tbuckley/cabot-search huggingface dataset:
AB0971 Change in Sonographic Cartilage Thickness Correlates with Change in Radiographic Joint Space Narrowing in The Metacarphalangeal Joints of Patients with Rheumatoid Arthritis
Authors: P. Mandl, H. Radner, G. Supp, D. Aletaha, J.S. Smolen
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> It was previosly shown that metacarpal cartilage thickness (MCT) as assessed by ultrasound (US) correlates with both radiographic joint space width (JSW) and joint space narrowing (JSN) in the metacarpophalangeal joints (MCP) of patients with rheumatoid arthritis (RA). <h3>Objectives</h3> To correlate change in MCT with change in radiographic JSW and JSN in a longitudinal study of patients with RA. <h3>Methods</h3> We performed US examination of 19 consecutive outpatients with RA fulfilling the 2010 ACR/EULAR classification criteria with recent hand X-rays. Metacarpal cartilage of MCP 2–5 was assessed bilaterally by US at baseline and after 3 years in mm with an integrated caliper on static images (Figure 1A). JSN was evaluated on X-rays taken &lt;1 year before the sonographic assessment as well as within 6 months of the second sonographic assessment by the van der Heijde modified Sharp method (vdHS). In addition, JSW was measured on the very same hand X-rays using an integrated calliper (Figure 1B). The relationship between sonographic and radiographic measures was investigated by Spearman correlation. <h3>Results</h3> Over the study period of 3 years a mean change of MCT of 0.00±0.01mm, was paralleled by a mean change of JSW of -0.08±0.20mm and a change of 0.12±0.37 in the JSN component of the vdHS. Change in MCT correlated with change in JSW (r: 0.37; p:&lt;0.001) as well as with change in JSN (r:-0.26; p:&lt;0.001). We could also demonstrate correlation between the two radiographic measures (r: 0.33; p:&lt;0.001). Change in erosion did not correlate with either sonographic MCT or with the radiographic measures. <h3>Conclusions</h3> Change in sonographic cartilage thickness correlates with radiographic measures of joint space narrowing in the MCP joints of RA patients over time. Thus, ultrasound may be a valid tool for the longitudinal assessment of metacarpal cartilage in RA patients, but also the radiographic assessments appear to reflect "true" cartilage dimensions. <h3>Disclosure of Interest</h3> None declared
Enhanced Anti-Breast Cancer Cytotoxicity after Autologous Peripheral Blood Stem Cell Transplant (PBSCT) by Boosting with Multiple Infusions of Activated T Cells (ATC) Armed with Anti-CD3 x Anti-Her2 Bispecific Antibody (Her2Bi) Prior to PBSCT.
Authors: Lawrence G. Lum, Zaid Al-Kadhimi, Cassara Skuba, Voravit Ratanatharathorn, Joseph P. Uberti
Journal: Blood (2007)
Criteria for CAPS, is it all in the name?
Authors: Isabelle Touitou, Guillaume Sarrabay
Journal: Annals of the Rheumatic Diseases (2016)

This paper1 describes an original work conducted by an International team of 16 recognised clinical experts in the field of autoinflammatory diseases. The aim of this consortium was to develop diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). They resulted in a model that indisputably is relevant to describe these rare and heterogeneous diseases among other autoinflammatory diseases. Their proposed CAPS diagnosis criteria are primarily clinical.

We would like to comment on the pathophysiological mechanism underlying ‘CAPS’. The NLRP3 gene encodes cryopyrin, the historical name of the …
Increased Relapse Associated with Mixed Donor-Donor Chimerism Following Double Umbilical Cord Blood Transplantation (dUCBT)
Authors: Michael R. Verneris, Lucie M. Turcotte, Qing Cao, Margaret L. MacMillan, Jeffrey S. Miller, Daniel Weisdorf, Claudio G Brunstein, John E. Wagner
Journal: Blood (2012)
High-Mobility Group A1 Protein
Authors: Mandy Bloch, André Prock, Francesco Paonessa, Verena Benz, Ilse N. Bähr, Lena Herbst, Henning Witt, Kai Kappert, Joachim Spranger, Philipp Stawowy, Thomas Unger, Alfredo Fusco, Daniel Sedding, Antonio Brunetti, Anna Foryst-Ludwig, Ulrich Kintscher
Journal: Circulation Research (2011)

The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of gene transcription in vascular cells and mediates the vascular protection observed with antidiabetic glitazones.To determine the molecular mechanism of ligand-dependent transrepression in vascular smooth muscle cells and their impact on the vascular protective actions of PPARγ.Here, we report a molecular pathway in vascular smooth muscle cells by which ligand-activated PPARγ represses transcriptional activation of the matrix-degrading matrix metalloproteinase-9 (MMP-9) gene, a crucial mediator of vascular injury. PPARγ-mediated transrepression of the MMP-9 gene was dependent on the presence of the high-mobility group A1 (HMGA1) protein, a gene highly expressed in vascular smooth muscle cells, newly identified by oligonucleotide array expression analysis. Transrepression of MMP-9 by PPARγ and regulation by HMGA1 required PPARγ SUMOylation at K367. This process was associated with formation of a complex between PPARγ, HMGA1, and the SUMO E2 ligase Ubc9 (ubiquitin-like protein SUMO-1 conjugating enzyme). After PPARγ ligand stimulation, HMGA1 and PPARγ were recruited to the MMP-9 promoter, which facilitated binding of SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), a nuclear corepressor involved in transrepression. The relevance of HMGA1 for vascular PPARγ signaling was underlined by the complete absence of vascular protection through a PPARγ ligand in HMGA1(-/-) mice after arterial wire injury.The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPARγ complexes facilitates PPARγ SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPARγ-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPARγ ligands in the vasculature.
Natural Killer Cells to the Attack: Combination Therapy against Neuroblastoma
Authors: Olatz Zenarruzabeitia, Joana Vitallé, Itziar Astigarraga, Francisco Borrego
Journal: Clinical Cancer Research (2016)

TGFβ in the tumor microenvironment diminishes natural killer (NK) cell-mediated anti-disialoganglioside (anti-GD2) mAb elimination of neuroblastoma cells. Consequently, blockade of TGFβ signaling with galunisertib in combination with the anti-GD2 mAb dinutuximab plus adoptively transferred NK cells is a promising tool for the treatment of neuroblastoma. Clin Cancer Res; 23(3); 615-7. ©2016 AACRSee related article by Tran et al., p. 804.
The BCL11B Tumor Suppressor Is Mutated In Human T-Cell Acute Lymphoblastic Leukemia
Authors: Alejandro Gutierrez, Alex Kentsis, Takaomi Sanda, Julia Etchin, Alexei Protopopov, Jianhua Zhang, Lynda Chin, Lewis B. Silverman, Stuart Winter, Stephen Hunger, Stephen E. Sallan, Shan Zha, Frederick Alt, A. Thomas Look
Journal: Blood (2010)
Dendritic Cell Reconstitution Following Autologous Stem Cell Transplant for Multiple Myeloma.
Authors: Annette J. Schlueter, Judith K. Glasgow, Werner W. Wilke, Jacquie R. Marietta, Raymond J. Hohl, Thomas H. Carter, Roger D. Gingrich, Margarida D. Magalhaes-Silverman
Journal: Blood (2005)
AB0100 IL-22-Mediated BCL-2 Expression in Rheumatoid Arthritis Fibroblast-like Synoviocytes through STAT3 Activation
Authors: M. Liu, Y. Pan, Y. Liu, Y. Wu, M. Yang, B. Mo
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Interleukin-22 (IL-22) is a novel cytokine that is mostly produced by T cells and innate lymphoid cells but selectively stimulates non- immune cells, which immediately caught the attention of many fields such as tumor, chronic inflammatory disease and infectious disease. Considering the persistent biological abnormalities in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and transient effects of current best treatment such as anti-TNF biologics, other cytokines might be involved and we focus here on the role of IL-22. <h3>Objectives</h3> To test the effect of IL-22 on the survival of RA-FLSs and to investigate whether signal transducer and activator of transcription 3 (STAT3) is implicated in this process. <h3>Methods</h3> Bcl-2 mRNA and Bcl-xL mRNA expression in the RA-FLSs, osteoarthritis-FLSs and trauma-FLSs were determined using the Real-time quantitative polymerase chain reaction (RT-qPCR), Bcl-2 protein expression in FLSs were detected by the Western Blotting analysis. The effects of recombinant human interleukin-22 (rhIL-22) at concentrations of 0, 1, 10, 100 ng/mL and STA-21 (a STAT3 inhibitor at concentrations of 0, 25μM, 50μM) on the protein levels of Bcl-2 and p-STAT3 in the RA-FLSs were determined by Western blotting analysis. RA-FLSs were co-cultured with rhIL-22 in the presence or absence of STA21 for 24 h, and the protein levels of Bcl-2 and p-STST3 were evaluated by Western blotting analysis. <h3>Results</h3> The anti-apoptotic Bcl-2 (<i>P</i>&lt;0.05) and Bcl-xL (<i>P</i>&lt;0.01) are increased in RA-FLSs compared with osteoarthritis-FLSs and trauma-FLSs, and so is Bcl-2 protein (<i>P</i>&lt;0.01). IL-22 increased, and STA-21 decreased the protein levels of Bcl-2 and p-STAT3 (IL-22: <i>F</i><sub>Bcl-2</sub>=48.63, <i>P</i><sub>Bcl-2</sub>&lt;0.01; <i>F</i><sub>P-STAT3</sub>=25.7, <i>P</i><sub>P-STAT3</sub>&lt;0.01 STA-21: <i>F</i><sub>Bcl-2</sub>=49.74, <i>P</i><sub>Bcl-2</sub>&lt;0.01l; <i>F</i><sub>P-STAT3</sub>=109.97, <i>P</i><sub>P-STAT3</sub>&lt;0.01) in the RA-FLSs obviously. Additionally, treatment with STAT3 inhibitor STA-21 reversed the effect of IL-22-induced Bcl-2 upregulation in the RA-FLSs (<i>F</i><sub>Bcl-2</sub>=84.67, <i>P</i><sub>Bcl-2</sub>&lt;0.01; <i>F</i><sub>P-STAT3</sub>=82.46, <i>P</i><sub>P-STAT3</sub>&lt;0.01). <h3>Conclusions</h3> STAT3 is critical in the process which IL-22-induced Bcl-2 upregulation in the RA-FLSs. The effects of IL-22/STAT3 confer on them the potential to be used for therapeutic applications in RA. <h3>Disclosure of Interest</h3> None declared
Presence of TET2 Mutation Predicts A Higher Response Rate to Azacitidine In MDS and AML Post MDS
Authors: Raphael Itzykson, Olivier Kosmider, Thomas Cluzeau, Veronique De Mas, Francois Dreyfus, Bruno Quesnel, Odile Beyne-Rauzy, Norbert Vey, Veronique Gelsi-Boyer, Sophie Raynaud, Claude Preudhomme, Lionel Ades, Pierre Fenaux, Michaela Fontenay
Journal: Blood (2010)
Revisions to the Nutrition Facts Label—Reply
Authors: Vasanti S Malik, Walter C. Willett, Frank B. Hu
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
High Incidence of BK-Virus-Related Hemorrhagic Cystitis after Busulfan/Fludarabine Myeloablative Conditioning in Allogeneic Stem Cell Transplantation Recipients.
Authors: Gorgun Akpek, Ashraf Badros, Aaron P. Rapoport, Kathleen Ruehle, Kristen Barton, Barry Meisenberg, Saul Yanovich
Journal: Blood (2006)
Paroxysmal Nocturnal Hemoglobinuria and Pregnancy: The French Experience.
Authors: Sophie de Guibert, Régis Peffault de Latour, Nathalie Varoqueaux, Hélène Labussiere, Bernard Rio, Dominique Jaulmes, Jean-Richard Eveillard, Stéphanie Dulucq, Anne Marie Stoppa, Didier Bouscary, François Girodon, Bernard Bonnotte, Gérard Socié, Thierry Lamy
Journal: Blood (2009)
Academies urge UK government to invest in research after Brexit vote
Authors: Jacqui Wise
Journal: BMJ (2016)

Four national academies have urged the government to show that it is committed to attracting and retaining researchers from around the world in post-Brexit Britain.

The Academy of Medical Sciences, the British Academy, the Royal Academy of Engineering, and the Royal Society have issued a joint statement calling on the chancellor to send a positive message in the autumn statement on 23 …
Mobilization of Ph-Negative Peripheral Blood Stem Cells (PBSCs) with rHu-G-CSF in Chronic Myeloid Leukemia (CML) Patients Achieving Complete Cytogenetic Response with Imatinib Mesilate (Glivec).
Authors: Ester Pungolino, Michela Draisci, Livio Gargantini, Renata Farioli, Valentina Rossi, Paola Cozzi, Sara Miqueleiz Alamos, Anna Maria Cafro, Enrica Morra
Journal: Blood (2004)
Aberrant Expression of Hepatocyte Growth Factor Induces Autocrine MET Activation Providing a Novel Therapeutic Target In Acute Myeloid Leukemia.
Authors: Alex Kentsis, Takaomi Sanda, Vu Ngo, Scott J. Rodig, Jeffery Kutok, Eleni Tholouli, Richard Byers, George Vande Woude, Andrew L. Kung, Louis M. Staudt, A. Thomas Look
Journal: Blood (2010)
Gemtuzumab Ozogamicin in Combination with Vorinostat and Azacitidine As Induction and Post-Remission Therapy in Older Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML): A Phase 1 Study
Authors: Roland B. Walter, Bruno C. Medeiros, Kelda M. Gardner, Elihu H. Estey
Journal: Blood (2011)
Automated and Rapid Detection of BCR-ABL Kinase Domain Mutations in IM Resistant Patients with Ph+ Leukemias.
Authors: Ruriko Tanaka, Shinya Kimura, Toshiya Hosomi, Mitsuharu Hirai, Rina Nagao, Asumi Yokota, MMSc, Yuri Kamitsuji, Eri Kawata, Hisayuki Yao, Kazuki Sakai, Hideyo Hirai, Eishi Ashihara, Souichi Adachi, Taira Maekawa
Journal: Blood (2009)
The Gene Encoding Nuclear Erythroid Factor 2 (NFE2) Is Recurrently Mutated in Acute Myeloid Leukemia
Authors: Mathijs A. Sanders, Annelieke Zeilemakers, Jasper Koenders, Remco Hoogenboezem, François Kavelaars, Rob Henderson, Bob Lowenberg, Peter J. M. Valk
Journal: Blood (2012)
Combination Therapy with BCNU/Etoposide/Melphalan (BEM) as Conditioning Regimen for Autologous Stem Cell Transplant In Multiple Myeloma.
Authors: Shanshan Liu, Ann Mohrbacher, Dan Douer, Vishesh R Kothary, Lisa Hanna, Tanya Price, Sikander Ailawadhi
Journal: Blood (2010)
Front-Line Autologous Stem Cell Transplantation (ASCT) in Primary Mediastinal Large B-Cell Lymphoma: The GEL-TAMO Experience.
Authors: Jose Rodriguez, Eulogio Conde, Antonio Gutierrez, Juan Carlos Garcia-Ruiz, Juan Jose Lahuerta, Maria Rosario Varela, Encarnacion Perez-Equiza, Julian Marin, Carmen Albo, Maria Dolores Caballero
Journal: Blood (2006)
Cardiac extracellular matrix is associated with adverse outcome in patients with chronic heart failure
Authors: Franz Duca, Caroline Zotter‐Tufaro, Andreas A. Kammerlander, Adelheid Panzenböck, Stefan Aschauer, Daniel Dalos, Benedikt Köll, Benedikt Börries, Hermine Agis, Renate Kain, Klaus Aumayr, Florian Klinglmüller, Julia Mascherbauer, Diana Bonderman
Journal: European Journal of Heart Failure (2016)
Histone Deacetylase 11 (HDAC11) As a Novel Transcriptional Regulator of C/EBP-β, in Immature Myeloid Cell to Myeloid Derived Suppressor Cell Transition
Authors: Jie Chen, Eva Sahakian, John J. Powers, Maritza LienlafMoreno, Limin Xing, Susan Deng, Allison Distler, Fengdong Cheng, Alejandro Villagra, Pedro Horna, Eduardo M. Sotomayor, Javier Pinilla-Ibarz
Journal: Blood (2014)
HLA Matching Is More Critical Than CMV Matching in Predicting Non-Relapse-Mortality of Patients Undergoing HSCT From An Unrelated Donor: A Retrospective Monocenter Study.
Authors: Roberto Crocchiolo, Sophie Ducastelle, Hélène Labussière, Franck Emmanuel Nicolini, Xavier Thomas, Fiorenza Barraco, Giovanna Cannas, Samia Madene, Youcef Chelghoum, Nathalie Tedone, Mohamad Sobh, Mauricette Michallet
Journal: Blood (2009)
Treatment of Elderly Acute Myeloid Leukemia (AML) Patients with the Combination of Mitoxantrone and Cytarabine (MAC).
Authors: Theodoros Marinakis, Athanasios G. Galanopoulos, Athanasios Zomas, Euridiki Michalis, George Gortzolidis, Anastasia Tsakiridou, Vasilios Xanthopoulos, George Theodoropoulos, Helen Goumakou, Maria Georgiakaki, Vasiliki Grigoraki, Nikolaos I. Anagnostopoulos
Journal: Blood (2005)
Allo-Immunity to Erythrocytes in Relation to Blood Transfusion and Pregnancy: Cooperative Study of Allo-Immunity to Antigen Diversity in Asian Populations.
Authors: Akihiro Takeshita, Hiroko Watanabe, Dae Won Kim, Kyou Sup Han, So Yong Kwon, Jang Soo Suh, Chan Pui Ha Natalie, Veera Sekaran Nadarajan, Nuranissa Bte Yacob Marican, Parichart Permpikul, Makoto Uchikawa, Shuichi Kino, Hitoshi Ohto
Journal: Blood (2009)
ATIM-08. SURVIVAL AND EFFICACY DATA FOR PATIENTS WITH GLIOBLASTOMA TREATED WITH IPILIMUMAB IN COMBINATION WITH BEVACIZUMAB
Authors: Thomas Carter, Nicholas Brown, Heather Shaw, Kerry Chester, Denise Cohn-Brown, Paul Mulholland
Journal: Neuro-Oncology (2016)

Median survival in glioblastoma is under one year and there is increasing interest in the potential of immunotherapy. We have previously published encouraging initial responses and toxicity data for 20 poor-prognosis patients treated with the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab in combination with the anti-VEGF mAb bevacizumab, and we have now treated 37 patients with this regimen. Thirty-seven patients were consented for treatment with ipilimumab and bevacizumab in combination. Ipilimumab was dosed at 3mg/kg and all patients received concurrent G-CSF or GM-CSF. Bevacizumab was dosed at 10mg/kg every two weeks. Toxicity, radiological responses, progression free survival and overall survival were analysed for all patients. Ten patients were treated following first-line palliative (chemo)radiotherapy for newly diagnosed glioblastoma and 17 were treated with recurrent disease. Best response evaluation MRI scans were available for 35 patients; 14 patients (40%) showed a partial response (5 treated following (chemo)radiotherapy, 9 with recurrent disease), 13 patients (37%) showed stable disease (5 treated following (chemo)radiotherapy, 8 with recurrent disease) and 8 patients (23%) showed disease progression. 12 months survival data were available for 16 patients treated with recurrent disease; 7 patients (44%) were alive, 2 of whom (13%) were progression free. Four of those who progressed received subsequent treatment with pembrolizumab and bevacizumab. For the patients treated following first-line therapy for whom 12 month survival data is available (n=7), 3 were progression free at 12 months, 1 had disease progression but remained alive and 3 had died. Combination therapy with ipilimumab or pembrolizumab and bevacizumab is tolerable in patients with newly diagnosed and recurrent glioblastoma, with evidence of activity. These results warrant further investigation in randomised clinical trials. Data on this patient cohort continues to be collected and will be updated.
Bortezomib Induces Rapid Upregulation of Topoisomerase IIα and Demonstrates Schedule-Dependent Synergistic Cytotoxicity with Anthracyclines and Etoposide in Acute Myeloid Leukemia and Myeloma Cell Lines.
Authors: Michael P. Carroll, Olin Feuerbacher, Andrew M. Yeager, Terry H. Landowski
Journal: Blood (2005)
Protein Kinase Gene Expression Profile in Adult Acute Lymphocytic Leukemia (ALL): Identification of Novel Therapeutic Targets.
Authors: Monica Messina, Sabina Chiaretti, Simona Tavolaro, Irene Della Starza Miss, Antonella Vitale, Cristina Ariola, Alina Negulici Miss, Loredana Elia, Anna Guarini, Robert Foa
Journal: Blood (2006)
[18F]FLT Is Superior to [18F]FDG to Early Predict Response to Specific Inhibitors of NPM-ALK-Dependent Pathways In a Human ALCL Xenograft Model
Authors: Nicolas Graf, Zhoulei Li, Ken Herrmann, Alexandra Junger, Daniel Weh, Christian Peschel, Markus Schwaiger, Andreas Buck, Tobias Dechow
Journal: Blood (2010)
Clinical Outcome of Immunoglobulin Light Chain Amyloidosis Affecting the Kidney
Authors: Morie Abraham Gertz, Nelson Leung, Martha Q Lacy, Angela Dispenzieri, Steven R Zeldenrust, Suzanne R Hayman, Francis K. Buadi, David Dingli, Philip R. Greipp, Shaji Kumar, John A Lust, S. Vincent Rajkumar, Stephen J Russell, Thomas E. Witzig
Journal: Blood (2008)
Vinorelbine, Paclitaxel, Etoposide, Cisplatin and Cytarabine (VTEPA) Is An Effective Salvage Therapy for Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL) but Not for R/R Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Rajni Sinha, Nassoma King, Pareen J Shenoy, Mary Jo Lechowicz, Kevin Bumpers, Donald Hutcherson, Martha Arellano, Amelia Langston, Jonathan L. Kaufman, Leonard T. Heffner, Edmund K Waller, Christopher R Flowers, Sagar Lonial
Journal: Blood (2011)
ACTR-54. PHASE I TRIAL OF GENETICALLY MODIFIED HEMATOPOETIC PROGENITOR CELLS FACILITATING BONE MARROW CHEMOPROTECTION AND ENABLING TMZ/O6BG DOSE ESCALATION RESULTING IN IMPROVED SURVIVAL
Authors: Andrew Sloan, Hua Fung, Jane Reese-Kroc, Lisa Rogers, Christopher Murphy, Hilard Lazrus, Boro Dropulic, Stanton Gerson
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) is the most common malignant brain tumor with a median survival of 15 months despite surgery and aggressive radio-chemotherapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene which repairs temozolamide-induced DNA methylation. The MGMT inhibitor O6-benzylguanine (BG) has demonstrated efficacy in depleting MGMT and maximizing tumor response in early phase clinical trials. However, because MGMT expression is also low in hematopoietic cells, this has resulted in unacceptable bone marrow toxicity, and this approach has been abandoned. We hypothesized that chemoprotection of hematopoieticprogenitor cells (HPC) with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity coupled with low affinity for BG, would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. We thus performed a phase I trial to test this hypothesis. We treated 7 consecutive patients with newly diagnosed GBM with standard surgery and radiation, followed by transplantation with autologous CD34+hematopoetic progenitor cells engineered to express MGMT-P140K using a lentiviral vector in three arms. To assess chemo-protection, patients’ blood counts and transgene marking were monitored during the treatment as was tumor growth and survival. The viral transduction rates were 2.5–75% and were clearly improved in the third arm with intra-patient dose escalation. P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild-moderate (Grade 2–3) mylosuppression consistent with chemo-selection and chemo-protection as hypothesized. Survival ranged from 20–36 months which exceeded their RPA predicted survival by 1.9–3.2 fold suggesting clinical benefit (mean 2.0). Viral insertion site analysis failed to demonstrate evidence of clonal dominance. These preliminary result demonstrates that this chemoprotection strategy is tolerable, safe, and facilitates TMZ & BG dose escalation resulting in increased survival in a small cohort of selected patients. A phase II study is planned.
Treatment of Secondary Central Nervous System Lymphoma with Intrathecal Rituximab, High Dose Methotrexate and R-DHAP, Followed by Autologous Stem Cell Transplantation. A Phase II HOVON Study
Authors: Jeanette K Doorduyn, Gustaaf W van Imhoff, Kees CAGM van Montfort, Harry C Schouten, Martyn Ronald Schaafsma, Johanna W. Baars, Marie Jose Kersten, Elly Lugtenburg, Martin M.J. van den Bent, Roelien Enting, Philip M.P. Poortmans, Jacoline J.E.C. Bromberg
Journal: Blood (2012)