BIOM-16. NTRK (NEUROTROPHIC TYROSINE RECEPTOR KINASE) FUSIONS IN GLIOMA PATIENTS: A PROMISING MOLECULAR TARGET?

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi13-vi13
Author(s):  
Anastasia Vernadou ◽  
Theodoros Argyrakos ◽  
Eirini Papadopoulou ◽  
Georgios Rigakos ◽  
Konstantinos Tsoukalas ◽  
...  
Keyword(s):  
Median Survival ◽  
Malignant Gliomas ◽  
Unmet Need ◽  
Small Sample ◽  
The Other ◽  
Lower Grade ◽  
Egfr Expression ◽  
Clinical Interest ◽  
Trk Inhibitors ◽  
Tyrosine Receptor Kinase

Abstract BACKGROUND NTRK gene fusions are rare in gliomas (less than 2%). The use of TRK inhibitors in NTRK-fused solid tumors has generated significant clinical interest. It is likely that the unmet need for effective therapies in glioma will lead to routine testing for NTRK fusions. METHODS We performed a retrospective review of 22 patients with malignant gliomas accrued between 2007 and 2021. We collected tumor samples from those patients and NTRK fusions were tested using either immunohistochemistry or FISH or NGS. We then evaluated their association with clinical characteristics, histology and other markers (IDH1/2 mutation, MGMT methylation, BRAF mutation, EGFR expression, ATRX expression, TERT mutation). RESULTS Median age at diagnosis was 50 years. NTRK1 translocation was detected in 3 out of 22 patient tumors, while NTRK1 duplication was present in 1 patient (probably related to a translocation, but not proven). All NTRK1 translocations were not found in glioblastomas and their median survival was 15.8 months. On the other hand, median survival of gliomas without NTRK translocations was 11 months. In one NTRK1-translocated patient a TRK inhibitor (entrectinib) was used (for a few days), but we cannot evaluate its efficacy as the patient deteriorated and died. As far as the other biomarkers are concerned, 2 out of 3 NTRK1-translocated gliomas were MGMT methylated. CONCLUSION NTRK fusions are rare in gliomas, as confirmed in our small sample analysis. Although adult NTRK-fused gliomas are considered to predominantly involve high-grade histology, in our study all patients had initially lower grade gliomas. NTRK alterations can be detected by different laboratory assays, but each of these approaches has specific advantages and limitations and more data are needed in order to identify the best method. For glioblastomas, NTRK fusions and TRK inhibitors are potentially a new targeted therapeutic strategy but more data are needed.

scholarly journals A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

2020 ◽  
Vol 78 (1) ◽  
pp. 34-38
Author(s):  
Burcu BITERGE-SUT
Keyword(s):  
Glioblastoma Multiforme ◽  
Malignant Gliomas ◽  
Genetic Alterations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Nonsense Mutations ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

scholarly journals Receptor-Targeted Glial Brain Tumor Therapies

2018 ◽  
Vol 19 (11) ◽  
pp. 3326 ◽  
Author(s):  
Puja Sharma ◽  
Waldemar Debinski
Keyword(s):  
Brain Tumors ◽  
Malignant Gliomas ◽  
Unmet Need ◽  
Normal Brain ◽  
Therapeutic Approaches ◽  
Multiple Tumor ◽  
Multiple Receptors ◽  
Clinical Responses ◽  
Drug Activation ◽  
Targeted Therapeutic

Among primary brain tumors, malignant gliomas are notably difficult to manage. The higher-grade tumors represent an unmet need in medicine. There have been extensive efforts to implement receptor-targeted therapeutic approaches directed against gliomas. These approaches include immunotherapies, such as vaccines, adoptive immunotherapy, and passive immunotherapy. Targeted cytotoxic radio energy and pro-drug activation have been designed specifically for brain tumors. The field of targeting through receptors progressed significantly with the discovery of an interleukin 13 receptor alpha 2 (IL-13RA2) as a tumor-associated receptor over-expressed in most patients with glioblastoma (GBM) but not in normal brain. IL-13RA2 has been exploited in novel experimental therapies with very encouraging clinical responses. Other receptors are specifically over-expressed in many patients with GBM, such as EphA2 and EphA3 receptors, among others. These findings are important in view of the heterogeneity of GBM tumors and multiple tumor compartments responsible for tumor progression and resistance to therapies. The combined targeting of multiple receptors in different tumor compartments should be a preferred way to design novel receptor-targeted therapeutic approaches in gliomas.

An Evaluation of the Application of Minimum Chi-Square Procedures to Stochastic Models of Brand Choice

1973 ◽  
Vol 10 (4) ◽  
pp. 421-427 ◽  
Author(s):  
Robert C. Blattberg ◽  
Subrata K. Sen
Keyword(s):  
Stochastic Models ◽  
Brand Choice ◽  
Choice Models ◽  
Statistical Test ◽  
Small Sample ◽  
The Other ◽  
Chi Square ◽  
Small Sample Properties

This paper investigates the small sample properties of minimum chi-square estimates of the parameters of stochastic brand choice models. It also describes and evaluates a statistical test which is appropriate for discriminating between two stochastic brand choice models when one is a constrained version of the other.

scholarly journals Epigenetic Reprogramming for Targeting IDH-Mutant Malignant Gliomas

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1616 ◽  
Author(s):  
Jong-Whi Park ◽  
Şevin Turcan
Keyword(s):  
Treatment Effectiveness ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Malignant Gliomas ◽  
Current Treatment ◽  
Epigenetic Therapy ◽  
Lower Grade ◽  
Recurrent Mutations ◽  
Tumor Immunogenicity ◽  
Dna Methylation Inhibitors

Targeting the epigenome has been considered a compelling treatment modality for several cancers, including gliomas. Nearly 80% of the lower-grade gliomas and secondary glioblastomas harbor recurrent mutations in isocitrate dehydrogenase (IDH). Mutant IDH generates high levels of 2-hydroxyglutarate (2-HG) that inhibit various components of the epigenetic machinery, including histone and DNA demethylases. The encouraging results from current epigenetic therapies in hematological malignancies have reinvigorated the interest in solid tumors and gliomas, both preclinically and clinically. Here, we summarize the recent advancements in epigenetic therapy for lower-grade gliomas and discuss the challenges associated with current treatment options. A particular focus is placed on therapeutic mechanisms underlying favorable outcome with epigenetic-based drugs in basic and translational research of gliomas. This review also highlights emerging bridges to combination treatment with respect to epigenetic drugs. Given that epigenetic therapies, particularly DNA methylation inhibitors, increase tumor immunogenicity and antitumor immune responses, appropriate drug combinations with immune checkpoint inhibitors may lead to improvement of treatment effectiveness of immunotherapy, ultimately leading to tumor cell eradication.

Biomarkers of hyperprogression and pseudoprogression with immune checkpoint inhibitor therapy

2019 ◽  
Vol 15 (22) ◽  
pp. 2645-2656 ◽  
Author(s):  
Jarrett J Failing ◽  
Olivia A Dudek ◽  
Julian A Marin Acevedo ◽  
Razvan M Chirila ◽  
Haidong Dong ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Small Sample ◽  
Inhibitor Therapy ◽  
Laboratory Findings ◽  
Therapeutic Decisions ◽  
Checkpoint Inhibitor Therapy

Hyperprogression and pseudoprogression are two atypical responses to immune checkpoint inhibitor therapy that affect therapeutic decisions and prognosis. Identification of predictive biomarkers for atypical responses either before or during treatment remains a huge unmet need in cancer immunotherapy. Many studies have looked at potential biomarkers, including clinical factors and laboratory findings (e.g., peripheral blood counts, circulating tumor DNA, cytokine levels). The results of these studies have been inconsistent, possibly due to small sample sizes, different tumor types and heterogeneity of the definition of these atypical responses.

Individual and Group Performance

1967 ◽  
Vol 21 (2) ◽  
pp. 341-344
Author(s):  
Robert Pawlicki ◽  
Walter Gunn
Keyword(s):  
Grade Level ◽  
Group Performance ◽  
Individual Performance ◽  
The Other ◽  
Lower Grade ◽  
Clear Cut ◽  
Significant Difference ◽  
Upper Level ◽  
Shift Change

Two freshman psychology classes were presented a series of factual statements and asked to respond either true or false both individually and collectively to determine the importance of individual performance preceding group performance and vice versa in terms of shift (change of an answer given to a statement in one situation from an answer previously given to the same statement in another situation), the influence on accuracy of one situation preceding the other and the amount of shift observed in students with high grades and those with low grades. The data indicated that students at the extreme lower grade level (quartile IV) tended to shift more than students at the extreme upper level (quartile I), but no clear-cut differentiation appeared in central areas (quartiles II and III). No significant difference in shift occurred when group performance preceded individual performance or vice versa. Group performance preceding individual performance did prove to have a beneficial influence upon the individual's performance in that Ss conform somewhat to the performance of the group. The accuracy of the group performance was superior to that of the individuals.

Infliximab for the Treatment of Chronic Graft Versus Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2889-2889
Author(s):  
Ethan Tolbert ◽  
Ned Waller ◽  
H. Jean Khoury ◽  
Mary Jo Lechowicz ◽  
Christopher Flowers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Survival ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Response Rate ◽  
The Other ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Steroid Refractory

Abstract Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and non relapse mortality after allogeneic stem cell transplantation. Tumor necrosis factor alpha (TNF-α) is a cytokine involved in the pathogenesis of GVHD. Infliximab is a murine-human chimeric monoclonal antibody that binds TNF-α, preventing interaction with its receptor and its ability to mediate the development of GVHD. Infliximab is active in the treatment of steroid refractory acute GVHD, particularly for patients with GI GVHD (Couriel et al Blood. 2004 Aug 1;104(3):649–54).We performed a retrospective analysis to evaluate the activity of infliximab in 22 patients with AML/MDS (n=5), lymphoma (n=8), ALL (n=3), and others (n=6) with steroid refractory chronic extensive GVHD. Response was measured according to standard response criteria (Pavletic et al. Biology of Blood and Marrow Transplantation 2006 Mar;12(3):252–66). The median age of the patients was 50 years (range 20 – 64). Fourteen (64%) patients had matched sibling donors, 8 (36%) had matched unrelated donors, 9 (41%) underwent nonmyeloablative conditioning, one patient had a bone marrow transplant and the other 21 patients had peripheral blood stem cell transplants. All patients were given standard doses of tacrolimus or cyclosporine for GVHD prophylaxis with either short course methotrexate or mycophenolate mofetil. All patients were treated with systemic steroids at the onset of GVHD. Fifty percent of the patients initially presented with acute GVHD that progressed to chronic extensive GVHD. The other half presented with late onset or de novo chronic extensive GVHD. Nineteen had skin involvement (86%), 15 (68%) had gastrointestinal involvement, and 10 (45%) had liver involvement at the time of treatment with infliximab. All patients were considered refractory to tacrolimus/cyclosporine and systemic steroids, had intolerable side effects from steroids or could not be successfully tapered off steroids prior to infliximab administration. Median time from transplant to infliximab administration was 337days (range 122 to 932 days). The patients received a median of 4 weekly courses (range 1–20 courses) of infliximab at 10mg/kg. The overall response rate was 64% (n=14); 11 (50%) experienced a complete response (CR); 3 (14%) experienced a partial response (PR); 8 (36%) had progressive GVHD. The response rate for skin GVHD was 68%, GI was 60% and liver was 50%. One patient suffered an acute infusion reaction after the first infliximab dose and had no further drug administered. Median survival of all patients following initiation of infliximab was 223 days. Median survival of all responders was 625 days after infliximab, while median survival of the non-responders was 70 days after infliximab. Six patients remain alive at a median follow-up of 55 months (27%). Three of six survivors are on minimal immunosuppression with limited cGVHD and three are off all immunosuppression with no evidence of cGVHD. Of the patients who died, 7 (32%) died from infectious complications, 5 (23%) died from complications of progressive cGVHD, 4 (18%) died from hemorrhagic or embolic strokes, 2 died from complications of post-transplant lymphoproliferative disorder (PTLD), and one patient from relapse. In conclusion, infliximab has activity for cGVHD. Prospective trials investigating the activity of infliximab, the infectious risks, predictive measures responding patients and optimal timing of administration are needed.

Xanthine oxidoreductase and chemosensitivity in non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11077-11077
Author(s):  
R. Myint ◽  
M. Batus ◽  
P. Bonomi ◽  
P. Gattuso ◽  
W. H. Warren ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Median Survival ◽  
Cell Lung Cancer ◽  
Small Sample Size ◽  
Small Cell ◽  
Small Sample ◽  
Xanthine Oxidoreductase ◽  
Small Cell Lung ◽  
Clin Pathol

11077 Background: Xanthine oxidoreductase (XOR) is an enzyme involved in the degradation of purines into uric acid and reactive oxygen species and activation of the MAP kinase pathway involved in apoptosis. Decreased XOR expression was shown in recent studies to be associated with more aggressive disease in breast (Linder et al. Clin Cancer Res. 2005;11:4372–4381) and gastric cancers (Linder et al. J Clin Pathol. 2006;59:965–971). The goal of our study was to show that decreased XOR expression was associated with decreased survival in non-small cell lung cancer (NSCLC). Methods: Tissue specimens from 82 patients (pts) were stained using a XOR specific antibody (36 male and 46 female, age range from 40 to 92 years). These included 41 adenocarcinoma, 31 squamous cell, 8 poorly/moderately differentiated, and 2 bronchioloalveolar. XOR staining intensity was measured on a scale of 0 through 4 (0 being no staining). XOR intensity was correlated with clinical characteristics and outcomes using log rank and COX PH regression analysis. Results: Of the 82 pts, 34 received adjuvant chemo, and of these, 15 specimens had low XOR intensity (0–1). These 15 pts received adjuvant chemo and had a median survival of 543 days. In comparison, 19 of the 34 pts receiving adjuvant chemo had specimens with high XOR intensity (2–4). Their median survival was significantly longer at 2,023 days (p=0.007, hazard ratio=0.33). Conclusions: Although we had a small sample size, in our retrospective study, we found that pts who received adjuvant chemo had a longer survival if their tumors expressed high levels of XOR. XOR could be a potential predictor for responsiveness to adjuvant chemo in patients with NSCLC. Pts with decreased XOR may be less responsive to chemo and thus be able to avoid a toxic treatment if it is not significantly beneficial. [Table: see text] No significant financial relationships to disclose.

An in vivo microanalytical technique for measuring the local biochemical milieu of human skeletal muscle

2005 ◽  
Vol 99 (5) ◽  
pp. 1977-1984 ◽  
Author(s):  
Jay P. Shah ◽  
Terry M. Phillips ◽  
Jerome V. Danoff ◽  
Lynn H. Gerber
Keyword(s):  
Soft Tissue ◽  
Neck Pain ◽  
Capillary Electrochromatography ◽  
Small Sample ◽  
The Other ◽  
Active Group ◽  
Myofascial Trigger Points ◽  
Permeable Membrane ◽  
Microanalytical Technique

Myofascial pain associated with myofascial trigger points (MTrPs) is a common cause of nonarticular musculoskeletal pain. Although the presence of MTrPs can be determined by soft tissue palpation, little is known about the mechanisms and biochemical milieu associated with persistent muscle pain. A microanalytical system was developed to measure the in vivo biochemical milieu of muscle in near real time at the subnanogram level of concentration. The system includes a microdialysis needle capable of continuously collecting extremely small samples (∼0.5 μl) of physiological saline after exposure to the internal tissue milieu across a 105-μm-thick semi-permeable membrane. This membrane is positioned 200 μm from the tip of the needle and permits solutes of <75 kDa to diffuse across it. Three subjects were selected from each of three groups (total 9 subjects): normal (no neck pain, no MTrP); latent (no neck pain, MTrP present); active (neck pain, MTrP present). The microdialysis needle was inserted in a standardized location in the upper trapezius muscle. Due to the extremely small sample size collected by the microdialysis system, an established microanalytical laboratory, employing immunoaffinity capillary electrophoresis and capillary electrochromatography, performed analysis of selected analytes. Concentrations of protons, bradykinin, calcitonin gene-related peptide, substance P, tumor necrosis factor-α, interleukin-1β, serotonin, and norepinephrine were found to be significantly higher in the active group than either of the other two groups ( P < 0.01). pH was significantly lower in the active group than the other two groups ( P < 0.03). In conclusion, the described microanalytical technique enables continuous sampling of extremely small quantities of substances directly from soft tissue, with minimal system perturbation and without harmful effects on subjects. The measured levels of analytes can be used to distinguish clinically distinct groups.

Simplifying the Six Sigma Toolbox through Application of Shainin DOE Techniques

2009 ◽  
Vol 34 (1) ◽  
pp. 13-30 ◽  
Author(s):  
Sunil Sharma ◽  
Anuradha R Chetiya
Keyword(s):  
Design Of Experiments ◽  
Six Sigma ◽  
Paired Comparison ◽  
Good Alternative ◽  
Small Sample ◽  
The Other ◽  
Statistical Tools ◽  
Root Cause ◽  
Junior Staff ◽  
Wide Range

The success of a Six Sigma programme in an organization depends to a large extent on the success of the Six Sigma projects, which in turn depends on how the team handles the problem and whether the right combination of tools is being applied to address the root cause. The Six Sigma toolbox consists of a wide range of tools comprising, on the one hand, simple and commonly used tools like flow charts, Pareto analysis, and cause-and-effect diagram and the more advanced statistical tools like design of experiments, regression analysis and many more, on the other hand. While the simple tools are easy to apply, understand, and analyse, engineers perceive the more advanced tools difficult to comprehend. Design of experiments (DOE) is one such tool. Two well-known approaches of design of experiments are the Classical DOE, pioneered by Sir Ronald A Fisher and the Taguchi approach, pioneered by Dr Genichii Taguchi. A third approach to experimental design—the Shainin DOE techniques, offered by Dr Dorian Shainin—can be considered as a very good alternative to the other approaches. They are much simpler than the factorial designs, response surface designs, and orthogonal arrays of the conventional approaches of DOE, but at the same time are recognized as being very powerful and effective in solving the chronic quality problems that plague most manufacturers. Shainin DOE basically works at eliminating suspected process variables by mostly using seven different tools, viz., Multi-Vari Charts Component Search Paired Comparison Variable Search Full Factorials B vs. C (Better vs. Current) Analysis Scatter Plots or Realistic Tolerance Parallelogram Plots. Though not very well documented, these tools have proved to be the key drivers in the success of many companies, e.g., Motorola. This article examines two projects of a leading automotive and general lighting lamp manufacturing company, in which a combination of the standard Six Sigma tools and Shainin tools has been successfully used to address the root cause of the problems. The advantage of using Shainin tools is that: Very small sample sizes are required to analyse the problem. Often samples as small as 2 or 3 are enough to make statistically valid conclusions. Statistical software is not required to analyse the data. In fact, Shainin DOE does not even require knowledge of complex statistical tools. It involves employees at all levels, including workers and junior staff in problem solving that was hitherto a domain of senior technical experts. Also, the success of the projects had a very positive effect on the morale of the employees in terms of convincing them that Six Sigma is not all about using complex statistical tools.

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