bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of brain metastases in tyrosine kinase inhibitor-treated epidermal growth factor receptor-mutant non-small-cell lung cancer from the perspective of long-term radiation brain damage: A multi-institutional retrospective analysis.
Authors: Zhuang Hongqing , Wang Xin , Yuan Zhiyong , Wang Enmin , Wang Junjie 
Published: May 2019

e13587 Background: To investigate the relationship between the timing of SRS intervention and the complications of cerebral radiation necrosis(CRN) and its impact on the cognitive function and quality of life(QOL) in patients with brain metastases of lung adenocarcinoma who received TKI treatment. Methods: A total of 361 targets from 257 patients with brain oligo-metastases of lung adenocarcinoma who received Cyberknife treatment between 2010 and 2017 were collected from three Cyberknife centers. The difference in brain necrosis between patients with or without TKI application was statistically counted. Logistic regression analysis was used to analyze the effect of applying TKI on the occurrence of CRN in patients, and the effect of SRS before and after TKI resistance on CRN. The effects of CRN on the cognitive function and quality of life of surviving patients were analyzed. Results: The rate of CRN in the TKI group was significantly higher than that in the non-TKI group. The incidence of brain necrosis in patients undergoing SRS after drug resistance was significantly higher than that in patients undergoing SRS before drug resistance. Regression analysis showed that combination of TKI with SRS, and SRS after TKI resistance were important influencing factors for CRN. The follow-up results of currently surviving patients showed that the occurrence of brain necrosis seriously affected the cognitive function and QOL of patients. Conclusions: Long-term radiation-induced brain damage needs to be seriously monitored in lung adenocarcinoma patients with brain metastasis undergoing combination of radiotherapy and TKI. Clinicians need to pay attention to this problem and make reasonable recommendations for radiotherapy and TKI treatment.
Real-world outcome analysis of EGFR-mutated lung adenocarcinoma with brain metastases.
Authors: Kuan Feng-Che , Yang Wei-Hsun , Lai Hung-Yi , Huang Chun-Chieh , Yang Cheng-Ta , Shi Chung-Sheng 
Published: May 2019

e13588 Background: BM represent a common problem in EGFR-mutated lung adenocarcinoma. The updated Lung-molGPA elucidates the survival in patients with non-small-cell lung cancer and BM by incorporating the effect of EGFR gene alterations. However, the nature history and differences of prognostic implication between common and uncommon EGFR mutations remain unsolved. Methods: By retrospective analysis of Chang-Gung Research Database (CGRD), patients with EGFR-mutated lung adenocarcinoma and BM were included into analysis of PFS and OS. EGFR mutations were categorized into exon 19 deletions (Del19), exon 21 Leu858Arg substitution (L858R) and uncommon mutations. Kaplan-Meier method was used to estimate survival, and multivariate Cox proportional hazard models was performed to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI). The p-value was set to be statistically significant at 0.05 or less. Results: From April 1, 2014 to June 30, 2015, 269 out of 818 patients with EGFR-mutated lung adenocarcinoma and BM were included, of which 115 patients with Del19, 131 patients with L858R, and 23 patients with uncommon EGFR mutations. The baseline characteristics were balanced in age, gender, KPS, ECM, number of BM, and timing of BM. In comparison with those with L858R, uncommon mutations is a poor prognostic factor for PFS (HR 2.24, 95% CI: 1.34-3.75, p = 0.002). The median PFS of Del 19, L858R, and uncommon EGFR mutations were 10.4, 10.0, and 3.2 months, respectively (log-rank p = 0.03). Besides, the median OS of Del 19, L858R, and uncommon EGFR mutations were 18.1, 17.4, and 12.5 months, respectively (log-rank p = 0.05). In comparison with those treated with gefitinib, afatinib treatment is a good prognostic factor for PFS and OS (PFS, HR 0.57, 95% CI: 0.35-0.94, p = 0.03; OS, HR 0.48, 95% CI: 0.26-0.91, p = 0.03). The median PFS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 11.0, 8.5, and 10.3, respectively (log-rank p = 0.63). In addition, the median OS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 18.7, 15.2, and 18.2 months, respectively (log-rank p = 0.50). Conclusions: Among patients with EGFR-mutated adenocarcinoma, common and uncommon EGFR mutations have distinct natural history and prognostic implications in patients with BM.
Presenting symptoms and patient prognosticators in neoplastic meningitis: A single institution experience.
Authors: Ghatnekar Shilpa , Hachem Hilal , Patel Rima , Dowd Richard , Godara Amandeep , Chang Hong , Jeyapalan Suriya A. 
Published: May 2019

e13593 Background: Neoplastic meningitis (NM) occurs in 5-15% of cancer patients, with less than 15% surviving one year. Untreated, median survival is estimated at 1.5-2 months. The purpose of this study is to identify the presenting symptoms of NM disease and the patient characteristics which are prognostic of overall survival (OS). Methods: We performed a single-institution retrospective analysis of 123 patients diagnosed with NM disease at TMC between January 2006 and January 2016. Patients were identified via cytopathology and radiology. Patient data was obtained from the hospital electronic medical record. Survival analysis was generated using Kaplan-Meier methods and chi square tests for categorical data. Results: Breast cancer was the most common primary malignancy (22%, n = 27), followed by lymphoma (19%, n = 23), and lung cancer (15%, n = 18). The most common presenting symptoms were headache (33%, n = 41), extremity weakness (33%, n = 41), and gait abnormalities (25%, n = 31). Median age and Karnofsky performance status (KPS) at diagnosis were 56 years [18-93] and 58 [10-100], respectively. Median OS was 4.08 months [0-130], with a 23% one-year survival rate. Higher KPS was associated with a significantly improved OS (p < 0.05). Although survival was worse in the age group > 67 yrs compared to < 45 yrs the difference was not significant (p = 0.053, 95% CI (0.994- 2.944)). Conclusions: To our knowledge, this is one of the largest analyses of patient characteristics and outcomes in NM. Results show that KPS, when adjusted for confounders, is an important prognostic biomarker. In contrast to other studies, age was not a significant prognosticator of survival. Headaches combined with extremity weakness were the most common presenting symptoms of NM disease. When present together in the cancer patient, the treating physician should strongly consider further workup for the presence of NM disease.
Computational design of novel tetra-specific antibody (PD-1/CD47/VEGF/TGF-ß) with IgG-like architecture against non-small cell lung cancer (NSCLC).
Authors: Zhao Lei , Zhang Fan , Li Lingling , Chen Shixue , Hu Yi 
Published: May 2019

e14002 Background: Although monoclonal antibodies (mAbs) are widely used for the treatment of cancer, the acquired resistance is one of the prime obstacles for cancer treatment. There is an urgent need to development of novel antibodies with potent anti-tumor activities and specificities against cancer. Due to the complexity and heterogeneity of cancer, mAb with a single target could not be significantly improved to combat cancer. Nowadays, bispecific antibodies with the capacity to blockade of multiple targets or binding sites are showing improved therapeutic efficacy against cancer both in clinical trials and preclinical studies, suggesting that multi-specific antibodywith great potential for administration of cancer in near future. Although more than 30 bispecific antibodies with IgG architecture are being explored in clinical trials, tetra-specific antibody with IgG-like architecture against NSCLC has not been reported. Methods: Recently, we have successfully solved the correct assembling of heavy-heavy chain and heavy-light chain of multi-specific antibody through the Lock-and-Key and FabX technologies we have previously described. By using these two technologies, we have designed the tetra-specific antibody with IgG-like architecture against NSCLC. Then, we have performed long-time molecule dynamic simulation (6 µs) to evaluate and improve the structure stability of tetra-specific antibody. Results: With the benefits of tetra-specific antibody and whole IgG architecture, the tetra-specific antibody PD-1/CD47/VEGF/TGF-ßexhibits potent anti-tumor efficacy than the parent antibody Atezolizumab, Hu5F9-G4, Bevacizumab or Fresolimumab and the combination of these parent antibodies. Conclusions: Tetra-specific antibody with IgG-like structure shows the advantages in cancer treatment. Antagonism of PD-1, CD47, VEGF and TGF-ß through multi-specific antibody could be a promising anti-tumor strategy against NSCLC.
AGEN2373 is a conditionally-active agonist antibody targeting the costimulatory receptor CD137 for the treatment of human malignancies.
Authors: Galand Claire , Xiao Yanping , Mundt Cornelia , Morin Benjamin , Chand Dhan , Riordan Christina , Venkatraman Vignesh , Ward Rebecca , Gombos Randi , Lim Min , Costa Matthew , Joyce Cailin , Ignatovich Olga , Findeis Mark , Underwood Dennis , Stein Robert Benjamin , van Dijk Marc , Wilson Nicholas , Savitsky David 
Published: May 2019

e14005 Background: Agonist antibodies targeting CD137 are potent inducers of tumor-reactive T cell proliferation, cytokine production, and cytotoxicity, and have been explored clinically for their ability to enhance immune cell-mediated destruction of tumor cells. Despite early signs of clinical activity, the development of first-generation anti-CD137 antibodies has been hampered by on-target dose-limiting hepatotoxicity or poor clinical activity. Subsequent CD137 therapies have therefore sought to localize CD137 agonism to the tumor microenvironment (TME) to potentially improve tolerability in patients. However, these approaches may also limit the potential benefit of CD137 signaling outside the TME that contributes to anti-tumor immunity, such as T cell priming in tumor draining lymph nodes. Here we describe the pharmacologic and non-clinical safety profile of a next-generation anti-CD137 monospecific antibody, AGEN2373. Methods: Flow cytometry and surface plasmon resonance-based binding, superantigen-driven immune cell activation, and luminescent reporter cell line assays were developed to test the ability of AGEN2373 to induce CD137 signaling. A non-clinical, multi-dose safety study was conducted wherein cynomolgus monkeys were injected intravenously with 100 mg/kg doses of AGEN2373. Results: AGEN2373 engages cell-expressed human and cynomolgus monkey CD137, and provides potent CD137 co-stimulation only in the presence of CD137 ligand and/or Fc gamma receptor-expressing antigen presenting cells. No changes in clinical parameters, importantly no sign of liver toxicity, were observed after administration of AGEN2373 in cynomolgus monkeys. Conclusions: AGEN2373, a novel conditionally-active anti-CD137 agonist antibody that is well-tolerated in non-human primates, is expected to have clinical activity in patients with human malignancies by its ability to selectively enhance tumor immunity in the context of immune co-stimulation.
Measuring T-cell avidity and enrichment using acoustic force-based technology.
Authors: Anderson Leif Stefan , Braster Rens , Sitters Gerrit , Candelli Andrea , Schumacher Ton N. , Scheper Wouter 
Published: May 2019

e14010 Background: The key driver for effective immune cell therapies is the overall binding strength of the immune cell and the target cell (e.g. tumor cells). The overall strength is known as ‘avidity’, a parameter reflecting interaction efficiency. The key to success for immune cell therapies is generating effective and long-lasting immune responses. The avidity of an immune cell to its target is predicative of its function, but current techniques to measure avidity are low-throughput and ineffective. Herein, we describe the use of acoustic forces to discriminate immune cells based on their avidity to tumor cells. The force required to separate a cell from its target is called the ‘rupture force’, and in this study, we were able to identify the rupture forces of tumor specific and non-specific T cells and enrich these different populations for downstream characterization. Methods: T cells from a healthy donor were transduced with either a non-relevant, or a melanoma recognizing T cell receptor and selected with puromycin resistance. Melanoma cells were seeded in the flow cell and allowed to adhere overnight to form a monolayer. For confocal experiments CFSE and Cell Trace far red stained T cells were mixed in a 1:1 ratio before co-culturing them in the flow cell. An acoustic force ramp was applied within the flow cell and cell detachment was monitored. Results: T cells engineered with a melanoma antigen-recognizing T-cell receptor needed 6 times more force than non-specific T cells to be separated from the melanoma target cells. Furthermore, 1.4 to 3.6-fold enrichment of high-avidity T cells was obtained from a mixed population of specific and non-specific T cells using acoustic forces. Conclusions: These findings indicate that melanoma-specific T cells bind with a higher avidity than non-specific T cells and that they can be separated with this approach. In conclusion, we demonstrate a novel method to measure cell avidity and sort cells by utilizing acoustic forces.
Receptor-triggered lymphocyte apoptosis PC to replace Cy/Flu PC for CART.
Authors: Deisher Theresa , Ashok Arya , Jarzyna Peter , Zahid Yumna , Poulin Kendra , Lee-Diaz Stephanie , Parthasarathy Vaishnavi , Taylor Margaret 
Published: May 2019

e14011 Background: Chimeric antigen receptor T-cell (CAR-T) therapy is a relatively novel regimen for the treatment of acute lymphoblastic leukemia that has already shown promising results. Two FDA-approved CAR-T therapies, Kymriah and Yescarta have an 80% success rate in sending patients into remission. However, both of these treatments require preconditioning (PC) with chemotherapy to ensure CarT expansion and engraftment. Chemotherapy severely compromises patient’s immune-system, a further economic burden up to $70K per patient due to hospitalization, and fuels side effects of CAR-T therapy such as cytokine release syndrome (CRS) and neuroedema, driven by the release of IL-6 and GM-CSF respectively. Also, up to one third of cancer patients are too frail to tolerate chemotherapy and do not qualify for potentially life-saving therapies. A single acute dose of AVM0703 induces lymphodepletion equivalent to chemotherapy, and transiently eliminates the sites in the spleen where therapeutic cells accumulate without inducing toxicities associated with chemotherapy. Methods: Mice with subcutaneously implanted melanoma were preconditioned with AVM0703 prior to treatment with a mouse Pmel CAR-T therapy. Tumor growth was tracked and spleens were analyzed after dissection for binding of labeled CAR-T cells. In a separate study, four human patients were dosed with low doses of AVM0703 and the levels of released cytokines in the blood were quantified. Results: The mice demonstrated reduced T-cell sequestration in the spleen as noted by a reduction of fluorescently labeled cells. AVM0703 alone significantly delayed tumor growth, and as PC before Pmel T-cells, dramatically improved CAR-T-driven delay of tumor growth. In humans, a significant increase in beneficial IL-2 and IL-15 was observed, as well as a lack of released IL-6. In addition, existing literature demonstrate that AVM0703 reduces the release of GM-CSF. Conclusions: AVM0703 shows efficacy as preconditioning agent in a mouse solid tumor model of melanoma, reduces the binding of CAR-T cells in the spleen, and stimulates the release of beneficial cytokines. AVM0703 could be a non-toxic, effective preconditioning agent for patients receiving CAR-T therapy.
Safety and efficacy of PD-1 blockade-activated multiple antigen specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: A pooled analysis of two prospective trials.
Authors: Liang Lijun , Wen Yixuan , Hui Kaiyuan , Jiang Xiaodong 
Published: May 2019

e14014 Background: The cancer-cell-killing property of Multiple Antigen Specific Cellular Therapy (MASCT) may be enhanced by blocking PD-1 in vitro and reversing vascular endothelial growth factor (VEGF)/VEGF receptor 2-mediated immunosuppression with apatinib. We analyzed pooled data from our phase Ⅰ/Ⅱ trials to assess the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in patients with advanced solid tumors. Methods: Patients with selected types of advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The primary endpoint was the safety profile; antitumor response, progression-free survival (PFS), and overall survival (OS) were the secondary endpoints. Circulating regulatory T cells (Tregs) were quantified before and after aMASCT infusion. Results: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively; fever and chills were the most frequently observed AEs. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate was improved with aMASCT plus apatinib group compared with aMASCT group (34.2% and 18.8%, respectively); PFS was longer (median, 6.0 and 4.5 months, respectively, P < 0.05), but OS was not improved (median, 10.0 and 8.2 months, respectively, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent favorable prognostic factor of PFS and OS. Circulating Tregs decreased in both groups after one cycle of aMASCT treatment (P < 0.05). Conclusions: Treatment with aMASCT plus apatinib was safe and effective in advanced solid tumors. Apatinib plus aMASCT may be beneficial for patients with advanced solid tumors. Clinical trial information: NCT02844881; NCT02858232.
Phase Ia clinical trial of adoptively transferring peripheral blood-derived cytotoxic T lymphocytes targeting individual neo-antigens to treat patients with advanced solid tumor.
Authors: Li Bo , Zhang Xiaoshi , Liu Geng , Qiu Si , Liang Zhaoduan , Liu Mingming , Gao Yan , Xu Rui-hua 
Published: May 2019

e14025 Background: Adoptive transfer of tumor infiltrating lymphocytes (TILs) targeting neo-antigens mediates complete and durable regression of solid tumor. However, the limited availability of fresh tumor samples hinders the application of TILs treatment. Based on neo-antigen specific T cells occurring in the circulation, we carried out a phase Ia clinical trial that adoptive transfer of peripheral blood-derived cytotoxic T lymphocytes (CTLs) targeting individual neo-antigens administrated patients with advanced solid tumor. Methods: This phase Ia clinical trial (NCT02959905) is designed to test the safety and objective response of CTL targeting individual neo-antigens treatment. Patients underwent apheresis on day -25, 0, 25, 50, 85 and 110, then CD8+T cells were isolated from peripheral blood and co-cultured with autologous dendritic cells pulsed with neo-antigens, which generated the infused CTLs targeting neo-antigens. On day 0, 25, 50, 85, 110 and 135, patients received CTLs respectively, which were prepared prior to 25 days. Patients received evaluations on day 55 and 140, and were followed up from day 150 for 32 weeks. The survival of the infused CTLs was analyzed according to the sequence of CDR3 regions of the T-cell receptor. Results: Until October 16th, 2018, a total of 10 patients were enrolled, 9 patients were infused 0.35-4×108 of CTLs for 1-6 times in this trial, in which 8 cases were metastatic melanoma and 1 case was colorectal cancer. Of the 10 participants who were enrolled, 7 participants had been evaluated, in which 1 case was evaluated as partial response (PR), 1 case was evaluated as iPR (evaluated as PR based on iRECIST), 3 cases were evaluated as stable disease (SD), 2 case were evaluated as progression of disease (PD), the objective reaction rate was 28.57%, and the disease control rate was 71.4%. All the subjects had safe tolerance, and the highest grade of adverse events related to adoptive cell transfer was grade 2. Neo-antigen specific CTLs persistently occurred in peripheral blood of 2 participants with PR or iPR for 140 days. Conclusions: Adoptively transferring peripheral blood-derived cytotoxic T lymphocytes targeting individual neo-antigens to treat patients with advanced solid tumor was safe under our current dose and preliminarily efficient. Clinical trial information: NCT02959905.
Influence of agomelatine and trastuzumab on the HER2/neu(+), MT1 (+) and MT2 (+) chemo and immunoresistant breast cancer cells lines from the previously treated patients by targeted therapy with trastuzumab.
Authors: Tavartkiladze Alexandre , Revazishvili Pati , Gvajaia Ani 
Published: May 2019

e14056 Background: Agomelatine is a melatonin receptor agonist (MT1 and MT2) and a 5-HT2C receptor antagonist. Melatonin is a lipophilic compound that is capable of binding to cell surface receptors, cytosolic sites (calmodulin), and directly to nuclear DNA binding sites (nuclear receptors RZR/RORα). Its direct antioxidant, antimitotic, antiestrogenic, prodifferentiating and antimetastatic effects have been well characterized. Nitric oxide (NO) is an inorganic free radical gas synthesized from L-arginine by a family of isoenzymes called NO synthases. Two of these are constitutively expressed and a third is inducible by immunological stimules. The NO released by the constitutive enzymes acts as an important signaling molecule in the cardiovascular and nervous systems and NO released by the inducible NO synthase (iNOS) is generated for long periods, by cells of the immune system among others, and has been shown to be cytostatic/cytotoxic for tumor cells and a variety of microorganisms. Methods: We have studied oncostatic/citostatic influence by ATP-TCA method of agomelatine and agomelatine + trastuzumab solution on the cellular cultures Her2/neu (+), MT1 and MT2 receptor (+) mammary ductal adenocarcinoma (17 cases). Data of ATP-TCA test in healthy patients breast’s cellular cultures with only trastuzumab were used as control. In parallel, we have studied expression of enzyme universal nitric oxide synthase (u-NOS) in cellular cultures of mammary ductal adenocarcinoma all three cells lines using Western blot method. The findings were compared to the data of u-NOS expression in healthy patients breast’s breast cellular cultures. Results: The study demonstrated that influence of citostatic effect of only agomelatine by ATP-TCA method are increased by 32.5% and citostatic effect of agomelatine + trastuzumab by ATP-TCA method also are increased by 45% in compared to control. Expression of universal nitric oxide synthase (u-NOS) is increased in case of mammary ductal adenocarcinoma by 14.2% in case only agomelatine and by 26.7% in case agomelatin + trastuzumab compared to control. Conclusions: Results of this research describe the positive role of agonists melatonin receptors (agomelatin) in the treatment previously treated and after progressed breast cancer (while this mechanism in details is unknown for us) and increased expression of NOS indicate the possibly augmentation sensitivity the cells lines for the citostatics medicines.