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Vlahovic, Gordana

Positions:

Associate Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Assistant Professor in Surgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

M.D. — University of Zagreb (Croatia)

Medical Resident, Medicine

Duke University

Fellow In Hematology Oncology, Medicine

Duke University

Grants:

A Phase 1 Dose Escalation Study Evaluating the Safety and Tolerability of PF-06840003 in Patients with Malignant Glioma

Administered By
Duke Cancer Institute
AwardedBy
Pfizer, Inc.
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 2020

A randomized phase 2 single blind study of temo plus XRT combined with nivolumab or placebo

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
August 01, 2016
End Date
July 31, 2020

Phase 3 Open Label Study of Nivolumab vs Temozolomide with unmethylated MGMT

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
August 01, 2016
End Date
July 31, 2020

Lilly H9H-MC-JBEF

Administered By
Duke Cancer Institute
AwardedBy
Eli Lilly and Company
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2020

AVeRT: Anti-PD-1 monoclonal antibody (nivolumab) in combination with DC Vaccines for Grade III/ IV brain tumors

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
November 01, 2015
End Date
October 31, 2019

Quantitative Staging and Therapeutic Response in IDH-1 Mutated Glioblastomas

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
March 01, 2017
End Date
February 28, 2019

A Randomized Phase IIB Open Label Study of Nivolumab in combination with Ipilimumab versus Bevacizumab Recurrent GBM

Administered By
Duke Cancer Institute
AwardedBy
The Bristol-Myers/Sanofi Pharmaceuticals, Inc. Partnership
Role
Principal Investigator
Start Date
February 01, 2014
End Date
January 31, 2018

Therapeutic Vaccine Targeting CMV Antigens in Glioblastoma

Administered By
Neurosurgery
AwardedBy
Annias Immunotherapeutics, Inc.
Role
Principal Investigator
Start Date
August 10, 2015
End Date
July 31, 2017

Mentored Clinical Research Scholar Program

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Faculty Associate
Start Date
September 30, 2002
End Date
September 29, 2006
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Publications:

Immunotherapy approaches in the treatment of malignant brain tumors.

Glioblastoma is the most common malignant primary brain tumor. Despite standard-of-care treatment, consisting of maximal surgical resection followed by chemoradiation, both morbidity and mortality associated with this disease remain very poor. Therefore, there is an urgent need for more efficacious and well tolerated therapies. Advancing knowledge of the intricate interplay between malignant gliomas and the immune system, coupled with the recent launch of immunotherapy research for other cancers, has led to a veritable increase in immunotherapy investigation for glioblastoma and other malignant gliomas. This clinical review highlights the recent breakthroughs in cancer immunotherapy and the complex correlation of the immune system with primary brain tumors, with special attention to multiple immunotherapy modalities currently being investigated for malignant glioma, including peptide vaccines, dendritic cell vaccines, oncolytic viruses, chimeric T-cell receptors, and checkpoint inhibitors. Cancer 2016. © 2016 American Cancer Society.

Authors
Dunn-Pirio, AM; Vlahovic, G
MLA Citation
Dunn-Pirio, AM, and Vlahovic, G. "Immunotherapy approaches in the treatment of malignant brain tumors." Cancer (November 22, 2016). (Review)
PMID
27875627
Source
epmc
Published In
Cancer
Publish Date
2016
DOI
10.1002/cncr.30371

A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors.

To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor.This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation.Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (K(trans)), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease.AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment. Clin Cancer Res; 22(18); 4574-84. ©2016 AACR.

Authors
Dowlati, A; Vlahovic, G; Natale, RB; Rasmussen, E; Singh, I; Hwang, YC; Rossi, J; Bass, MB; Friberg, G; Pickett, CA
MLA Citation
Dowlati, A, Vlahovic, G, Natale, RB, Rasmussen, E, Singh, I, Hwang, YC, Rossi, J, Bass, MB, Friberg, G, and Pickett, CA. "A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors." Clinical cancer research : an official journal of the American Association for Cancer Research 22.18 (September 2016): 4574-4584.
PMID
27076631
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Issue
18
Publish Date
2016
Start Page
4574
End Page
4584
DOI
10.1158/1078-0432.ccr-15-2145

Embracing rejection: Immunologic trends in brain metastasis.

Brain metastases represent the most common type of brain tumor. These tumors offer a dismal prognosis and significantly impact quality of life for patients. Their capacity for central nervous system (CNS) invasion is dependent upon induced disruptions to the blood-brain barrier (BBB), alterations to the brain microenvironment, and mechanisms for escaping CNS immunosurveillance. In the emerging era of immunotherapy, understanding how metastases are influenced by the immunologic peculiarities of the CNS will be crucial to forging therapeutic advances. In this review, the immunology of brain metastasis is explored.

Authors
Farber, SH; Tsvankin, V; Narloch, JL; Kim, GJ; Salama, AKS; Vlahovic, G; Blackwell, KL; Kirkpatrick, JP; Fecci, PE
MLA Citation
Farber, SH, Tsvankin, V, Narloch, JL, Kim, GJ, Salama, AKS, Vlahovic, G, Blackwell, KL, Kirkpatrick, JP, and Fecci, PE. "Embracing rejection: Immunologic trends in brain metastasis." Oncoimmunology 5.7 (July 2016): e1172153-. (Review)
PMID
27622023
Source
epmc
Published In
OncoImmunology
Volume
5
Issue
7
Publish Date
2016
Start Page
e1172153
DOI
10.1080/2162402x.2016.1172153

Vaccine Therapy, Oncolytic Viruses, and Gliomas.

After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary.

Authors
Desjardins, A; Vlahovic, G; Friedman, HS
MLA Citation
Desjardins, A, Vlahovic, G, and Friedman, HS. "Vaccine Therapy, Oncolytic Viruses, and Gliomas." Oncology (Williston Park, N.Y.) 30.3 (March 2016): 211-218.
PMID
26984213
Source
epmc
Published In
Oncology
Volume
30
Issue
3
Publish Date
2016
Start Page
211
End Page
218

Detecting somatic mutations in genomic sequences by means of Kolmogorov-Arnold analysis.

The Kolmogorov-Arnold stochasticity parameter technique is applied for the first time to the study of cancer genome sequencing, to reveal mutations. Using data generated by next-generation sequencing technologies, we have analysed the exome sequences of brain tumour patients with matched tumour and normal blood. We show that mutations contained in sequencing data can be revealed using this technique, thus providing a new methodology for determining subsequences of given length containing mutations, i.e. its value differs from those of subsequences without mutations. A potential application for this technique involves simplifying the procedure of finding segments with mutations, speeding up genomic research and accelerating its implementation in clinical diagnostics. Moreover, the prediction of a mutation associated with a family of frequent mutations in numerous types of cancers based purely on the value of the Kolmogorov function indicates that this applied marker may recognize genomic sequences that are in extremely low abundance and can be used in revealing new types of mutations.

Authors
Gurzadyan, VG; Yan, H; Vlahovic, G; Kashin, A; Killela, P; Reitman, Z; Sargsyan, S; Yegorian, G; Milledge, G; Vlahovic, B
MLA Citation
Gurzadyan, VG, Yan, H, Vlahovic, G, Kashin, A, Killela, P, Reitman, Z, Sargsyan, S, Yegorian, G, Milledge, G, and Vlahovic, B. "Detecting somatic mutations in genomic sequences by means of Kolmogorov-Arnold analysis." Royal Society open science 2.8 (August 26, 2015): 150143-.
PMID
26361546
Source
epmc
Published In
Royal Society Open Science
Volume
2
Issue
8
Publish Date
2015
Start Page
150143
DOI
10.1098/rsos.150143

Programmed death ligand 1 (PD-L1) as an immunotherapy target in patients with glioblastoma.

Authors
Vlahovic, G; Fecci, PE; Reardon, D; Sampson, JH
MLA Citation
Vlahovic, G, Fecci, PE, Reardon, D, and Sampson, JH. "Programmed death ligand 1 (PD-L1) as an immunotherapy target in patients with glioblastoma." Neuro-oncology 17.8 (August 2015): 1043-1045.
PMID
25964311
Source
epmc
Published In
Neuro-Oncology
Volume
17
Issue
8
Publish Date
2015
Start Page
1043
End Page
1045
DOI
10.1093/neuonc/nov071

Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies.

Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies.Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m(2) starting dose was doubled (one patient/dose) until 1.0 mg/m(2) based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response.Ixazomib was escalated from 0.125 to 2.34 mg/m(2) to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m(2): grade 3 pruritic rash; 2.34 mg/m(2): grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m(2). Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8-7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement.In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects.

Authors
Smith, DC; Kalebic, T; Infante, JR; Siu, LL; Sullivan, D; Vlahovic, G; Kauh, JS; Gao, F; Berger, AJ; Tirrell, S; Gupta, N; Di Bacco, A; Berg, D; Liu, G; Lin, J; Hui, A-M; Thompson, JA
MLA Citation
Smith, DC, Kalebic, T, Infante, JR, Siu, LL, Sullivan, D, Vlahovic, G, Kauh, JS, Gao, F, Berger, AJ, Tirrell, S, Gupta, N, Di Bacco, A, Berg, D, Liu, G, Lin, J, Hui, A-M, and Thompson, JA. "Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies." Investigational new drugs 33.3 (June 2015): 652-663.
PMID
25777468
Source
epmc
Published In
Investigational New Drugs
Volume
33
Issue
3
Publish Date
2015
Start Page
652
End Page
663
DOI
10.1007/s10637-015-0230-x

AT-46 * VORINOSTAT AND BEVACIZUMAB FOR RECURRENT HIGH-GRADE GLIOMA: INTERIM ANALYSIS OF A PHASE II CLINICAL TRIAL

Authors
Peters, K; Reardon, D; Randazzo, D; Dutton, S; Edwards, A; Lipp, E; Herndon, J; McSherry, F; Desjardins, A; Ranjan, T; Vlahovic, G; Friedman, H
MLA Citation
Peters, K, Reardon, D, Randazzo, D, Dutton, S, Edwards, A, Lipp, E, Herndon, J, McSherry, F, Desjardins, A, Ranjan, T, Vlahovic, G, and Friedman, H. "AT-46 * VORINOSTAT AND BEVACIZUMAB FOR RECURRENT HIGH-GRADE GLIOMA: INTERIM ANALYSIS OF A PHASE II CLINICAL TRIAL." Neuro-Oncology 16.suppl 5 (November 1, 2014): v18-v18.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v18
End Page
v18
DOI
10.1093/neuonc/nou237.45

AT-20 * SINGLE INSTITUTION RETROSPECTIVE REVIEW OF PERFORMANCE STATUS AND CORTICOSTEROID USE IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS (PTS) TREATED ON BEVACIZUMAB (BEV)

Authors
Desjardins, A; Herndon, J; McSherry, F; Ravelo, A; Lipp, E; Healy, P; Peters, K; Vlahovic, G; Sampson, J; Friedman, A; Friedman, H
MLA Citation
Desjardins, A, Herndon, J, McSherry, F, Ravelo, A, Lipp, E, Healy, P, Peters, K, Vlahovic, G, Sampson, J, Friedman, A, and Friedman, H. "AT-20 * SINGLE INSTITUTION RETROSPECTIVE REVIEW OF PERFORMANCE STATUS AND CORTICOSTEROID USE IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS (PTS) TREATED ON BEVACIZUMAB (BEV)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v12-v13.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v12
End Page
v13
DOI
10.1093/neuonc/nou237.20

AT-21 * FINAL RESULTS OF A PHASE 1 TRIAL OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA (GBM)

Authors
Desjardins, A; Sampson, J; Peters, K; Vlahovic, G; Threatt, S; Herndon, J; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, E; Friedman, A; Friedman, H; Bigner, D; Gromeier, M
MLA Citation
Desjardins, A, Sampson, J, Peters, K, Vlahovic, G, Threatt, S, Herndon, J, Boulton, S, Lally-Goss, D, McSherry, F, Lipp, E, Friedman, A, Friedman, H, Bigner, D, and Gromeier, M. "AT-21 * FINAL RESULTS OF A PHASE 1 TRIAL OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA (GBM)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v13-v13.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v13
End Page
v13
DOI
10.1093/neuonc/nou237.21

MS-19 * LONG-TERM OUTCOMES FOR PATIENTS WITH INTRACRANIAL MENINGIOMAS: A SINGLE-INSTITUTION RETROSPECTIVE ANALYSIS

Authors
Mowery, Y; Wright, A; Desjardins, A; Peters, K; Ranjan, T; Vlahovic, G; Friedman, H; Zomorodi, A; Kaylie, D; Adogwa, O; Nimjee, S; Sperduto, W; Chagoya, G; Fatemi, P; McLendon, R; Cummings, T; Friedman, A; Sampson, J; Kirkpatrick, J
MLA Citation
Mowery, Y, Wright, A, Desjardins, A, Peters, K, Ranjan, T, Vlahovic, G, Friedman, H, Zomorodi, A, Kaylie, D, Adogwa, O, Nimjee, S, Sperduto, W, Chagoya, G, Fatemi, P, McLendon, R, Cummings, T, Friedman, A, Sampson, J, and Kirkpatrick, J. "MS-19 * LONG-TERM OUTCOMES FOR PATIENTS WITH INTRACRANIAL MENINGIOMAS: A SINGLE-INSTITUTION RETROSPECTIVE ANALYSIS." Neuro-Oncology 16.suppl 5 (November 1, 2014): v130-v131.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v130
End Page
v131
DOI
10.1093/neuonc/nou260.18

AT-22 * PHASE II TRIAL OF BEVACIZUMAB, RADIATION THERAPY (RT) AND TEMOZOLOMIDE FOLLOWED BY BEVACIZUMAB AND TEMOZOLOMIDE WITH CONTINUATION OF BEVACIZUMAB BEYOND PROGRESSION

Authors
Ghiaseddin, A; Dunn-Pirio, A; Peters, K; Vlahovic, G; Herndon, J; Threatt, S; Sampson, J; Friedman, A; Friedman, H; Desjardins, A
MLA Citation
Ghiaseddin, A, Dunn-Pirio, A, Peters, K, Vlahovic, G, Herndon, J, Threatt, S, Sampson, J, Friedman, A, Friedman, H, and Desjardins, A. "AT-22 * PHASE II TRIAL OF BEVACIZUMAB, RADIATION THERAPY (RT) AND TEMOZOLOMIDE FOLLOWED BY BEVACIZUMAB AND TEMOZOLOMIDE WITH CONTINUATION OF BEVACIZUMAB BEYOND PROGRESSION." Neuro-Oncology 16.suppl 5 (November 1, 2014): v13-v13.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v13
End Page
v13
DOI
10.1093/neuonc/nou237.22

IT-34 * PILOT STUDY OF COMBINATION OF ANTITUMOR IMMUNOTHERAPY TARGETED AGAINST CYTOMEGALOVIRUS (CMV) PLUS REGULATORY T-CELL INHIBITION IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM)

Authors
Vlahovic, G; Archer, G; Lally-Goss, D; Reap, E; Batich, K; Desjardins, A; Peters, K; Ranjan, T; Healy, P; Herndon, J; Friedman, A; Friedman, H; Bigner, D; Sampson, J
MLA Citation
Vlahovic, G, Archer, G, Lally-Goss, D, Reap, E, Batich, K, Desjardins, A, Peters, K, Ranjan, T, Healy, P, Herndon, J, Friedman, A, Friedman, H, Bigner, D, and Sampson, J. "IT-34 * PILOT STUDY OF COMBINATION OF ANTITUMOR IMMUNOTHERAPY TARGETED AGAINST CYTOMEGALOVIRUS (CMV) PLUS REGULATORY T-CELL INHIBITION IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v117-v117.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v117
End Page
v117
DOI
10.1093/neuonc/nou258.32

SM-02 * LEVETIRACETAM USAGE IN POST-OPERATIVE SEIZURE MANAGEMENT IN MALIGNANT GLIOMA

Authors
Kang, J; Desjardins, A; Healy, P; Herndon, J; Lipp, E; Peters, K; Vlahovic, G; Sampson, J; Friedman, H; Friedman, A; Adamson, C
MLA Citation
Kang, J, Desjardins, A, Healy, P, Herndon, J, Lipp, E, Peters, K, Vlahovic, G, Sampson, J, Friedman, H, Friedman, A, and Adamson, C. "SM-02 * LEVETIRACETAM USAGE IN POST-OPERATIVE SEIZURE MANAGEMENT IN MALIGNANT GLIOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v206-v206.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v206
End Page
v206
DOI
10.1093/neuonc/nou277.2

AT-48 * A PHASE 1 TRIAL OF CARBOXYAMIDOTRIAZOLE OROTATE (CTO) IN COMBINATION WITH BEVACIZUMAB FOR ADULT PATIENTS WITH RECURRENT MALIGNANT GLIOMA POST-BEVACIZUMAB FAILURE

Authors
Ranjan, T; Peters, KB; Vlahovic, G; Watts, J; Dutton, S; Boulton, S; Lipp, E; Herndon, J; Healy, P; Miller, E; Friedman, H; Karmali, R; Desjardins, A
MLA Citation
Ranjan, T, Peters, KB, Vlahovic, G, Watts, J, Dutton, S, Boulton, S, Lipp, E, Herndon, J, Healy, P, Miller, E, Friedman, H, Karmali, R, and Desjardins, A. "AT-48 * A PHASE 1 TRIAL OF CARBOXYAMIDOTRIAZOLE OROTATE (CTO) IN COMBINATION WITH BEVACIZUMAB FOR ADULT PATIENTS WITH RECURRENT MALIGNANT GLIOMA POST-BEVACIZUMAB FAILURE." Neuro-Oncology 16.suppl 5 (November 1, 2014): v19-v19.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v19
End Page
v19
DOI
10.1093/neuonc/nou237.47

QL-21 * SPIRITUAL WELL-BEING AND ITS ASSOCIATION WITH HEALTH-RELATED QUALITY OF LIFE IN PRIMARY BRAIN TUMOR PATIENTS

Authors
Randazzo, D; Affronti, M; Lipp, E; McSherry, F; Herndon, J; Flahiff, C; Miller, E; Woodring, S; Freeman, M; Healy, P; Minchew, J; Boulton, S; Desjardins, A; Ranjan, T; Vlahovic, G; Friedman, H; Peters, K
MLA Citation
Randazzo, D, Affronti, M, Lipp, E, McSherry, F, Herndon, J, Flahiff, C, Miller, E, Woodring, S, Freeman, M, Healy, P, Minchew, J, Boulton, S, Desjardins, A, Ranjan, T, Vlahovic, G, Friedman, H, and Peters, K. "QL-21 * SPIRITUAL WELL-BEING AND ITS ASSOCIATION WITH HEALTH-RELATED QUALITY OF LIFE IN PRIMARY BRAIN TUMOR PATIENTS." Neuro-Oncology 16.suppl 5 (November 1, 2014): v182-v183.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v182
End Page
v183
DOI
10.1093/neuonc/nou269.20

AT-19 * SINGLE INSTITUTION RETROSPECTIVE COMPARISON OF GLIOBLASTOMA (GBM) PATIENTS (PTS) INITIATED ON BEVACIZUMAB (BEV) BEFORE VERSUS AFTER RECURRENCE IN CLINICAL PRACTICE

Authors
Desjardins, A; Herndon, J; McSherry, F; Ravelo, A; Lipp, E; Healy, P; Boulton, S; Peters, K; Vlahovic, G; Sampson, J; Friedman, A; Friedman, H
MLA Citation
Desjardins, A, Herndon, J, McSherry, F, Ravelo, A, Lipp, E, Healy, P, Boulton, S, Peters, K, Vlahovic, G, Sampson, J, Friedman, A, and Friedman, H. "AT-19 * SINGLE INSTITUTION RETROSPECTIVE COMPARISON OF GLIOBLASTOMA (GBM) PATIENTS (PTS) INITIATED ON BEVACIZUMAB (BEV) BEFORE VERSUS AFTER RECURRENCE IN CLINICAL PRACTICE." Neuro-Oncology 16.suppl 5 (November 1, 2014): v12-v12.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v12
End Page
v12
DOI
10.1093/neuonc/nou237.19

QL-20 * PROGNOSTIC IMPORTANCE OF HEALTH-RELATED QUALITY OF LIFE AND FATIGUE IN NEWLY DIAGNOSED GLIOBLASTOMA

Authors
Peters, K; Randazzo, D; Affronti, M; Lipp, E; McSherry, F; Herndon, J; Flahiff, C; Miller, E; Woodring, S; Freeman, M; Healy, P; Minchew, J; Boulton, S; Desjardins, A; Ranjan, T; Vlahovic, G; Jones, L; Friedman, H
MLA Citation
Peters, K, Randazzo, D, Affronti, M, Lipp, E, McSherry, F, Herndon, J, Flahiff, C, Miller, E, Woodring, S, Freeman, M, Healy, P, Minchew, J, Boulton, S, Desjardins, A, Ranjan, T, Vlahovic, G, Jones, L, and Friedman, H. "QL-20 * PROGNOSTIC IMPORTANCE OF HEALTH-RELATED QUALITY OF LIFE AND FATIGUE IN NEWLY DIAGNOSED GLIOBLASTOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v182-v182.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v182
End Page
v182
DOI
10.1093/neuonc/nou269.19

IT-28 * VACCINATION AGAINST EPIDERMAL GROWTH FACTOR RECEPTOR VARIANT III IN GLIOBLASTOMA: THE RINDOPEPIMUT COMPASSIONATE USE EXPERIENCE

Authors
Razis, E; Vlahovic, G; Recht, L; Wheeler, H; Reardon, D; Fisher, PG; Owen, S; Nicholas, K; Paradise, E; Yellin, M; Davis, T; Weller, M; Stupp, R; Hottinger, AF
MLA Citation
Razis, E, Vlahovic, G, Recht, L, Wheeler, H, Reardon, D, Fisher, PG, Owen, S, Nicholas, K, Paradise, E, Yellin, M, Davis, T, Weller, M, Stupp, R, and Hottinger, AF. "IT-28 * VACCINATION AGAINST EPIDERMAL GROWTH FACTOR RECEPTOR VARIANT III IN GLIOBLASTOMA: THE RINDOPEPIMUT COMPASSIONATE USE EXPERIENCE." Neuro-Oncology 16.suppl 5 (November 1, 2014): v115-v116.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v115
End Page
v116
DOI
10.1093/neuonc/nou258.26

A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors.

Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.

Authors
Vlahovic, G; Karantza, V; Wang, D; Cosgrove, D; Rudersdorf, N; Yang, J; Xiong, H; Busman, T; Mabry, M
MLA Citation
Vlahovic, G, Karantza, V, Wang, D, Cosgrove, D, Rudersdorf, N, Yang, J, Xiong, H, Busman, T, and Mabry, M. "A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors." Investigational new drugs 32.5 (October 2014): 976-984.
PMID
24894650
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
5
Publish Date
2014
Start Page
976
End Page
984
DOI
10.1007/s10637-014-0116-3

A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors

© Springer Science+Business Media New York 2014.Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.

Authors
Vlahovic, G; Karantza, V; Wang, D; Cosgrove, D; Rudersdorf, N; Yang, J; Xiong, H; Busman, T; Mabry, M
MLA Citation
Vlahovic, G, Karantza, V, Wang, D, Cosgrove, D, Rudersdorf, N, Yang, J, Xiong, H, Busman, T, and Mabry, M. "A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors." Investigational New Drugs 32.5 (January 1, 2014): 976-984.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
5
Publish Date
2014
Start Page
976
End Page
984
DOI
10.1007/s10637-014-0116-3

Editorial on "heat shock protein peptide complex-96 (HSPPC-96) vaccination for recurrent glioblastoma: a phase II, single arm trial".

Authors
Sampson, JH; Vlahovic, G
MLA Citation
Sampson, JH, and Vlahovic, G. "Editorial on "heat shock protein peptide complex-96 (HSPPC-96) vaccination for recurrent glioblastoma: a phase II, single arm trial"." Neuro-oncology 16.2 (January 2014): 169-170.
PMID
24443362
Source
epmc
Published In
Neuro-Oncology
Volume
16
Issue
2
Publish Date
2014
Start Page
169
End Page
170
DOI
10.1093/neuonc/not311

PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions.

OBJECTIVE: Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis(N4-methylthiosemicarbazone) ((62)Cu-ATSM) have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another PET imaging agent, copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) ((62)Cu-PTSM), which can detect areas of perfusion, can augment the information obtained in (62)Cu-ATSM PET scans. SUBJECTS AND METHODS: To characterize tumors on the basis of both perfusion and hypoxia, 10 patients were studied using both (62)Cu-ATSM and (62)Cu-PTSM PET scans. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed. RESULTS: Six of 10 patients had evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using (62)Cu-ATSM and (62)Cu-PTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between epidermal growth factor levels and (62)Cu-ATSM-detected hypoxia. CONCLUSION: This initial series of (62)Cu-ATSM and (62)Cu-PTSM PET scans shows that evaluating lung masses by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of (62)Cu-ATSM and (62)Cu-PTSM PET techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care.

Authors
Zhang, T; Das, SK; Fels, DR; Hansen, KS; Wong, TZ; Dewhirst, MW; Vlahovic, G
MLA Citation
Zhang, T, Das, SK, Fels, DR, Hansen, KS, Wong, TZ, Dewhirst, MW, and Vlahovic, G. "PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions." AJR Am J Roentgenol 201.5 (November 2013): W698-W706.
PMID
24147499
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
201
Issue
5
Publish Date
2013
Start Page
W698
End Page
W706
DOI
10.2214/AJR.12.9698

A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors.

PURPOSE: Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination. METHODS: Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. RESULTS: Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months. CONCLUSIONS: The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

Authors
Vlahovic, G; Meadows, KL; Uronis, HE; Morse, MA; Blobe, GC; Riedel, RF; Zafar, SY; Alvarez-Secord, A; Gockerman, J; Starodub, AN; Ready, NE; Anderson, EL; Bendell, JC; Hurwitz, HI
MLA Citation
Vlahovic, G, Meadows, KL, Uronis, HE, Morse, MA, Blobe, GC, Riedel, RF, Zafar, SY, Alvarez-Secord, A, Gockerman, J, Starodub, AN, Ready, NE, Anderson, EL, Bendell, JC, and Hurwitz, HI. "A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors." Cancer Chemother Pharmacol 70.1 (July 2012): 95-102.
PMID
22638798
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
1
Publish Date
2012
Start Page
95
End Page
102
DOI
10.1007/s00280-012-1889-8

Retraction: characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma.

Authors
Stevenson, M; Mostertz, W; Acharya, CR; Kim, W; Walters, K; Barry, W; Higgins, K; Tuchman, SA; Crawford, J; Vlahovic, G; Ready, N; Onaitis, M; Potti, A
MLA Citation
Stevenson, M, Mostertz, W, Acharya, CR, Kim, W, Walters, K, Barry, W, Higgins, K, Tuchman, SA, Crawford, J, Vlahovic, G, Ready, N, Onaitis, M, and Potti, A. "Retraction: characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma." Clin Cancer Res 18.6 (March 15, 2012): 1818-.
PMID
22355011
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
6
Publish Date
2012
Start Page
1818
DOI
10.1158/1078-0432.CCR-12-0337

Cancer- and chemotherapy-induced anemia: Clinical practice guidelines in oncology

Anemia is prevalent in 30% to 90% of patients with cancer. Anemia can be corrected through either treating the underlying cause or providing supportive care through transfusion with packed red blood cells or administration of erythropoiesis-stimulating agents (ESAs), with or without iron supplementation. Recent studies showing detrimental health effects of ESAs sparked a series of FDA label revisions and a sea change in the perception of these once commonly used agents. In light of this, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer- and Chemotherapy-Induced Anemia underwent substantial revisions this year. The purpose of these NCCN Guidelines is twofold: 1) to operationalize the evaluation and treatment of anemia in adult cancer patients, with an emphasis on those who are receiving concomitant chemotherapy, and 2) to enable patients and clinicians to individualize anemia treatment options based on patient condition. © JNCCN-Journal of the National Comprehensive Cancer Network.

Authors
III, GMR; Becker, PS; Blinder, M; Cella, D; Chanan-Khan, A; Cleeland, C; Coccia, PF; Djulbegovic, B; Gilreath, JA; Kraut, EH; Matulonis, UA; Millenson, MM; Reinke, D; Rosenthal, J; Schwartz, RN; Soff, G; Stein, RS; Vlahovic, G; III, ABW
MLA Citation
III, GMR, Becker, PS, Blinder, M, Cella, D, Chanan-Khan, A, Cleeland, C, Coccia, PF, Djulbegovic, B, Gilreath, JA, Kraut, EH, Matulonis, UA, Millenson, MM, Reinke, D, Rosenthal, J, Schwartz, RN, Soff, G, Stein, RS, Vlahovic, G, and III, ABW. "Cancer- and chemotherapy-induced anemia: Clinical practice guidelines in oncology." JNCCN Journal of the National Comprehensive Cancer Network 10.5 (2012): 628-653.
PMID
22570293
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
10
Issue
5
Publish Date
2012
Start Page
628
End Page
653

Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles. On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer (NSCLC), we aimed to assess efficacy and safety of this combination in a phase 3 trial. METHODS: In our double-blind, placebo-controlled, randomised phase 3 trial (BeTa), we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment. Patients were randomly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab (bevacizumab group) or erlotinib plus placebo (control group) according to a computer-generated randomisation sequence by use of an interactive voice response system. The primary endpoint was overall survival in all enrolled patients. Patients, study staff, and investigators were masked to treatment assignment. We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses. This trial is registered with ClinicalTrials.gov, number NCT00130728. FINDINGS: Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group (hazard ratio [HR] 0·97, 95% CI 0·80-1·18, p=0·7583). Median overall survival was 9·3 months (IQR 4·1-21·6) for patients in the bevacizumab group compared with 9·2 months (3·8-20·2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3·4 months [1·4-8·4]) than in the control group (1·7 months [1·3-4·1]; HR 0·62, 95% CI 0·52-0·75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate. In the bevacizumab group, 130 (42%) of 313 patients with safety data had a serious adverse event, compared with 114 (36%) controls. There were 20 (6%) grade 5 adverse events, including two arterial thromboembolic events, in the bevacizumab group, and 14 (4%) in the control group. INTERPRETATION: Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC. FUNDING: Genentech.

Authors
Herbst, RS; Ansari, R; Bustin, F; Flynn, P; Hart, L; Otterson, GA; Vlahovic, G; Soh, C-H; O'Connor, P; Hainsworth, J
MLA Citation
Herbst, RS, Ansari, R, Bustin, F, Flynn, P, Hart, L, Otterson, GA, Vlahovic, G, Soh, C-H, O'Connor, P, and Hainsworth, J. "Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial." Lancet 377.9780 (May 28, 2011): 1846-1854.
PMID
21621716
Source
pubmed
Published In
The Lancet
Volume
377
Issue
9780
Publish Date
2011
Start Page
1846
End Page
1854
DOI
10.1016/S0140-6736(11)60545-X

MHC class I-presented lung cancer-associated tumor antigens identified by immunoproteomics analysis are targets for cancer-specific T cell response.

The development of potent cancer vaccines for common malignancies such as lung cancer requires identification of suitable target antigens. We hypothesized that peptide epitopes naturally presented by MHC class I molecules on the surface of cancer cells would be the most relevant targets. We used LC/MS/MS analysis and identified 68 MHC class I-presented peptides from lung cancer cells. Using the criteria of strong consensus for HLA-A2 binding and relevance of the source proteins to malignant phenotype, we selected 8 peptides for functional characterization. These peptides, with a range of binding affinities, were confirmed to stabilize HLA-A2 molecules and were used to activate peptide-specific CTLs that efficiently recognized lung tumor cells. No correlation between the transcript levels of the source proteins and the extent of peptide-specific T cell recognition of lung cancer cells was observed. Furthermore, the peptide specific CTLs failed to recognize HLA-A2+ normal lung cells despite expression of the mRNA encoding the source proteins from which the peptides were derived. We conclude that MHC class I associated peptide epitopes are a more relevant source of authentic tumor antigens than over-expressed proteins and the identified peptides may be used as antigens for therapeutic vaccine strategies to treat lung cancer.

Authors
Shetty, V; Sinnathamby, G; Nickens, Z; Shah, P; Hafner, J; Mariello, L; Kamal, S; Vlahović, G; Lyerly, HK; Morse, MA; Philip, R
MLA Citation
Shetty, V, Sinnathamby, G, Nickens, Z, Shah, P, Hafner, J, Mariello, L, Kamal, S, Vlahović, G, Lyerly, HK, Morse, MA, and Philip, R. "MHC class I-presented lung cancer-associated tumor antigens identified by immunoproteomics analysis are targets for cancer-specific T cell response." J Proteomics 74.5 (May 1, 2011): 728-743.
PMID
21362506
Source
pubmed
Published In
Journal of Proteomics
Volume
74
Issue
5
Publish Date
2011
Start Page
728
End Page
743
DOI
10.1016/j.jprot.2011.02.020

Lower incidence of deletions in the survival of motor neuron gene and the neuronal apoptosis inhibitory protein gene in children with spinal muscular atrophy from Serbia.

Spinal muscular atrophy (SMA) is the second most frequent autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular atrophy. SMA is classified into three types according to disease severity and age-onset: severe (type I), intermediate (type II) and mild (type III). Deletions in the survival motor neuron (SMN) gene, located in the chromosome region 5q11.2- 5q13.3, are major determinants of SMA phenotype. Extended deletions that include the neuronal apoptosis inhibitory protein (NAIP) gene may correlate with the severtity of SMA. SMN gene is present in two highly homologous copies, SMN1 and SMN2, but only deletions of the SMN1 gene (exons 7 and 8 or exon 7) are responsible for clinical manifestations of SMA. Here, we present the deletion profiling of SMN1 and NAIP genes in 89 children with SMA from Serbia: 52 patients with type I, 26 with type II, and 11 with type III. The homozygous deletion of the SMN1 gene was confirmed in 72 of 89 (81%) patients, being the most frequent in SMA type I (48/52): 68 patients (94.4%) with deletion of exons 7 and 8 and 4 patients (5.6%) with deletion of exon 7. The extended deletion including the NAIP gene was detected in 18 of 89 (20.2%) patients, mostly affected with type I. This study has revealed the lower incidence of deletions in the SMN1 and NAIP genes in families with SMA in Serbia and will provide important information for genetic counselling in these families.

Authors
Miskovic, M; Lalic, T; Radivojevic, D; Cirkovic, S; Vlahovic, G; Zamurovic, D; Guc-Scekic, M
MLA Citation
Miskovic, M, Lalic, T, Radivojevic, D, Cirkovic, S, Vlahovic, G, Zamurovic, D, and Guc-Scekic, M. "Lower incidence of deletions in the survival of motor neuron gene and the neuronal apoptosis inhibitory protein gene in children with spinal muscular atrophy from Serbia." Tohoku J Exp Med 225.3 (2011): 153-159.
PMID
21971302
Source
pubmed
Published In
The Tohoku journal of experimental medicine
Volume
225
Issue
3
Publish Date
2011
Start Page
153
End Page
159

Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor.

BACKGROUND: Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy. METHODS: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m⁻²), or CP-868,596 (60 mg BID), docetaxel (75 mg m⁻²), and VEGFR inhibitor axitinib (5 mg BID). RESULTS: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m⁻² docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles. CONCLUSIONS: The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.

Authors
Michael, M; Vlahovic, G; Khamly, K; Pierce, KJ; Guo, F; Olszanski, AJ
MLA Citation
Michael, M, Vlahovic, G, Khamly, K, Pierce, KJ, Guo, F, and Olszanski, AJ. "Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor." Br J Cancer 103.10 (November 9, 2010): 1554-1561.
PMID
20959830
Source
pubmed
Published In
British Journal of Cancer
Volume
103
Issue
10
Publish Date
2010
Start Page
1554
End Page
1561
DOI
10.1038/sj.bjc.6605941

Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma.

PURPOSE: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways. EXPERIMENTAL DESIGN: Lung cancer cell lines with corresponding gene expression data and genes associated with an embryonic stem cell identity were used to develop a signature of embryonic stemness (ES) activity specific to lung adenocarcinoma. Biological characteristics were elucidated as a function of cancer biology/oncogenic pathway dysregulation. The ES signature was applied to three independent early-stage (I-IIIa) lung adenocarcinoma data sets with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin (current standard of care) sensitivity was evaluated. RESULTS: Pathway analysis identified specific regulatory networks [Ras (P = 0.0005), Myc (P = 0.0224), wound healing (P < 0.0001), chromosomal instability (P < 0.0001), and invasiveness (P < 0.0001)] associated with the ES phenotype. The prognostic relevance of the ES signature, as related to patient survival, was characterized in three cohorts [CALGB 9761 (n = 82; P = 0.0001), National Cancer Institute Director's Challenge Consortium (n = 442; P = 0.0002), and Duke (n = 45; P = 0.06)]. The ES signature was not prognostic in prostate, breast, or ovarian adenocarcinomas. Lung tumors (n = 569) and adenocarcinoma cell lines (n = 31) expressing the ES phenotype were more likely to be resistant to cisplatin (P < 0.0001 and P = 0.006, respectively). CONCLUSIONS: Lung adenocarcinomas that share a common gene expression pattern with normal human embryonic stem cells were associated with decreased survival, increased biological complexity, and increased likelihood of resistance to cisplatin. This indicates the aggressiveness of these tumors.

Authors
Stevenson, M; Mostertz, W; Acharya, C; Kim, W; Walters, K; Barry, W; Higgins, K; Tuchman, SA; Crawford, J; Vlahovic, G; Ready, N; Onaitis, M; Potti, A
MLA Citation
Stevenson, M, Mostertz, W, Acharya, C, Kim, W, Walters, K, Barry, W, Higgins, K, Tuchman, SA, Crawford, J, Vlahovic, G, Ready, N, Onaitis, M, and Potti, A. "Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma." Clin Cancer Res 15.24 (December 15, 2009): 7553-7561.
PMID
19996213
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
24
Publish Date
2009
Start Page
7553
End Page
7561
DOI
10.1158/1078-0432.CCR-09-1939

Hypoxia, angiogenesis, and lung cancer.

Lung cancer is responsible for more deaths than any other cancer in America. As a result, novel ways to treat it are needed to improve patient outcomes. A tumor must form new blood vessels to grow and metastasize to distant sites; this angiogenesis is mediated by factors such as vascular endothelial growth factor (VEGF). Because it increases VEGF levels, hypoxia has been thought to be a primary trigger of angiogenesis. Tumor hypoxia and higher levels of serum markers of angiogenesis have been associated with poor prognosis in non-small cell lung cancer (NSCLC). In recent years, antiangiogenic compounds have been developed and tested in various solid malignancies, including NSCLC, for which bevacizumab, a monoclonal antibody against VEGF, was recently approved. Combinations of antiangiogenic drugs and conventional cytotoxic chemotherapy are currently under development.

Authors
Goudar, RK; Vlahovic, G
MLA Citation
Goudar, RK, and Vlahovic, G. "Hypoxia, angiogenesis, and lung cancer." Curr Oncol Rep 10.4 (July 2008): 277-282. (Review)
PMID
18778551
Source
pubmed
Published In
Current Oncology Reports
Volume
10
Issue
4
Publish Date
2008
Start Page
277
End Page
282

PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator.

OBJECTIVE: Copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) and copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) are being studied as potential markers of hypoxia and perfusion, respectively. The use of short-lived radionuclides (e.g., 62Cu) has advantages for clinical PET, including a lower radiation dose than long-lived radionuclides and serial imaging capability. A 62Zn/62Cu microgenerator and rapid synthesis kits now provide a practical means of producing 62Cu-PTSM and 62Cu-ATSM on-site. Tumors can be characterized with 62Cu-PTSM, 62Cu-ATSM, and 18F-FDG PET scans during one session. We present the initial clinical data in two patients with lung neoplasms. CONCLUSION: Hypoxia and perfusion are important parameters in tumor physiology and can have major implications in diagnosis, prognosis, treatment planning, and response to therapy. We have shown the feasibility of performing 62Cu-ATSM and 62Cu-PTSM PET together with FDG PET/CT during a single imaging session to provide information on both perfusion and hypoxia and tumor anatomy and metabolism.

Authors
Wong, TZ; Lacy, JL; Petry, NA; Hawk, TC; Sporn, TA; Dewhirst, MW; Vlahovic, G
MLA Citation
Wong, TZ, Lacy, JL, Petry, NA, Hawk, TC, Sporn, TA, Dewhirst, MW, and Vlahovic, G. "PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator." AJR Am J Roentgenol 190.2 (February 2008): 427-432.
PMID
18212229
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
190
Issue
2
Publish Date
2008
Start Page
427
End Page
432
DOI
10.2214/AJR.07.2876

Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts.

Imatinib, an inhibitor of PDGF-Rbeta and other tyrosine kinase receptors, has been shown to decrease microvessel density and interstitial fluid pressure in solid tumours, thereby improving subsequent delivery of small molecules. The purpose of this study was to test whether pretreatment with imatinib increases the efficacy of traditional chemotherapy in mice bearing non-small cell lung carcinoma xenografts, and to investigate the effects of imatinib on liposomal drug delivery. Efficacy treatment groups included (n=9-10): saline control, imatinib alone (oral gavage, 100 mg kg(-1) x 7 days), docetaxel alone (10 mg kg(-1) i.p. 2 x /week until killing), and imatinib plus docetaxel (started on day 7 of imatinib). Tumours were monitored until they reached four times the initial treatment volume (4 x V) or 28 days. A separate experiment compared tumour doxorubicin concentrations (using high performance liquid chromatography) 24 h after treatment with liposomal doxorubicin alone (6 mg kg(-1) i.v., n=9) or imatinib plus liposomal doxorubicin (n=16). Imatinib plus docetaxel resulted in significantly improved antitumour efficacy (0/10 animals reached 4 x V by 28 days) when compared to docetaxel alone (3/9 reached 4 x V, P=0.014) or imatinib alone (9/10 reached 4 x V, P=0.025). Pretreatment with imatinib also significantly increased tumour concentrations of liposomal doxorubicin. Overall, these preclinical studies emphasise the potential of imatinib as an adjunct to small molecule or liposomal chemotherapy.

Authors
Vlahovic, G; Ponce, AM; Rabbani, Z; Salahuddin, FK; Zgonjanin, L; Spasojevic, I; Vujaskovic, Z; Dewhirst, MW
MLA Citation
Vlahovic, G, Ponce, AM, Rabbani, Z, Salahuddin, FK, Zgonjanin, L, Spasojevic, I, Vujaskovic, Z, and Dewhirst, MW. "Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts." Br J Cancer 97.6 (September 17, 2007): 735-740.
PMID
17712313
Source
pubmed
Published In
British Journal of Cancer
Volume
97
Issue
6
Publish Date
2007
Start Page
735
End Page
740
DOI
10.1038/sj.bjc.6603941

Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer.

BACKGROUND: Localized rectal cancer responds well to 5-fluorouracil and radiation-based regimens. A phase I-II trial is currently testing the efficacy of adding bevacizumab, a VEGF-specific antibody, to standard chemoradiotherapy. The case presented here is a complete pathological response seen in a patient with extensive and locally invasive carcinoma after receiving this combined treatment. INVESTIGATIONS: Physical examination, rectal ultrasound, PET-CT scan, laboratory tests, proctoscopic examination, chest radiograph, rectal forcep biopsies with immunohistochemistry, and protein and flow cytometric analyses. DIAGNOSIS: Large, invasive, ultrasound stage T4 carcinoma of the rectum, which was positive for survivin. MANAGEMENT: One 2-week cycle of bevacizumab alone, followed by 3 cycles of bevacizumab with continuous 5-fluorouracil infusion, and external-beam radiation therapy given 5 days per week to the pelvis, abdominoperineal resection with posterior vaginectomy, hysterectomy and bilateral salpingo-oophorectomy.

Authors
Willett, CG; Duda, DG; di Tomaso, E; Boucher, Y; Czito, BG; Vujaskovic, Z; Vlahovic, G; Bendell, J; Cohen, KS; Hurwitz, HI; Bentley, R; Lauwers, GY; Poleski, M; Wong, TZ; Paulson, E; Ludwig, KA; Jain, RK
MLA Citation
Willett, CG, Duda, DG, di Tomaso, E, Boucher, Y, Czito, BG, Vujaskovic, Z, Vlahovic, G, Bendell, J, Cohen, KS, Hurwitz, HI, Bentley, R, Lauwers, GY, Poleski, M, Wong, TZ, Paulson, E, Ludwig, KA, and Jain, RK. "Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer." Nat Clin Pract Oncol 4.5 (May 2007): 316-321.
PMID
17464339
Source
pubmed
Published In
Nature Clinical Practice Oncology
Volume
4
Issue
5
Publish Date
2007
Start Page
316
End Page
321
DOI
10.1038/ncponc0813

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation.

Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta. We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression.

Authors
Vlahovic, G; Rabbani, ZN; Herndon, JE; Dewhirst, MW; Vujaskovic, Z
MLA Citation
Vlahovic, G, Rabbani, ZN, Herndon, JE, Dewhirst, MW, and Vujaskovic, Z. "Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation." Br J Cancer 95.8 (October 23, 2006): 1013-1019.
PMID
17003785
Source
pubmed
Published In
British Journal of Cancer
Volume
95
Issue
8
Publish Date
2006
Start Page
1013
End Page
1019
DOI
10.1038/sj.bjc.6603366

[Aetiological aspects of West Syndrome].

INTRODUCTION: West Syndrome involves epileptic encephalopathy in infants, occurring with an incidence of 5/10000 live births. Its main clinical feature are spasms that occur in clusters, which are associated with an EEG pattern called hypsarrhythmia and psychomotor retardation in most patients. West Syndrome is associated with many underlying conditions and the terms idiopathic, cryptogenic, and symptomatic are used for its aetiological subgroups. OBJECTIVE: The objective of this investigation was to determine the aetiological diagnosis of patients with West Syndrome and to compare the results with other studies. METHOD: In this 34-year longitudinal prospective one-centre study, 404 patients were studied. All patients exhibiting the diagnostic criteria for West Syndrome were investigated by clinical and neurological examination, EEG, ophthalmologic, psychological, metabolic, genetic, as well as neuroradiological methods, according to their particular indications. RESULTS: 36 (8.9%) patients had normal development, in whom infantile spasms occurred without any identifiable underlying cause, forming the idiopathic group. 51 patients (12.6%) with neurological impairment of unknown aetiology formed the cryptogenic group. The greatest number of patients (317 or 78.5%) formed the symptomatic group, in which neurological features and developmental delay preceded the onset of spasms. Disgenetic disorders and hereditary metabolic diseases were aetiological factors 44 (10.8%) patients. Prenatal and perinatal aetiological factors were revealed in one third of the patients (134 or 31%). Postnatal aetiological factors were revealed in 42 (10.2%) patients. In our study, disgenetic disorders were registered less frequently and perinatal complications more frequently than in other studies. CONCLUSION: Our results indicate the possibility of preventing West Syndrome with good quality obstetric and neonatal care, as well as the early prenatal diagnosis of brain malformations. Modern, sophisticated investigation makes the more accurate aetiological diagnosis of West Syndrome possible.

Authors
Marjanović, B; Durić, M; Zamurović, D; Kravljanac, R; Vlahović, G; Komazec, D
MLA Citation
Marjanović, B, Durić, M, Zamurović, D, Kravljanac, R, Vlahović, G, and Komazec, D. "[Aetiological aspects of West Syndrome]." Srp Arh Celok Lek 134 Suppl 1 (May 2006): 45-49.
PMID
16796164
Source
pubmed
Published In
Srpski arhiv za celokupno lekarstvo
Volume
134 Suppl 1
Publish Date
2006
Start Page
45
End Page
49

Activation of tyrosine kinases in cancer.

Receptor and nonreceptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating certain types of cancer. Epidermal growth factor receptor (EGFR)-TK is a transmembrane receptor TK that is overexpressed or aberrantly activated in the most common solid tumors, including non-small cell lung cancer and cancers of the breast, prostate, and colon. Activation of the EGFR-TK enzyme results in autophosphorylation, which drives signal transduction pathways leading to tumor growth and malignant progression. Randomized clinical trials of the EGFR-TK inhibitor gefitinib have demonstrated clinical benefits in patients with advanced non-small cell lung cancer whose disease had previously progressed on platinum- and docetaxel-based chemotherapy regimens. Bcr-Abl is a constitutively activated nonreceptor TK enzyme found in the cytoplasm of Philadelphia chromosome-positive leukemia cells. STI571 (imatinib mesylate) inhibits the Bcr-Abl TK, blocks the growth of these leukemia cells, and induces apoptosis. STI571 also inhibits other TKs, including the receptor TK c-kit, which is expressed in gastrointestinal stromal tumors. As TK inhibitors become available for clinical use, new challenges include predicting which patients are most likely to respond to these targeted TK inhibitors. Additional clinical trials are needed to develop the full potential of receptor and nonreceptor TK inhibitors for cancer treatment.

Authors
Vlahovic, G; Crawford, J
MLA Citation
Vlahovic, G, and Crawford, J. "Activation of tyrosine kinases in cancer." Oncologist 8.6 (2003): 531-538. (Review)
PMID
14657531
Source
pubmed
Published In
The oncologist
Volume
8
Issue
6
Publish Date
2003
Start Page
531
End Page
538

[Schimke immuno-osseous dysplasia].

Schimke immuno-osseous dysplasia (OMIM *242900) is a rare autosomal recessive disorder that affects primarily the bone, the immune system, the kidneys, the skin and the vascular system. The patients have intrauterine growth retardation, short stature with short neck and trunk, peculiar clinical phenotype: triangular face, broad nasal bridge, bulbous nasal tip, small palpebral fissures, long upper lip and low hairline. The characteristic features include spondyloepiphyseal dysplasia, hyperpigmented maculae, proteinuria with progressive renal failure, lymphopenia with recurrent infections and cerebral ischaemia. We describe a girl, 5 years old, with short-trunk type of dwarfism (height 75 cm, below 3rd centile), short neck, accentuated lumbal lordosis and protruding abdomen. The patient had peculiar face with a broad, depressed nasal bridge, bulbous nasal tip, and slightly elongated upper lip. The hair was thin and sparse. Numerous pigmented spots resembling lentigines were visible on the trunk and abdomen. Radiographs showed spondyloepiphyseal dysplasia. At the age of 2 years laboratory analyses showed normal growth hormone secretion, normal thyroid function tests, normal female karyotype and no mucopolisachariduria. Since the age of 4 years, several episodes of transitory right-sided hemiparesis with spontaneous recovery, were observed. Seizures occurred at 5 years of age, when the MRI brain imaging showed multiple areas of ischaemia. She also experienced transient nephrotic syndrome, lymphopenia and low IgG accompanied by septicaemia.

Authors
Stajić, N; Rajić, V; Zdravković, D; Marjanović, B; Zamurović, D; Gujanica, Z; Vlahović, G; Bogdanović, R
MLA Citation
Stajić, N, Rajić, V, Zdravković, D, Marjanović, B, Zamurović, D, Gujanica, Z, Vlahović, G, and Bogdanović, R. "[Schimke immuno-osseous dysplasia]." Srp Arh Celok Lek 129 Suppl 1 (May 2001): 63-67.
PMID
15637995
Source
pubmed
Published In
Srpski arhiv za celokupno lekarstvo
Volume
129 Suppl 1
Publish Date
2001
Start Page
63
End Page
67

Cellular and connective tissue changes in alveolar septal walls in emphysema.

Emphysema is commonly defined as enlargement of airspaces distal to terminal bronchioles accompanied by destruction of alveolar walls, but without obvious fibrosis. Morphometric techniques were used to correlate changes in components of the alveolar septa surrounding enlarged airspaces in human emphysema with the mean linear intercept (Lm) of those airspaces. Alveolar and capillary surface density decreased with increased Lm, but the ratio of these surface densities to each other remained close to normal for mild to moderate increases in Lm. This suggests that the decreased gas exchange observed in emphysema is initiated by a total loss of septa and not by selective pathological changes of the microvasculature. Increases in septal wall thickness directly correlated with increases in Lm. For the mild to moderate emphysema lesions included in this study, an increase of 100% in Lm correlated with a 130% increase in the relative volume of the alveolar septal interstitium. Significant increases occurred in both elastin (0.14 to 0.56 microm(3)/microm(2) basement membrane [BM]) and collagen (0.49 to 1. 63 microm(3)/microm(2) BM). The increase in elastin and collagen raises the possibility of a remodeling process in the connective matrix in alveolar walls. Whether or not the new connective tissue represents a disordered, nonfunctional regional response needs to be determined.

Authors
Vlahovic, G; Russell, ML; Mercer, RR; Crapo, JD
MLA Citation
Vlahovic, G, Russell, ML, Mercer, RR, and Crapo, JD. "Cellular and connective tissue changes in alveolar septal walls in emphysema." Am J Respir Crit Care Med 160.6 (December 1999): 2086-2092.
PMID
10588633
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
160
Issue
6
Publish Date
1999
Start Page
2086
End Page
2092
DOI
10.1164/ajrccm.160.6.9706031
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