EXTH-56. ZIKA VIRUS TREATMENT SIGNIFICANTLY PROLONGS SURVIVAL IN A GLIOBLASTOMA PATIENT DERIVED XENOGRAFT MODEL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi175-vi176
Author(s):  
Parvez Akhtar ◽  
Samuel Zwernik ◽  
Deborah Donohoe ◽  
Catherine Warner ◽  
Dmitry Bosenko ◽  
...  
Keyword(s):  
Median Survival ◽  
Zika Virus ◽  
Oncolytic Virus ◽  
Xenograft Model ◽  
Standard Of Care ◽  
Control Group ◽  
Current Standard ◽  
Patient Derived Xenograft ◽  
Current Standard Treatment ◽  
Tumor Remission

Abstract The poor median survival for patients with glioblastoma (GBM) of 15 months has not budged for the past 15 years, when the current standard treatment was first approved. There is no standard of care chemotherapy for recurrent GBM. We previously showed that Zika virus (ZIKV) tropism for GBM cells is mediated through the receptor tyrosine kinase, AXL. This infection is cytotoxic. In this study we show that ZIKV is an effective oncolytic virus in a patient derived xenograft model. Fox N1 Nude homozygous female mice 6-8-weeks-old were grouped into 4 experimental arms: two patient derived cell lines, each with a ZIKV treated and a control group. There were 12 mice in each arm. Animals received subcutaneous flank injections of GBM 8049 or its AXL CRISPR knockout 8049 AXLKO (2x106 cells). When tumors reached 200 mm3, mice received intra-tumoral injection of 2.5x106 ZIKV particles or saline. ZIKV induced complete tumor remission in 22 of 24 animals (8049: 11/12; 8049 AXLKO: 11/12). There was no tumor remission in the saline treated animals. Median survival of 8049 and 8049 AXLKO ZIKV treated mice was 124 days and 125 days, respectively. This is compared to median survival of control animals 8049: 42 days; 8049 AXLKO: 46 days (P= 0.001). Among ZIKV treated mice, there were two recurrences: one in the 8049 tumor (24 days after significant tumor remission) and one 8049 AXLKO tumor (7 days after significant tumor remission). We conclude that ZIKV should be considered a candidate oncolytic virus for GBM.

Analyzing a Health-System's Use of Unfractionated Heparin to Ensure Optimal Anticoagulation

2005 ◽  
Vol 21 (2) ◽  
pp. 69-77 ◽  
Author(s):  
Samantha P Jellinek ◽  
Victor Cohen ◽  
Antonios Likourezos ◽  
William M Goldman ◽  
Eustace L Lashley
Keyword(s):  
Decision Support ◽  
Unfractionated Heparin ◽  
Medical Literature ◽  
Standard Of Care ◽  
Control Group ◽  
Computerized Physician Order Entry ◽  
Order Entry ◽  
Current Standard ◽  
Dosing Strategy ◽  
Physician Order Entry

Background: Although unfractionated heparin (UH) dosing nomograms have proven to be superior to standard dosing, the latter remains the mainstay at our institution. We hypothesize that the incorporation of technology integrated with a decision support algorithm will facilitate the use of a UH nomogram by clinicians. Objective: To critically appraise the steps involved with the use of UH, create a decision support algorithm to aid in the management of UH, and determine whether the use of this algorithm can improve achievment of rapid and safe anticoagulation compared with the current standard of care. Methods: We analyzed the steps involved with the use of UH and subsequently reviewed the medical literature for risk factors for bleeding that patients may harbor when initiating UH. Based on this information, we designed a computerized physician order entry (CPOE), factor-based, weight-adjusted decision support algorithm with the primary goal of minimizing the risk of bleeding while optimizing and ensuring optimal anticoagulation. We compared the CPOE strategy with our current standard of care. Results: The CPOE factor–based dosing strategy significantly improved the rates and decreased the time to achieving an initial activated partial thromboplastin time (aPTT) that was ≥60 seconds compared with the control group. At the time of first aPTT measurement, the CPOE factor-based group achieved a 92.9% therapeutic rate compared with the standard heparin dosing group, which achieved a 60.8% therapeutic rate (p < 0.01). Conclusions: The institution of a CPOE factor-based dosing strategy in collaboration with pharmacists' interventions optimizes anticoagulation treatment with UH.

A Direct Comparison of High Dose Cytarabine to Combination of Gemtuzumab and High Dose Cytarabine for Acute Myeloid Leukemia Patients in First Relapse Confirmed the Benefit of Gemtuzumab Based Regimens.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2051-2051
Author(s):  
Thomas Prébet ◽  
Aude Charbonnier ◽  
Anne Etienne ◽  
Evelyne D'Incan ◽  
Sabine Fürst ◽  
...  
Keyword(s):  
Overall Survival ◽  
Response Rate ◽  
Standard Of Care ◽  
Allogeneic Transplantation ◽  
Control Group ◽  
High Dose ◽  
Current Standard ◽  
Advanced Phase ◽  
High Dose Cytarabine ◽  
First Relapse

Abstract Abstract 2051 Poster Board II-28 Acute meyloid leukemia (AML) in first relapse is associated with a poor outcome when treated with standard dose cytarabine regimens and intermediate to high dose cytarabine (IHDAraC) is the current standard of care. During the last years, Gemtuzumab Ozogamycin (GO) has demonstrated a relevant clinical activity in relapsed and refractory AML. This antibody directed against CD33 is conjugated to calicheamycin that triggers apoptosis when hydrolyzed in the leukemic blasts. Combination regimen of GO are currently extensively studied in both frontline and advanced phase disease. Nevertheless, analysis of the litterature showed that only few data are available regarding a direct comparison of IHDAraC and IHDAraC+GO regimen. To this respect, we conduced a retrospective analysis of response (CR and CRi) and survival for patients with first relapse AML treated in our centre with either IHDAraC or IHDAraC+GO regimen. A total of 84 patients were included in the analysis: 28 were induced in the IHDAraC+GO group (mean GO dose: 6mg/m2, range:[3-9], including 82% of combination with anthracyclines or etoposide) and 56 in the IHDAraC group (including 57% of combination with other agents, mostly etoposide and anthracyclines). Patients characteristics were comparable between the IHDAraC+GO group and the control group in terms of median age (51y vs 49y), Performance Status at relapse (1 vs 1), median time to relapse (221 days vs 280 days), cytogenetic risk group clustering and previous allogeneic transplantation in first CR (21% vs 16%). Median Follow-up was 24 months. Univariate analysis showed that IHDAraC+GO induction, as compared with IHDAraC, was associated with a better response rate (68% vs 48%, p=0.08), a lower relapse rate (31% vs 66%, p=0.02), a better Overall Survival (median 35 months vs 19 months, p=0.02) and a better Event Free Survival (median Not Reached vs 10 months, p=0.02). Of note, the better response rate in the IHDAraC+GO group allowed to bring more patients to allogeneic transplantation in second CR (33% vs 16% respectively, p=0.08).Multivariate analysis using logistic regression method for response evaluation and Cox model for survival showed that treatment in the IHDAraC+GO group was an independent prognosis factor with a favorable impact on both response (HR:2.8, 95%CI:[1.1-7.7], p=0.048) and Overall Survival (HR:1.9, 95%CI:[1.1-3.4], p=0.047). It is already known that combination of IHDAraC and GO could give good results for advanced phase AML patients but, to our knowledge, this report is the first that directly compared the results of IHDAraC+GO with the current standard of care regimen on an homogeneous sample of patients in first relapse. This report also underline the importance of a prospective comparison in order to define the best combination therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Novel Treatment Strategies for Glioblastoma

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2883
Author(s):  
Stanley S. Stylli
Keyword(s):  
Median Survival ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
Standard Of Care ◽  
Invasive Disease ◽  
Central Nervous System Tumor ◽  
Current Standard ◽  
Novel Treatment ◽  
Novel Treatment Strategies ◽  
Molecular Landscape

Glioblastoma (GBM) is the most common primary central nervous system tumor in adults. It is a highly invasive disease, making it difficult to achieve a complete surgical resection, resulting in poor prognosis with a median survival of 12–15 months after diagnosis, and less than 5% of patients survive more than 5 years. Surgical, instrument technology, diagnostic and radio/chemotherapeutic strategies have slowly evolved over time, but this has not translated into significant increases in patient survival. The current standard of care for GBM patients involving surgery, radiotherapy, and concomitant chemotherapy temozolomide (known as the Stupp protocol), has only provided a modest increase of 2.5 months in median survival, since the landmark publication in 2005. There has been considerable effort in recent years to increase our knowledge of the molecular landscape of GBM through advances in technology such as next-generation sequencing, which has led to the stratification of the disease into several genetic subtypes. Current treatments are far from satisfactory, and studies investigating acquired/inherent resistance to current therapies, restricted drug delivery, inter/intra-tumoral heterogeneity, drug repurposing and a tumor immune-evasive environment have been the focus of intense research over recent years. While the clinical advancement of GBM therapeutics has seen limited progression compared to other cancers, developments in novel treatment strategies that are being investigated are displaying encouraging signs for combating this disease. This aim of this editorial is to provide a brief overview of a select number of these novel therapeutic approaches.

CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues

Blood ◽  
2021 ◽  
Author(s):  
Xiaobing Yu ◽  
Leonel Munoz-Sagredo ◽  
Karolin Streule ◽  
Patricia Muschong ◽  
Elisabeth Bayer ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Residual Disease ◽  
Embryonic Stem ◽  
Xenograft Model ◽  
Standard Of Care ◽  
Loss Of Function ◽  
Current Standard ◽  
Induced Apoptosis ◽  
Biomolecular Fluorescence Complementation

Acute myeloid leukemia (AML) has a poor prognosis under the current standard of care. In recent years, venetoclax, a BCL-2 inhibitor, was approved to treat patients, ineligible for intensive induction chemotherapy. Complete remission rates with venetoclax-based therapies are, however, hampered by minimal residual disease (MRD) in a proportion of patients, leading to relapse. MRD is due to leukemic stem cells retained in bone marrow protective environments; activation of the CXCL12/CXCR4 pathway was shown to be relevant to this process. An important role is also played by cell adhesion molecules such as CD44, which has been shown to be crucial for AML development. Here we show that CD44 is involved in CXCL12 promotion of resistance to venetoclax-induced apoptosis in human AML cell lines and AML patient samples which could be abrogated by CD44 knockdown, knockout or blocking with an anti-CD44 antibody. Split-Venus biomolecular fluorescence complementation showed that CD44 and CXCR4 physically associate at the cell membrane upon CXCL12 induction. In the venetoclax-resistant OCI-AML3 cell line, CXCL12 promoted an increase in the proportion of cells expressing high levels of embryonic-stem-cell core transcription factors (ESC-TFs: Sox2, Oct4, Nanog), abrogated by CD44 knockdown. This ESC-TF-expressing subpopulation which could be selected by venetoclax treatment, exhibited a basally-enhanced resistance to apoptosis, and expressed higher levels of CD44. Finally, we developed a novel AML xenograft model in zebrafish, showing that CD44 knockout sensitizes OCI-AML3 cells to venetoclax treatment in vivo. Our study shows that CD44 is a potential molecular target to sensitize AML cells to venetoclax-based therapies.

Survival Advantage for Patients (pts) with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) Treated with Imatinib.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1006-1006
Author(s):  
Jorge Cortes ◽  
Moshe Talpaz ◽  
Susan O’Brien ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi-Kashami ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Median Survival ◽  
Clonal Evolution ◽  
Standard Of Care ◽  
Cytogenetic Response ◽  
Survival Advantage ◽  
Control Group ◽  
Significant Prognostic Factor ◽  
Hematologic Response

Abstract When treated with imatinib, pts with CML in AP have a hematologic response rate of over 80%, and 25% achieve a major cytogenetic (CG) response. These results are superior to any other therapy available and have established imatinib as the standard of care for AP CML. However, a survival benefit was not defined in these single-arm studies. With longer follow-up of pts in AP treated with imatinib, we investigated whether imatinib therapy led to a survival advantage over other therapies that have been used for this disease. For this analysis, AP was defined as the presence of any of the following: blasts ≥15%, blasts + promyelocytes ≥30%, basophils ≥20%, platelets (plts) &lt;100 x109/L unrelated to therapy, or clonal evolution. Since 1982, 395 pts with AP have been treated at MDACC: 177 (45%) with imatinib and 218 (55%) with other therapies including IFN-α-based therapy (n=102), homoharringtonine (n=36), decitabine (n=47), daunorubicin + ara −C (n=24), or others (n=9). The rate of complete hematologic response was 82% with imatinib and 38% with others (p &lt; 0.0001), and major cytogenetic response was 48% and 13%, respectively (p &lt;0.0001). The median follow-up is 41 months (mo) (range, 3 – 206): 38 mo (3 to 63) for the imatinib group and 82 mo (3 to 206) for the others. A total of 249 pts have died: 67 in the imatinib cohort and 182 in the control group. The median survival was 21 months for the control group, and has not been reached for the imatinib cohort (estimated rate 53% at 3 yrs). Clinical characteristics adversely affecting survival (p&lt;0.05) included time from diagnosis to treatment &gt;36 mo, splenomegaly, Hgb &lt;10 g/dl, plts &lt;100 x109/L, peripheral or marrow blasts ≥5%, marrow basophils &gt;5%, blasts + promyelocytes &gt;5%, clonal evolution, and treatment with imatinib. Pts treated with imatinib were older, but had fewer pts with splenomegaly, high blasts or clonal evolution than the control group. By multivariate analysis, the independent pre-treatment characteristics associated with survival (p&lt;0.05) were splenomegaly, anemia, presence of peripheral blood blasts, and disease duration &gt;1 yr. After adjusting for these differences in a multivariate analysis, treatment with imatinib was the most significant prognostic factor associated with improved survival (p&lt;0.0001). We conclude that treatment with imatinib has changed the natural history of AP CML with an expected median survival in excess of 3 years.

Alternative Schedule of Filgrastim after Autologous Transplantation: Less Dosing, Same Efficacy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4334-4334
Author(s):  
Aida B. Sousa ◽  
Fatima Costa ◽  
Gilda Ferreira
Keyword(s):  
Pilot Study ◽  
Median Time ◽  
Autologous Transplantation ◽  
Standard Of Care ◽  
Control Group ◽  
Study Group ◽  
Current Standard ◽  
Transfusion Requirements ◽  
Clinical Instability ◽  
Grade 3

Abstract Administration of colony-stimulating factors (CSF) after autologous peripheral-blood progenitor cell transplantation is the current standard of care, and G-CSF is usually given from day +5 or +7 until engraftment. Recent preliminary data in a non-transplant setting suggest that 2 doses of G-CSF may be equivalent to the standard schedule. In this pilot study, we evaluated the safety and efficacy of giving only 2 doses of filgrastim post-transplant (days +7 and +9) in non-myeloma pts; exclusion criteria were re-transplants and clinical instability at day +7. From July 07 to June 08, 19 consecutive pts were included (16 lymphomas, 3 acute leukaemias) and their outcome was compared to a historical control group of 42 similar pts transplanted from Jan 06 to Jun 07, who received filgrastim from d+7 until 1000 neutrophils/ul (4–18 days, median 9). There were no significant differences in primary endpoints: median time to neutrophil engraftment (500/ul reached on day +12 vs +11) rate of documented infections (with bacteremia in 23% of transplants in the study group vs 36% in the control group) and median length of hospitalisation (both 22 days). Median duration of intravenous antibiotics (11 vs 12 days) median time to platelet engraftment (20,000/ul reached on day +13 vs +14) incidence of grade 3/4 mucositis and transfusion requirements were also similar. There were no deaths at day +30 in the study group. In 2 of the 19 pts a secondary prescription of filgrastim was made (for 2 and 4 days). In this pilot study, reducing filgrastim administration to 2 doses seems possible without undue risks. If confirmed in a randomized trial, these findings could have a significant impact on the cost of transplantation.

scholarly journals The use of immunotherapy treatment in malignant pheochromocytomas/paragangliomas: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Robin Raquel Rodriguez ◽  
Saleha Rizwan ◽  
Khaled Alhamad ◽  
Gene Grant Finley
Keyword(s):  
Clinical Trials ◽  
Radiation Therapy ◽  
Case Report ◽  
Neural Crest Cell ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Chemotherapeutic Agents ◽  
Current Standard ◽  
Off Label ◽  
Current Standard Treatment

Abstract Background Pheochromocytomas are a subset of paragangliomas, which are a rare group of neural crest cell-derived tumors. Malignant cases of both pheochromocytomas and paragangliomas are even rarer, and currently there is no standard of care. This case report details the use of off-label immunotherapy and its efficacy in the management of the aforementioned tumor. Case presentation Herein is presented a case of a 60-year-old Caucasian female with a rare malignant pheochromocytoma. The tumor was determined to be unresectable because of involvement of surrounding organs. Radiation therapy was also not a viable option because of concerns over appreciable toxicity in relation to mass size. As there is no standard of care for malignant cases, the patient was started on chemotherapeutic agents but was soon shown to be intolerant to this treatment. As she was ineligible for several clinical trials, the patient was started on the off-label immunotherapeutic agents nivolumab and ipilimumab. Immunotherapy use resulted in decreased tumor size, improved quality of life, and reconsideration for radiation therapy. Conclusions The use of immunotherapy in pheochromocytoma in this patient clearly demonstrated substantial benefit, as she was able to be reconsidered for radiation therapy. Not only has the patient been tolerant of this treatment, but she has exhibited progression-free survival of over 20 months. As there is no current standard treatment for malignant pheochromocytomas, the success of its use in this patient lends support to the ongoing clinical trials regarding the use of immunotherapy in rare tumors, including pheochromocytomas.

Clinical-Reported Outcomes Of Deferoxamine Versus Deferasirox In The Treatment Of Homozygous BetaThalassemia

2018 ◽  
Vol 9 (SPL1) ◽  
Author(s):  
Zeina A Munim Al-Thanoon ◽  
Zeina A Munim Al-Thanoon ◽  
Mustafa Basil ◽  
Nasih A Al-Kazzaz
Keyword(s):  
Serum Ferritin ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Beta Thalassemia ◽  
Control Group ◽  
Current Standard ◽  
Cross Sectional ◽  
Significant Difference ◽  
Multiple Blood ◽  
Group 2

Iron chelation therapy with deferoxamine (DFO),the current standard for the treatment of iron overload in patients with betathalassemia,requires regular subcutaneous or intravenous infusions. This can lead to reduced quality of life and poor adherence,resulting in increased morbidity and mortality in iron-overloaded patients with beta-thalassemia. Deferasirox (DFX) is an orally administered iron chelator that has been approved for use in many countries. The requirement of an effective,well tolerated iron chelator with a less demanding mode of administration has led to the development of deferasirox. The present study was aimed to compare the satisfaction and compliance with deferoxamine versus deferasirox (Exjade®),a novel oral iron chelator in patients with transfusion - dependent beta- thalassemia. A cross-sectional,single-center investigation study was carried out in the Thalassemia Center of Ibn-Atheer Teaching Hospital in Nineveh province,Iraq. One hundred and eight thalassemic patients aged between 2- 20 years old having received multiple blood transfusions and a serum ferritin greater than 1500 ng/ml. Patients were randomised into two groups. Group 1 received deferoxamine at a dose of 20-50mg/kg/day and group 2 received deferasirox at the dose of 10-30 mg/kg/day. Another 56 apparently healthy volunteers were used as a control group. The assessment of chelation was done during the period between November 2013 and February 2014 by measurement of serum ferritin. Satisfaction and compliance was assessed by using a special questionnaire prepared by the researcher. Out of the 108 thalassemic patients enrolled there was no discontinuation in treatment with the two drugs under study. The serum ferritin did not change significantly in any of the chelation groups. In comparison with the patients who were treated with DFO,those receiving DFX reported a significantly higher rate of compliance and satisfaction (P < 0.05). However,no significant difference was observed between the two groups regarding their satisfaction (P > 0.05).Compliance with deferasirox (50 %) was more than that with deferoxamine (20 %). Satisfaction with deferoxamine was significantly lower than deferasirox (p= 0.00).

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