer (1.8%). Compared to other GI sites lower MSI /MMR deficiency rates were observed in pancreatic /hepatobiliary tumors, significantly higher PD-L1 positivity was observed in gastrooesophageal cancer types, increased MET-amplifications in gastrooesophageal and small intestinal cancer types and lower RAS-mutation rate in gastrooesophageal cancer. Conclusions: Molecular profiling analyzing druggable biomarkers can help identify patients with increased likelihood for benefit from immune-checkpoint-inhibitors and targeted therapies. Further investigations are needed to evaluate the different findings in various GI cancer types.
Arenavirus-based vector platform for massive tumor self-antigen-specific CD8 T cell immunity.
Authors: Orlinger Klaus Karl , Bonilla Weldy V. , Kallert Sandra M , Kirchhammer Nicole , Marx Anna-Friederike , Krzyzaniak Magdalena , Schmidt Sarah , Raguz Josipa , Berka Ursula , Guenther Stephan , Zippelius Alfred , Pinschewer Daniel 
Published: May 2019

e14297 Background: The induction of powerful CD8+ T cell immunity to tumor associated self-antigens (TAAs) represents a critical yet challenging goal. Here we report on the development of an arenavirus-based delivery platform meeting this challenge. Previously we have shown that genetically engineered replication-attenuated lymphocytic choriomeningitis virus (LCMV) vectors, TheraT(LCMV), induce strong TAA-specific CD8 T cell immunity, but these responses can not be substantially augmented upon TheraT(LCMV) readministration. Counter to expectations, vector-neutralizing antibodies were not accountable for limited homologous prime-boosting capacity. Instead, dominant viral backbone-reactive CD8+ T cells competed against subdominant TAA-specific responses, limiting their magnitude. Methods: Herein we engineered and characterized delivery systems based on the arenaviruses Mopeia, Candid#1 and Pichinde (TheraT(MOP), TheraT(CAND), TheraT(PIC)). Results: We demonstrate that heterologous TheraT(CAND) – TheraT(LCMV) and TheraT(PIC)-TheraT(LCMV) prime-boost substantially augment TAA-specific CD8 T cell responses by rendering them immunodominant. Accordingly, intravenous administration of mice triggered up to 50% TAA epitope-specific CD8+ T cells and cured established tumors. Conversely, TheraT(MOP) – TheraT(LCMV) prime-boost was poorly immunogenic owing to cross-reactive T cell epitopes in the respective viral backbones. Conclusions: These findings establish heterologous arenavirus prime-boost combinations as a powerful new modality in tumor immunotherapy and highlight CD8 T cell epitope dominance as a significant hurdle to overcome in the vectored delivery of TAAs.
Enhanced CD138 peptide-specific cytotoxic T lymphocyte activities against breast, colon and pancreatic cancers in combination with pembrolizumab (anti-PD1).
Authors: Bae Jooeun , Hideshima Teru , Tai Yu-Tzu , Munshi Nikhil C. , Anderson Kenneth Carl 
Published: May 2019

e14302 Background: We investigated the ability of CD138 antigen-specific CD8+ cytotoxic T lymphocytes (CD138-CTL), generated using a novel HLA-A2-specific CD138260-268 (GLVGLIFAV) peptide, in combination with various immune checkpoint inhibitors, to target breast, colon, and pancreatic cancer. Methods: This study was designed to evaluate anti-tumor activities of CD138-CTL, alone or in combination with Pembrolizumab (anti-PD1), against solid tumors. Results: Upregulation of CD138 protein expression was detected on breast, colon, and pancreatic cancer cells. CD138-CTL induced ex vivo by repeated stimulations with HLA-A2-specific CD138260-268 (GLVGLIFAV) peptide were enriched for CD45RO+ memory CTL and demonstrated antigen-specific and HLA-A2-restricted anti-tumor activities. Treatment of CD138-CTL with anti-PD1, anti-TIM3, or anti-LAG3 or tumor cells with anti-PDL1, anti-Gal9 or anti-LAG3 resulted in an increased proliferation of CD138-specific CD8+ CTL, which express costimulatory and activation markers (CD28, CD40L, 41BB, CD69, CD38). However, expression of immune checkpoints (PD1, LAG3, CTLA4) was also induced on these CD138-CTL upon stimulation. Importantly, anti-tumor activities of CD138 peptide-CTL was significantly enhanced in combination with Pembrolizumab, especially within the antigen-specific memory CD8+ T cell subsets (central memory > effector memory), directed against HLA-A2+ breast cancer, colon cancer and pancreatic cancer. Conclusions: These data provide the framework for an immunotherapeutic strategy encompassing a CD138260-268 (GLVGLIFAV) peptide-based cancer vaccine in combination with Pembrolizumab to enhance antigen-specific central memory cells with more potent and long-lasting CD8+ CTL immune responses in patients with solid tumors. Based on these result, clinical trials evaluating CD138260-268 (GLVGLIFAV) in multi-peptide cancer vaccine are on-going in patients with triple negative breast cancer in combination with anti-PD1 (Pembrolizumab) in metastatic setting (NCT 03362060) or anti-PD-L1 (Durvalumab) in stage II/III, adjuvant setting (NCT 02826434).