Publications by authors named "Robin Humphreys"

40 Publications

Quality improvement initiative to improve inpatient outcomes for Neonatal Abstinence Syndrome.

J Perinatol 2018 08 8;38(8):1114-1122. Epub 2018 May 8.

Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.

Objectives: To improve Neonatal Abstinence Syndrome (NAS) inpatient outcomes through a comprehensive quality improvement (QI) program.

Design: Inclusion criteria were opioid-exposed infants ≥36 weeks. QI methodology including stakeholder interviews and plan-do-study-act (PDSA) cycles were utilized. We compared pre- and post-intervention NAS outcomes after a QI initiative that included: A non-pharmacologic care bundle, function-based assessments consisting of symptom prioritization and then the "Eat, Sleep, Console" (ESC) Tool; and a switch to methadone for pharmacologic treatment.

Results: Pharmacologic treatment decreased from 87.1 to 40.0%; adjunctive agent use from 33.6 to 2.4%; hospitalization length from a mean 17.4 to 11.3 days, and opioid treatment days from 16.2 to 12.7 (p < 0.001 for all). Total hospital charges decreased from $31,825 to $20,668 per infant. Parental presence increased from 55.6 to 75.8% (p < 0.0001). No adverse events were noted.

Conclusions: A comprehensive QI program focused on non-pharmacologic care, function-based assessments, and methadone resulted in significant sustained improvements in NAS outcomes. These findings have important implications for establishing potentially better practices for opioid-exposed newborns.
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http://dx.doi.org/10.1038/s41372-018-0109-8DOI Listing
August 2018

Revision of Breastfeeding Guidelines in the Setting of Maternal Opioid Use Disorder: One Institution's Experience.

J Hum Lact 2016 May 29;32(2):382-7. Epub 2015 Oct 29.

Department of Pediatrics, Boston Medical Center, Boston, MA, USA.

Breastfeeding is recommended for women with opioid use disorder who are treated with methadone or buprenorphine. Infants with neonatal abstinence syndrome (NAS) secondary to in-utero opioid exposure have unique challenges related to breastfeeding but also have significant benefits including improved NAS symptoms with a decreased need for pharmacotherapy. Poor understanding of substance use disorder and treatment, lack of evidence-based recommendations, and vague guidelines from national academies create controversy about breastfeeding eligibility for these women. Defining breastfeeding guidelines is often difficult, particularly in large institutions with multiple providers caring for the mother-infant dyad. Based on the available evidence and review of our institutional data, we revised our breastfeeding guidelines for mothers with opioid use disorder. The aims of our new guidelines are (a) to safely promote breastfeeding in all mothers with opioid use disorder who are in recovery, (b) to improve NAS outcomes through use of breastfeeding as a key nonpharmacologic treatment modality, and (c) to improve staff communication and consistency on the subject of breastfeeding in this patient population.
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http://dx.doi.org/10.1177/0890334415613823DOI Listing
May 2016

Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib.

Oncoimmunology 2015 Sep 27;4(9):e1038011. Epub 2015 May 27.

Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; The University of Melbourne ; Parkville, VIC, Australia ; The ACRF Translational Research Laboratory; Royal Melbourne Hospital ; Parkville, VIC, Australia ; Department of Clinical Hematology and Bone Marrow Transplantation; Royal Melbourne Hospital ; Parkville, VIC, Australia.

There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8 T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses.
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http://dx.doi.org/10.1080/2162402X.2015.1038011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570118PMC
September 2015

Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer.

Clin Lung Cancer 2014 May 27;15(3):188-196.e2. Epub 2013 Dec 27.

Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO.

Background: This phase II study examined the efficacy of mapatumumab in combination with paclitaxel and carboplatin in patients with non-small-cell lung cancer (NSCLC).

Patients And Methods: Patients with stage IIIB or stage IV advanced primary NSCLC were randomly assigned (1:1:1) to receive up to 6 courses of standard-dose paclitaxel and carboplatin or a combination of paclitaxel, carboplatin, and mapatumumab (10 mg/kg or 30 mg/kg). Primary efficacy end points were overall response rate and median progression-free survival (PFS). Secondary efficacy end points included disease control rate, overall survival (OS), time to response, and duration of response. Exploratory studies included evaluation of historical biopsy materials for TRAIL-R1 expression by immunohistochemical analysis and serum levels of M30, a marker of apoptosis, before and after the first 2 doses of mapatumumab. Safety parameters, including adverse events (AEs), laboratory tests, and immunogenicity, were assessed.

Results: The majority of patients had stage IV disease (79%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%); baseline characteristics were similar across treatment arms. No improvements in response or disease control rates, PFS, or OS were gained from the addition of mapatumumab. Adverse events in the mapatumumab arms were generally consistent with toxicities seen in the carboplatin and paclitaxel control arm. Levels of M30 were highly variable, and consistent patterns were not seen across treatment arms.

Conclusion: This study showed no clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC. The combination was generally well tolerated. The possibility of subgroups sensitive to mapatumumab is discussed.
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http://dx.doi.org/10.1016/j.cllc.2013.12.005DOI Listing
May 2014

Sorafenib sensitizes solid tumors to Apo2L/TRAIL and Apo2L/TRAIL receptor agonist antibodies by the Jak2-Stat3-Mcl1 axis.

PLoS One 2013 26;8(9):e75414. Epub 2013 Sep 26.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.

Background: Approximately half of tumor cell lines are resistant to the tumor-selective apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (Apo22L/TRAIL). Previously, we showed that combining Apo2L/TRAIL with sorafenib, a multikinase inhibitor, results in dramatic efficacy in Apo2L/TRAIL-resistant tumor xenografts via inhibition of Mcl-1. Soluble Apo2L/TRAIL is capable of binding to several surface receptors, including the pro-apoptotic death receptors, DR4 and DR5, and decoy receptors, DcR1 and DcR2. Monoclonal antibodies targeting either of these death receptors are being investigated as antitumor agents in clinical trials. We hypothesized that sorafenib and Apo2L/TRAIL or Apo2L/TRAIL death receptor agonist (TRA) antibodies against DR4 (mapatumumab) and DR5 (lexatumumab) will overcome resistance to Apo2L/TRAIL-mediated apoptosis and as increase antitumor efficacy in Apo2L/TRAIL-sensitive solid tumors.

Methodology/principal Findings: We found that Apo2L/TRAIL or TRA antibodies combined with sorafenib synergistically reduce cell growth and increase cell death across a panel of solid tumor cell lines in vitro. This panel included human breast, prostate, colon, liver and thyroid cancers. The cooperativity of these combinations was also observed in vivo, as measured by tumor volume and TUNEL staining as a measure of apoptosis. We found that sorafenib inhibits Jak/Stat3 signaling and downregulates their target genes, including cyclin D1, cyclin D2 and Mcl-1, in a dose-dependent manner.

Conclusions/significance: The combination of sorafenib with Apo2L/TRAIL or Apo2L/TRAIL receptor agonist antibodies sensitizes Apo2L/TRAIL-resistant cells and increases the sensitivity of Apo2L/TRAIL-sensitive cells. Our findings demonstrate the involvement of the Jak2-Stat3-Mcl1 axis in response to sorafenib treatment, which may play a key role in sorafenib-mediated sensitization to Apo2L/TRAIL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075414PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784419PMC
July 2014

Fusion toxin BLyS-gelonin inhibits growth of malignant human B cell lines in vitro and in vivo.

PLoS One 2012 9;7(10):e47361. Epub 2012 Oct 9.

Department of Oncology Research, Human Genome Sciences, Inc., Rockville, Maryland, United States of America.

B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines. The biological activity of BLyS is mediated by three cell surface receptors: BR3/BAFF-R, TACI and BCMA. The expression of these receptors is highly restricted to B cells, both normal and malignant. A BLyS-gelonin fusion toxin (BLyS-gel) was generated consisting of the recombinant plant-derived toxin gelonin fused to the N-terminus of BLyS and tested against a large and diverse panel of B-NHL cell lines. Interestingly, B-NHL subtypes mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and B cell precursor-acute lymphocytic leukemia (BCP-ALL) were preferentially sensitive to BLyS-gel mediated cytotoxicity, with low picomolar EC(50) values. BLyS receptor expression did not guarantee sensitivity to BLyS-gel, even though the construct was internalized by both sensitive and resistant cells. Resistance to BLyS-gel could be overcome by treatment with the endosomotropic drug chloroquine, suggesting BLyS-gel may become trapped within endosomal/lysosomal compartments in resistant cells. BLyS-gel induced cell death was caspase-independent and shown to be at least partially mediated by the "ribotoxic stress response." This response involves activation of p38 MAPK and JNK/SAPK, and BLyS-gel mediated cytotoxicity was inhibited by the p38/JNK inhibitor SB203580. Finally, BLyS-gel treatment was shown to localize to sites of disease, rapidly reduce tumor burden, and significantly prolong survival in xenograft mouse models of disseminated BCP-ALL, DLBCL, and MCL. Together, these findings suggest BLyS has significant potential as a targeting ligand for the delivery of cytotoxic "payloads" to malignant B cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047361PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467252PMC
May 2013

RIP1 protein-dependent assembly of a cytosolic cell death complex is required for inhibitor of apoptosis (IAP) inhibitor-mediated sensitization to lexatumumab-induced apoptosis.

J Biol Chem 2012 Nov 27;287(46):38767-77. Epub 2012 Aug 27.

Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, 60528 Frankfurt, Germany.

Searching for new strategies to trigger apoptosis in rhabdomyosarcoma (RMS), we investigated the effect of two novel classes of apoptosis-targeting agents, i.e. monoclonal antibodies against TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (mapatumumab) and TRAIL receptor 2 (lexatumumab) and small-molecule inhibitors of inhibitor of apoptosis (IAP) proteins. Here, we report that IAP inhibitors synergized with lexatumumab, but not with mapatumumab, to reduce cell viability and to induce apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1). Cotreatment-induced apoptosis was accompanied by enhanced activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and caspase-dependent apoptosis. In addition, IAP inhibitor and lexatumumab cooperated to stimulate the assembly of a cytosolic complex containing RIP1, FADD, and caspase-8. Importantly, knockdown of RIP1 by RNA interference prevented the formation of the RIP1·FADD·caspase-8 complex and inhibited subsequent activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and apoptosis upon treatment with IAP inhibitor and lexatumumab. In addition, RIP1 silencing rescued clonogenic survival of cells treated with the combination of lexatumumab and IAP inhibitor, thus underscoring the critical role of RIP1 in cotreatment-induced apoptosis. By comparison, the TNFα-blocking antibody Enbrel had no effect on IAP inhibitor/lexatumumab-induced apoptosis, indicating that an autocrine TNFα loop is dispensable. By demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent but TNFα-independent manner in RMS cells, our findings substantially advance our understanding of IAP inhibitor-mediated regulation of TRAIL-induced cell death.
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http://dx.doi.org/10.1074/jbc.M112.398966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493919PMC
November 2012

Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors: evidence for the role of c-Jun N-terminal kinase activation.

Cell Cycle 2012 Sep 16;11(17):3312-23. Epub 2012 Aug 16.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Penn State College of Medicine, Hershey, PA, USA.

The discovery of the molecular targets of chemotherapeutic medicines and their chemical footprints can validate and improve the use of such medicines. In the present report, we investigated the effect of mitomycin C (MMC), a classical chemotherapeutic agent on cancer cell apoptosis induced by TRAIL. We found that MMC not only potentiated TRAIL-induced apoptosis in HCT116 (p53-/-) colon cancer cells but also sensitized TRAIL-resistant colon cancer cells HT-29 to the cytokine both in vitro and in vivo. MMC also augmented the pro-apoptotic effects of two TRAIL receptor agonist antibodies, mapatumumab and lexatumumab. At a mechanistic level, MMC downregulated cell survival proteins, including Bcl2, Mcl-1 and Bcl-XL, and upregulated pro-apoptotic proteins including Bax, Bim and the cell surface expression of TRAIL death receptors DR4 and DR5. Gene silencing of DR5 by short hairpin RNA reduced the apoptosis induced by combination treatment of MMC and TRAIL. Induction of DR4 and DR5 was independent of p53, Bax and Bim but was dependent on c-Jun N terminal kinase (JNK) as JNK pharmacological inhibition and siRNA abolished the induction of the TRAIL receptors by MMC.
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http://dx.doi.org/10.4161/cc.21670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466529PMC
September 2012

Pediatric neurosurgery at the Hospital for Sick Children, The University of Toronto.

Childs Nerv Syst 2012 Aug;28(8):1127-8

The Division of Neurosurgery, The Hospital for Sick Children, Suite 1503, 555 University Avenue, Toronto, ON, Canada.

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http://dx.doi.org/10.1007/s00381-012-1855-0DOI Listing
August 2012

Prediction of proapoptotic anticancer therapeutic response in vivo based on cell death visualization and TRAIL death ligand-receptor interaction.

Cancer Biol Ther 2011 Aug 15;12(4):335-48. Epub 2011 Aug 15.

Department of Bioengineering, University of Pennsylvania School of Engineering and Applied Science, Philadelphia, USA.

Tumor growth is often associated with insufficient apoptosis. The Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) and its proapoptotic receptors death receptor 4 (DR4) and DR5 agonistic monoclonal antibodies are being developed as targeted therapeutics because they kill cancer cells while sparing normal cells. A challenge to targeted therapeutics is the selection of patients who are most likely to benefit from targeted drugs because of the heterogeneity of cancer. Molecular imaging may be useful in targeted drug development by assessing the target expression and drug-target interaction, and for predicting therapeutic response. We hypothesized that the cell surface expression level of DR4/5 may predict the proapoptotic targeted therapeutic response if the signaling pathway downstream is intact. The goal of this proof-of-concept study was to develop a molecular imaging strategy to predict proapoptotic anti-cancer therapy response at an early stage of treatment. TRAIL and the DR5 agonistic monoclonal antibody HGS-ETR2 (Lexatumumab, TRM-2) were labeled with a near-infrared dye and these were used to image the TRAIL receptors on cultured TRAIL sensitive and TRAIL resistant human tumor cells as well as tumor xenografts. Imaging of cells and tumor-bearing animals was conducted with near infrared fluorescence imagers and apoptosis in cells was assessed by western blots of PARP-cleavage and flow cytometry of sub-G1 content. Apoptosis in tumors was evaluated by imaging near-infrared dye-labeled Annexin V and tumor tissue activated caspase-3 staining. Both in vitro and in vivo studies showed that imaging of death inducing ligand-receptor interaction was consistent with the apoptosis readout. Thus TRAIL sensitive tumors that express TRAIL receptors underwent cell death following treatment whereas tumors lacking TRAIL receptor expression were shown to be TRAIL resistant. In vivo molecular imaging of TRAIL receptor expression correlated with response to TRAIL therapy and an apoptotic response in vivo.
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http://dx.doi.org/10.4161/cbt.12.4.17174DOI Listing
August 2011

Spectral imaging-based methods for quantifying autophagy and apoptosis.

Cancer Biol Ther 2011 Aug 15;12(4):349-56. Epub 2011 Aug 15.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine, Penn State College of Medicine, Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, PA, USA.

Spectral imaging systems are capable of detecting and quantifying subtle differences in light quality. In this study we coupled spectral imaging with fluorescence and white light microscopy to develop new methods for quantifying autophagy and apoptosis. For autophagy, we employed multispectral imaging to examine spectral changes in the fluorescence of LC3-GFP, a chimeric protein commonly used to track autophagosome formation. We found that punctate autophagosome-associated LC3-GFP exhibited a spectral profile that was distinctly different from diffuse cytosolic LC3-GFP. We then exploited this shift in spectral quality to quantify the amount of autophagosome-associated signal in single cells. Hydroxychloroquine (CQ), an anti-malarial agent that increases autophagosomal number, significantly increased the punctate LC3-GFP spectral signature, providing proof-of-principle for this approach. For studying apoptosis, we employed the Prism and Reflector Imaging Spectroscopy System (PARISS) hyperspectral imaging system to identify a spectral signature for active caspase-8 immunostaining in ex vivo tumor samples. This system was then used to rapidly quantify apoptosis induced by lexatumumab, an agonistic TRAIL-R2/DR5 antibody, in histological sections from a preclinical mouse model. We further found that the PARISS could accurately distinguish apoptotic tumor regions in hematoxylin and eosin-stained sections, which allowed us to quantify death receptor-mediated apoptosis in the absence of an apoptotic marker. These spectral imaging systems provide unbiased, quantitative and fast means for studying autophagy and apoptosis and complement the existing methods in their respective fields.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230317PMC
http://dx.doi.org/10.4161/cbt.12.4.17175DOI Listing
August 2011

Off-target lapatinib activity sensitizes colon cancer cells through TRAIL death receptor up-regulation.

Sci Transl Med 2011 Jun;3(86):86ra50

Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine, Institute for Translational Medicine and Therapeutics, Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Lapatinib, a dual HER2/EGFR (human epidermal growth factor receptor 2/epidermal growth factor receptor) inhibitor, is a recently approved targeted therapy for metastatic breast cancer. Because lapatinib enhances the efficacy of the chemotherapeutic agent capecitabine in breast cancer patients, we tested whether lapatinib also enhances the activity of anticancer agents in colorectal cancer. We found that lapatinib improved the proapoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab. Tumors from mice treated with a combination of lapatinib and TRAIL exhibited more immunostaining for cleaved caspase-8, a marker of the extrinsic cell death pathway, than did tumors from mice treated with lapatinib or TRAIL alone. Furthermore, combination therapy suppressed tumor growth more effectively than either agent alone. Lapatinib up-regulated the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonists. This activity of lapatinib was independent of EGFR and HER2. The off-target induction of DR5 by lapatinib resulted from activation of the c-Jun amino-terminal kinase (JNK)/c-Jun signaling axis. This activity of lapatinib on TRAIL death receptor expression and signaling may confer therapeutic benefit when increased doses of lapatinib are used in combination with TRAIL receptor-activating agents.
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http://dx.doi.org/10.1126/scitranslmed.3001384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769950PMC
June 2011

TRAIL-induced apoptosis is preferentially mediated via TRAIL receptor 1 in pancreatic carcinoma cells and profoundly enhanced by XIAP inhibitors.

Clin Cancer Res 2010 Dec 12;16(23):5734-49. Epub 2010 Oct 12.

University Children's Hospital, Ulm University, Ulm, Germany.

Purpose: We previously reported that small molecule X-linked inhibitor of apoptosis (XIAP) inhibitors synergize with soluble TRAIL to trigger apoptosis in pancreatic carcinoma cells. Because cancers may preferentially signal via 1 of the 2 agonistic TRAIL receptors, we investigated these receptors as a therapeutic target in pancreatic cancer in the present study.

Experimental Design: We examined TRAIL receptor expression and cytotoxicity of specific monoclonal antibodies to TRAIL-R1 (HGS-ETR1, mapatumumab) or TRAIL-R2 (HGS-ETR2, lexatumumab) and of TRAIL receptor selective mutants alone and in combination with small molecule XIAP inhibitors in pancreatic cancer cell lines, in primary specimens, and in a xenotransplant model in vivo.

Results: The majority of primary pancreatic carcinoma samples and all cell lines express one or both agonistic TRAIL receptors. Nine of 13 cell lines are more sensitive to mapatumumab-induced apoptosis, whereas lexatumumab requires cross-linking for maximal activity. Similarly, TRAIL-R1 selective mutants display higher cytotoxicity than TRAIL-R2 selective mutants. Small molecule XIAP inhibitors preferentially act in concert with mapatumumab to trigger caspase activation, caspase-dependent apoptosis, and suppress clonogenic survival. Also, primary cultured pancreatic carcinoma cells are more susceptible to mapatumumab than lexatumumab, which is significantly enhanced by a XIAP inhibitor. Importantly, combined treatment with mapatumumab and a XIAP inhibitor cooperates to suppress tumor growth in vivo.

Conclusions: Mapatumumab exerts antitumor activity, especially in combination with XIAP inhibitors against most pancreatic carcinoma cell lines, whereas lexatumumab requires cross-linking for optimal cytotoxicity. These findings have important implications for the design of TRAIL-based protocols for pancreatic cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-0985DOI Listing
December 2010

Human monomeric antibody fragments to TRAIL-R1 and TRAIL-R2 that display potent in vitro agonism.

MAbs 2009 Nov-Dec;1(6):552-62. Epub 2009 Nov 11.

MedImmune, Cambridge, Cambridgeshire, UK.

Apoptosis through the TRAIL receptor pathway can be induced via agonistic IgG to either TRAIL-R1 or TRAIL-R2. Here we describe the use of phage display to isolate a substantive panel of fully human anti-TRAIL receptor single chain Fv fragments (scFvs); 234 and 269 different scFvs specific for TRAIL-R1 and TRAIL-R2 respectively. In addition, 134 different scFvs that were cross-reactive for both receptors were isolated. To facilitate screening of all 637 scFvs for potential agonistic activity in vitro, a novel high-throughput surrogate apoptosis assay was developed. Ten TRAIL-R1 specific scFv and 6 TRAIL-R2 specific scFv were shown to inhibit growth of tumor cells in vitro in the absence of any cross-linking agents. These scFv were all highly specific for either TRAIL-R1 or TRAIL-R2, potently inhibited tumor cell proliferation, and were antagonists of TRAIL binding. Moreover, further characterization of TRAIL-R1 agonistic scFv demonstrated significant anti-tumor activity when expressed and purified as a monomeric Fab fragment. Thus, scFv and Fab fragments, in addition to whole IgG, can be agonistic and induce tumor cell death through specific binding to either TRAIL-R1 or TRAIL-R2. These potent agonistic scFv were all isolated directly from the starting phage antibody library and demonstrated significant tumor cell killing properties without any requirement for affinity maturation. Some of these selected scFv have been converted to IgG format and are being studied extensively in clinical trials to investigate their potential utility as human monoclonal antibody therapeutics for the treatment of human cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791312PMC
http://dx.doi.org/10.4161/mabs.1.6.10057DOI Listing
June 2010

Tumor Necrosis Factor-related apoptosis-inducing ligand (TRAIL) Receptor-1 and Receptor-2 agonists for cancer therapy.

Expert Opin Biol Ther 2010 Jan;10(1):1-18

Human Genome Sciences, Rockville, MD 20850, USA.

Importance Of The Field: Agents that activate the TNF-related apoptosis-inducing ligand death receptors, TRAIL-R1 and TRAIL-R2, have attracted substantial attention and investment as potential anti-cancer therapies. Preclinical studies of TRAIL-R agonists indicate that they may be efficacious in a wide range of tumor types, especially when combined with chemotherapeutic agents.

Areas Covered In This Review: The rationale for clinical development of TRAIL-R agonists is described, including the basis for combining these agents with other agents that modulate the 'checks and balances' of the apoptotic pathways. Accruing data that highlight differences between TRAIL-R1 and TRAIL-R2 that could affect the clinical significance of their specific agonists are described. The clinical experience to date with each of the agonists is summarized.

What The Reader Will Gain: The reader will gain an understanding of the rationale for the clinical development of TRAIL-R agonists, as well as the current status of clinical trials of these interesting new agents.

Take Home Message: Ongoing clinical trials will provide important information regarding the future development of TRAIL-R agonists.
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http://dx.doi.org/10.1517/14712590903319656DOI Listing
January 2010

Efficacy of triple therapies including ionising radiation, agonistic TRAIL antibodies and cisplatin.

Oncol Rep 2009 Jun;21(6):1455-60

CCC Tübingen, Department of Radiation Oncology, 72076 Tübingen, Germany.

The detection of molecular targeted agents is a milestone in cancer treatment. Despite the achievements, the efficacy of single targeted agents in combination with radiotherapy is limited by putative treatment resistance. We therefore tested a rationally designed triple therapy consisting of an agonistic antibody against either TRAIL-R1 (mapatumumab/HGS-ETR1) or TRAIL-R2 (lexatumumab/HGS-ETR2) in combination with the established chemotherapeutic drug cisplatin in a panel of solid tumour cell lines derived from head and neck as well as colorectal carcinomas. Induction of apoptosis after monotherapy, double or triple treatment was determined in FaDu (squamous cancer cell line of the head and neck), Colo205 and HCT116 cells (colorectal adenocarcinoma cell lines) by Hoechst 33342 stain. Double and triple therapies were compared using analysis of variance followed by post hoc tests. The degree of interaction was determined by 3D-isobologram analysis. A knockout variant of HCT116 was used to examine Bax-dependence of the triple therapy to gain insight into the underlying molecular signaling pathways possibly responsible for the observed effects. Dose-response relationships revealed different baseline activities of the modalities dependent on cell type. Triple therapy was more effective than double therapy in most cases according to the induction of apoptosis. Furthermore, a synergistic efficacy of the triple therapy was demonstrated in a subset of tumour cell lines. The efficacy of this multimodal approach was highly dependent on the presence of Bax. Our data suggest that targeted agents can be effectively added to existing multimodal therapy approaches which might open new perspectives in radiation oncology.
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http://dx.doi.org/10.3892/or_00000374DOI Listing
June 2009

A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR.

Cancer Res 2009 May 14;69(9):3856-65. Epub 2009 Apr 14.

Department of Pathology, Division of Cancer Biology and Angiogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

As tumor development relies on a coordination of angiogenesis and tumor growth, an efficient antitumor strategy should target both the tumor and its associated vessels. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner. Additionally, thrombospondin-1, a naturally occurring inhibitor of angiogenesis, and a recombinant protein containing functional domains of thrombospondin-1, 3TSR, have been shown to be necessary and sufficient to inhibit tumor angiogenesis. Here, we show that a combination of a TRAIL receptor 2 agonist antibody, Lexatumumab, and 3TSR results in a significantly enhanced and durable tumor inhibition. We further observed that 3TSR induces apoptosis in primary endothelial cells by up-regulating the expression of TRAIL receptors 1 and 2 in a CD36 and Jun NH(2)-terminal kinase-dependent manner leading to the activation of both intrinsic and extrinsic apoptotic machineries. The modulation of these pathways is critical for 3TSR-induced apoptosis as disrupting either via specific inhibitors reduced apoptosis. Moreover, 3TSR attenuates the Akt survival pathway. These studies indicate that 3TSR plays a critical role in regulating the proapoptotic signaling pathways that control growth and death in endothelial cells and that a combination of TRAIL and 3TSR acts as a double hit against tumor and tumor-associated vessels.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-2940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981788PMC
May 2009

Efficacy of a triple treatment with irradiation, agonistic TRAIL receptor antibodies and EGFR blockade.

Strahlenther Onkol 2009 Jan 18;185(1):8-18. Epub 2009 Feb 18.

Department of Radiation Oncology, CCC Tübingen, Tübingen, Germany.

Background And Purpose: : Since the efficacy of a single targeted agent in combination with ionizing radiation is limited by putative treatment resistances, a rationally designed triple treatment consisting of an agonistic antibody targeting either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab), radiation and an epidermal growth factor receptor-(EGFR-)inhibiting antibody (cetuximab) was tested.

Material And Methods: : Induction of apoptosis after triple treatment was determined in Colo205, HCT116 and FaDu cells by Hoechst 33342 stain. The degree of interaction was determined by isobologram analysis. A knockout variant of HCT116 was used to examine Bax dependence of the triple treatment. The role of Akt/PKB signaling was analyzed using the phosphatidylinositol 3-kinase inhibitor LY294002. Clonogenic assays were performed to examine the effect on clonogenic survival of tumor cells.

Results: : A synergistic effect of radiation, cetuximab and agonistic TRAIL-R antibodies was demonstrated in cell lines derived from colorectal tumors or head-and-neck cancers. The efficacy of this multimodal approach was dependent on Bax and inhibition of Akt/PKB in the cell systems used. The results also show a positive impact on clonogenic cell death in several cell lines.

Conclusion: : These data suggest that rationally designed multimodal therapy approaches integrating radiation with more than one targeted agent will open new perspectives in radiation oncology.
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http://dx.doi.org/10.1007/s00066-009-1856-4DOI Listing
January 2009

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib.

Mol Cancer Ther 2009 Feb 27;8(2):292-302. Epub 2009 Jan 27.

Oncology Research Department, Human Genome Sciences, Inc., Rockville, MD 20850, USA.

Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezomib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients.
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http://dx.doi.org/10.1158/1535-7163.MCT-08-0918DOI Listing
February 2009

Trail receptors: targets for cancer therapy.

Adv Exp Med Biol 2008 ;615:127-58

Human Genome Sciences, Oncology Research Department, Rockville, MD 20850, USA.

A human tumor cell's ability to avoid the normal regulatory mechanisms of cell growth, division, and death are the hallmarks of transformation and cancer. Numerous novel therapeutic agents currently in preclinical or clinical evaluation aim to revive the normal regulation or evade these regulatory defects and induce growth arrest and cell death. One of the cell death pathways that has garnered significant interest, as a potential target for therapeutic intervention, is the programmed cell death pathway regulated by the tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-RS). Receptor agonist molecules including forms of the native ligand and monoclonal antibodies are being developed and tested as therapeutics in the treatment of human cancer.
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http://dx.doi.org/10.1007/978-1-4020-6554-5_7DOI Listing
May 2008

The history of neurosurgery at the Hospital for Sick Children in Toronto.

Neurosurgery 2007 Sep;61(3):612-24; discussion 624-5

Division of Neurosurgery, Department of Surgery, Hospital for Sick Children, University of Toronto Faculty of Medicine, Toronto, Canada.

The tradition of selfless charity for children in Toronto was established by Elizabeth McMaster, founder of the Hospital for Sick Children, or "Sick Kids," in 1875. The tradition of fortitude and perseverance in trying to cure children who were deemed incurable by others was sealed into the history of the Hospital by early pioneering surgeons, including Drs. Clarence Starr, A.W. Farmer, and William Gallie. Dr. William Gallie recognized the importance of neurosurgery for the future of the Hospital and encouraged Dr. William Keith to acquire training in pediatric neurosurgery in Chicago and London. Dr. Keith began the practice of pediatric neurosurgery at Sick Kids in 1935 and worked in the primordial phase of the subspecialty for the next 20 years until he was joined by Dr. E. Bruce Hendrick in 1955. In time, Dr. Hendrick was joined by Drs. Harold Hoffman and Robin Humphreys who led a decidedly strong pediatric neurosurgery unit between 1975 and 1995. During this epoch, the pediatric neurosurgery service grew to become one of the busiest and most progressive units in the world. Over the years, numerous neurosurgery fellows and faculty from all over the world have trained at or have visited Sick Kids to learn how pediatric neurosurgery is practiced in Toronto. The purpose of this article is to review the history of the individuals who founded the Hospital for Sick Children and its Division of Neurosurgery.
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http://dx.doi.org/10.1227/01.NEU.0000290910.32600.7EDOI Listing
September 2007

Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding.

J Biol Chem 2007 Sep 31;282(38):28189-94. Epub 2007 Jul 31.

Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA.

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a cytokine that preferentially induces apoptosis in tumor cells compared with normal cells through two receptors (DR4 and DR5). Somatic mutations in these receptors have been found in different kinds of cancer; however, it is poorly understood how the mutations affect signaling. We found that point mutations (L334F, E326K, E338K, and K386N) that were identified in human tumors result in the DR5 receptor losing its ability to form a functional death-inducing signaling complex and induce apoptosis. The mutant receptors also have a "dominant negative" effect whereby they inhibit the ability of TRAIL to induce apoptosis through functional DR4 receptors. This dominant negative mechanism is achieved through competition for TRAIL binding as shown by experiments where the ability of the mutant DR5 receptor to bind with the ligand was abolished, thus restoring TRAIL signaling through DR4. The inhibitory effect on signaling through the wild-type DR4 protein can be overcome if the inhibitory mechanism is bypassed by using a DR4-agonistic antibody that is not subject to this competition. This study provides a molecular basis for the use of specific therapeutic agonists of TRAIL receptors in people whose tumors harbor somatic DR5 mutations.
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http://dx.doi.org/10.1074/jbc.M704210200DOI Listing
September 2007

Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels.

Cancer Res 2007 Jul;67(14):6987-94

Division of Molecular Therapeutics, Departments of Oncology and Biochemistry, St. Jude Children's Research Hospital, 322 North Lauderdale, Memphis, TN 38105, USA.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumab-induced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21(+/+) cells but not in the HCT116 p21(-/-) cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-0812DOI Listing
July 2007

A small molecule Smac mimic potentiates TRAIL-mediated cell death of ovarian cancer cells.

Gynecol Oncol 2007 May 9;105(2):481-92. Epub 2007 Feb 9.

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Objectives: Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (Smac) has been described to sensitize for apoptosis. We have explored the proapoptotic activity of a small molecule mimic of Smac/DIABLO on ovarian cancer cell lines (A2780 cells and its chemoresistant derivatives A2780/ADR and A2780/DDP), cancer cell lines and in primary ovarian cancer cells.

Methods: The effects of a small molecule mimic of Smac/DIABLO on ovarian cancer cell lines and primary ovarian cancer cells were determined by cell proliferation, apoptosis and biochemical assays.

Results: This compound added alone elicited only a weak proapoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or agonistic TRAILR2 antibody (Lexatumumab) in inducing apoptosis of ovarian cancer cells.

Conclusions: These observations suggest that small molecule mimic of Smac/DIABLO could be useful for the development of experimental strategies aiming to treat ovarian cancer. Interestingly, in addition to its well known proapoptotic effects, Smac/DIABLO elicited a significant increase of pro-caspase-3 levels.
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http://dx.doi.org/10.1016/j.ygyno.2007.01.011DOI Listing
May 2007

Proteasome inhibitors sensitize ovarian cancer cells to TRAIL induced apoptosis.

Apoptosis 2007 Apr;12(4):635-55

Medical Oncology Section, Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

In the present study we have explored the sensitivity of ovarian cancer cells to TRAIL and proteasome inhibitors. Particularly, we have explored the capacity of proteasome inhibitors to bypass TRAIL resistance of ovarian cancer cells. For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/DDP and A2780/ADR, providing evidence that: (i) the three cell lines are either scarcely sensitive (A2780 and A2780/ADR) or moderately sensitive (A2780/DDP) to the cytotoxic effects of TRAIL; (ii) the elevated c-FLIP expression observed in ovarian cancer cells is a major determinant of TRAIL resistance of these cells; (iii) proteasome inhibitors (PS-341 or MG132) are able to exert a significant pro-apoptotic effect and to greatly enhance the sensitivity of both chemosensitive and chemoresistant A2780 cells to TRAIL; (iv) proteasome inhibitors damage mitochondria through stabilization of BH3-only proteins, Bax and caspase activation and significantly enhance TRAIL-R2 expression; (v) TRAIL-R2, but not TRAIL-R1, mediates the apoptotic effects of TRAIL on ovarian cancer cells. Importantly, studies on primary ovarian cancer cells have shown that these cells are completely resistant to TRAIL and proteasome inhibitors markedly enhance the sensitivity of these cells to TRAIL. Given the high susceptibility of ovarian cancer cells to proteasome inhibitors, our results further support the experimental use of these compounds in the treatment of ovarian cancer.
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http://dx.doi.org/10.1007/s10495-006-0025-9DOI Listing
April 2007

Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies.

Mol Cancer Ther 2006 Dec 5;5(12):2991-3000. Epub 2006 Dec 5.

Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Box 4221515, Holcombe Boulevard, Houston, TX 77230-1402, USA.

Susceptibility to apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is mediated through cognate death receptor signaling. We hypothesized that auto-amplification of this apparatus would enhance antitumor effects in vivo and could be optimized using the results obtained from novel imaging techniques. We therefore imaged mice bearing human colorectal cancer (Colo205) tumor xenografts with HGS-ETR1 and HGS-ETR2 agonist antibodies to TRAIL receptor-1 (TRAIL-R1) and TRAIL-R2, respectively, after radiolabeling the antibodies. Paclitaxel significantly increased in vivo expression of TRAIL-R1 and TRAIL-R2 in a time-dependent manner. The imaging results were confirmed by immunoblots for steady-state protein levels (>20-fold increase in TRAIL-R1 and TRAIL-R2 levels in tumor xenografts by 48 h after paclitaxel administration). TRAIL-R1 and TRAIL-R2 mRNA expression did not change, suggesting that these effects were posttranscriptional. Sequential treatment with paclitaxel followed by HGS-ETR1 or HGS-ETR2 after 48 h resulted in markedly enhanced antitumor activity against Colo205 mouse xenografts. Our experiments suggest that sequential taxane treatment followed by TRAIL-R agonist antibodies could be applied in the clinic, and that novel imaging techniques using radiolabeled receptor antibodies may be exploitable to optimize sequence timing and patient selection.
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http://dx.doi.org/10.1158/1535-7163.MCT-06-0188DOI Listing
December 2006

Pediatric arteriovenous malformation: University of Toronto experience using stereotactic radiosurgery.

Childs Nerv Syst 2007 Feb 18;23(2):195-9. Epub 2006 Nov 18.

Division of Neurosurgery, Sunnybrook Health Sciences Centre (SHSC), Suite A129, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.

Introduction And Background: Arteriovenous malformations (AVMs) are congenital vascular lesions of the brain, which behave differently in pediatric population compared to adults. Treatment of pediatric AVMs includes a combination of microsurgery, embolization and radiation therapies. However, the role of radiosurgery in the treatment of pediatric AVMs is not fully accepted because of concerns regarding the long-term effects of radiation on the pediatric brain.

Discussion: In this study, we review our experience at the University of Toronto with treating pediatric AVMs using linear accelerator-based (LINAC) radiosurgery over the past 15 years. We report our results, obliteration rates, and complications on a total of 40 patients. In addition, we provide a review of series published to date combined with our own results to determine whether radiosurgery is a safe and reasonable treatment modality for pediatric AVMs.
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http://dx.doi.org/10.1007/s00381-006-0207-3DOI Listing
February 2007

History of surgery for cerebrovascular disease in children. Part I. Intracranial arterial aneurysms.

Neurosurg Focus 2006 Jun 15;20(6):E9. Epub 2006 Jun 15.

Division of Pediatric Neurosurgery, University of Alabama at Birmingham/Children's Hospital of Alabama, Birmingham, Alabama 35233, USA.

Intracranial aneurysms are rare in children, and their origins and treatment methods tend to be different from those in these same entities in adults. These lesions tend to be congenital or to have an infectious or traumatic origin. In the current paper the authors trace the historical evolution of the diagnosis and treatment of intracranial aneurysms in children. Based on the literature, these lesions appear to occur in children in less than 3% of all series. The literature also supports the suggestion that symptoms from these aneurysms are often from mass effect and that giant aneurysms and lesions in the posterior cranial fossa are relatively more common in children than in adults. The termination of the carotid artery and the anterior cerebral artery seem to be disproportionately common sites of aneurysm formation in this cohort. Interestingly, surgical outcomes in children appear to be moderately better than in adults. Based on the literature, the claim can be made that a multidisciplinary approach to the management of such aneurysms can yield good outcomes in a very high percentage of children treated.
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June 2006

History of surgery for cerebrovascular disease in children. Part III. Arteriovenous malformations.

Neurosurg Focus 2006 Jun 15;20(6):E11. Epub 2006 Jun 15.

Division of Pediatric Neurosurgery, University of Alabama at Birmingham/Children's Hospital of Alabama, Birmingham, Alabama 35233, USA.

Arteriovenous malformations (AVMs) are the most common cause of intracerebral hemorrhage in children. In this paper the authors trace the historical evolution of the recognition, diagnosis, and treatment of pediatric intracerebral AVMs, and they summarize the contemporary approach and current controversies surrounding treatment of these lesions. Important distinctions between adult and pediatric AVMs are emphasized.
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June 2006