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1
Cirlot, Victoria. "The pathos formulae and their survival (ENG/ESP)." Comparative Cinema 7, no. 12 (May 18, 2019): 7–21. http://dx.doi.org/10.31009/cc.2019.v7.i12.01.
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This article attempts to set out and understand what art historian Aby Warburg called Pathosformel (pathos formulae), a key concept in his studies, though he never expressly offered a definition, nor explained what his understanding of it was. The emergence of the concept is traced in his work, deciphering its meaning and its implications for the analysis of images, also from the most significant and recent bibliography on the subject. Finally, the Pathosformel concept is applied to a contemporary photographic image which enables us to better understand its effect in the way it is received by its viewers, thus establishing a dialogue between the iconographic tradition of the past and the present.
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Bruno, R., J. Lu, Y. Sun, and L. Claret. "Simulation of survival with first- and second-line non-small cell lung cancer (NSCLC) therapy using a public domain drug-disease modeling framework." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 8087. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.8087.
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8087 Background: Modeling and simulation approaches are advocated to support drug development decisions. In this study, we evaluated the ability of a drug-disease model recently developed by scientists at the FDA using data from pivotal studies in NSCLC (Wang et al. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008–4351b1–00-index.htm ) to simulate survival and tumor response for approved therapies in NSCLC. Methods: The modeling framework comprises a longitudinal tumor size model and a survival model relating change in tumor size at first visit (week 8) and patient characteristics (tumor size and ECOG performance status at baseline) to survival time. The tumor size and survival models were used to simulate change in tumor size at first visit and expected survival in the carboplatin/paclitaxel (CP) arm of the E4599 study (first-line NSCLC, N Eng J Med. 2006;355:2542–2550) and in the erlotinib arm in the BR.21 study (second-line NSCLC, N Eng J Med. 2005;353:123–132). The predictive distributions (95% prediction interval [PI]) of survival times were derived from multiple replicates (500) of 400 CP patients and 500 erlotinib patients with similar characteristics to patients in the original studies. Results: There was a high level of concordance between the results of the simulation and the observed results in the two arms, indicating that the modeling framework successfully predicted survival and tumor response. Expected median survival was 9.8 (95% PI, 8.2–11.8) months (vs 10.3 months observed) for the CP arm and 6.8 (95% PI, 5.3–8.9) months (vs 6.7 months observed) for the erlotinib arm. The median change in relative tumor size from baseline at week 8 predicted by the model was 12.1% for the CP arm and 9.5% for the erlotinib arm. Conclusions: The modeling framework can be used to perform simulations of survival of approved treatments. These results suggest that the model could be used to simulate survival for investigational treatments based on tumor shrinkage data observed in early clinical studies (e.g. phase II) to support end-of-phase II decisions and the design of phase III studies. [Table: see text]
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Wang, Xinyu, Jiaojiao Yang, and Xueren Gao. "Identification of key genes associated with lung adenocarcinoma by bioinformatics analysis." Science Progress 104, no. 1 (January 2021): 003685042199727. http://dx.doi.org/10.1177/0036850421997276.
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Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, comprising around 40% of all lung cancer. Until now, the pathogenesis of LUAD has not been fully elucidated. In the current study, we comprehensively analyzed the dysregulated genes in lung adenocarcinoma by mining public datasets. Two sets of gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database. The dysregulated genes were identified by using the GEO2R online tool, and analyzed by R packages, Cytoscape software, STRING, and GPEIA online tools. A total of 275 common dysregulated genes were identified in two independent datasets, including 54 common up-regulated and 221 common down-regulated genes in LUAD. Gene Ontology (GO) enrichment analysis showed that these dysregulated genes were significantly enriched in 258 biological processes (BPs), 27 cellular components (CCs), and 21 molecular functions (MFs). Furthermore, protein-protein interaction (PPI) network analysis showed that PECAM1, ENG, KLF4, CDH5, and VWF were key genes. Survival analysis indicated that the low expression of ENG was associated with poor overall survival (OS) of LUAD patients. The low expression of PECAM1 was associated with poor OS and recurrence-free survival of LUAD patients. The cox regression model developed based on age, tumor stage, ENG, PECAM1 could effectively predict 5-year survival of LUAD patients. This study revealed some key genes, BPs, CCs, and MFs involved in LUAD, which would provide new insights into understanding the pathogenesis of LUAD. In addition, ENG and PECAM1 might serve as promising prognostic markers in LUAD.
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Mu-Mosley, Hong, Lauren B. Ostermann, Ran Zhao, Challice L. Bonifant, Stephen Gottschalk, Mireya Paulina Velasquez, and Michael Andreeff. "Venetoclax Enhances Anti-Leukemia Activity of CD123-Specific BiTE-Secreting T-Cells in AML." Blood 136, Supplement 1 (November 5, 2020): 12–13. http://dx.doi.org/10.1182/blood-2020-139625.
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Background: CD123 is frequently expressed in hematologic malignancies including AML. CD123 has been a potential immunotherapeutic target in AML due to its association with leukemic stem cells that play an essential role in disease progression and relapse. Our previous study using T-cells secreting CD123/CD3-bispecific T-cell engagers (BiTEs) (CD123-ENG T-cells) has shown activity in preclinical studies, recognizing and killing acute myeloid leukemia (AML) blasts in vitro and in vivo. CD123-ENG T-cells secrete bispecific molecules that recognize CD3 (T-cells) and CD123 (AML blasts), and are able to direct transduced T-cells and recruit bystander T-cells to kill CD123-positive blasts. Venetoclax is a BCL-2 inhibitor that can restore functional apoptosis signaling in AML cells, and has been FDA approved for the treatment of AML patients in combination with hypomethylating agents. To improve the efficacy of CD123-ENG T-cells we explored efficacy in AML by combining targeted immunotherapy (CD123-ENG T cells) with targeted inhibition of anti-apoptotic BCL-2 (venetoclax) in vitro and in vivo models of AML. Methods : CD123-ENG T-cells were generated by retroviral transduction and in vitro expansion. Non-transduced (NT) T-cells served as control. In vitro, GFP+ MOLM-13 AML cells were pretreated with venetoclax (0, 10µM, and 20µM) for 24 hours prior to co-culture with CD123-ENG or NT T-cells at an effector/target ratio of 1:10. After 16 hours, MOLM-13 AML cells were analyzed by flow cytometry and quantitated using counting beads; cytotoxicity was calculated relative to untreated MOLM-13 control. The anti-AML activity of the combination was further evaluated in a MOLM-13-luciferase xenograft AML mouse model. Leukemia progression was assessed by bioluminescence imaging. The frequency of MOLM13 AML and human T cells in periphera blod (PB) was determined by flow cytometry. Results: In vitro, we demonstrated that pretreatment of Molm13 AML cells with venetoclax enhanced the cytolytic activity of CD123-ENG T-cells compared to NT- or no T-cell controls. Interestingly, venetoclax sensitized Molm13 to CD123-ENG T-cell killing in a dose-dependent manner (Fig.1; 50%/31% killing by CD123-ENG T-cells versus 27%/14% of killing by NT T cells post pretreatment with 10µM or 20µM ventoclax, p<0.001). In the Molm13 luciferase xenograft model, NSGS mice were randomized into 5 groups after AML engraftment was confirmed: 1) vehicle control, 2) Venetoclax (Ven) only, 3) CD123-ENG T-cells only, 4) Ven+CD123-ENG T-cells, 5) Ven+CD123-ENG T-cells/2-day-off Ven post T-cell infusion (Ven[2-day-off]+CD123-ENG). Venetoclax treatment (100 µg/kg daily via oral gavage) was started on day 4 post Molm13 injection, and on day 7, mice received one i.v. dose of CD123-ENG T-cells (5x106 cells/mouse). Venetoclax or CD123-ENG T-cell monotherapy reduced leukemia burden compared to the control group, and combinational treatments further inhibited leukemia progression as judged by BLI and circulating AML cells (%GFP+mCD45-/total live cells) by flow cytometry on day 15 post MOLM-13 injection: vehicle control: 19.6%; Ven+: 3.4%; CD123-ENG T-cells:1.2 %; Ven+CD123-ENG T-cells: 0.3%; Ven[2-day-off]+CD123-ENG T-cells (p<0.01 Ven+ or CD123-ENG T-cells versus control; p<0.001 Ven+CD123-ENG or Ven[2-day-off]+CD123-ENG T cells versus CD123-ENG T cells, n=5). The enhanced anti-AML activity of combining venetoclax and CD123-ENG T-cells translated into a significant survival benefit in comparison to single treatment alone (Fig. 2). However, while Ven+CD123-ENG and Ven[2-day-off]+CD123-ENG T-cell treated mice had a survival advantage, they had reduced circulating numbers of human CD3+ T cells on day 8 post T-cells infusion compared to mice that received CD123-ENG T-cells, indicative of potential adverse effect of venetoclax on T-cell survival in vivo. Conclusion: Our data support a concept of combining pro-apoptotic targeted and immune therapy using venetoclax and CD123-ENG T-cells in AML. While it has been reported that venetoclax does not impair T-cell functionality, more in-depth analysis of the effect of Bcl-2 inhibition on T-cell function and survival appears warranted, as it could diminish survival not only of AML blasts but also of immune cells. Disclosures Bonifant: Patents filed in the field of engineered cellular therapies: Patents & Royalties: Patents filed in the field of engineered cellular therapies. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy; TESSA Therapeutics: Other: research collaboration. Velasquez:Rally! Foundation: Membership on an entity's Board of Directors or advisory committees; St. Jude: Patents & Royalties. Andreeff:Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees.
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Mitry, E., A. Fields, H. Bleiberg, R. Labianca, G. Portier, D. Tu, V. Torri, et al. "Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer. A meta-analysis of two randomized trials." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3524. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3524.
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3524 Background: Adjuvant systemic chemotherapy (CT) administered after resection of colorectal cancer (CRC) metastases (M) may reduce the risk of recurrence and improved survival but its benefit has never been demonstrated. Two phase III trials (FFCD 9002 and EORTC/NCIC CTG/GIVIO (ENG) trials) with a very similar design showed a trend for improvement in survival after adjuvant CT but had to close prematurely because of slow accrual, lacking the statistical power to demonstrate any significant difference in survival. We report here a pooled analysis based on individual data from these trials. Methods: Patients were required to have a WHO performance status ≤2 and a histologically proven CRC with a complete (R0) surgical resection of the primary tumour and of ≤4 liver or lung metastases. They were randomized between chemotherapy (CT arm) [5FU 400 mg/m2 (FFCD) or 370 mg/m2 (ENG) IV q.d. x 5 days plus dl-leucovorin 200 mg/m2 (FFCD) or l-leucovorin 100 mg/m2 (ENG) IV q.d. x 5 days, 6 cycles at 28 days intervals] or surgery alone (S arm). Results: 129 pts were included in the ENG trial between 1994 and 1998, 173 in the FFCD trial between 1991 and 2001. 24 pts (ENG: 22, FFCD: 2) were excluded from analysis for missing post-baseline data: 278 pts were included in the present analysis (CT: 138, S: 140). Patients’ characteristics by treatment arm (% CT/S): males 58.0/63.6, age <70 years: 79.7/79.3, stage IV primary tumor: 29.0/47.1 (p=0.02), liver M 94.2/93.6, ≥2 M resected: 33.3/31.4. Conclusion: Adjuvant CT with a 5FU bolus based regimen tends to improve survival after complete resection of CRC metastases. The observed improvement in median PFS was almost statistically significant whereas the improvement in median OS (more than 1 year) was not (lack of statistical power?). This pooled analysis supports the use of adjuvant CT, with a more effective regimen, after potentially curative resection of CRC metastases. Updated results will be presented. (Supported by AROLD) [Table: see text] No significant financial relationships to disclose.
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Li, Shan, Yan Zhang, Aishe Gao, Yue Zhang, and Jiong Zhang. "Engelharquinone suppresses lipopolysaccharide-induced inflammation and proliferation of human liver cancer SMCC7721 cells via inhibition of NF-κB and MAPK signaling pathway." Tropical Journal of Pharmaceutical Research 19, no. 4 (May 14, 2020): 699–706. http://dx.doi.org/10.4314/tjpr.v19i4.4.
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Purpose: To investigate the anti-tumor effect of engelharquinone (Eng) on human liver cancer SMCC7721 cells.Methods: GFP-labeled SMCC7721 cells were used to establish a tumor-bearing mice model used for determination of the effect of different concentrations of Eng on tumor growth. The effect of Eng on SMCC7721 cell viability was determined with MTT assay and cell cycle analysis. The anti-inflammatory effect of Eng on lipopolysaccharide (LPS)-treated SMCC7721 cells were determined through assay of pro-inflammatory cytokines. Besides, the effect of Eng on the expressions of mitogen-activated protein kinase (MAPK), toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) was determined.Results: Cell proliferation was suppressed by different concentrations of Eng in LPS-treated SMCC7721 cells. Treatment of nude mice with Eng at high and low doses resulted in significant suppression of tumor growth and marked increases in percentage survival. Treatment of SMCC7721 cells with LPS upregulated the expressions of NF-κB, p65 and MAPK. However, pre-treatment of the cells with Eng suppressed the LPS-induced upregulation of the NF-κB, p65 and MAPK signaling pathways, and further downregulated the production of inflammatory cytokines in SMCC7721 cells.Conclusion: These results indicate that Eng inhibits LPS-induced inflammation and proliferation of human liver cancer SMCC7721 cells via a mechanism involving regulation of NF-κB and MAPK signaling pathways. Thus, Eng has potentials for the clinical management of inflammatory diseases and liver cancer.
Keywords: Inflammation, Engelharquinone, Lipopolysaccharide, SMCC7721 cells, Toll-like receptor 4
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Mitry, Emmanuel, Anthony L. A. Fields, Harry Bleiberg, Roberto Labianca, Guillaume Portier, Dongsheng Tu, Donato Nitti, et al. "Adjuvant Chemotherapy After Potentially Curative Resection of Metastases From Colorectal Cancer: A Pooled Analysis of Two Randomized Trials." Journal of Clinical Oncology 26, no. 30 (October 20, 2008): 4906–11. http://dx.doi.org/10.1200/jco.2008.17.3781.
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Purpose Adjuvant systemic chemotherapy administered after surgical resection of colorectal cancer metastases may reduce the risk of recurrence and improve survival, but its benefit has never been demonstrated. Two phase III trials (Fédération Francophone de Cancérologie Digestive [FFCD] Trial 9002 and the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia [ENG] trial) used a similar design and showed a trend favoring adjuvant chemotherapy, but both had to close prematurely because of slow accrual, thus lacking the statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from these two trials. Patients and Methods After complete resection of colorectal liver or lung metastases, patients were randomly assigned to chemotherapy (CT arm; fluorouracil [FU] 400 mg/m2 administered intravenously [IV] once daily plus dl-leucovorin 200 mg/m2 [FFCD] × 5 days or FU 370 mg/m2 plus l-leucovorin 100 mg/m2 IV × 5 days [ENG] for six cycles at 28-day intervals) or to surgery alone (S arm). Results A total of 278 patients (CT, n = 138; S, n = 140) were included in the pooled analysis. Median progression-free survival was 27.9 months in the CT arm as compared with 18.8 months in the S arm (hazard ratio = 1.32; 95% CI, 1.00 to 1.76; P = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI, 0.95 to 1.82; P = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis. Conclusion This pooled analysis shows a marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus–based regimen after complete resection of colorectal cancer metastases.
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Salmukhanbetova, Zhuldyz, A. A. Imanalinova, L. A. Dimeyeva, and N. E. Zverev. "State of Saxaul Plantations in Kazakhstan’s Section of the Aral Sea Region." Central Asian Journal of Water Research 7, no. 1 (June 30, 2020): 128–57. http://dx.doi.org/10.29258/cajwr/2020-r1.v7-1/128-157.eng.
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The article aims to assess the survival rate of saxaul plantations on the dry seabed of the Aral Sea (DSAS) and these close to the villages along the original seacoast. Protective black saxaul (Haloxylon ammodendron) plantations on the DSAS were established in the course of 2009-2019 with the grant support of the International Fund for Saving the Aral Sea (IFAS), Japan’s environmental funds, UNDP Kazakhstan, as well as under the Grass-Roots Program of the Embassy of Japan in Kazakhstan. During September 1-14, 2020, the target plantation plots at 24 sites adjacent to the villages of Aralkum and Karateren underwent examination, including forest surveying, projected species cover determination, as well as seed regeneration and survival rate assessment. The findings of 2020 revealed the varying condition of target saxaul plantations. Thus, the survival rate of saxaul inside forest plantations ranged between 0.12 and 78.0%. The actual number of saxaul trees varied from 1 (one) to 1,000 per ha on the DSAS and from 888 to 2,633 per ha in Aralkum village. The novelty of the obtained results is due to the fact that they clearly demonstrate that the survival rate and development of forest plantations, as well as saxaul seed self-renewal, above all, depend on the overall ecological conditions at specific sites. Saxaul demonstrated the best survival rate and growth at the sites with sandy loam and saline light loamy soils with sandy cover, and the worst – at the sites with crusty and takyr (dry-type playa) saline soils.
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Velasquez, Mireya Paulina, Kota Iwahori, David L. Torres, Sunitha Kakarla, Caroline Arber, Tania Rodriguez-Cruz, Claudia Gerken, Xiao-Tong Song, and Stephen Gottschalk. "T Cells Expressing Engager and Costimulatory Molecules for the Immunotherapy of CD19+ Malignancies." Blood 124, no. 21 (December 6, 2014): 2433. http://dx.doi.org/10.1182/blood.v124.21.2433.2433.
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Abstract Background: Immunotherapy with anti-CD19/anti-CD3 bispecific engager molecules has shown promise in clinical studies for CD19+ malignancies. However engager molecules have short half-lives and do not accumulate at tumor sites. In addition, co-delivery of other immunostimulatory molecules to enhance antitumor effects is difficult to achieve. We have recently shown that T cells can be genetically modified to secrete bispecific engager molecules (ENG-T cells). ENG-T cells are activated by tumor cells in an antigen-dependent manner, redirect bystander T cells to tumor cells, and have antitumor activity in preclinical models. We now wanted to explore if additional genetic modifications of ENG-T cells can enhance their effector function in vitro and in vivo. Since bispecific engager molecules do not provide co-stimulation, we focused on the provision of co-stimulatory signals by coexpressing CD80 and CD137L on the cell surface of ENG-T cells. Thus, the aim of the study was to compare the effector function of CD19-specific T-cell engagers (CD19-ENG T cells) and CD19-ENG T cells co-expressing CD80 and 41BBL (CD19-ENG/Costim T cells). Methods: CD19-ENG T cells were generated by transducing T cells with a retroviral vector encoding a CD19-specific T-cell engager and mOrange separated by an IRES (SFG.CD19-ENG-I-mO), and CD19-ENG/Costim T cells were generated by double transducing T cells with SFG.CD19-ENG-I-mO and a 2nd retroviral vector encoding 41BBL and CD80 separated by an IRES. The effector function of ENG T-cells was evaluated in vitro and in a leukemia xenograft model. Results: After single or double transduction 60-80% of T cells were positive for mOrange, and ~80% of CD19-ENG/Costim T cells were positive for CD80 and 30-40% positive for 41BBL. In coculture assays CD19-ENG and CD19-ENG/Costim T cells recognized CD19+ lymphoma (Daudi, Raji) and acute leukemia (BV173) cells as judged by IFN-g secretion in contrast to negative controls. While CD19+ target cells that express CD80 and CD86 (Daudi and Raji) induced robust IL2 production of CD19-ENG and CD19-ENG/Costim T cells, CD19-ENG/Costim T cells produced significantly higher levels of IL2 in comparison to CD19-ENG T cells after stimulation with CD19+/CD80-/CD86- negative target cells (BV173). Cytokine production was antigen dependent since ENG and ENG/Costim T cells specific for an irrelevant antigen (EphA2) did not produce cytokines. Specificity was confirmed in cytotoxicity assays. In transwell assays containing inserts preventing T-cell migration, only ENG T cells redirected bystander T cells in the bottom well to CD19+ tumor cells. To assess in vivo anti-tumor activity of CD19-ENG T cells and CD19-ENG/Costim T cells we used the BV173/NSG mouse xenograft model in which BV173 cells are genetically modified with firefly luciferase (ffLuc-BV173) to allow for serial bioluminescence imaging. While therapy with CD19-ENG T cells on day 7 post ffLuc-BV173 injection resulted in the cure of all mice, when therapy was delayed to day 14, only 1/10 mice was alive on day 80. In contrast therapy of mice on day 14 with CD19-ENG/Costim T cells resulted in long-term survival of 7/10 mice. Control T cells (EphA2-ENG T cells or EphA2-ENG/Costim T cells) had no antitumor effects. Conclusions: We have generated CD19-ENG T cells and CD19-ENG/Costim T cells with the ability to direct bystander T cells to CD19+ malignancies. Both ENG T-cell populations had potent antitumor activity in a preclinical ALL model, and provision of costimulation further enhanced antitumor effects. Genetically modifying T cells to express engager molecules and additional molecules to enhance their effector function may present a promising alternative to current CD19-targeted immunotherapies. Disclosures Velasquez: Celgene, Bluebird bio: Other. Iwahori:Celgene, Bluebird bio: Other. Kakarla:Celgene, Bluebird bio: Other. Song:Celgene, Bluebird bio: Other. Gottschalk:Celgene, Bluebird bio: Other.
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Mu-Mosley, Hong, Lauren B. Ostermann, Muharrem Muftuoglu, Wendy Schober, Nalini B. Patel, Abishek Vaidya, Challice L. Bonifant, Stephen Gottschalk, Mireya Paulina Velasquez, and Michael Andreeff. "Transgenic Expression of IL15 in CD123-Specific BiTE-Secreting Engager T-Cells Results in Improved Anti-AML Activity." Blood 134, Supplement_1 (November 13, 2019): 3917. http://dx.doi.org/10.1182/blood-2019-125928.
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Background: CD123 is frequently expressed on hematologic malignancies including 96-98% of AML. CD123 has been a potential immunotherapeutic target in AML due to its association with leukemic stem cells that play an essential role in disease progression and relapse. Our previous study using T-cells secreting CD123/CD3-bispecific T-cell engagers (BiTEs) (CD123-ENG T-cells) showed a promising approach anti-AML activity, however T-cell persistence was limited. Interleukin-15 (IL15) has emerged as a candidate immunomodulator as it enhances T-cell expansion and persistence, and induces long-lasting memory T-cells. To improve the efficacy and persistence of CD123-ENG T-cells we developed IL15 expressing CD123-ENG T-cells. Here, we report on the characterization and efficacy of IL15-secreting CD123-ENG T cells in vitro and in vivo models of adult AML. Methods/Results: A cDNA encoding IL15 was cloned into retroviral vectors encoding CD123-ENG or CD19-ENG (CD123-ENG.IL15; CD19-ENG.IL15). ENG T-cells were generated from human peripheral blood mononuclear cells (PBMCs) from normal donors or T-cells from AML patients by retroviral transduction and in vitro expansion. Non-transduced (NT) T-cells and T-cells expressing CD123 (CD123-ENG T-cells) served as controls. IL15 production of CD19-ENG.IL15 and CD123-ENG.IL15 T cells was confirmed by ELISA (144-159 pg/ml vs 38 and 46 pg/ml of NT and CD123-ENG T cells, p<0.01, n=6). Both CD123-ENG and CD123-ENG.IL15 T-cells recognized CD123+ AML cells as judged by IL2 and interferon γ (IFNγ) production (p<0.01, n=5). In contrast, NT and CD19-ENG.IL15 T-cells did not, confirming specificity. In addition, CD123-ENG.IL15 and CD123-ENG T-cells induced killing of only CD123-positive target cells as well as of primary adult patients' AML blasts in luciferase- or 7AAD-based cytotoxicity assays (p<0.001, n=10). CD123-ENG.IL15 T-cells showed greater cytolytic activity than CD123-ENG T-cells as determined by luciferase activity (p=0.0002, n=3). In a Molm13 AML xenograft model, CD123-ENG.IL15 and CD123-ENG T-cells exhibited potent anti-leukemic activity as judged by bioluminescence imaging. Moreover, CD123-ENG.IL15 T cells had enhanced anti-leukemic activity and greater persistence in BMs, spleens, and livers in comparison to CD123-ENG T cells, resulting in improved anti-AML activity (Figure 1, p<0.01 vs CD123-ENG T-cell group, n=12 per group) and extended survival (Figure 2, p=0.0097 vs CD123-ENG T-cell group). Finally, AML PDX models and ENG T-cells were generated from AML blasts and T-cells from 3 patients with active AML. Infusion of autologous ENG T-cells (1.5x106 cells/mouse, n=7) in AML PDX#6697688 mouse model revealed significant reduction of leukemia burden in the CD123-ENG.IL15 or CD123-ENG T-cells mouse groups but not in the mouse group with NT or CD19-ENG.IL15 T-cells or PBS (p=0.004, n=6-8). We are currently monitoring survival of these PDX models. Conclusion: We here demonstrated that transgenic expression of IL15 in CD123-ENG T-cells results in improved expansion and persistence, and anti-AML activity. These results warrant further exploration of IL15-modified CD123-targeted T-cells as immunotherapy for AML. Disclosures Bonifant: Patents filed in the field of engineered cellular therapies: Patents & Royalties: Patents filed in the field of engineered cellular therapies. Gottschalk:EMD Serono: Honoraria; Inmatics: Membership on an entity's Board of Directors or advisory committees; ASSISI fundation of Memphis: Research Funding; TESSA Therapeutics: Other: Research Collaboration; ViraCyte: Consultancy; NHLBI: Research Funding; America Lebanese Syrian Associated Charities: Research Funding; California Institute for Regenerative Medicine: Research Funding; Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; Sanofi: Honoraria; Tidal: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy. Velasquez:St. Jude: Patents & Royalties: Patent Applications in the Fields of Cell and Gene Therapy ; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Andreeff:Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AstaZeneca: Consultancy; Amgen: Consultancy; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; CPRIT: Research Funding; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding.
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Mu, Hong, Huaxian Ma, Abishek Vaidya, Challice L. Bonifant, Stephen Gottschalk, Mireya P. Velasquez, and Michael Andreeff. "IL15 Expressing CD123-Targeted Engager T-Cell Therapy for Adult Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 2724. http://dx.doi.org/10.1182/blood-2018-99-116811.
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Abstract Background: CD123 is a potential immunotherapeutic target in AML due to its overexpression on leukemic stem cells that play an essential role in disease progression and relapse. Our previous study using T cells secreting CD123/CD3 bispecific engager molecules (CD123-ENG T cells) showed promising results in pediatric AML. Interleukin-15 (IL15) has emerged as a candidate immunomodulator as it enhances the cytolytic activity of CD8+ T-cells and induces long-lasting memory T cells. To improve the efficacy and persistence of CD123-ENG T-cells we developed IL-15 expressing CD123-ENG T cells. Here, we report characterization and efficacy of IL15 secreting CD123-ENG T cells in adult AML. Methods/Results: A cDNA encoding IL15 was cloned into retroviral vectors encoding CD123-ENG or CD19-ENG and the CD20 suicide gene separated by 2A sequences (CD20.2A.CD123-ENG.2A.IL15; CD20.2A.CD19-ENG.2A.IL15). ENG T cells were generated from human peripheral blood mononuclear cells (PBMCs) from normal donors by retroviral transduction and expanded in vitro. Non-transduced (NT) T cells and T cells expressing CD20 and CD123 (CD20.CD123-ENG T cells) served as controls. The transduction efficiency was between 62.81-95% (average 72%, n=3) and phenotypic analysis by flow cytometry showed reproducible CD4+, CD8+, central memory (CCR7+CD45RA-), effector memory (CCR7-CD45RA-), and naïve (CCR7+CD45RA+) T cells populations compared to NT cells. IL15 production of CD20.CD19-ENG.IL15 and CD20.CD123-ENG.IL15 T cells was confirmed by ELISA (84-154 pg/ml vs 32 and 44 pg/ml of NT and CD20.CD123-ENG T cells, p<0.01, n=3). Both, CD20.CD123-ENG and CD20.CD123-ENG.IL15 T cells recognized CD123+ AML cell lines as determined by IL2 and interferon γ (IFNγ) production (p<0.01, n=3). In contrast, NT and CD20.CD19-ENG.IL15 T cells did not, confirming specificity. In addition, CD20.CD123-ENG and CD20.CD123-ENG.IL15 T cells induced killing of only CD123-positive target cells in luciferase-and 7AAD-based cytotoxicity assay. CD20.CD123-ENG.IL15 T cells showed greater cytolytic activity than CD20.CD123-ENG T cells (p=0.0002, n=3). Finally, we evaluated the cytolytic activity of ENG T cells against two CD123+ adult AML PDX samples with clinically high-risk features (PDX#440778 [Flt3-ITD and D835 double mutations], and PDX#LFS [p53 mutant Li Fraumeni syndrome]). Both, CD20.CD123-ENG and CD20.CD123-ENG.IL15 T cells significantly killed AML PDX cells compared to NT and CD20.CD19-ENG.IL15 T cells (p<0.001, n=3). Adoptive transfer of CD20.CD123-ENG or CD20.CD123-ENG.IL15 T cells into the AML PDX#440778 mouse model revealed a significant reduction of leukemia burden in mice that received CD20.CD123-ENG.IL15 T cells 5 days post infusion (p=0.004, n=7). We are currently monitoring AML burden, frequency of infused ENG T cells, body weight and survival of treated mice, and conducting experiments in the 2nd AML PDX model. These results will be presented at the meeting. Conclusion: We demonstrate here that genetically engineering CD123-ENG T cells that express IL15 enhances their effector function resulting in improved anti-AML activity in in vitro and in vivo. The results warrant further exploration of IL15 secreting CD123-specific ENG T-cell therapy in AML. Disclosures Andreeff: Celgene: Consultancy; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Jazz Pharma: Consultancy; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; Astra Zeneca: Research Funding; Oncolyze: Equity Ownership; Amgen: Consultancy, Research Funding.
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ESPINOZA, JIMMY. "ANGIOGENIC IMBALANCES IN THE PATHOGENESIS OF PREGNANCY COMPLICATIONS." Fetal and Maternal Medicine Review 25, no. 1 (February 2014): 42–58. http://dx.doi.org/10.1017/s0965539514000096.
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Endothelial cell proliferation and survival require continuous low levels of vascular endothelial growth factor (VEGF). The bioavailability of this angiogenic factor appears to be regulated by anti-angiogenic factors, including the soluble form of VEGF receptor 1 (sFlt-1) in the non-pregnant and pregnant states. During pregnancy a VEGF antagonist (sFlt-1) and other anti-angiogenic factors, including soluble endoglin (s-Eng), are produced by the human placenta and released into the maternal circulation; an excess of these anti-angiogenic factors can lead into angiogenic imbalances and pregnancy complications. This is important because regulation of VEGF action on angiogenic balances appears to be essential for a successful pregnancy.
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Vaidya, Abishek, Erin E. Doherty, Xiya Wu, Challice L. Bonifant, Stephen Gottschalk, and Mireya Paulina Velasquez. "Inducible MyD88 Signaling Enhances the Anti-AML Activity of BiTE-Secreting ENG T-Cells." Blood 134, Supplement_1 (November 13, 2019): 4441. http://dx.doi.org/10.1182/blood-2019-125395.
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Background: Pediatric and adult acute myeloid Leukemia (AML) is a disease with poor prognosis due to its high relapse rate and treatment related mortality. Adoptive immunotherapy has the potential to improve outcomes and CD123 present a promising immunotherapy target for AML. CD123-specific engager (ENG) T-cells are cells genetically modified to secrete bispecific T-cell engagers (BiTEs) that recognize CD3+ on T-cells and CD123+ on AML. We had previously shown that inclusion of an inducible MyD88/CD40 costimulatory molecule, which is activated by a chemical inducer of dimerization (CID), improved anti-tumor effect against CD123+ targets in vitro. We now wanted to determine, which component of the costimulatory molecule is critical for the improved effector function of CD123-ENG T cells and perform in vivo studies. Methods: We generated a panel of retroviral vectors encoding CD20 as a safety switch, CD123-ENG, and an inducible costimulatory molecule consisting of a myristoylation sequence, FKBP dimerizer domains and one of three signaling costimulatory domains (MyD88 (iM) ,CD40(iC) or MyD88/CD40(iMC)). A vector specific for CD19 (CD20.CD19-ENG.iMC) and non-transduced (NT) T-cells served as controls. We genetically modified T-cells using a retroviral transduction protocol and evaluated their effector function +/- CID. We assessed the effector function of transduced T-cells using flow cytometry, ELISA and luciferase based cytotoxicity assays. We evaluated antitumor activity and persistence in vivo in a xenograft AML model. Results: We successfully generated CD20.CD123-ENG.iM, CD20.CD123-ENG.iC and CD20.CD123-ENG.iMC T-cells. Transduction efficiency ranged from 45 to 70% (±5). The immunophenotype of CD123-ENG T-cells was predominandly CD8+ effector memory. CD20.CD123-ENG T-cells expressing inducible costimulatory molecules secreted higher levels of CD123-specific BiTEs, IL2 and IFNγ in comparison to CD20.CD123-ENG T-cells when cocultured with of MOLM-13 (CD123+) and CID (p<0.005, N=3). In the presence of CID, CD20.CD123-ENG.iM or CD20.CD123-ENG.iMC T-cells were able to sequentially kill AML cells for up to 5 stimulations, as opposed to CD20.CD123 ENG, CD20.CD123 ENG.iC and NT T-cells (n=3, E:T=1:1). We evaluated the in vivo anti-AML activity of ENG T cells using an AML cell line expressing firefly luciferase (MOLM-13.ffluc) to allow for serial bioluminescence imaging. MOLM-13.ffluc bearing mice were treated with one i.v. dose of effector cells (CD20.CD123-ENG, CD20.CD123-ENG iM, CD20.CD123-ENG.iC, CD20.CD123-ENG.iMC or NT T-cells ) and 2 doses/week of CID for 2 weeks (100mg/mice, i.p.). CD20.CD123-ENG.iMC and iM T-cells had potent anti-leukemic activity, resulting in a significant survival advantage in comparison to CD20.CD123-ENG T-cells group (P<0.005, n=10 animals per group). Conclusion: We demonstrate here that inducible MyD88/CD40 costimulation significantly enhances the anti-AML activity of CD123-ENG T cells in vitro and in xenograft models. Mechanistic studies revealed that MyD88 costimulation is critical for the observed benefit. Thus, genetically modifying T-cells to express BiTEs and an inducible MyD88 costimulatory molecule may present a promising cell product for the immunotherapy of CD123+ hematological malignancies. Disclosures Bonifant: Patents filed in the field of engineered cellular therapies: Patents & Royalties: Patents filed in the field of engineered cellular therapies. Gottschalk:TESSA Therapeutics: Other: Research Collaboration; Tidal: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Inmatics: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; EMD Serono: Honoraria; ViraCyte: Consultancy; NHLBI: Research Funding; ASSISI fundation of Memphis: Research Funding; California Institute for Regenerative Medicine: Research Funding; Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; America Lebanese Syrian Associated Charities: Research Funding. Velasquez:Rally! Foundation: Membership on an entity's Board of Directors or advisory committees; St. Jude: Patents & Royalties: Patent Applications in the Fields of Cell and Gene Therapy .
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Sharma, Atul, Surendra Pal Chaudhary, N. K. Shukla, B. K. Mohanti, S. V. S. Deo, Sujoy Pal, Vinod Raina, et al. "A randomized controlled trial comparing modified gemcitabine plus oxaliplatin (mGEMOX) to gemcitabine plus cisplatin in the management of unresectable gall bladder cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): TPS4162. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps4162.
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TPS4162 Background: In a recently conducted study we have shown that combination of gemcitabine and oxaliplatin is superior to 5 fluorouracil and leucoverine or best supportive care. (Sharma A, Dwary AD, Mohanti BK,et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer:A randomized controlled study. J Clin Oncol. 2010; 28: 4581-4586.) In another recent publication from UK, gemcitabine and cisplatin combination was found superior to gemcitabine alone in biliary tract cancers (J W Valle, HS Wasan, DD Palmer, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Eng J Med. 2010;362:1273-1281.).The current study is being planned to see whether the combination of gemcitabine and oxaliplatin is equivalent (equivalence study) to gemcitabine and cisplatin in these patients. Methods: Primary end point of the study is overall survival in subjects receiving mGEMOX or GemCis regimen. Secondary end points are: a) Comparison of progression free survival in 2 groups; b) Response rates in two groups; c) Identification of genes predictive of responses in a subset of patients; d) To evaluate role of PET CT in GBC patients predicting disease activity. Sample size was calculated taking median survival of 9.5 months in our previous study with mGEMOX and 11.7 months with GemCis. For this total of 216 patients are required (108 in each arm); to make for major protocol violation and lost to follow up additional 22 patients in each arm will be enrolled. Thus in total 260 patients (130) in each arm will be recruited. This will have alpha and beta values of 0.05 and 0.20 respectively. So far 103 patients have been enrolled and interim analysis is being planned. Treatment protocol: Cycles will be repeated every 3 weeks. Arm A- mGEMOX. Inj Oxaliplatin 80 mg/m22 hours infusion in Dextrose 5% Day 1 and 8. Inj Gemcitabine 900 mg/m2IV 30 minutes infusion day 1 and 8 maximum of 6 cycles. Arm B- GEMCIS. Inj Cisplatin 25 mg/m2PO Days 1 and 8. Inj Gemcitabine 1000 mg/m2IV 30 minutes infusion day1and 8 maximum of 8 cycles. Clinical trial information: CTRI/2010/091/001406.
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Cassidy, J., S. Clarke, E. Diaz-Rubio, W. Scheithauer, A. Figer, R. Wong, S. Koski, M. Lichinitser, T. Yang, and L. Saltz. "XELOX compared to FOLFOX4: Survival and response results from XELOX-1/ NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4030. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4030.
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4030 Background: In a phase II study in untreated MCRC patients, XELOX (capecitabine + oxaliplatin) appeared to have similar efficacy compared with previously published FOLFOX4 data [1]. We therefore started a phase III 2-arm open-label non-inferiority study comparing XELOX with FOLFOX4. In 2003 the addition of bevacizumab (Bev) to irinotecan/5-FU/LV was shown to improve progression-free survival (PFS) and overall survival [2]. We then amended our trial to a 2x2 partially blinded study to assess the addition of Bev. Methods: Original 2-arm study: XELOX (oxaliplatin 130 mg/m2 iv, capecitabine 1,000 mg/m2 bid oral d1- 14, q3w) vs. FOLFOX4 (oxaliplatin, 5-FU, leucovorin as described previously) [3]. In August 2003, amended to 2x2 partially blinded study: by adding Bev 7.5 mg/kg iv q3w or placebo (Pla) to XELOX and Bev 5 mg/kg iv q2w or Pla to FOLFOX4. Results: The original 2-arm study recruited 634 pts; after transition to 2x2, an additional 1400 patients were recruited. We previously reported non-inferiority in terms of PFS of XELOX vs. FOLFOX4 for the whole study population [4]. With 404 events, the overall survival data from the original 2-arm study are mature and show a HR for XELOX vs. FOLFOX4 of 0.93 (97.5% CI, 0.74–1.16). The response rates by investigator and independent review for the whole study population are shown in the table . Conclusions: XELOX is non-inferior to FOLFOX4. Overall survival data for the whole 2034 patient study population will be presented at the meeting. *no response assessment. 1. Cassidy J et al. J Clin Oncol 2004;22:2084–91. 2. Hurwitz H et al. N Eng J Med 2004;350:2335–42 3. De Gramont A et al. J Clin Oncol 2000;18:2938–47. 4. Cassidy J et al. Ann Oncol 2006;17(Suppl. 9):LBA3. [Table: see text] [Table: see text]
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Bonifant, Challice L., David Torres, Mireya Paulina Velasquez, Kota Iwahori, Caroline Arber, Xiao-Tong Song, Michele S. Redell, and Stephen Gottschalk. "CD123-Engager T Cells As a Novel Immunotherapeutic for AML." Blood 124, no. 21 (December 6, 2014): 3762. http://dx.doi.org/10.1182/blood.v124.21.3762.3762.
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Abstract Background: The outcome for patients with high risk acute myeloid leukemia (AML) remains poor. Thus new targeted therapies are needed and immunotherapies have the potential to fulfill this need. Adoptive transfer of tumor-specific T cells is one promising approach; however infused T cells do not redirect the large reservoir of resident T cells to tumors. To overcome this limitation we have recently developed a new approach to render T cells specific for tumor cells, which relies on genetically modifying T cells with a secretable, bispecific T cell engager (ENG-T cells). Secretion of bispecific protein should activate infused cells as well as bystander T cells against tumor. Consistent and prolonged synthesis of engagers by T cells should be superior to the intermittent, direct infusion of the recombinant bispecific antibody, not only because these recombinant proteins have short half-lives but also because they do not accumulate at tumor sites. The goal of this project was to generate T cells secreting IL3Rα (CD123) and CD3 bispecific T cell engagers (CD123-ENG T cells) and to evaluate their effector function in vitro and in vivo. Methods: CD123-ENG T cells were generated by transducing T cells with a retroviral vector encoding a CD123-specific T cell engager consisting of an scFv recognizing CD123 linked to an scFv recognizing CD3. The retroviral vector was also fashioned to include an mOrange gene downstream of an IRES element. The effector function of CD123-ENG T cells was evaluated in vitro and in a xenograft model. Results: Transduction of CD3/CD28-activated T cells resulted in mOrange expression in transduced T cells (median transduction efficiency 78%, range 49-92%) The presence of CD123-ENG molecules on the cell surface of both transduced and non-transduced T cells was demonstrated by FACS analysis using an F(ab) antibody that recognizes the CD123 scFv. Coculture of CD123+ AML cells (MV-4-11, MOLM-1, KG1a) and K562 cells genetically modified to express CD123 (K562-CD123) with engager T cells resulted in robust T-cell activation as judged by IFNγ and IL2 secretion. In contrast CD123-negative cells (K562) did not activate T cells. Likewise, control engager T cells (targeting an irrelevant antigen) were not activated when cultured with CD123+ cells. Antigen-dependent recognition was confirmed with cytotoxicity assays, in which engager T cells specifically killed CD123+ AML cells at an effector:target ratios ranging from 40:1-5:1 (p<0.05) Since CD123 is expressed at low levels on normal hematopoietic progenitor cells (HPCs), we evaluated the ability of CD123-ENG T cells to recognize normal HPCs in colony formation assays. Only at high CD123-ENG to HPC ratios did we observe a decline in colony formation, indicating that CD123+ AML cells can be targeted while preserving normal HPCs. In vivo anti-tumor activity was assessed using a modified KG1a AML cell line expressing firefly luciferase (KG1a.ffluc) to allow for serial bioluminescence imaging. NSG (NOD-SCID, IL2γR deficient) mice were sublethally irradiated 24 hours prior to leukemia infusion and were then treated with two intravenous doses of CD123-ENG T cells or control T cells on days 7 and 14. CD123-ENG T cells had potent anti-leukemia activity resulting in a significant survival advantage of treated animals (p=0.002; n=5 CD123-ENG, n=5 Control-ENG, n=10 control animals). Conclusions: We have generated CD123-ENG T cells with the potential to direct bystander T cells to CD123+ AML in a tumor antigen-specific manner. These CD123-ENG T cells have potent anti-AML activity in vivo, presenting a promising addition to currently available AML therapies. Disclosures Bonifant: Celgene, Bluebird bio: Baylor College of Medicine has a Research Collaboration with Celgene and Bluebirdbio to develop gene-modified T-cell Therapies. MPV, KI, XT, and SG have patent applications in the field of T-cell and gene-modified T-cell Therapy for cancer Other. Torres:Celgene, Bluebird bio: Baylor College of Medicine has a Research Collaboration with Celgene and Bluebirdbio to develop gene-modified T-cell Therapies. MPV, KI, XT, and SG have patent applications in the field of T-cell and gene-modified T-cell Therapy for cancer Other. Velasquez:Celgene, Bluebird bio: Baylor College of Medicine has a Research Collaboration with Celgene and Bluebirdbio to develop gene-modified T-cell Therapies. MPV, KI, XT, and SG have patent applications in the field of T-cell and gene-modified T-cell Therapy for cancer Other. Iwahori:Celgene, Bluebird bio: Baylor College of Medicine has a Research Collaboration with Celgene and Bluebirdbio to develop gene-modified T-cell Therapies. MPV, KI, XT, and SG have patent applications in the field of T-cell and gene-modified T-cell Therapy for cancer Other. Arber:Celgene, Bluebird bio: Baylor College of Medicine has a Research Collaboration with Celgene and Bluebirdbio to develop gene-modified T-cell Therapies. MPV, KI, XT, and SG have patent applications in the field of T-cell and gene-modified T-cell Therapy for cancer Other. Song:Celgene, Bluebird bio: Baylor College of Medicine has a Research Collaboration with Celgene and Bluebirdbio to develop gene-modified T-cell Therapies. MPV, KI, XT, and SG have patent applications in the field of T-cell and gene-modified T-cell Therapy for cancer Other. Gottschalk:Celgene, Bluebird bio: Baylor College of Medicine has a Research Collaboration with Celgene and Bluebirdbio to develop gene-modified T-cell Therapies. MPV, KI, XT, and SG have patent applications in the field of T-cell and gene-modified T-cell Therapy for cancer Other.
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Feldman, D. R., J. Sheinfeld, D. F. Bajorin, P. Fischer, S. Turkula, N. Ishill, S. Patil, M. Bains, G. J. Bosl, and R. J. Motzer. "Paclitaxel (T) plus ifosfamide (I) followed by high-dose carboplatin (C) and etoposide (E) with autologous stem cell support for patients (pts) with previously treated germ cell tumors (GCT): TI-CE results and prognostic factor analysis in 107 pts." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 5027. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.5027.
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5027 Background: Pts with incomplete response (IR) to first-line chemotherapy or relapsed primary mediastinal non-seminomatous GCT (NSGCT) have <10% 3-year (yr) survival with conventional-dose salvage regimens (Cancer. 67:1305). The doses, schedule, and safety of TI-CE in this population were previously reported (J Clin Oncol. 25: 85). Efficacy and prognostic factor analysis are now presented. Methods: Phase I/II trial of TI-CE conducted in GCT pts with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, IR to first-line therapy, or relapse/IR to ifosfamide/cisplatin-based conventional-dose salvage). Univariate and multivariate analyses of prognostic factors were performed. Einhorn (N Eng J Med. 357:340) and Beyer (J Clin Oncol. 14: 263) prognostic models were also assessed. Results: Of 107 pts, primary site was testis in 72, mediastinum (all NSGCT) in 21, and other in 14. 81 had 1 prior line of therapy and 26 had ≥2. 79 were platinum-refractory and 7 had late relapses. A complete response was achieved in 54 (50%) and partial response with negative markers in 8 (8%). 5-yr disease-free survival (DFS) was 47% and overall survival 52% with a median follow-up of 61 months (m). No relapses occurred after 2 yrs. 5/21 (24%) primary mediastinal NSGCT and 2/7 late relapses are continuously disease-free. On multivariate analysis, primary mediastinal site (p = 0.0002), ≥2 lines of prior therapy (p = 0.0005), baseline HCG >1000 (p = 0.01), and lung metastases (p = 0.02) significantly predicted adverse DFS. By Beyer model, 79% were intermediate and 21% poor risk (0 good risk). DFS was better for intermediate than poor risk pts (p < 0.002), with 2-year rates of 54% and 23%, respectively. By Einhorn model, 15% pts were good, 38% intermediate, and 47% poor risk; good/intermediate risk pts had superior DFS compared to poor risk pts (p < 0.05) with DFS at 2 yrs of 69% vs. 44%. Conclusions: TI-CE is effective salvage therapy for GCT pts with poor prognostic features. Mediastinal primary site and ≥2 lines of prior therapy were most predictive of adverse DFS. Beyer & Einhorn models can assist in predicting outcome. No significant financial relationships to disclose.
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Pilot, Thomas, Aurélie Fratti, Chloé Thinselin, Anaïs Perrichet, Lucie Demontoux, Emeric Limagne, Valentin Derangère, et al. "Heat shock and HSP70 regulate 5-FU-mediated caspase-1 activation in myeloid-derived suppressor cells and tumor growth in mice." Journal for ImmunoTherapy of Cancer 8, no. 1 (May 2020): e000478. http://dx.doi.org/10.1136/jitc-2019-000478.
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BackgroundWe have previously shown that 5-fluorouracil (5-FU) selectively kills myeloid-derived suppressor cells (MDSCs) and activates NLRP3 (NOD-leucine rich repeat and pyrin containing protein 3) inflammasome. NLRP3 activation leads to caspase-1 activation and production of IL-1β, which in turn favors secondary tumor growth. We decided to explore the effects of either a heat shock (HS) or the deficiency in heat shock protein (HSP) 70, previously shown to respectively inhibit or increase NLRP3 inflammasome activation in macrophages.MethodsCaspase-1 activation was detected in vitro in MSC-2 cells by western blot and in vivo or ex vivo in tumor and/or splenic MDSCs by flow cytometry. The effects of HS, HSP70 deficiency and anakinra (an IL-1 inhibitor) on tumor growth and mice survival were studied in C57BL/6 WT orHsp70−/−tumor-bearing mice. Finally, Th17 polarization was evaluated by qPCR (Il17a, Rorc) and angiogenic markers by qPCR (Pecam1, Eng) and immunohistochemistry (ERG).ResultsHS inhibits 5-FU-mediated caspase-1 activation in vitro and in vivo without affecting its cytotoxicity on MDSCs. Moreover, it enhances the antitumor effect of 5-FU treatment and favors mice survival. Interestingly, it is associated to a decreased Th17 and angiogenesis markers in tumors. IL-1β injection is able to bypass HS+5-FU antitumor effects. In contrast, inHsp70−/−MDSCs, 5-FU-mediated caspase-1 activation is increased in vivo and in vitro without effect on 5-FU cytotoxicity. InHsp70−/−mice, the antitumor effect of 5-FU was impeded, with an increased Th17 and angiogenesis markers in tumors. Finally, the effects of 5-FU on tumor growth can be restored by inhibiting IL-1β, using anakinra.ConclusionThis study provides evidence on the role of HSP70 in tuning 5-FU antitumor effect and suggests that HS can be used to improve 5-FU anticancer effect.
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MENDES, ALEXANDRE C., and NASSER FARD. "ACCELERATED FAILURE TIME MODELS COMPARISON TO THE PROPORTIONAL HAZARD MODEL FOR TIME-DEPENDENT COVARIATES WITH RECURRING EVENTS." International Journal of Reliability, Quality and Safety Engineering 21, no. 02 (April 2014): 1450010. http://dx.doi.org/10.1142/s0218539314500107.
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This paper presents an analysis of parametric survival models and compares their applications to time to event data used to validate the approximation for repeated events applying the Proportional Hazard Model (PHM) proposed in Mendes and Fard [Int. J. Reliab., Qual. Saf. Eng.19(6) (2012) 1240004.1–1240004.18]. The subjects studied do not show degrading failures, allowing the comparison between accelerated failure time models with the PHM. Results showed the applicability of the Weibull model and the versatility of the PHM not only to match the results of the parametric model, but also to allow the implementation of time-dependent covariates, resulting in superior model fit and more insightful interpretation for the covariate hazards. The paper contribution is to present the PHM as a simpler, more robust model to determine the acceleration factor for reliability testing when compared to the formidable task of fitting a parametric model for the distribution of failure. The Kaplan–Meier method may provide misleading guidance for covariate significance when time-dependent covariates are applied; however, relevant graphical screening is supplied. Notwithstanding, the PHM provides additional options to treat the repeated observations applying robust covariance correction for lack of heterogeneity in the fixed effects model or adopting the stratified model that absorbs the error using the stratification concept.
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Hanna, Karen B. "A Call for Healing: Transphobia, Homophobia, and Historical Trauma in Filipina/o/x American Activist Organizations." Hypatia 32, no. 3 (2017): 696–714. http://dx.doi.org/10.1111/hypa.12342.
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I argue that for those who migrate to other countries for economic survival and political asylum, historical trauma wounds across geographical space. Using the work of David Eng and Nadine Naber on queer and feminist diasporas, I contend that homogeneous discourses of Filipino nationalism simplify and erase transphobia, homophobia, and heterosexism, giving rise to intergenerational conflict and the passing‐on of trauma among activists in the United States. Focusing on Filipina/o/x American activist organizations, I center intergenerational conflict among leaders, highlighting transphobic and homophobic struggles that commonly arise in cisgender women majority spaces. I contextualize these struggles, linking them to traumas inherited through legacies of colonialism, feudalism, imperialism, hetero‐patriarchy, capitalism, and white supremacy. I inquire: how does historical and personal trauma merge and shape activist relationships and conflict, and what are activists doing to disrupt and work through historical trauma? I advocate for a decolonizing approach for “acting out” and “working through” trauma and healing collectively. By exploring conflict in organizations shaped by dominant Filipino nationalist ideologies, I resist romantic notions of the diaspora. Revealing the ways that dominant Filipino nationalism perpetuates a simultaneous erasure of nonnormative histories and bodies and epistemological and interpersonal violence among activists, I reject homogeneous conceptions of nationalism and open up possibilities for decolonial organizing praxis.
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Klepin, Heidi D., Brandy Pitcher, Karla V. Ballman, Gretchen Genevieve Kimmick, Alice B. Kornblith, Harvey Jay Cohen, Arti Hurria, Eric P. Winer, Clifford Hudis, and Hyman Bernard Muss. "Comorbidity, chemotherapy toxicity, and outcomes among older women receiving adjuvant chemotherapy for breast cancer (BC)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 6015. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.6015.
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6015 Background: Comorbidity increases with age. We evaluated how comorbidity was associated with toxicity and clinical outcomes among older women with BC who received adjuvant chemotherapy. Methods: Cancer and Leukemia Group B (CALGB 49907) enrolled 633 women ≥65 years with early stage BC and randomized them to standard adjuvant chemotherapy (AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). 329 women on the Quality of Life companion study completed a pre-treatment health survey (Older American Resources and Services Questionnaire, physical health subscale). The survey evaluates 14 conditions and the degree to which each interferes with daily activities (rated from 1 “not at all” to 3 “a great deal”). Comorbidity was analyzed as follows: 1) total number 2) comorbidity burden score (summed conditions multiplied by interference rating); and 3) individual diseases. Primary outcomes were: 1) grade 3-5 toxicity (incident and cumulative); 2) time to relapse (TTR), and 3) overall survival (OS). Contingency table methods were used to evaluate the association between comorbidity and toxicity. Cox proportional hazards models were used to evaluate TTR and survival outcomes. Results: Among 329 women [median age 71 years (range 65-89), 86% white, 98% ECOG performance score 0-1, 75% stage 1-2] the median number of comorbidities was 2 (0-10), median comorbidity burden score was 3 (0-25), and most common conditions were arthritis (58%) and hypertension (54%). Few patients had diabetes (17%), heart disease (16%), and pulmonary disease (9%). No comorbidity measure was associated with toxicity or TTR. With a median follow-up of 5.4 years, increasing comorbidity was associated with shorter OS. For each additional comorbid condition the hazard of death increased by 18% (HR 1.18 [95% CI; 1.06-1.33]) after adjusting for age, tumor size, treatment, node status and receptor status. Comorbidity burden score was similarly associated with OS (HR 1.08 [95% CI; 1.03-1.14]), while no specific condition was independently associated. Conclusions: Among older women with good functional status, comorbidity was not associated with toxicity or BC relapse. However, comorbidity burden was associated with shorter OS.
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Posadas, Edwin Melencio, Hiram Alberto Gay, Stephanie L. Pugh, Todd Matthew Morgan, James B. Yu, Stanislav Lechpammer, and Felix Y. Feng. "RTOG 3506 (STEEL): A study of salvage radiotherapy with or without enzalutamide in recurrent prostate cancer following surgery." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS5601. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps5601.
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TPS5601 Background: Salvage radiotherapy (SRT) is an important intervention for men with prostate cancer (PCa) who experience biochemical recurrence (BCR) after radical prostatectomy (RP). These patients are in need of cure or else they will develop metastatic disease. NRG/RTOG 9601 (WU Shipley, N Eng J Med 2017) identified a survival benefit from the addition of androgen receptor (AR) inhibition to SRT that was most prominent in men with high-risk features. Enzalutamide (Enza) is a non-steroidal anti-androgen that improves survival in castration-resistant and -sensitive PCa. We hypothesized that enhanced AR suppression with Enza would augment the benefit of SRT + androgen deprivation therapy (ADT) in BCR with high risk features. Methods: RTOG 3506 (STEEL, NCT03809000) is a randomized phase II study of SRT in BCR after RP with a serum PSA ≥ 0.2 ng/mL active in the USA and Canada. Patients are stratified by number of high-risk features including Gleason score (8-10), locoregional node involvement at RP, seminal vesicle invasion, persistently elevated PSA after RP, and PSA > 0.7 ng/mL. All patients receive SRT with 2 years of ADT. The experimental arm also receives Enza 160 mg daily for 2 years. Patients are followed by PSA every 3 months. SRT can be highly individualized per treating physician beyond the mandatory treatment of the prostatic fossa. Treatment of the pelvis and/or para-aortic nodes, as well as sequential or concurrent boosts to a prostatic fossa mass and/or suspicious lymph nodes, are allowed options. This permits individualization of radiotherapy guided by CT, MRI, PET, and/or biopsy findings. The primary goal of this study is to determine whether SRT enhanced ADT with Enza, will improve progression-free survival (PFS) compared to SRT with standard ADT. PFS defined as the first occurrence of biochemical failure, clinical failure, or initiation of new anticancer treatment. STEEL is designed to demonstrate a 35% reduction in the risk of progression at 5 years. An accrual goal of 242 patients will provide 80% power with a one-sided alpha = 0.10. Secondary endpoints include disease control rates, acute and late physician- and patient-reported toxicity, and quality of life. This study was activated in February 2019. Site recruitment and activation are underway. Conclusions: There is an unmet and urgent need for individualized strategies to optimize systemic therapy used with SRT for men with BCR. Outcomes from this study will further clarify the approach to systemic therapy for SRT in high-risk BCR patients. Support: Provided by Pfizer. Clinical trial information: NCT03809000 .
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Bai, Zhu, Coffman, Vlad, Schwartz, Elishaev, Drapkin, and Buckanovich. "CD105 Is Expressed in Ovarian Cancer Precursor Lesions and Is Required for Metastasis to the Ovary." Cancers 11, no. 11 (November 2, 2019): 1710. http://dx.doi.org/10.3390/cancers11111710.
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: Most high‐grade serous ovarian cancers (HGSCs) initiate from the fallopian tube epithelium and then metastasize to the ovary and throughout the abdomen. Genomic analyses suggest that most HGSCs seed the ovary prior to abdominal dissemination. Similarly, animal models support a critical role for the ovary in driving abdominal dissemination. Thus, HGSC cell recruitment to the ovary appears to be a critical component of HGSC cell metastasis. We sought to identify factors driving HGSC recruitment to the ovary. We identified CD105 (endoglin, or ENG, a TGF‐ receptor family member) as a mediator of HGSC cell ovarian recruitment. We found that CD105 was expressed on both serous tubal intraepithelial carcinoma (STIC) cells (STICs‐HGSC precursors in the fallopian tube epithelium) and HGSC cells. Using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), we showed that high CD105 expression by HGSC cells correlated with a metastatic signature. Furthermore, intravenous injection of CD105(+) HGSC tumor cells, but not CD105(−), resulted in ovarian-specific metastasis and abdominal dissemination of disease. CD105 knockdown or blockade with a clinically relevant CD105-neutralizing mAb (TRC105), inhibited HGSC metastasis, reduced ascites, and impeded growth of abdominal tumor nodules, thereby improving overall survival in animal models of ovarian cancer. CD105 knockdown was associated with a reduction in TGF-signaling. Together, our data support CD105 as a critical mediator of ovarian cancer spread to the ovary and implicate it as a potential therapeutic target.
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Dumontet, C. M., J. C. Reed, M. Krajewska, I. Treilleux, J. R. Mackey, M. Martin, C. Vogel, M. Rupin, E. Brunel, and J. Hugh. "BCIRG 001 molecular analysis: Identification of prognostic factors in patients (pts) receiving adjuvant therapy for node- positive (N+) breast cancer (BC)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 525. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.525.
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525 Background: BCIRG 001 (1,491 pts) demonstrated significant superiority of docetaxel/doxorubicin/cyclophosphamide (TAC) over fluorouracil/doxorubicin/cyclophosphamide (FAC) given as adjuvant therapy for N+ operable BC in terms of disease-free survival (DFS) and overall survival (OS) (Martin et al, N Eng J Med, 2005). This ancillary study was aimed to identify tumor-associated factors related to DFS and OS. Methods: Formalin-fixed primary tumors from pts in BCIRG 001 were analysed by immunohistochemistry. Protocol- specified assessment of histological grade (GR), tumor size (TS), estrogen (ER) and progesterone receptors (PR), lymph node status (LN), HER2, MUC1, Mib, p53, Bcl-2, Bax, Bcl-X, Bag-1, tubulin β isotypes II, III and IV, tau protein and detyrosinated a tubulin was performed. Parameters were scored as the percentage of positive cells and analysed as lower or greater than median values. The samples were randomly split into training (2/3) and validation (1/3) sets. Associations between selected parameters and DFS or OS were tested through univariate analyses using the Kaplan Meier method (log-rank test) on the training set. A backward stepwise Cox regression analysis was performed to identify the final model of prognostic factors on the training set. Multivariate analyses were applied to the validation set. Results: 1,350 samples were split into a training (n=906) and a validation (n=444) set. In univariate GR, TS, LN, ER and PR, Mib, tau protein and HER2 were correlated with DFS in both sets. In multivariate ER, PR, TS, LN, Mib (all p<0.01) and tau (p=0.043) were significantly associated with DFS in the training set. In univariate GR, TS, LN, ER and PR, Mib, MUC1, Bcl-2, tubulin III and IV and tau were correlated with OS in both sets, with a trend for p53. In multivariate ER, TS, LN, Mib, p53 (all p<0.01) and PR (p=0.028) were independently correlated with OS in the training set. Conclusions: These data suggest that tau and p53 are independent markers of DFS and OS, respectively, while Mib is correlated with both DFS and OS in pts receiving these forms of adjuvant chemotherapy for N+ BC. Complementary analyses will be presented. No significant financial relationships to disclose.
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Quillen, Karen, Daniel G. Wright, David C. Seldin, Martha Skinner, Karim Malek, Kathleen T. Finn, and Vaishali Sanchorawala. "Feasibility of Second Autologous Peripheral Blood Stem Cell (PBSC) Collection Followed by a Second Cycle of High Dose Melphalan (HDM) in Patients Relapsing after an Initial Course of HDM for the Treatment of AL Amyloidosis." Blood 104, no. 11 (November 16, 2004): 5226. http://dx.doi.org/10.1182/blood.v104.11.5226.5226.
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Abstract High-dose melphalan and autologous stem cell transplant (HDM/SCT) can induce complete hematologic responses (CR), defined as disappearance of the underlying monoclonal gammopathy from serum and urine by immunofixation electrophoresis, and of the clonal plasma cell dyscrasia by bone marrow immunohistochemistry, and extend survival in patients with AL amyloidosis. HDM/SCT results in a CR in 40% of patients, and leads to clinical improvements in organ function in >70% of those who achieve a CR. However, hematologic and clinical relapses occur in ~5% of patients who initially achieve a CR. Tandem cycles of HDM/SCT, for which sufficient PBSC collected during the initial cycle are saved for the second cycle of treatment, have been shown to achieve a higher ultimate CR rate of >60%. Among patients who do not achieve a CR following a single cycle of HDM/SCT, 30% nonetheless experience improvements in organ function. However, in this latter group, clinical improvements are not durable. Because there is limited experience with second PBSC collections in patients who have undergone prior myeloablative chemotherapy and because of the potential benefits of repeated cycles of HDM/SCT, we designed a study to explore the feasibility, and efficacy, of a second PBSC mobilization and collection followed by a second cycle of HDM/SCT in patients who relapse after initially responding to a first cycle of HDM/SCT. Results: Five patients, median age 52 (range 43–59), M:F 1.5:1.0, who had achieved hematologic and clinical responses after an initial cycle of HDM/SCT, were treated with a second cycle of HDM/SCT when a hematologic and/or clinical relapse occurred after a median time interval of 39 mo.(range 16–63 mo.). After G-CSF mobilization a mean of 5.2 million CD34 cells/kg was collected in a median of 3 days (range 2–4 days). The yields were not significantly different from those of the first cycle of HDM/SCT. Engraftment occurred at a median of 10 days for neutrophils, and 13 days for platelets (two days without platelet transfusion support); this engraftment timing is similar to that following initial transplants (11 and 12 days respectively). There was no treatment-related mortality, but toxicity was moderate; all patients experienced grade III/IV non-hematologic toxicities. For the 3 patients evaluable at 1 year, no hematologic CR was observed; these patients expired at 38, 37 and 15 mo. Two patients are alive at 5 and 11 mo. post transplant. Conclusion: Patients with AL amyloidosis who experience a hematologic or clinical relapse after responding to an initial course of HDM/SCT can successfully be re-mobilized, and undergo a second cycle of HDM/SCT, with prompt hematopoietic recovery. Clinical benefits of second cycles of HDM/SCT in this setting have yet to be determined. Patient data prior Rx CD34 yield #1/#2 (10E6 cells/kg) HDM #1/#2 (melphalan dose mg/m2) Days to WBC eng #1/#2 Days to PLT eng #1/#2 CR#1/CR#2 Survival (mo.) #1/#2 refer to first/second transplant 1 none 8.0/4.1 200/200 9/11 9/12 yes/no 38 2 M/P x2 8.8/7.7 200/200 11/10 12/34 no/no 37 3 VAD x3 7.9/4.6 200/140 11/10 17/13 no/no 15 4 M/P x2 5.9/6.2 200/200 9/9 12/24 no/? alive at 11 mo. 5 none 4.3/3.4 200/140 11/10 11/11 no/? alive at 5 mo.
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Davids, Matthew S., Anuja Chatterjee, Arliene Ravelo, Sheila Shapouri, Beenish S. Manzoor, Kavita Sail, Gijs Van de Wetering, and Michael Hallek. "Cost-Effectiveness of a 12-Month Fixed Duration of Venetoclax in Combination with Obinutuzumab in First-Line Chronic Lymphocytic Leukemia in the United States." Blood 134, Supplement_1 (November 13, 2019): 4741. http://dx.doi.org/10.1182/blood-2019-123706.
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INTRODUCTION: Historically chemoimmunotherapy has been the standard of care in the treatment of first-line (1L) chronic lymphocytic leukemia (CLL). More recently several effective oral targeted agents, such as ibrutinib-based regimens, have provided effective chemotherapy-free treatment options in CLL. However, these therapies require continuous treatment until disease progression. Recently FDA approved (May 2019), venetoclax plus obinutuzumab (VenG) is a highly effective chemotherapy-free therapy that is used over a 12-month fixed treatment duration (Fischer et al, N Eng J Med 2019). The objective of this study is to estimate the cost-effectiveness of VenG in the treatment of 1L CLL from a US-payer perspective. METHODS: A three-state partitioned-survival model was used to extrapolate progression-free survival and overall survival over a lifetime horizon (20 years). Cost-effectiveness was estimated by comparing a 12-month fixed duration of VenG versus (vs.) chlorambucil-obinutuzumab (ClbG) based on the CLL14 clinical trial (NCT02242942). Other comparators included treat-to-progression therapies, such as ibrutinib (IBR), IBR + rituximab (IR), and IBR + G (IG), and a 6-month course of bendamustine + rituximab (BR). Using a network meta-analysis, the relative efficacy of VenG and ClbG vs. other selected comparators was estimated. Health state utilities and adverse event (AE) disutilities were derived from a systematic literature review and published health-technology assessment reports. To generate total quality-adjusted life years (QALYs), these health state utilities and AE disutilities were applied to the relative efficacy data. US-specific costs included those for CLL treatment, routine care and monitoring, AEs, disease progression (including subsequent treatment), and end-of-life care. Cost-effectiveness results are presented in terms of incremental cost per QALY. A new treatment that is both lower in total cost and more efficacious (in QALYs) vs. identified comparator treatments is described as being "dominant". Uncertainty in the model was tested through deterministic, probabilistic, and scenario analyses. RESULTS: The benefits in the cost-effectiveness model (CEM) were measured in terms of total discounted QALYs which were 6.47 for VenG, 6.12 for ClbG, 6.11 for IBR, 6.08 for IR, 6.41 for IG, and 5.98 for BR. The total discounted costs incurred by VenG and ClbG were $322,613 and $847,571, respectively. IBR-based treat-to-progression regimens incurred total discounted costs of $1,485,368 for IBR, $1,447,010 for IR, and $1,988,706 for IG. BR incurred total discounted costs of $808,756. Compared to these regimens, VenG is less costly (incremental cost ranges between: -$1,666,093 to -$486,143). The incremental discounted QALYs of VenG was: 0.36 vs. GC, 0.49 vs. BR, 0.37 vs. IBR, 0.06 vs. IG, and 0.39 vs. IR. Thus, VenG with a 12-month fixed duration, has lower total costs and is more efficacious ("dominant") over all comparators in the CEM. The probabilistic sensitivity analysis results were in line with the deterministic results. Sensitivity analysis indicated the post-progression survival utility was the most influential parameter on the model outcomes. As the CLL14 trial data matures, these cost-effectiveness estimates may change and additional scenarios for post-progression survival for VenG will be explored. Updated results will be presented. CONCLUSIONS: VenG is projected to be cost-effective vs. ClbG within accepted US cost-effectiveness thresholds. Compared with BR and IBR-based treat-to-progression regimens (IBR, IR, and IG), a 12-month fixed-duration treatment option with VenG seems cost saving and more efficacious based on the CEM. Taken together, VenG appears to be a cost-effective standard therapy for 1L CLL patients. Disclosures Davids: AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Ravelo:Genentech: Employment, Equity Ownership. Shapouri:Roche: Equity Ownership; Genentech, Inc.: Employment. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Sail:AbbVie: Employment, Other: and may hold stock or stock options. Van de Wetering:AbbVie: Consultancy. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau.
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Jantrakajorn, S., and J. Wongtavatchai. "Egg surface decontamination with bronopol increases larval survival of Nile tilapia, Oreochromis niloticus." Czech Journal of Animal Science 60, No. 10 (July 15, 2016): 436–42. http://dx.doi.org/10.17221/8523-cjas.
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Recher, Christian, Bertrand Coiffier, Corinne Haioun, Christophe Fermé, Thierry Jo Molina, Olivier Casasnovas, Christian Gisselbrecht, et al. "A Prospective Randomized Study Comparing Dose Intensive Immunochemotherapy with R-ACVBP vs Standard R-CHOP In Younger Patients with Diffuse Large B-Cell Lymphoma (DLBCL). Groupe d'Etude Des Lymphomes De l'Adulte (GELA) Study LNH03-2B." Blood 116, no. 21 (November 19, 2010): 109. http://dx.doi.org/10.1182/blood.v116.21.109.109.
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Abstract Abstract 109 Two previous studies conducted in the prerituximab era have demonstrated the superiority of the intensive chemotherapy regimen ACVBP over standard CHOP in DLBCL (Tilly H et al. Blood 2003;102:4284; Reyes F et al. N Eng J Med 2005;352:1197). In order to investigate the role of intensive chemotherapy associated with rituximab, the GELA initiated in 2003 a multicenter, phase III open-label, randomized trial comparing efficacy and safety of R-ACVBP vs R-CHOP in younger DLBCL patients with an age-adjusted IPI (aaIPI) of 1. Patients and methods: Patients between 18 and 59y with DLBCL and aaIPI=1 were eligible. R-ACVBP consisted of 4 induction courses given every 2 weeks: rituximab (375 mg/m2) on d1, doxorubicin (75 mg/m2) on d1, cyclophosphamide (1200 mg/m2) on d1, vindesine (2mg/m2) on d1 and 5, bleomycin (10 mg) on d 1 and 5, prednisone (60 mg/m2) from d1 to d5, and intrathecal methotrexate (IT) (15 mg) on d2, G-CSF from d6 to d13. Patients then received a sequential consolidation therapy: 2 courses of methotrexate (3 g/m2) plus leucovorin rescue, 4 courses of rituximab (375 mg/m2), etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on d1, and 2 courses of cytosine-arabinoside (100 mg/m2, SC) for 4 days, each consolidation course being administered at a 14-day interval. Standard R-CHOP was delivered every 3 weeks for 8 cycles along with IT methotrexate at d1 of the first 4 cycles. The primary objective was to evaluate the efficacy of R-ACVBP compared to R-CHOP as measured by the event-free survival (EFS). Secondary endpoints were response rate, progression free survival (PFS), disease-free survival (DFS) for complete responders, overall survival, neuro-meningeal relapse rate and toxicities. Results are presented on an intend-to-treat basis. Response to treatment was evaluated according to 1999 Cheson criteria. Results: From December 2003 to December 2008, 380 patients were randomized in 73 hematology/oncology departments of the GELA. One patient withdrew his consent the day of randomization and 379 received at least one day of study treatment, 196 with R-ACVBP and 183 with R-CHOP. Median age was 47y (18-59). Patient characteristics were well-balanced in terms of demography and baseline disease status: male gender, 59%; stage III-IV, 55%; elevated LDH, 44%; mass>10 cm, 22%; B symptoms, 28%; number of extra-nodal sites >1, 26%; bone marrow involvement, 13%. Overall response rate was 90.3% in the R-ACVBP group and 88.5% in the R-CHOP group (p=0.57). Complete remission rate (CR+CRu), was 82.7% for R-ACVBP and 80.3% for R-CHOP (p=0.56). At the time of this final analysis, in June 2010, the median follow-up was 44 months. The 3-year EFS was 80.9% (95% confidence interval (CI) 74.5–85.9) in the R-ACVBP group and 66.7% (CI 59.2–73.2) in the R-CHOP group (p=0.0035, hazard ratio (HR) 0.559). Significant differences were also observed for PFS (86.8% at 3 years (CI 80.9–91.0) vs 73.4% (CI 66.1–79.3), p=0.0015, HR 0.482), DFS (91.3% at 3 years (CI 85.1–95.0) vs 80.3% (CI 72.8–85.9), p=0.0019, HR 0.393) and overall survival (92.2% at 3 years (CI 87.1–95.3) vs 83.8% (CI 77.2–88.6), p=0.0071, HR 0.439). Patients in the R-ACVBP group experienced more frequently a serious adverse event (42% vs 15% in the R-CHOP group). Grade 3–4 hematological toxicity was more frequent in the R-ACVBP group, with a higher proportion of patients receiving red cell (51% vs 7% for R-CHOP) or platelet transfusions (13% vs 1%) and/or experiencing febrile neutropenia (39% vs 9%). There were 3 deaths (1.5%) attributed to toxicity of study treatment in the R-ACVBP group and 2 (1.1%) in the R-CHOP group. Conclusions: Compared to standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves EFS, PFS, DFS and overall survival with increased but manageable hematological toxicity in younger patients with DLBCL. Disclosures: Coiffier: Roche: Honoraria, Research Funding; Genentech: Research Funding. Gisselbrecht:Roche: Research Funding. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Tilly:Amgen: Honoraria.
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Agosta, F., E. G. Spinelli, N. Riva, A. Fontana, S. Basaia, E. Canu, V. Castelnovo, et al. "Survival prediction models in motor neuron disease." European Journal of Neurology 26, no. 9 (April 20, 2019): 1143–52. http://dx.doi.org/10.1111/ene.13957.
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Ataharul Islam, M., and Karan P. Singh. "Multistate survival models for partially censored data." Environmetrics 3, no. 2 (1992): 223–34. http://dx.doi.org/10.1002/env.3170030207.
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Borges, Moacir Alves, Harethusa Junia Botós, Ricardo Funes Bastos, Moacir Fernandes Godoy, and Nely Silvia Aragão de Marchi. "Emergency EEG: study of survival." Arquivos de Neuro-Psiquiatria 68, no. 2 (April 2010): 174–78. http://dx.doi.org/10.1590/s0004-282x2010000200004.
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OBJECTIVE: To determine the survival rate according to the main findings of emergency electroencephalography (EEGs) of patients treated in a tertiary hospital. METHOD: In this prospective study, the findings of consecutive emergency EEGs performed on inpatients in Hospital de Base in São José do Rio Preto, Brazil were correlated with survival utilizing Kaplan-Meyer survival curves. RESULTS: A total of 681 patients with an average age of 42 years old (1 day to 96 years) were evaluated, of which 406 were male. The main reasons for EEGs were epileptic seizures (221 cases), hepatic encephalopathy [116 cases of which 85 (73.3%) were men, p-value=0.001], status epilepticus (104 cases) and impaired consciousness (78 cases). The underlying disease was confirmed in 578 (84.3%) cases with 119 (17.5%) having liver disease [91 (76.0%) were men, p-value=0.001], 105 (15.4%) suffering strokes, 67 (9.9%) having metabolic disorders, 51 (7.5%) central nervous system infections and 49 (7.2%) epilepsy. In the three months following EEG, a survival rate of 75% was found in patients with normal, discreet slow activity or intermittent rhythmic delta activity EEGs, of 50% for those with continuous delta activity and generalized epileptiform discharges, and of 25% for those with burst-suppression, diffuse depression, and in alpha/theta-pattern coma. Death was pronounced immediately in patients with isoelectric EEGs. CONCLUSION: The main findings of EEGs, differentiated different survival rates and are thus a good prognostic tool for patients examined in emergencies.
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McCormick, Frank. "Survival pathways meet their end." Nature 428, no. 6980 (March 2004): 267–69. http://dx.doi.org/10.1038/428267a.
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Brennan, B., L. Siu, B. Dhesy-Thind, C. Cripps, A. Gandhi, M. Abt, K. Smith, K. Rittweger, S. Hussain, and S. Choudhury. "Pharmacokinetic (PK) interactions between capecitabine (X), oxaliplatin (O) and bevacizumab (A) when used in combination for first-line treatment of metastatic colorectal cancer (MCRC)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2554. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2554.
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2554 Background: X + O in combination (XELOX) has similar efficacy to FOLFOX-4 in untreated MCRC patients (pts) [1]. The addition of A to irinotecan/5-FU/LV improves progression-free survival (PFS) and overall survival [2], and the potential improvement of adding A to XELOX in MCRC is currently being investigated. Here we present the first PK evaluation of the effects of X on O, O on X, X+A on O, and O+A on X in a multicenter open-label study of pts with untreated MCRC. Methods: Pts received treatment for up to 16 cycles with blood samples for PK analysis taken during cycles 1–3. Treatment: cycle 1: X 1000 mg/m2 orally on morning of d1, O 130 mg/m2 i.v. infusion d2, X 1000 mg/m2 bid orally d5–14, rest d15–21; cycle 2: O 130 mg/m2 i.v. infusion d1 + X 1000 mg/m2 bid orally d1–14, rest d15–21; cycle 3 (XOA): A 7.5 mg/kg i.v. infusion d1 + O 130 mg/m2 i.v. infusion d1 + X 1000 mg/m2 bid orally d1–14, q3w. Treatment with the XOA regimen continued for a further 13 cycles. Safety was evaluated throughout. Results: 36 pts were enrolled; 26 pts completed cycles 1–3 and were evaluable for PK analysis; all pts were evaluable for safety. Baseline characteristics were: M/F 42%/58%; median age 60 years (range 22–74). The primary parameter for PK analysis of X, AUC0-8 of 5’-DFUR, was slightly lower in cycle 2 d1 (XO) and cycle 3 d1 (XOA) vs. cycle 1 d1 (X) (10% and 13% lower, respectively, with CV 27–33%); a decrease in the Cmax of 5’-DFUR was also observed (26% and 36% lower, respectively, with CV 48–54%). However these differences were not considered clinically important. The primary parameter for PK analysis of O, AUC0-8 of free platinum, was very similar among cycle 2 d1 (XO), cycle 3 d1(XOA), and cycle 1 d2 (O), with geometric mean ratios very close to 1. Treatment with X, O and A in combination was generally well tolerated. Conclusions: No large differences in exposure of X or its metabolites, free platinum or total platinum occur when X, O and A are administered in combination. This provides further support for the development of the above dosing regimen in MCRC. References: 1. Cassidy J et al. J Clin Oncol 2004;22:2084–91. 2. Hurwitz H et al. N Eng J Med 2004;350:2335–42. No significant financial relationships to disclose.
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Pavlovsky, Santiago, Claudia Corrado, Miguel A. Pavlovsky, Virginia Prates, Lucia Zoppegno, Mario Giunta, Ider Cerutti, Elsa Palomino, Graciela Avila, and Francisco Lastiri. "Prospective Evaluation of the International Prognostic Score (IPS) in All Stages of Hodgkin’s Lymphoma Treated with ABVD Plus Involved-Field Radiotherapy (IFRT)." Blood 112, no. 11 (November 16, 2008): 1454. http://dx.doi.org/10.1182/blood.v112.11.1454.1454.
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Abstract Background: The prognostic score for Hodgkin’s lymphoma was defined as the number of adverse prognostic factors presented at diagnosis. Seven factors had similar independent prognostic effects. This model was validated retrospectively in advanced disease using different therapeutic approaches (D Hasenclever et al N Eng J Med339:1506–14, 1998). Methods: From December 1996 up to October 2005, the GATLA completed a risk-adapted therapy with ABVD and IFRT. Patients with stages I-IIIA without bulky disease, who achieved complete remission (CR) after three cycles of ABVD, favorable group (FG) received only IFRT 25 GY to areas of >2 cm at diagnosis. Patients with FG not in CR after three cycles of ABVD, slow responders (FGSR), all stages IIIB-IV and all bulky disease, unfavorable group (UG) received six cycles of ABVD and IFRT 30 GY at remaining areas after 3 cycles of ABVD. A total of 584 patients, completed therapy; of them 513 were evaluated with the IPS. Patients were divided in three groups according to the number of adverse prognostic factors 0–1, 2–3, and ≥ 4. Results: The number of patients, complete remission (CR) rate, event-free survival (EFS) and overall survival (OSV) at 5 years according to prognostic factors in the 513 patients were as follows: IPS # patients (%) # CR (%) % EFS % OSV 0–1 224 (44) 217 (97) 86 95 2–3 241 (47) 213 (88) 73 90 ≥4 48 (9) 40 (83) 65 72 P< 0.020 0.001 0.001 A total of 200 patients with FG had a 5 years EFS and OSV of 89% and 98% while 53 patients with FGSR had an EFS and OSV of 66% and 88% respectively (P<0.001). The IPS in FG and FGSR was 0–1 of 61% versus 49%, 2–3 of 38.5% versus 43% and ≥4 of 0.5% versus 8% respectively (p=0.003). In UG with an EFS and OSV of 72% and 87%, the incidence of IPS 0–1 was 29%, 2–3 was 54% and ≥4 was 17%. Conclusion: The IPS is an excellent tool to predict outcome. Patients with stages I-IIIA without bulky tumour who did not achieve CR after three cycles of ABVD (FGSR) had poorer IPS than FG. In spite of receiving six cycles of ABVD, those with FGSR instead of three of those with FG had statistically a poor outcome. In the PET-TC era, patients who remain positive after three cycles of ABVD will need an intensified therapy with the purpose of improving the bad prognosis.
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Agarwal, S., R. M. Ahmed, M. D'Mello, D. Foxe, C. Kaizik, M. C. Kiernan, G. M. Halliday, O. Piguet, and J. R. Hodges. "Predictors of survival and progression in behavioural variant frontotemporal dementia." European Journal of Neurology 26, no. 5 (January 29, 2019): 774–79. http://dx.doi.org/10.1111/ene.13887.
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Gupta, Ramesh C., and Richard A. Albanese. "Survival analyses of radiated animals incorporating competing risks and covariates." Environmetrics 5, no. 4 (December 1994): 365–79. http://dx.doi.org/10.1002/env.3170050402.
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Peng, Zhen-Wei, Yao-Jun Zhang, Min-Shan Chen, Li Xu, Hui-Hong Liang, Xiao-Jun Lin, Rong-Ping Guo, Ya-Qi Zhang, and Wan Yee Lau. "Radiofrequency Ablation With or Without Transcatheter Arterial Chemoembolization in the Treatment of Hepatocellular Carcinoma: A Prospective Randomized Trial." Journal of Clinical Oncology 31, no. 4 (February 1, 2013): 426–32. http://dx.doi.org/10.1200/jco.2012.42.9936.
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Purpose To compare radiofrequency ablation (RFA) with or without transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC). Patients and Methods A randomized controlled trial was conducted on 189 patients with HCC less than 7 cm at a single tertiary referral center between October 2006 and June 2009. Patients were randomly asssigned to receive TACE combined with RFA (TACE-RFA; n = 94) or RFA alone (n = 95). The primary end point was overall survival. The secondary end point was recurrence-free survival, and the tertiary end point was adverse effects. Results At a follow-up of 7 to 62 months, 34 patients in the TACE-RFA group and 48 patients in the RFA group had died. Thirty-three patients and 52 patients had developed recurrence in the TACE-RFA group and RFA group, respectively. The 1-, 3-, and 4-year overall survivals for the TACE-RFA group and the RFA group were 92.6%, 66.6%, and 61.8% and 85.3%, 59%, and 45.0%, respectively. The corresponding recurrence-free survivals were 79.4%, 60.6%, and 54.8% and 66.7%, 44.2%, and 38.9%, respectively. Patients in the TACE-RFA group had better overall survival and recurrence-free survival than patients in the RFA group (hazard ratio, 0.525; 95% CI, 0.335 to 0.822; P = .002; hazard ratio, 0.575; 95% CI, 0.374 to 0.897; P = .009, respectively). There were no treatment-related deaths. On logistic regression analyses, treatment allocation, tumor size, and tumor number were significant prognostic factors for overall survival, whereas treatment allocation and tumor number were significant prognostic factors for recurrence-free survival. Conclusion TACE-RFA was superior to RFA alone in improving survival for patients with HCC less than 7 cm.
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Bouchagier, Pavlos. "Survival of Root-Knot nematodes and their egg-parasitic fungus Pochonia chlamydosporia (Goddard) on weed roots." SDRP Journal of Plant Science 2, no. 2 (2018): 1–8. http://dx.doi.org/10.25177/jps.2.2.4.
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Ponséro, A., and P. Joly. "Clutch size, egg survival and migration distance in the agile frog (Rana dalmatina) in a floodplain." Fundamental and Applied Limnology 142, no. 3 (July 7, 1998): 343–52. http://dx.doi.org/10.1127/archiv-hydrobiol/142/1998/343.
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Lunney, June R., and Ann O'Mara. "The end of the survival journey." Seminars in Oncology Nursing 17, no. 4 (November 2001): 274–78. http://dx.doi.org/10.1053/sonu.2001.27924.
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Smith, Stephen J., and J. Ellen Marsden. "Factors Affecting Sea Lamprey Egg Survival." North American Journal of Fisheries Management 29, no. 4 (August 2009): 859–68. http://dx.doi.org/10.1577/m07-196.1.
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Knight, K. "Thermocline essential for squid egg survival." Journal of Experimental Biology 218, no. 23 (December 1, 2015): 3712. http://dx.doi.org/10.1242/jeb.134601.
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Peng, Ding, Zhi-song He, Xue-song Li, Qi Tang, Lei Zhang, Kai-wei Yang, Xiao-teng Yu, Cui-jian Zhang, and Li-qun Zhou. "A Novel Predictor of Survival with Renal Cell Carcinoma After Nephrectomy." Journal of Endourology 31, no. 4 (April 2017): 397–404. http://dx.doi.org/10.1089/end.2016.0786.
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Maul, A. "A discrete time logistic regression model for analyzing censored survival data." Environmetrics 5, no. 2 (June 1994): 145–57. http://dx.doi.org/10.1002/env.3170050205.
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Kortazar‐Zubizarreta, Izaro, Rebeca Ruiz‐Onandi, Arrate Pereda, Yerai Vado, Gonzalo González‐Chinchon, Hasier Eraña, Guiomar Perez de Nanclares, and Joaquín Castilla. "Sporadic Creutzfeldt–Jakob disease with extremely long 14‐year survival period." European Journal of Neurology 28, no. 9 (June 26, 2021): 2901–6. http://dx.doi.org/10.1111/ene.14946.
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Umeda, A., M. Sawada, N. Watanabe, M. Suzuki, T. Naganawa, K. Ashihara, M. Kurumizawa, et al. "AB0619 PROGNOSTIC FACTORS OF PATIENTS WITH ANTI-MDA5 ANTIBODY-POSITIVE DERMATOMYOSITIS COMPLICATED WITH INTERSTITIAL PNEUMONIA -A JAPANESE SINGLE CENTER STUDY-." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1605.1–1605. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2708.
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Background:Anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) is frequently associated with rapidly progressive interstitial pneumonia (RPIP), whose prognosis is assumed to be poor[1]. Although outcome of DM-RPIP has been reported to be improved by early immunosuppressive therapy, we still experience the cases with severe outcome. Only several reports mentioned the prognostic factors and they have not been fully elucidated.Objectives:To identify the predictors of prognosis in patients with anti-MDA5 Ab-positive DM associated with interstitial pneumonia (DM-IP).Methods:Anti-MDA5 Ab-positive DM-IP patients admitted to Fujita Health University Hospital between January 2010 and October 2019 were consecutively included and stratified into 2 groups, the survived and the deceased groups. DM was diagnosed according to the criteria proposed by Bohan and Peter[2]. Clinically amyopathic DM was diagnosed according to the criteria proposed by Sontheimer [3]. Diagnosis of IP was based on findings of high resolution CT scan (HRCT). The definition of RPIP was rapid exacerbation of hypoxemia or HRCT findings in a period of days to one month after the onset. Clinical features and prognosis of the patients were collected retrospectively and compared between groups. Candidates of predictors are extracted by the univariable analysis using Fisher’s exact test for dichotic parameters and Wilcoxon signed-rank test for continuous parameters and multivariable analysis using logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was examined to obtain the cut-off level. Survival was examined using Kaplan-Meier method and Log-rank test.Results:Twenty-one patients were involved. Eight were deceased and 13 were survived. The deceased group had a higher ratio of male (75% versus 25%, p= 0.018). All deceased cases were with RPIP and 67 % in the survived cases. Levels of serum ferritin (4490 versus 646 ng/mL, p = 0.0026), CRP (2.1 versus 0.9 mg/dL, p = 0.0490), CK (1150 versus 290 U/L, p = 0.017), AST (194 versus 108 U/L, p = 0.025) and LDH (674 versus 368 U/L, p = 0.011) were higher in the deceased group. Interestingly, skin ulcers were tended to be more frequent (12.5% versus 87.5%, p= 0.0587), and anti-SS-A antibody was also more frequently detected (14.3% versus 85.7%, p=0.0072) in the survived group. Using ROC analysis cut-off values were 963 ng/mL for serum ferritin level (sensitivity 100%, specificity 83%), 0.7 mg/dL for CRP (sensitivity 75%, specificity 69%), 308 U/L for CK (sensitivity 88%, specificity 77%), 62 U/L for ALT (sensitivity 100%, specificity 62%), and 454 U/L for LDH (sensitivity 88%, specificity 77%). Patients were divided into two groups based on these cut-offs or based on dichotic parameters and survival was examined between 2 groups. Except CRP and anti-SS-A antibody, survival was significantly worse in parameter-positive or higher groups. Interestingly, anti-SS-A antibody-positive group had better outcome compared with those without.Conclusion:In our analysis, novel candidates such as serum CK, AST, and LDH levels were newly extracted and parameters previously reported was also included and those were also associated with the clinical outcome. In addition, anti-SS-A antibody was identified as a novel protective factor associated with a good outcome.References:[1]Nakashima R, Hosono Y, Mimori T. Clinical significance and new detection system of autoantibodies in myositis with interstitial lung disease. Lupus 2016;25:925-33.[2]Bohan A, Peter JB. Polymyositis and dermatomyositis. N Eng J Med 1975;292:344-7.[3]Sontheimer RD. Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects. Dermatol Clin 2000;20:387-408.Disclosure of Interests:None declared
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Policar, T., P. Podhorec, V. Stejskal, P. Kozák, V. Švinger, and S. M. Hadi Alavi. "Growth and survival rates, puberty and fecundity in captive common barbel (Barbus barbus L.) under controlled conditions." Czech Journal of Animal Science 56, No. 10 (October 17, 2011): 433–42. http://dx.doi.org/10.17221/3236-cjas.
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Growth and survival rates (specific growth rate – SGR; survival rate – S) of Barbus barbus L. were recorded in captivity during three years from the larval period (final body weight – W = 0.2 ± 0.03 g; SGR = 13.6 ± 1.1%/day and cumulative survival – S = 76.0 ± 2.5%) to the first reproductive season (W = 62.55 ± 13.5 g; SGR = 0.89 ± 0.05%/day; S = 59.3 ± 1.5%). Final body size and SGR were compared between both sexes. Females reached the significantly higher growth rate (SGR = 0.84 ± 0.01%/day) compared to males (SGR = 0.77 ± 0.01%/day). Early puberty was observed in 17 and 32 months old males and females, respectively. Multi-stripping activity was found out in both sexes during the first reproductive season. In total, 20%, 25.8%, 30.3%, 14.6% and 9% of females were stripped once, twice and three, four and five times, respectively. But all males produced sperm during the entire reproductive season. The highest and the lowest egg production was recorded in the middle (April) and at the beginning (March) of the reproductive season (2155 ± 925 vs. 1279 ± 298 eggs per stripping). The highest and the lowest sperm production was observed at the beginning (March) and at the end (May) of the reproductive season (7.9 ± 0.08 × 10<sup>9</sup> vs. 1.9 ± 0.06 × 10<sup>9</sup> per stripping).
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Best, A. F., J. E. Hilbert, L. Wood, W. B. Martens, N. Nikolenko, C. Marini‐Bettolo, H. Lochmüller, et al. "Survival patterns and cancer determinants in families with myotonic dystrophy type 1." European Journal of Neurology 26, no. 1 (September 16, 2018): 58–65. http://dx.doi.org/10.1111/ene.13763.
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Park, Jin Sun, Soo Jin Yun, Jung Kuk Lee, So Young Park, and Sang Ouk Chin. "Descriptive Epidemiology and Survival Analysis of Prolactinomas and Cushing’s Disease in Korea." Endocrinology and Metabolism 36, no. 3 (June 30, 2021): 688–96. http://dx.doi.org/10.3803/enm.2021.1000.
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Van Driesche, R. G., T. S. Bellows, D. N. Ferro, R. Hazzard, and A. Maher. "ESTIMATING STAGE SURVIVAL FROM RECRUITMENT AND DENSITY DATA, WITH REFERENCE TO EGG MORTALITY IN THE COLORADO POTATO BEETLE, LEPTINOTARSA DECEMLINEATA (SAY) (COLEOPTERA: CHRYSOMELDIAE)." Canadian Entomologist 121, no. 3 (March 1989): 291–300. http://dx.doi.org/10.4039/ent121291-3.
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AbstractStage survival is typically calculated from estimates of numbers entering two successive life stages. We present a method that estimates stage survival by reference to the difference between directly measured recruitment to the stage and the estimate of recruitment obtained from Southwood and Jepson’s graphical technique. The method assumes mortality is constant within the stage. The method is applied to two generations (at two sites) of the egg stage of the Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae), and the predicted stage survivals are compared, for two generations, with direct field measurements of egg mortality.