207 results on '"Hutchison A"'
Search Results
2. Ibrutinib for Steroid Refractory Chronic Graft Vs Host Disease - Real World Experience
- Author
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Gaurav Sutrave, Tishya Indran, Yatika Jivan, Andrew Hutchison, Nada Hamad, Sui Tan, Duncan Purtill, Andrew Grigg, Siok-Keen Tey, David J. Curtis, David J Gottlieb, and Abir Bhattacharyya
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm
- Author
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Yang, Yue, Akada, Hajime, Nath, Dipmoy, Hutchison, Robert E., and Mohi, Golam
- Published
- 2016
- Full Text
- View/download PDF
4. Ibrutinib for Steroid Refractory Chronic Graft Vs Host Disease - Real World Experience
- Author
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Sutrave, Gaurav, primary, Indran, Tishya, additional, Jivan, Yatika, additional, Hutchison, Andrew, additional, Hamad, Nada, additional, Tan, Sui, additional, Purtill, Duncan, additional, Grigg, Andrew, additional, Tey, Siok-Keen, additional, Curtis, David J., additional, Gottlieb, David J, additional, and Bhattacharyya, Abir, additional
- Published
- 2022
- Full Text
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5. A Machine-Learning Derived Red Blood Cell Morphology Tool Enables Differential Diagnosis and Novel Single-Cell Analyses
- Author
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Foy, Brody, primary, Stefely, Jonathan, additional, Bendapudi, Pavan K., additional, Hasserjian, Robert P., additional, Al-Samkari, Hanny, additional, Louissaint, Abner, additional, Fitzpatrick, Megan J, additional, Hutchison, Bailey, additional, Mow, Christopher, additional, Collins, Julia, additional, Patel, Hasmukh P., additional, Patel, Chhaya, additional, Patel, Nikita, additional, Ho, Samantha, additional, Kaufman, Richard M, additional, Dzik, Walter, additional, Higgins, John M., additional, and Makar, Robert S, additional
- Published
- 2022
- Full Text
- View/download PDF
6. A Machine-Learning Derived Red Blood Cell Morphology Tool Enables Differential Diagnosis and Novel Single-Cell Analyses
- Author
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Brody Foy, Jonathan Stefely, Pavan K. Bendapudi, Robert P. Hasserjian, Hanny Al-Samkari, Abner Louissaint, Megan J Fitzpatrick, Bailey Hutchison, Christopher Mow, Julia Collins, Hasmukh P. Patel, Chhaya Patel, Nikita Patel, Samantha Ho, Richard M Kaufman, Walter Dzik, John M. Higgins, and Robert S Makar
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant
- Author
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Leung, Nelson, Bridoux, Frank, Hutchison, Colin A., Nasr, Samih H., Cockwell, Paul, Fermand, Jean-Paul, Dispenzieri, Angela, Song, Kevin W., and Kyle, Robert A.
- Published
- 2012
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8. Tyrosine 201 is required for constitutive activation of JAK2V617F and efficient induction of myeloproliferative disease in mice
- Author
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Yan, Dongqing, Hutchison, Robert E., and Mohi, Golam
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- 2012
- Full Text
- View/download PDF
9. Efficacy of vorinostat in a murine model of polycythemia vera
- Author
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Akada, Hajime, Akada, Saeko, Gajra, Ajeet, Bair, Alicia, Graziano, Stephen, Hutchison, Robert E., and Mohi, Golam
- Published
- 2012
- Full Text
- View/download PDF
10. Critical requirement for Stat5 in a mouse model of polycythemia vera
- Author
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Yan, Dongqing, Hutchison, Robert E., and Mohi, Golam
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- 2012
- Full Text
- View/download PDF
11. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)
- Author
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Asselin, Barbara L., Devidas, Meenakshi, Wang, Chenguang, Pullen, Jeanette, Borowitz, Michael J., Hutchison, Robert, Lipshultz, Steven E., and Camitta, Bruce M.
- Published
- 2011
- Full Text
- View/download PDF
12. Autologous Stem Cell Transplantation in AL-Amyloidosis Following Yttrium-90 Labelled Anti-CD66 Monoclonal Antibody As Sole Conditioning Is Associated with Low Toxicity and Demonstrable Disease Responses
- Author
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Orchard, Kim H., primary, Langford, Jon, additional, Lloyd-Evans, Paul, additional, Phillips, Denise, additional, Guy, Matthew, additional, Michopoulou, Sofia, additional, Lewis, Gemma, additional, Williams, Julian, additional, Zvavamwe, Clint, additional, Hutchison, Claire, additional, Nunnick, Jane, additional, Blackwell, Amanda, additional, Chan, Pei-San, additional, Wickham, Caspar, additional, Quigley, Ann-Marie, additional, Cook, Mark, additional, Jackson, Graham, additional, Hawkins, Philip N, additional, and Wechalekar, Ashutosh D., additional
- Published
- 2021
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13. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera–like disease
- Author
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Akada, Hajime, Yan, Dongqing, Zou, Haiying, Fiering, Steven, Hutchison, Robert E., and Mohi, M. Golam
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- 2010
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14. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425
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Schwartz, Cindy L., Constine, Louis S., Villaluna, Doojduen, London, Wendy B., Hutchison, Robert E., Sposto, Richard, Lipshultz, Steven E., Turner, Charles S., deAlarcon, Pedro A., and Chauvenet, Allen
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- 2009
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15. Autologous Stem Cell Transplantation in AL-Amyloidosis Following Yttrium-90 Labelled Anti-CD66 Monoclonal Antibody As Sole Conditioning Is Associated with Low Toxicity and Demonstrable Disease Responses
- Author
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Paul Lloyd-Evans, Kim Orchard, Matthew Guy, Denise A. Phillips, Pei-San Chan, Caspar Wickham, Claire Hutchison, Gemma Lewis, Jon Langford, Sofia Michopoulou, Clint Zvavamwe, Mark J. Cook, Julian Williams, Ashutosh D. Wechalekar, Ann-Marie Quigley, Graham Jackson, Philip N. Hawkins, Jane Nunnick, and Amanda Blackwell
- Subjects
Pathology ,medicine.medical_specialty ,Low toxicity ,medicine.drug_class ,business.industry ,Immunology ,chemistry.chemical_element ,Cell Biology ,Hematology ,Yttrium ,Disease ,Monoclonal antibody ,medicine.disease ,Biochemistry ,Autologous stem-cell transplantation ,chemistry ,medicine ,AL amyloidosis ,business - Abstract
Delayed diagnosis and lack of effective therapies results in the death of approximately 30% of patients with AL-amyloidosis (AL-A) within the first year of diagnosis. Autologous stem cell transplantation (ASCT) remains an important treatment option, resulting in improved organ function and survival in responders, however its utility is restricted due to the substantial toxicity of conventional ASCT conditioning in the vulnerable AL-A population. We report here the use of a monoclonal anti-CD66 monoclonal antibody (Besilesomab)radiolabelled with yttrium-90 (90Y-anti-CD66) as the sole conditioning agent prior to ASCT in a phase I study in AL-A patients. The study had full ethical and regulatory approvals (EudraCT 2015-002231-18; ISRCTN 13400668) and comprised 3 ascending radiation activity levels, 30, 40 and 45 MBq per kg body weight, each with 3 patients. Patients entered the study after fulfilling entry requirements and with informed consent. Prior to receiving 90Y-anti-CD66, organ dosimetry and biodistribution were determined using anti-CD66 labelled with indium-111 (111In-anti-CD66) with sequential gamma camera imaging. Estimated absorbed radiation to critical organs was determined from an established dosimetry model, organ radiation dose expressed in Gray (Gy). Radiation dose limits of 45Gy for the bone marrow, 15Gy for the liver were used as safety measures. Table 1 summarises patient characteristics, the majority of whom had received multiple lines of treatment including three who had previously undergone ASCT using high dose melphalan (HDM) conditioning. The primary end-point was treatment related toxicity as determined using CTCAE v4.0. Haematological toxicities (cytopenia) were excluded as adverse events (AEs) unless considered life-threatening. Secondary end-points were: clonal disease response determined by changes in serum free light chain assay (FLCa) and malignant plasma cell percentage in bone marrow (BM) as determined by multi-colour flow cytometry; cardiac toxicity using NT-proBNP measurements; overall survival and time to disease progression; biodistribution and dosimetry using SPECT-CT imaging; neutrophil and platelet engraftment (European Blood and Marrow Transplant criteria). Results: Ten patients were studied with 111In-anti-CD66, of whom 9 proceeded to 90Y-anti-CD66 conditioning with infused activity determined by study cohort and body weight; one patient failed dosimetry with excessive hepatic uptake and 2 received reduced activity to keep the BM dose within the 45Gy limit. In total 47 AEs were recorded the majority (41) grades 1-2 with no Serious Adverse Events (SAEs); 3 AEs recorded as grade 4; no transplant related deaths and all patients engrafted with median neutrophil recovery by D+13, platelets by D+11. Importantly no patients experienced mucositis or therapy related diarrhoea maintaining oral nutrition. All patients became profoundly cytopenic consistent with bone marrow suppression due to the targeted radiation. Only two patients experienced a fever post-transplant, neither life-threatening. Table 2 summarises the estimated absorbed radiation dose to critical organs and disease responses. Of the 9 patients treated with 90Y-anti-CD66 and ASCT, 2 had complete responses (CR) and 5 had partial responses (PR); 1 stable disease and 1 progressive disease determined by FLCa. Six of 8 evaluable patients showed a reduction in percentage of malignant plasma cells in the BM. The study collected data to D+100 post-transplant but 4 patients showed continuing reduction in clonal FLCa beyond D+100 with one achieving a near CR 9 months post-transplant. No dose limiting toxicity was seen. No cardiac AEs were recorded. All patients are alive with median follow-up of 32.8 months (15.3 - 58.4). Summary: We have demonstrated that 90Y-anti-CD66 therapy can be used safely as sole conditioning agent prior to ASCT in pre-treated AL patients, associated with low toxicity and promising disease response rates, including patients who previously had undergone ASCT using HDM. BM radiation doses of up to 45Gy were achieved using this targeted approach with acceptably low doses delivered to other critical organs. Further trials are required to determine the full potential of this agent in the context of stem cell transplantation for AL amyloidosis and other haematological diseases. This research was funded by the charity Blood Cancer UK. Figure 1 Figure 1. Disclosures Orchard: GSK: Current holder of individual stocks in a privately-held company; Pfizer: Speakers Bureau. Cook: BMS: Current Employment, Honoraria; Celegene: Honoraria, Other: Travel support, Research Funding; Jansen: Honoraria; Takeda: Honoraria, Other: Travel support. Jackson: amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau.
- Published
- 2021
16. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B
- Author
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Manno, Catherine S., Chew, Amy J., Hutchison, Sylvia, Larson, Peter J., Herzog, Roland W., Arruda, Valder R., Tai, Shing Jen, Ragni, Margaret V., Thompson, Arthur, Ozelo, Margareth, Couto, Linda B., Leonard, Debra G.B., Johnson, Frederick A., McClelland, Alan, Scallan, Ciaran, Skarsgard, Erik, Flake, Alan W., Kay, Mark A., High, Katherine A., and Glader, Bertil
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- 2003
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17. Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin
- Author
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Flinn, Ian W., Kopecky, Kenneth J., Foucar, M. Kathryn, Head, David, Bennett, John M., Hutchison, Robert, Corbett, William, Cassileth, Peter, Habermann, Thomas, Golomb, Harvey, Rai, Kanti, Eisenhauer, Elizabeth, Appelbaum, Frederick, Cheson, Bruce, and Grever, Michael R.
- Published
- 2000
- Full Text
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18. Tyrosine 201 is required for constitutive activation of JAK2V617F and efficient induction of myeloproliferative disease in mice
- Author
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Robert E. Hutchison, Golam Mohi, and Dongqing Yan
- Subjects
Cell Survival ,medicine.medical_treatment ,Blotting, Western ,Immunology ,Mutation, Missense ,Apoptosis ,Bone Marrow Cells ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Biochemistry ,Receptor tyrosine kinase ,Cell Line ,Mice ,STAT5 Transcription Factor ,medicine ,Animals ,Humans ,Tyrosine ,Bone Marrow Transplantation ,Cell Proliferation ,Mice, Inbred BALB C ,Myeloid Neoplasia ,Myeloproliferative Disorders ,biology ,Growth factor ,Cell Biology ,Hematology ,Janus Kinase 2 ,Flow Cytometry ,Molecular biology ,Enzyme Activation ,Transplantation ,Cell Transformation, Neoplastic ,HEK293 Cells ,biology.protein ,Phosphorylation ,Tyrosine kinase ,Protein Binding ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src - Abstract
The JAK2V617F mutation has been detected in most cases of Ph-negative myeloproliferative neoplasms (MPNs). The JAK2V617F protein is a constitutively activated tyrosine kinase that leads to transformation of hematopoietic progenitors. Previous studies have shown that several tyrosine residues within JAK2 are phosphorylated on growth factor or cytokine stimulation. However, the role of these tyrosine residues in signaling and transformation mediated by JAK2V617F remains unclear. In this study, we sought to determine the role of tyrosine 201, which is a potential binding site for Src homology 2 domain-containing proteins, in JAK2V617F-induced hematopoietic transformation by introducing a tyrosine-to-phenylalanine point mutation (Y201F) at this site. We observed that the Y201F mutation significantly inhibited cytokine-independent cell growth and induced apoptosis in Ba/F3-EpoR cells expressing JAK2V617F. The Y201F mutation also resulted in significant inhibition of JAK2V617F-mediated transformation of hematopoietic cells. Biochemical analyzes revealed that the Y201F mutation almost completely inhibited constitutive phosphorylation/activation of JAK2V617F. We also show that the Y201 site of JAK2V617F promotes interaction with Stat5 and Shp2, and constitutive activation of downstream signaling pathways. Furthermore, using a BM transduction/transplantation approach, we found that tyrosine 201 plays an important role in the induction of MPNs mediated by JAK2V617F.
- Published
- 2012
19. Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm
- Author
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Hajime Akada, Yue Yang, Robert E. Hutchison, Dipmoy Nath, and Golam Mohi
- Subjects
0301 basic medicine ,Immunology ,Mutation, Missense ,Mice, Transgenic ,macromolecular substances ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,Mice ,medicine ,Animals ,Enhancer of Zeste Homolog 2 Protein ,Myelofibrosis ,Myeloproliferative neoplasm ,Megakaryocyte Progenitor Cells ,Mutation ,business.industry ,Platelet Count ,EZH2 ,Cell Biology ,Hematology ,Janus Kinase 2 ,medicine.disease ,Transplantation ,Gene Expression Regulation, Neoplastic ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Amino Acid Substitution ,Primary Myelofibrosis ,Hematologic Neoplasms ,Cancer research ,Bone marrow ,business ,Chromatin immunoprecipitation ,Gene Deletion - Abstract
An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera-like disease, concomitant loss of Ezh2 significantly reduced the red blood cell and hematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion of megakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617F-expressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, and Hmga2 were transcriptionally derepressed, and the H3K27me3 levels in these gene promoters were significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617F mice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increased megakaryocytic colonies in the BM of Jak2V617F mice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice.
- Published
- 2015
20. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)
- Author
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Jeanette Pullen, Robert E. Hutchison, Steven E. Lipshultz, Bruce M. Camitta, Michael J. Borowitz, Chenguang Wang, Barbara L. Asselin, and Meenakshi Devidas
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Male ,Mucositis ,medicine.medical_specialty ,Pediatrics ,Randomization ,Adolescent ,medicine.medical_treatment ,Immunology ,Antineoplastic Agents ,Biochemistry ,Gastroenterology ,Disease-Free Survival ,law.invention ,Young Adult ,Randomized controlled trial ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Young adult ,Child ,Proportional Hazards Models ,Chemotherapy ,business.industry ,Lymphoblastic lymphoma ,Infant ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,medicine.disease ,Chemotherapy regimen ,Methotrexate ,Child, Preschool ,Female ,business ,medicine.drug - Abstract
The Pediatric Oncology Group (POG) phase 3 trial 9404 was designed to determine the effectiveness of high-dose methotrexate (HDM) when added to multi-agent chemotherapy based on the Dana-Farber backbone. Children with T-cell acute lymphoblastic leukemia (T-ALL) or advanced lymphoblastic lymphoma (T-NHL) were randomized at diagnosis to receive/not receive HDM (5 g/m2 as a 24-hour infusion) at weeks 4, 7, 10, and 13. Between 1996 and 2000, 436 patients were enrolled in the methotrexate randomization. Five-year and 10-year event-free survival (EFS) was 80.2% ± 2.8% and 78.1% ± 4.3% for HDM (n = 219) versus 73.6% ± 3.1% and 72.6% ± 5.0% for no HDM (n = 217; P = .17). For T-ALL, 5-year and 10-year EFS was significantly better with HDM (n = 148, 5 years: 79.5% ± 3.4%, 10 years: 77.3% ± 5.3%) versus no HDM (n = 151, 5 years: 67.5% ± 3.9%, 10 years: 66.0% ± 6.6%; P = .047). The difference in EFS between HDM and no HDM was not significant for T-NHL patients (n = 71, 5 years: 81.7% ± 4.9%, 10 years: 79.9% ± 7.5% vs n = 66, 5 years: 87.8% ± 4.2%, 10 years: 87.8% ± 6.4%; P = .38). The frequency of mucositis was significantly higher in patients treated with HDM (P = .003). The results support adding HDM to the treatment of children with T-ALL, but not with NHL, despite the increased risk of mucositis.
- Published
- 2011
21. Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera–like disease
- Author
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Hajime Akada, Robert E. Hutchison, Haiying Zou, Dongqing Yan, M. Golam Mohi, and Steven Fiering
- Subjects
medicine.medical_specialty ,Reticulocytosis ,Immunology ,Gene Dosage ,Mutation, Missense ,Mice, Transgenic ,Biology ,Biochemistry ,Mice ,Polycythemia vera ,hemic and lymphatic diseases ,Internal medicine ,STAT5 Transcription Factor ,medicine ,Animals ,Humans ,Leukocytosis ,Extracellular Signal-Regulated MAP Kinases ,Promoter Regions, Genetic ,Myelofibrosis ,Erythropoietin ,Polycythemia Vera ,Myeloid Neoplasia ,Hematology ,Thrombocytosis ,Essential thrombocythemia ,Homozygote ,Cell Biology ,Janus Kinase 2 ,medicine.disease ,Neutrophilia ,Disease Models, Animal ,Amino Acid Substitution ,Gene Expression Regulation ,Cancer research ,medicine.symptom ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
A somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in a majority of patients with polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. However, contribution of the JAK2V617F mutation in these 3 clinically distinct myeloproliferative neoplasms (MPNs) remained unclear. To investigate the role of JAK2V617F in the pathogenesis of these MPNs, we generated an inducible Jak2V617F knock-in mouse, in which the expression of Jak2V617F is under control of the endogenous Jak2 promoter. Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies. Homozygous Jak2V617F expression also resulted in a PV-like disease associated with significantly greater reticulocytosis, leukocytosis, neutrophilia and thrombocytosis, marked expansion of erythroid progenitors and Epo-independent erythroid colonies, larger spleen size, and accelerated bone marrow fibrosis compared with heterozygous Jak2V617F expression. Biochemical analyses revealed Jak2V617F gene dosage-dependent activation of Stat5, Akt, and Erk signaling pathways. Our conditional Jak2V617F knock-in mice provide an excellent model that can be used to further understand the molecular pathogenesis of MPNs and to identify additional genetic events that cooperate with Jak2V617F in different MPNs.
- Published
- 2010
22. Deletion of PTPN1 Promotes the Development of Myelofibrosis
- Author
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Jobe, Fatoumata, primary, Patel, Bhumika, additional, Makishima, Hideki, additional, Przychodzen, Bartlomiej P, additional, Hutchison, Robert E, additional, Bence, Kendra K, additional, Maciejewski, Jaroslaw P, additional, and Mohi, Golam, additional
- Published
- 2016
- Full Text
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23. Expression of HMGA2 Cooperates with Jak2V617F in the Development of Myelofibrosis
- Author
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Dutta, Avik, primary, Hutchison, Robert E, additional, and Mohi, Golam, additional
- Published
- 2016
- Full Text
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24. Oncology Care at Home: A Patient-Centered Approach to Managing Care for Bone Marrow Transplant and CAR-T Cell Therapy Patients
- Author
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Peterson, Glen, Moore, Susan, Montoya, Sarah, Hutchison, Carolyn, Hoople, Katherine, and Smith, Clayton
- Abstract
Introduction. More than half of patients with cancer who receive cytotoxic chemotherapy and/or immunotherapies experience deleterious side effects such as febrile neutropenia, infection, neurotoxicity, and cytokine release syndrome. Early intervention and treatment for these side effects can help avoid complications and improve outcomes, but delays in treatment administration are common as most outpatient management approaches depend on patient self-assessment and patient-initiated pursuit of follow-up care. Remote patient monitoring through digital health technologies offers the opportunity to bridge this gap without imposing undue burden on either patients or healthcare providers. This feasibility study assessed the results of a technology-assisted in-home oncology care program to remotely monitor bone marrow transplant and CAR T-cell therapy patients and provide early intervention for symptomatic episodes needing clinical management. The program also offered support for patients to obtain routine lab draws, hydration, antiemetics, intravenous antibiotics, and a provider assessment at home. Technical and operational feasibility were evaluated together with perceived user experience among patients, caregivers, and providers.
- Published
- 2023
- Full Text
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25. Deletion of PTPN1 Promotes the Development of Myelofibrosis
- Author
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Bhumika J. Patel, Hideki Makishima, Bartlomiej P Przychodzen, Jaroslaw P. Maciejewski, Fatoumata Jobe, Robert E. Hutchison, Kendra K. Bence, and Golam Mohi
- Subjects
Myeloid ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,Transplantation ,Haematopoiesis ,medicine.anatomical_structure ,White blood cell ,medicine ,Bone marrow ,Progenitor cell ,Myelofibrosis - Abstract
Deletion of chromosome 20q [del(20q)] is a common chromosomal abnormality associated with myeloid neoplasms including myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), MDS/MPN overlap disorders and acute myeloid leukemia (AML). The del(20q) lesion is often associated with myeloproliferative features; it is present in patients with myelofibrosis (MF) at a high frequency (24%) and thus considered to be one of the most frequent cytogenetic abnormalities in MF (Wassie et al., Br J Haematol. 2015). The del(20q) lesion can also coexist with JAK2V617F mutation in MPN/MF. However, the target tumor-suppressor gene(s) within chromosome 20q involved in the pathogenesis of MF remains unknown. The PTPN1 locus maps to human chromosome 20q13.1-q13.2. PTPN1 (also known as PTP1B) is a ubiquitously expressed non-receptor tyrosine phosphatase that has been linked to metabolism and cancer. Mice deficient in Ptpn1 exhibit resistance to diet-induced obesity and diabetes. Both oncogenic and tumor suppressor functions for PTPN1 have been suggested. PTPN1 can negatively regulate the JAK/STAT signaling, which is frequently found activated in MPN. Here, we report the identification and functional consequences of PTPN1 deletion in the pathogenesis of MF. Deletion of PTPN1 was identified in 14% cases of MF. Conditional deletion of Ptpn1 in the mouse hematopoietic compartment resulted in significant increases in white blood cell and neutrophil counts in the peripheral blood and enlargement of spleen size. Flow cytometric analyses showed significant expansion of myeloid (Gr-1+/Mac-1+) precursors in the bone marrow (BM) and spleens of Ptpn1-deleted mice compared with control animals. Megakaryocytic (CD41+/CD61+) precursors were also significantly increased in the spleens of Ptpn1-deleted mice. Flow cytometric analyses also revealed significant increases in absolute numbers of LSK cells (Lin-Sca1+c-kit+) and its subsets including long-term hematopoietic stem cells (LT-HSC), short-term HSC (ST-HSC) and multi-potent progenitors (MPP) in the spleens of Ptpn1-deleted mice. Hematopoietic progenitor colony assays showed significant increases in myeloid (CFU-GM) and megakaryocytic (CFU-Mk) colonies in the BM of Ptpn1-deleted mice compared with control mice BM. Histopathologic analysis demonstrated fibrosis (grade 2) in the BM and spleens of Ptpn1-deleted mice at 52 weeks after induction, whereas control animals did not exhibit fibrosis at that age. Together, these results suggest that deletion of Ptpn1 induces an MPN-like phenotype, which progresses to MF over time. Moreover, transplantation of Ptpn1-deficient BM into lethally irradiated wild-type animals resulted in fibrosis at 18 weeks after transplantation, demonstrating that the effect of Ptpn1 loss in the development of myelofibrosis is cell-intrinsic. Competitive repopulation assays using BM from control or Ptpn1-deficient (CD45.2+) mice with wild type congenic (CD45.1+) mice showed that deletion of Ptpn1 enhances the repopulation capacity of hematopoietic stem cells. Biochemical analyses revealed that depletion of Ptpn1 enhanced JAK2/STAT5, AKT and ERK signaling in the BM of Ptpn1-deleted mice. Furthermore, we observed that deletion of Ptpn1 in Jak2V617F knock-in mice accelerates the development of myelofibrosis. In conclusion, our results establish a tumor-suppressor function for PTPN1 in MF. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
26. Expression of HMGA2 Cooperates with Jak2V617F in the Development of Myelofibrosis
- Author
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Avik Dutta, Robert E. Hutchison, and Golam Mohi
- Subjects
biology ,business.industry ,MTOR Serine-Threonine Kinases ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Polycythemia vera ,HMGA2 ,medicine ,Cancer research ,biology.protein ,Erythroid Progenitor Cells ,Myelofibrosis ,business - Abstract
High Mobility Group AT Hook 2 (HMGA2) is a non-histone chromatin protein that regulates gene transcription and controls cell proliferation, survival and self-renewal of stem cells. HMGA2 is expressed at a low level in normal adult hematopoietic progenitors but is highly expressed in hematopoietic progenitors of patients with Myelofibrosis (MF). However, the contribution of HMGA2 to the pathogenesis of MF remains unknown. MF is the deadliest form of myeloprolifearative neoplasm (MPN) characterized by deposition of fibrous tissues in the bone marrow, increased megakaryopoiesis, ineffective erythropoiesis and extramedullary hematopoiesis. Median survival of patients with MF is less than 6 years. The JAK2V617F mutation has been found in 50-60% patients with MF. However, it is not clear whether JAK2V617F mutation alone is sufficient to cause MF. Interestingly, up-regulation of HMGA2 expression has been found in association with the JAK2V617F mutation in a significant percentage of patients with MF. To understand the role of JAK2V617F mutation in the pathogenesis of MPN, we previously generated a conditional Jak2V617F knock-in mouse. We observed that expression of heterozygous Jak2V617F in mouse hematopoietic compartments is sufficient to induce a polycythemia vera (PV)-like MPN. Recently, we have shown that deletion of EZH2 promotes the development of MF in Jak2V617F knock-in mice and EZH2 deletion increases the expression of HMGA2 in hematopoietic progenitors of EZH2-deleted Jak2V617F mice. To directly assess the effects of concomitant expression of HMGA2 and heterozygous Jak2V617F in mice hematopoietic compartments, we expressed control vector or HMGA2 in wild type and heterozygous Jak2V617F knock-in mice BM by lentiviral transduction and performed bone marrow transplantation into lethally irradiated C57BL/6 recipient mice. Whereas recipients of vector-transduced Jak2V617F knock-in BM cells exhibited a PV-like MPN characterized by increased red blood cells (RBC), hemoglobin, hematocrit and platelets in their peripheral blood, recipients of HMGA2-transduced Jak2V617F knock-in BM showed reduced hemoglobin and hematocrit parameters compared with recipients of vector-expressing Jak2V617F BM cells. Interestingly, peripheral blood neutrophil and platelet counts were further increased in transplanted animals receiving HMGA2-transduced Jak2V617F BM cells. Expression of HMGA2 also resulted in significantly larger spleen size in the transplanted animals receiving HMGA2-expressing Jak2V617F BM cells. Flow cytometric analysis showed significant increase in megakaryocytic precursors (CD41+) but decrease in erythroid precursors (CD71+/Ter119+) in the BM and spleens of transplanted animals receiving HMGA2-expressing Jak2V617F BM compared with control vector-expressing Jak2V617F BM. Furthermore, the frequency of hematopoietic stem/progenitor cells (LSK; Lin-Sca-1+c-kit+) was significantly increased in recipients of HMGA2-transduced Jak2V617F knock-in BM compared with control vector-transduced Jak2V617F knock-in BM or HMGA2-transduced wild type BM. Histopathologic analysis revealed extensive fibrosis in the BM and spleens from recipients of HMGA2-expressing Jak2V617F mice at 32 weeks after transplantation while BM and spleens from recipients of vector-transduced Jak2V617F knock-in BM or HMGA2-transduced wild type BM showed very little or no fibrosis at this age. Together, these data suggest that expression of HMGA2 promotes megakaryopoiesis and accelerates the development of MF in mice expressing Jak2V617F. To gain insights into the mechanisms by which expression of HMGA2 accelerates the development of MF in Jak2V617F mice, we performed RNA-sequencing analysis on purified LSK (Lin-Sca-1+c-kit+) cells. Gene set enrichment and pathway analyses revealed that the genes related to chemokine, TGF-β, MAP Kinase, PI3 kinase-Akt, mTOR and WNT signaling pathways were up-regulated in HMGA2-expressing Jak2V617F mice LSK compared with vector-expressing Jak2V617F LSK cells. We also found that HMGA2 directly binds to the promoter regions of some of these target genes and regulate their expression. Further studies will validate the targets of HMGA2 and determine their contribution in MF mediated by Jak2V617F. In conclusion, our studies show that expression of HMGA2 cooperates with Jak2V617F in the development of MF. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
27. Critical Role of SHP2 in the Initiation and Maintenance of Myeloproliferative Neoplasms Evoked By JAK2V617F
- Author
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Mohi, Golam, primary, Yan, Dongqing, additional, Jobe, Fatoumata, additional, and Hutchison, Robert E, additional
- Published
- 2015
- Full Text
- View/download PDF
28. Adult Patients With De Novo Acute Myeloid Leukemia and t(9; 11)(p22; q23) Have a Superior Outcome to Patients With Other Translocations Involving Band 11q23: A Cancer and Leukemia Group B Study
- Author
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Kristiina Heinonen, Robert E. Hutchison, Prasad Koduru, Kathleen W. Rao, Clara D. Bloomfield, Robert J. Mayer, Andrew J. Carroll, Charles A. Schiffer, Matthew P. Strout, Joseph O. Moore, David M. Lawrence, and Krzysztof Mrózek
- Subjects
medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Childhood Acute Myeloid Leukemia ,Immunology ,Cancer ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Gastroenterology ,Chemotherapy regimen ,Biochemistry ,Surgery ,Leukemia ,Internal medicine ,medicine ,Cytarabine ,business ,Neoadjuvant therapy ,medicine.drug - Abstract
Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.
- Published
- 1997
29. Efficacy of vorinostat in a murine model of polycythemia vera
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Stephen L. Graziano, Alicia K. Bair, Saeko Akada, Ajeet Gajra, Golam Mohi, Robert E. Hutchison, and Hajime Akada
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Erythroblasts ,Immunology ,Antineoplastic Agents ,Apoptosis ,Biology ,Hydroxamic Acids ,Biochemistry ,Mice ,Polycythemia vera ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Gene Knock-In Techniques ,Progenitor cell ,Protein kinase B ,Vorinostat ,Polycythemia Vera ,Janus kinase 2 ,Myeloid Neoplasia ,Cell Biology ,Hematology ,Cell Cycle Checkpoints ,Janus Kinase 2 ,medicine.disease ,Hematopoietic Stem Cells ,Mice, Mutant Strains ,Histone Deacetylase Inhibitors ,Haematopoiesis ,Disease Models, Animal ,Treatment Outcome ,biology.protein ,Cancer research ,Histone deacetylase ,K562 Cells ,Cell Division ,medicine.drug - Abstract
The discovery of the JAK2V617F mutation in most patients with Ph-negative myeloproliferative neoplasms has led to the development of JAK2 kinase inhibitors. However, JAK2 inhibitor therapy has shown limited efficacy and dose-limiting hematopoietic toxicities in clinical trials. In the present study, we describe the effects of vorinostat, a small-molecule inhibitor of histone deacetylase, against cells expressing JAK2V617F and in an animal model of polycythemia vera (PV). We found that vorinostat markedly inhibited proliferation and induced apoptosis in cells expressing JAK2V617F. In addition, vorinostat significantly inhibited JAK2V617F-expressing mouse and human PV hematopoietic progenitors. Biochemical analyses revealed significant inhibition of phosphorylation of JAK2, Stat5, Stat3, Akt, and Erk1/2 in vorinostat-treated, JAK2V617F-expressing human erythroleukemia (HEL) cells. Expression of JAK2V617F and several other genes, including GATA1, KLF1, FOG1, SCL, C/EPBα, PU.1, and NF-E2, was significantly down-regulated, whereas the expression of SOCS1 and SOCS3 was up-regulated by vorinostat treatment. More importantly, we observed that vorinostat treatment normalized the peripheral blood counts and markedly reduced splenomegaly in Jak2V617F knock-in mice compared with placebo treatment. Vorinostat treatment also decreased the mutant allele burden in mice. Our results suggest that vorinostat may have therapeutic potential for the treatment of PV and other JAK2V617F-associated myeloproliferative neoplasms.
- Published
- 2012
30. Critical Role of SHP2 in the Initiation and Maintenance of Myeloproliferative Neoplasms Evoked By JAK2V617F
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Robert E. Hutchison, Golam Mohi, Dongqing Yan, and Fatoumata Jobe
- Subjects
Immunology ,Spleen ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,Transplantation ,Haematopoiesis ,medicine.anatomical_structure ,Polycythemia vera ,medicine ,Bone marrow ,Stem cell ,Progenitor cell ,Myelofibrosis - Abstract
The JAK2V617F mutation has been found in a majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Expression of JAK2V617F results in constitutive activation of the JAK2 tyrosine kinase and its downstream signaling pathways. JAK2 inhibitor therapy can reduce splenomegaly and constitutional symptoms but is not sufficient to cure or produce complete remission in patients with MPNs. Identification of critical signaling pathways/molecules required for the initiation and maintenance of MPNs will facilitate the development of more effective targeted therapies. To determine the role of JAK2V617F mutation in MPNs, we previously generated a conditional Jak2V617F knock-in mouse. We observed that expression of heterozygous Jak2V617F in mice hematopoietic compartments is sufficient to induce a PV-like MPN, whereas homozygous Jak2V617F expression accelerates the development of myelofibrosis. We have found that SHP2, a protein tyrosine phosphatase that positively regulates hematopoietic signaling, is constitutively phosphorylated in mouse and human hematopoietic cells expressing JAK2V617F. However, the contribution of SHP2 in the pathogenesis of MPNs induced by JAK2V617F remains elusive. Here, we sought to determine the role of SHP2 in JAK2V617F-evoked MPNs using conditional SHP2 knockout (SHP2 floxed) and Jak2V617F knock-in mice and MxCre line. Whereas expression of heterozygous Jak2V617F induced a PV-like MPN characterized by increase in red blood cells (RBC), white blood cells (WBC), neutrophils and platelets in the peripheral blood and splenomegaly, deletion of SHP2 normalized the blood parameters and spleen size in Jak2V617F knock-in mice. Flow cytometric analysis showed that deletion of SHP2 inhibited the expansion of erythroid, megakaryocytic, and granulocytic precursors in the bone marrow (BM) and spleens of Jak2V617F mice. Deletion of SHP2 also inhibited the expansion of hematopoietic stem cells and megakaryocyte-erythroid progenitors in the BM and spleens of Jak2V617F knock-in mice. Furthermore, deletion of SHP2 markedly inhibited the erythropoietin (Epo)-independent CFU-E colonies in the BM and spleens of Jak2V617F mice. In order to determine whether the effects of SHP2 deletion in Jak2V617F mice were cell autonomous, BM cells from uninduced control, MxCre;V617F/+ and MxCre;V617F/+;SHP2fl/fl mice were transplanted into lethally irradiated syngeneic recipient mice. Four weeks after transplantation, mice were injected with pI-pC to induce deletion of SHP2 and expression of Jak2V617F simultaneously. Transplanted animals receiving MxCre;V617F/+ BM developed a PV-like disease within 6 weeks after pI-pC induction. However, recipients of MxCre;V617F/+;SHP2fl/fl BM failed to induce the PV disease due to deletion of SHP2. Together, these data suggest that SHP2 is required for the initiation of PV-like MPN mediated by Jak2V617F. To determine if SHP2 is required for the maintenance of MPN evoked by Jak2V617F, uninduced wild type or MxCre;SHP2fl/fl mice BM cells were transduced with retroviruses expressing Jak2V617F and transplanted into lethally irradiated syngeneic recipient animals. Five weeks after transplantation, we assessed the peripheral blood counts to confirm the development of MPN disease. Transplanted animals receiving Jak2V617F-transduced wild type or MxCre;SHP2fl/fl mice BM were then divided into two groups- one group was injected with pI-pC (to induce deletion of SHP2 after establishment of the MPN disease); another group (control group) was injected with saline. We observed that deletion of SHP2 by pI-pC induction significantly inhibited the RBC, hematocrit, WBC and platelet counts in the peripheral blood and reduced the spleen size in transplanted animals expressing Jak2V617F. Moreover, deletion of SHP2 markedly inhibited the Epo-independent erythroid colonies in the BM and spleens of transplanted animals expressing Jak2V617F. Thus, SHP2 is not only required for the initiation of MPN but also required for the maintenance of MPN mediated by Jak2V617F. We have also observed that deletion of SHP2 blocks the development of myelofibrosis in Jak2V617F knock-in mice. In conclusion, our results suggest that SHP2 plays a critical role in the initiation and maintenance of MPNs evoked by Jak2V617F. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
31. Clinicopathologic features and treatment outcome of children with large- cell lymphoma and the t(2;5)(p23;q35)
- Author
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C H Pui, W. M. Roberts, Hazem Mahmoud, Robert E. Hutchison, John T. Sandlund, Victor M. Santana, Costan W. Berard, William M. Crist, Stephan W. Morris, and Raul C. Ribeiro
- Subjects
medicine.medical_specialty ,Pathology ,Working Formulation ,CD30 ,business.industry ,Large cell ,Immunology ,Large-cell lymphoma ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Lymphoma ,Internal medicine ,Medicine ,Stage (cooking) ,Extranodal Involvement ,business - Abstract
The t(2;5)(p23;q35) was detected in 9 of the 18 cases of large-cell lymphoma with an abnormal karyotype among 115 children with large-cell lymphoma treated at St Jude Children's Research Hospital from 1975 to 1993. When the cases containing the t(2;5) were classified according to the National Cancer Institute Working Formulation, 7 were large-cell, immunoblastic and 2 were diffuse large cell; according to the Kiel classification system, 6 were anaplastic large cell, 2 immunoblastic, and 1 centroblastic. CD30 expression was documented in 6 of 8 cases tested. All patients had nodal disease and 6 had extranodal involvement (bone in 4 cases and skin in 3). Eight of nine had advanced disease at diagnosis (stage Ill in 7 and stage IV in 1). Complete remission (CR) was attained in all patients and 6 remain in first CR for 19+ to 97+ months. Three relapsed, but successfully obtained second remissions; 2 are 58+ and 80+ months after retrieval therapy for local recurrences, and 1 patient died of recurrent disease. The t(2;5)(p23;q35) is associated with, but not limited to, anaplastic histology, a CD30+ T- cell phenotype, advanced stage disease with nodal (+/- extranodal) involvement, and chemosensitivity at diagnosis and relapse.
- Published
- 1994
32. Clinicopathologic features and treatment outcome of children with large- cell lymphoma and the t(2;5)(p23;q35)
- Author
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JT Sandlund, CH Pui, WM Roberts, VM Santana, SW Morris, CW Berard, RE Hutchison, RC Ribeiro, H Mahmoud, and WM Crist
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
The t(2;5)(p23;q35) was detected in 9 of the 18 cases of large-cell lymphoma with an abnormal karyotype among 115 children with large-cell lymphoma treated at St Jude Children's Research Hospital from 1975 to 1993. When the cases containing the t(2;5) were classified according to the National Cancer Institute Working Formulation, 7 were large-cell, immunoblastic and 2 were diffuse large cell; according to the Kiel classification system, 6 were anaplastic large cell, 2 immunoblastic, and 1 centroblastic. CD30 expression was documented in 6 of 8 cases tested. All patients had nodal disease and 6 had extranodal involvement (bone in 4 cases and skin in 3). Eight of nine had advanced disease at diagnosis (stage Ill in 7 and stage IV in 1). Complete remission (CR) was attained in all patients and 6 remain in first CR for 19+ to 97+ months. Three relapsed, but successfully obtained second remissions; 2 are 58+ and 80+ months after retrieval therapy for local recurrences, and 1 patient died of recurrent disease. The t(2;5)(p23;q35) is associated with, but not limited to, anaplastic histology, a CD30+ T- cell phenotype, advanced stage disease with nodal (+/- extranodal) involvement, and chemosensitivity at diagnosis and relapse.
- Published
- 1994
33. CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia [see comments]
- Author
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J Ben-Ezra, J Wright, Robert E. Hutchison, TP Jr Loughran, Aysegul Hasegeli Uner, EC Russell, and Teresa C. Gentile
- Subjects
White pulp ,Pathology ,medicine.medical_specialty ,Immunology ,chemical and pharmacologic phenomena ,Spleen ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Natural killer cell ,Leukemia ,medicine.anatomical_structure ,B symptoms ,hemic and lymphatic diseases ,Red pulp ,medicine ,medicine.symptom ,T-Cell Large Granular Lymphocyte Leukemia ,CD8 - Abstract
Clonal expansions of CD3+ large granular lymphocytes (LGL) have been classified as T-LGL leukemia. The majority of patients with T-LGL leukemia have a chronic disease (years) manifested often by severe neutropenia, rheumatoid arthritis, and mild-to-moderate splenomegaly. The characteristic phenotype of the leukemic LGL is CD3+, CD8+, CD16+, CD57+, and CD56-. In this report we describe an aggressive variant of T- LGL leukemia in which leukemic LGL also expressed CD56, as identified by two-color flow-cytometry analysis. In contrast to the chronic nature typical of T-LGL leukemia, these patients presented with a severe systemic illness that was rapidly progressive and resistant to treatment. Atypical clinical features included rapidly increasing spleen size to massive proportions, extensive lymphadenopathy, and the presence of B symptoms (fever, nightsweats, weight loss). Hematologic and pathologic features were also unusual for T-LGL leukemia. These patients had very high LGL counts at diagnosis (range 11,692 to 26,312 microL), which increased rapidly despite treatment. Histopathologic examination of splenic sections showed extensive infiltration of red pulp cords and sinuses by leukemic cells with atrophy of the white pulp. These clinicopathologic features are similar to those described for patients with natural killer cell (NK)-LGL leukemia, whose cells are also CD56+. However, unlike NK-LGL leukemia, we could not show a direct pathogenic role for Epstein-Barr virus (EBV), as Southern-blot analyses using an EBV-joined termini probe were negative in these patients. Our findings suggest that CD3+, CD56+ LGL leukemia is a distinct clinicopathologic entity separate from the usual CD3+, CD56- T- LGL leukemia. The expression on leukemic LGL of CD56, an adhesion molecule, may determine the aggressive biologic nature of this newly described disease.
- Published
- 1994
34. CD3+, CD56+ aggressive variant of large granular lymphocyte leukemia [see comments]
- Author
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Hutchison Re, Russell Ec, John J. Wright, Teresa C. Gentile, Ben-Ezra J, Thomas P. Loughran, and Uner Ah
- Subjects
White pulp ,Pathology ,medicine.medical_specialty ,business.industry ,Immunology ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,Gene rearrangement ,medicine.disease ,Biochemistry ,Natural killer cell ,Leukemia ,medicine.anatomical_structure ,Immunophenotyping ,B symptoms ,medicine ,Red pulp ,medicine.symptom ,business ,T-Cell Large Granular Lymphocyte Leukemia - Abstract
Clonal expansions of CD3+ large granular lymphocytes (LGL) have been classified as T-LGL leukemia. The majority of patients with T-LGL leukemia have a chronic disease (years) manifested often by severe neutropenia, rheumatoid arthritis, and mild-to-moderate splenomegaly. The characteristic phenotype of the leukemic LGL is CD3+, CD8+, CD16+, CD57+, and CD56-. In this report we describe an aggressive variant of T- LGL leukemia in which leukemic LGL also expressed CD56, as identified by two-color flow-cytometry analysis. In contrast to the chronic nature typical of T-LGL leukemia, these patients presented with a severe systemic illness that was rapidly progressive and resistant to treatment. Atypical clinical features included rapidly increasing spleen size to massive proportions, extensive lymphadenopathy, and the presence of B symptoms (fever, nightsweats, weight loss). Hematologic and pathologic features were also unusual for T-LGL leukemia. These patients had very high LGL counts at diagnosis (range 11,692 to 26,312 microL), which increased rapidly despite treatment. Histopathologic examination of splenic sections showed extensive infiltration of red pulp cords and sinuses by leukemic cells with atrophy of the white pulp. These clinicopathologic features are similar to those described for patients with natural killer cell (NK)-LGL leukemia, whose cells are also CD56+. However, unlike NK-LGL leukemia, we could not show a direct pathogenic role for Epstein-Barr virus (EBV), as Southern-blot analyses using an EBV-joined termini probe were negative in these patients. Our findings suggest that CD3+, CD56+ LGL leukemia is a distinct clinicopathologic entity separate from the usual CD3+, CD56- T- LGL leukemia. The expression on leukemic LGL of CD56, an adhesion molecule, may determine the aggressive biologic nature of this newly described disease.
- Published
- 1994
35. Prognostic Factors and the Impact of Frontline Therapy in Peripheral T-Cell Lymphoma: A Multicenter Australian Study
- Author
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Kuzich, James Anton, Hutchison, Andrew Peter, Lim, Kenneth, Wright, Matthew P.F., Cull, Gavin, Leahy, Michael F., Joske, David John Longstaff, Radeski, Dejan, and Purtill, Duncan
- Published
- 2017
- Full Text
- View/download PDF
36. Loss of EZH2 Inhibits Erythropoiesis and Accelerates the Development of Myelofibrosis in Jak2V617F Knock-in Mice
- Author
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Yang, Yue, primary, Akada, Hajime, additional, Nath, Dipmoy, additional, Hutchison, Robert E, additional, and Mohi, Golam, additional
- Published
- 2014
- Full Text
- View/download PDF
37. A Phase II Trial of Bortezomib Added to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Previously Untreated Indolent Non-Hodgkin’s Lymphoma
- Author
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Cohen, Jonathon B., primary, Switchenko, Jeffrey, additional, Koff, Jean L., additional, Sinha, Rajni, additional, Kaufman, Jonathan L., additional, Khoury, H. Jean, additional, Bumpers, Nassoma K, additional, Colbert, Amanda, additional, Hutchison-Rzepka, Amanda A, additional, Nastoupil, Loretta J., additional, Heffner, Leonard T., additional, Langston, Amelia, additional, Lechowicz, Mary Jo, additional, Lonial, Sagar, additional, and Flowers, Christopher R., additional
- Published
- 2014
- Full Text
- View/download PDF
38. Bone Marrow Core Biopsy Adequacy and Variability in the United Stated and Canada: A Multicenter Retrospective Study
- Author
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Merzianu, Mihai, primary, Cheney, Richard, additional, Groman, Adrienne, additional, Deeb, George, additional, Wilding, Gregory, additional, Cotta, Claudiu, additional, Amre, Ramila, additional, Balasubramanian, Manjula, additional, Brandao, Guilherme, additional, Brynes, Russell K., additional, Cherian, Sindhu, additional, Courville, Elizabeth, additional, Czuchlewski, David, additional, Fan, Guang, additional, Grier, David, additional, Hoehn, Daniela, additional, Hutchison, Robert E, additional, Inamdar, Kedar V., additional, Juskevicius, Ridas, additional, Kaur, Prabhjot, additional, Lazarchick, John, additional, Lewis, Michael R, additional, Miles, Rodney R., additional, Myers, Jerome B., additional, Nasr, Michel, additional, Naushad, Hina, additional, Olteanu, Horatiu, additional, Orazi, Attilio, additional, Reddy, Vishnu VB, additional, Robu, Valentin G, additional, Salaru, Gratian, additional, Teruya-Feldstein, Julie, additional, Vajpayee, Neerja, additional, Vos, Jeffrey, additional, Zhang, Ling, additional, Zhang, Shanxing, additional, Sedelmeyer, Ashley V, additional, Arguello, Vivian, additional, Aye, Le, additional, Barouk, Sharon, additional, Brega, Elisa F, additional, Carpenter, Richie, additional, Coad, James E., additional, DiPonio, Alana, additional, Garcia, Fernandez, additional, Grantham, John, additional, Ivelja, Sinisa, additional, McKenna, Robert, additional, Sultan, Kieran, additional, Thomsen, Matthew B, additional, Xu, Jie, additional, Peterson, LoAnn, additional, and Neppalli, Vishala T., additional
- Published
- 2014
- Full Text
- View/download PDF
39. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425
- Author
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Louis S. Constine, Wendy B. London, Charles S. Turner, Doojduen Villaluna, Pedro A. deAlarcon, Richard Sposto, Allen R. Chauvenet, Robert E. Hutchison, Steven E. Lipshultz, and Cindy L. Schwartz
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Vincristine ,Time Factors ,Adolescent ,Clinical Trials and Observations ,medicine.medical_treatment ,Prednisolone ,Immunology ,Bleomycin ,Biochemistry ,Disease-Free Survival ,chemistry.chemical_compound ,Prednisone ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Child ,Survival rate ,Cyclophosphamide ,Etoposide ,Chemotherapy ,business.industry ,Radiotherapy Dosage ,Cell Biology ,Hematology ,medicine.disease ,Hodgkin Disease ,Surgery ,Survival Rate ,Regimen ,chemistry ,Doxorubicin ,Child, Preschool ,Female ,business ,Progressive disease ,medicine.drug - Abstract
Current treatment strategies for Hodgkin lymphoma result in excellent survival but often confer significant long-term toxicity. We designed ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) to (1) enhance treatment efficacy by dose-dense drug delivery and (2) reduce risk of long-term sequelae by response-based reduction of cumulative chemotherapy. Efficient induction of early response by dose-dense drug delivery supported an early-response–adapted therapeutic paradigm. The 216 eligible patients were younger than 22 years with intermediate- or high-risk Hodgkin lymphoma. ABVE-PC was administered every 21 days. Rapid early responders (RERs) to 3 ABVE-PC cycles received 21 Gy radiation to involved regions; RER was documented in 63% of patients. Slow early responders received 2 additional ABVE-PC cycles before 21 Gy radiation. Five-year event-free-survival was 84%: 86% for the RER and 83% for the slow early responders (P = .85). Only 1% of patients had progressive disease. Five-year overall survival was 95%. With this regimen, cumulative doses of alkylators, anthracyclines, and epipodophyllotoxins are below thresholds usually associated with significant long-term toxicity. ABVE-PC is a dose-dense regimen that provides outstanding event-free survival/overall survival with short duration, early-response–adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00005578.
- Published
- 2009
40. Loss of EZH2 Inhibits Erythropoiesis and Accelerates the Development of Myelofibrosis in Jak2V617F Knock-in Mice
- Author
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Robert E. Hutchison, Yue Yang, Golam Mohi, Hajime Akada, and Dipmoy Nath
- Subjects
Immunology ,CD34 ,macromolecular substances ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Transplantation ,Haematopoiesis ,medicine.anatomical_structure ,Fibrosis ,Gene knockin ,medicine ,Cancer research ,Erythropoiesis ,Bone marrow ,Myelofibrosis - Abstract
EZH2, a component of the polycomb repressive complex 2 (PRC2), catalyzes the trimethylation of histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Inactivating mutations of EZH2 have been found in myelodysplastic syndromes and myeloproliferative neoplasms (MPNs) including myelofibrosis (MF). EZH2 mutations are associated with poor prognosis in patients with MF. However, the contribution of EZH2 mutations in the pathogenesis of MF remains unknown. The JAK2V617F mutation has been found in a majority of cases of MPNs including ~50% patients with MF. However, it is not clear whether JAK2V617F mutation alone is sufficient to cause MF. Interestingly, inactivating EZH2 mutations co-exist with JAK2V617F mutation in significant cases of MF. To understand the role of JAK2V617F in MPNs, we previously generated a conditional Jak2V617F knock-in mouse, which exhibits all the features of human PV. To determine if EZH2 mutations cooperate with JAK2V617F mutation in MF, we crossed the conditional EZH2 knock-out mice with conditional Jak2V617F knock-in mice and assessed the effects of concomitant deletion of EZH2 and expression of heterozygous Jak2V617F in mice hematopoietic compartments. Whereas Jak2V617F expression resulted in significant increase in red blood cells (RBC), hemoglobin, hematocrit, white blood cells and platelets in the peripheral blood of the Jak2V617F knock-in mice, deletion of EZH2 significantly reduced the RBC, hemoglobin, and hematocrit parameters in Jak2V617F knock-in mice. Interestingly, platelet counts were further increased in EZH2-deleted Jak2V617F-expressing mice. Flow cytometric analysis showed significant increase in CD71+Ter119neg/lo early erythroid precursors and decrease in CD71+Ter119high late erythroid precursors in the bone marrow (BM) and spleens of EZH2-deleted Jak2V617F mice suggesting a defect in erythroid differentiation upon EZH2 deletion in Jak2V617F mice. Notably, megakaryocytic precursors (CD41+CD61+) were significantly increased in the BM and spleens of EZH2-deleted Jak2V617F mice consistent with increased number of platelets in the peripheral blood of these mice. Similar to human PV, Jak2V617F expression resulted in cytokine-independent CFU-E colonies in the BM and spleens of Jak2V617F knock-in mice. However, deletion of EZH2 markedly inhibited cytokine-independent CFU-E colonies in the BM and spleens of Jak2V617F knock-in mice. Histopathologic analysis revealed extensive fibrosis in the BM and spleens of EZH2-deleted Jak2V617F mice at 24 weeks after induction while heterozygous Jak2V617F knock-in mice BM and spleens showed very mild fibrosis at this age. Control and EZH2-deficient mice did not exhibit any fibrosis in their BM or spleens. In order to determine whether the effects of EZH2 deletion in Jak2V617F mice were cell autonomous, BM cells from pIpC induced control, EZH2-deficient, Jak2V617F knock-in and EZH2-deleted Jak2V617F-expressing mice were transplanted into lethally irradiated syngeneic recipient mice. Transplanted animals receiving EZH2-deleted Jak2V617F BM developed severe fibrosis in their BM and spleens within 8 weeks after transplantation. Furthermore, recipients of EZH2-deleted Jak2V617F BM exhibited severe anemia and became moribund by 8 weeks after transplantation. In contrast, transplanted animals receiving control, EZH2-deficient or Jak2V617F BM did not exhibit fibrosis at 8 weeks after transplantation. Thus, the phenotypes observed in EZH2-deficient Jak2V617F mice are hematopoietic cell-autonomous. Together, these data suggest that loss of EZH2 inhibits erythropoiesis, promotes megakaryopoiesis and accelerates the development of MF in mice expressing Jak2V617F. To gain insights into the mechanisms by which EZH2 deficiency accelerates the development of MF in Jak2V617F mice, we performed microarray gene expression analysis on purified long-term hematopoietic stem cells (LT-HSC; Lin-c-kit+Sca-1+CD34-Flk2-). Gene set enrichment analysis revealed that interferon response-related genes and the genes related to TNF signaling pathway were up-regulated in LT-HSC of EZH2-deficient Jak2V617F mice compared with Jak2V617F LT-HSC. Further studies will validate the targets of EZH2 that are de-repressed upon EZH2 deletion in MF induced by Jak2V617F. In conclusion, our studies show that loss of EZH2 cooperates with Jak2V617F mutation in the development of MF. Disclosures No relevant conflicts of interest to declare.
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- 2014
41. Bone Marrow Core Biopsy Adequacy and Variability in the United Stated and Canada: A Multicenter Retrospective Study
- Author
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LoAnn Peterson, Robert E. Hutchison, Elizabeth L. Courville, Mihai Merzianu, Fernandez Garcia, Sinisa Ivelja, Prabhjot Kaur, Claudiu V. Cotta, Vishnu Vb Reddy, Ridas Juskevicius, Vishala Neppalli, Sharon Barouk, Russell K. Brynes, Michael R. Lewis, John Lazarchick, Gratian Salaru, Ashley V Sedelmeyer, Vivian Arguello, David D. Grier, Shanxing Zhang, Hina Naushad, John T Grantham, James E. Coad, Alana DiPonio, Horatiu Olteanu, Ling Zhang, Manjula Balasubramanian, Rodney R. Miles, Robert W. McKenna, Kedar V. Inamdar, Jie Xu, Elisa F Brega, Neerja Vajpayee, Kieran Sultan, Adrienne Groman, George Deeb, Richie Carpenter, Julie Teruya-Feldstein, Guang Fan, Matthew B. Thomsen, Daniela Hoehn, Sindhu Cherian, Attilio Orazi, Richard T. Cheney, David R. Czuchlewski, Jerome B. Myers, Jeffrey A. Vos, Guilherme Brandao, Gregory E. Wilding, Michel R. Nasr, Ramila Amre, Le Aye, and Valentin G. Robu
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Biochemistry ,Surgery ,Bone marrow examination ,medicine.anatomical_structure ,Hematologic disorders ,Statistical significance ,Cohort ,medicine ,Sampling (medicine) ,Bone marrow ,Nuclear medicine ,business ,Core biopsy - Abstract
BACKGROUND Bone marrow examination is essential in diagnosis, staging and monitoring of various hematologic disorders. The aspirate smears and core biopsy are complementary samples; current clinical benchmarks recommend an optimal core sample length of at least 15-20 mm. We assessed the core length in 2 cross-sectional cohorts from 2001 and 2011 in 32 academic medical centers from the US and Canada, the first such study to date. METHODS After IRB approval, participants collected data from pathology reports (including the preprocessing length) and measured aggregate postprocessing and evaluable marrow length using a uniform validated methodology on 100 consecutive marrow samples in 2001 and 2011 at each institution. Deidentified data was centralized at Roswell Park Cancer Institute (RPCI) and centers were anonymized. A total of 6374 samples were accepted for statistical analysis, performed using SAS (v. 9.4 or higher; SAS Institute, Cary, NC) at RPCI. Relationship between core length and NCCN status, geographic location, gender, age, and staging was assessed using the PROC MIXED and PROC GLIMMIX procedure using a random center effect and a nominal significance level of 0.05. RESULTS The study cohort included 56% men and 44% women, mean age 51 (range, 1-102) years, 88% adults (³18) and 12% children ( A core biopsy was obtained in 90% of 2001 and in 95% of 2011 samples. Most cores were unilateral (85%); bilateral sampling decreased from 10% to 4% between 2001 and 2011. An aspirate specimen was received in the pathology department in 86% of the cases; however, a clot section was prepared in only 56% of the cases. Preprocessing core length (PreCL; n=3141) documentation in pathology reports was missing in 9 centers for both years; in 3 centers it was available only for one year; its mean (standard deviation) was 16.9 (9.9) mm, decreasing from 2001 to 2011 [17.7 (11.9) to 16.2 (8); p=0.002]. Postprocessing core length (PostCL; n=5742) mean (SD) was 14.2 (8.5) mm, significantly shorter in women than in men (p Evaluable marrow space length (EML; n=5617) mean (SD) was 10.7 (7.5) mm and decreased from 2001 to 2011 [10.9 (8.5) to 10.6 (6.6); p=0.002]. Ninety-one samples (1.6%) with measureable PostCL were entirely devoid of evaluable marrow. PostCL was 15% shorter than PreCL. The EML measured 24% less than the PostCL and 33% less than the PreCL. Lymphoma staging samples (n=1222) were obtained from adults (96%) and children (4%); of these, only 45% and 28% reached the PostCL of 15 mm and 20 mm, respectively. Lymphoma involvement rate was 16%, 25%, 32%, 30%, and 23% when PostCL was There was no significant difference of PostCL mean based on geographic region or NCCN status. PostCL mean ranged from 8.8 to 29.6 mm and its median was ³15 mm in only 12 of 23, 9 of 32, and 2 of 32 centers for PreCL, PostCL, and EML, respectively (Fig 3). When compared to current benchmarks, only 53%, 38%, and 22% of all samples were ³15 mm and only 30%, 19%, and 10% were ³20 mm for PreCL, PostCL, and EML, respectively. CONCLUSIONS Current benchmarks for bone marrow core biopsy adequacy are met in only a minority of cases. Samples from women were shorter than from men. Bilateral sampling decreased and PreCL and EML diminished significantly between 2001 and 2011, while PostCL showed only minimal decrease. This discrepancy may be due to technical differences. Although staging cores were longer than non-staging ones, most did not meet the benchmarks. The wide variability among different centers suggests significant institutional differences and lack of standardization in bone marrow sampling. Over a third of all centers did not record preprocessing length, an important parameter which may guide operator assessment of adequacy at the bedside. PostCL and/or EML can be measured by the pathologist and integrated in the report to document adequacy. In staging samples, a minimal marrow space sampling should be required to avoid understaging. Consensus definition of an inadequate core biopsy is currently lacking but would be desirable for uniform pathology reporting, clinical protocols and management. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
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- 2014
42. A Phase II Trial of Bortezomib Added to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Previously Untreated Indolent Non-Hodgkin’s Lymphoma
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Nassoma Bumpers, Jeffrey M. Switchenko, Amanda Hutchison-Rzepka, Rajni Sinha, Jonathon B. Cohen, Mary Jo Lechowicz, Leonard T. Heffner, Jean L. Koff, Jonathan L. Kaufman, Amelia Langston, H. Jean Khoury, Loretta J. Nastoupil, Sagar Lonial, Christopher R. Flowers, and Amanda Colbert
- Subjects
Oncology ,Bendamustine ,medicine.medical_specialty ,Vincristine ,Cyclophosphamide ,Bortezomib ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Non-Hodgkin's lymphoma ,Prednisone ,Internal medicine ,medicine ,Rituximab ,Marginal zone B-cell lymphoma ,business ,medicine.drug - Abstract
Background: Bortezomib-containing combination chemotherapy regimens are effective in non-Hodgkin's lymphoma (NHL), although there are limited data on toxicity in the front-line setting for indolent NHL when combined with reduced-dose vincristine-containing chemotherapy. Our group (Sinha et al, Cancer 2012) reported outcomes from a phase I study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (VR-CHOP) and found a maximum tolerated dose (MTD) of bortezomib (V) of 1.6mg/m2 with vincristine capped at 1.5 mg with an overall response rate (ORR) of 100%. Herein we report the results of our phase II study of this regimen. Patients and Methods: Eligible patients had untreated indolent NHL (small lymphocytic lymphoma [SLL], marginal zone lymphoma [MZL], or follicular lymphoma [FL] grades 1-3) meeting standard criteria for treatment or with FL international prognostic index (FLIPI) ≥3. Patients received V administered at a dose of 1.6mg/m2 on days 1 and 8 as well as rituximab (R) 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (capped at 1.5mg/dose) on day 1 and prednisone 100mg on days 1-5 of a 21-day cycle. Patients received at least 6 cycles and up to 8 cycles of therapy at the discretion of the treating physician. Patients who achieved a complete response (CR) after induction were assigned to receive maintenance R 375mg/m2 every 12 weeks for 2 years while patients with a partial response (PR) or stable disease received R 375mg/m2 along with V 1.6mg/m2 (VR), both administered weekly for 4 weeks every 6 months for up to 2 years. Response was assessed by Cheson 1999 criteria, and toxicity assessed by CTCAE version 3.0. One FL patient discontinued study therapy after cycle 2 when a central pathology review revised the diagnosis to diffuse large B-cell lymphoma. This patient was not included in the efficacy analysis but is included in the safety reports. CR rate and ORR were determined at the conclusion of induction therapy, and progression-free survival (PFS) and overall survival (OS) were evaluated by the Kaplan-Meier method from the date of study entry. Results: Thirty patients received at least 1 treatment of VR-CHOP, including 16 males and 14 females. The median age was 58 (range: 31-71), and histologies included MZL (n=5), SLL (n=4), and FL (Grade 1, n=7; Grade 2, n=12; Grade 3, n=2). FLIPI score for patients with FL were 1 (n=2), 2 (n=4), 3 (n=12), and 4 (n=3). Twenty-nine were evaluable for response, including 19 patients with CR and 10 patients with PR at the conclusion of induction therapy (CR rate of 66%; ORR of 100%). For 20 evaluable patients with FL, the CR rate was 75%. Twenty-five patients proceeded with maintenance therapy, including 6 patients who received VR and 19 patients who received R alone. Three patients with PR to induction converted to CR after maintenance with VR. Four patients received no maintenance due to refusal/lost to follow-up (n=2), toxicity (n=1), and progression (n=1). Three patients with PR received only R due to neuropathy. Four patients have relapsed or progressed on therapy, including 1 patient prior to starting maintenance, 2 patients during VR maintenance, and 1 patient who achieved a PR but was receiving R maintenance. One additional patient progressed after completing R maintenance. With a median follow-up of 39 months, 3-year PFS rate is 85.8%, and the 3-year OS rate is 96.4% (Figure). Grade ≥3 peripheral neuropathy was noted in 2 patients (7%), while grade 1-2 neuropathy occurred in 17 patients (57%). Grade 3-4 hematologic toxicities included neutropenia (n=14, 47%), thrombocytopenia (n=3, 10%), anemia (n=1, 3%), and febrile neutropenia (n=1, 3%). Eight patients experienced additional grade 3 non-hematologic toxicities, including the following which occurred in more than 1 patient: vomiting (n=3, 10%), abdominal pain (n=2, 7%), fatigue (n=2, 7%), hyperglycemia (n=2, 7%), hypokalemia (n=2, 7%), and nausea (n=2, 7%). Conclusion: VR-CHOP is highly efficacious in the front-line setting for management of patients with untreated indolent NHL, and toxicities are expected and manageable. Incidence of grade 3 peripheral neuropathy is low with incorporation of a decreased dose of vincristine, and the PFS compares favorably with previously reported outcomes in FL and indolent NHL for R-CHOP, R-Bendamustine, and R-CHOP plus maintenance R. Figure 1 Figure 1. Disclosures Cohen: Janssen: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Off Label Use: Bortezomib is not currently approved for follicular lymphoma, marginal zone lymphoma, or small lymphocytic lymphoma and is being evaluated in combination with a standard induction regimen.. Kaufman:Millennium: Consultancy; Janssen: Consultancy. Nastoupil:TG Therapeutics: Research Funding; Celgene: Honoraria; Genentech: Honoraria; Janssen: Research Funding. Lechowicz:Millennium: Consultancy. Lonial:Millennium, Celgene, Novartis, BMS, Onyx: Consultancy, Research Funding. Flowers:Gilead, Spectrum, Millennium, Janssen: Research Funding; Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy.
- Published
- 2014
43. Hmga2 promotes the development of myelofibrosis in Jak2V617F knockin mice by enhancing TGF-β1 and Cxcl12 pathways.
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Dutta, Avik, Hutchison, Robert E., and Mohi, Golam
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MYELOFIBROSIS , *MICE , *GENETIC mutation , *HEMATOPOIESIS , *BONE marrow transplantation - Abstract
Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617F mutation has been detected in ~50% cases of MF. Elevated expression of high-mobility group AT hook 2 (HMGA2) has also been frequently observed in patients withMF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617F mutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617F mutation in hematopoiesis, we transduced bone marrow cells from Jak2V617F knockin mice with lentivirus expressing Hmga2 and performed bone marrow transplantation. Expression of Hmga2 enhanced megakaryopoiesis, increased extramedullary hematopoiesis, and accelerated the development of MF inmice expressing Jak2V617F. Mechanistically, the data showthat expression of Hmga2 enhances the activation of transforming growth factor-β1 (TGF-β1) and Cxcl12 pathways in mice expressing Jak2V617F. In addition, expression of Hmga2 causes upregulationof Fzd2, Ifi27l2a, andTGF-b receptor 2.Forced expressionofCxcl12, Fzd2, or Ifi27l2a increases megakaryocytic differentiation and proliferation in the bonemarrow of Jak2V617Fmice, whereas TGF-β1 or Cxcl12 stimulation induces collagen deposition in the bone marrow mesenchymal stromal cells. Together, these findings demonstrate that expression of Hmga2 cooperates with Jak2V617F in the pathogenesis of MF. [ABSTRACT FROM AUTHOR]
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- 2017
- Full Text
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44. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B
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Margaret V. Ragni, Roland W. Herzog, Mark A. Kay, Debra G.B. Leonard, Fred Johnson, Erik D. Skarsgard, Arthur A. Thompson, Catherine S. Manno, Shing Jen Tai, Linda B. Couto, Valder R. Arruda, Peter J. Larson, Amy J. Chew, Margareth C. Ozelo, Bertil Glader, Alan McClelland, Katherine A. High, Sylvia Hutchison, Alan W. Flake, and Ciaran Scallan
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Adult ,Male ,medicine.medical_specialty ,Hepatitis, Viral, Human ,Transgene ,Genetic enhancement ,Biopsy ,Recombinant Fusion Proteins ,Immunology ,Genetic Vectors ,Mutation, Missense ,HIV Infections ,Recombinant virus ,Biochemistry ,Hemophilia B ,Injections, Intramuscular ,Factor IX ,Internal medicine ,medicine ,Coagulopathy ,Humans ,Muscle, Skeletal ,Aged ,business.industry ,Genetic transfer ,Skeletal muscle ,Cell Biology ,Hematology ,Genetic Therapy ,Dependovirus ,medicine.disease ,Virology ,Combined Modality Therapy ,medicine.anatomical_structure ,Endocrinology ,Amino Acid Substitution ,Feasibility Studies ,Safety ,Intramuscular injection ,business ,medicine.drug - Abstract
Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 1011 vector genomes (vg)/kg to 1.8 1012 vg/ kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Preexisting high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals. (Blood. 2003;101:2963-2972)
- Published
- 2003
45. Long-term follow-up of remission duration, mortality, and second malignancies in hairy cell leukemia patients treated with pentostatin
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I W, Flinn, K J, Kopecky, M K, Foucar, D, Head, J M, Bennett, R, Hutchison, W, Corbett, P, Cassileth, T, Habermann, H, Golomb, K, Rai, E, Eisenhauer, F, Appelbaum, B, Cheson, and M R, Grever
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Adult ,Aged, 80 and over ,Male ,Leukemia, Hairy Cell ,Antibiotics, Antineoplastic ,Interferon-alpha ,Neoplasms, Second Primary ,Interferon alpha-2 ,Middle Aged ,Disease-Free Survival ,Recombinant Proteins ,Survival Rate ,Humans ,Female ,Pentostatin ,Aged ,Follow-Up Studies - Abstract
The nucleoside analogue, pentostatin, has demonstrated high complete response rates and long relapse-free survival times in patients with hairy cell leukemia, a disease that historically had been unresponsive to treatment. Long-term data on duration of overall survival and relapse-free survival and incidence of subsequent malignancies with this agent are lacking. Patients completing the treatment phase of a randomized, intergroup study who received pentostatin as an initial treatment or who crossed over after failure of interferon alpha were followed for survival, relapse, and diagnosis of subsequent malignancies. Two hundred forty-one patients treated with pentostatin as initial therapy (n = 154) or who crossed over after failure of interferon alpha (n = 87) were followed for a median duration of 9.3 years. Estimated 5- and 10-year survival rates (95% confidence interval) for all patients combined were 90% (87%-94%) and 81% (75%-86%), respectively. In the 173 patients with a confirmed complete response to pentostatin treatment, 5- and 10-year relapse-free survival rates were 85% (80%-91%) and 67% (58%-76%), respectively. Survival curves for patients initially treated with pentostatin and those crossed over were similar. Only 2 of 40 deaths were attributed to hairy cell leukemia. The mortality rate and incidence of subsequent malignancies were not higher than expected in the general population. Pentostatin is a highly effective regimen for hairy cell leukemia that produces durable complete responses. Subsequent malignancies do not appear to be increased with pentostatin treatment.
- Published
- 2000
46. Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study
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K, Mrózek, K, Heinonen, D, Lawrence, A J, Carroll, P R, Koduru, K W, Rao, M P, Strout, R E, Hutchison, J O, Moore, R J, Mayer, C A, Schiffer, and C D, Bloomfield
- Subjects
Adult ,Chromosome Aberrations ,Chromosomes, Human, Pair 11 ,Remission Induction ,Zinc Fingers ,Histone-Lysine N-Methyltransferase ,Translocation, Genetic ,DNA-Binding Proteins ,Treatment Outcome ,Leukemia, Myeloid ,Acute Disease ,Proto-Oncogenes ,Humans ,Chromosomes, Human, Pair 9 ,Myeloid-Lymphoid Leukemia Protein ,Chromosomes, Human, Pair 8 ,Transcription Factors - Abstract
Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.
- Published
- 1997
47. Loss of Wild-Type Jak2 Allele Enhances Myeloid Cell Expansion and Accelerates Myelofibrosis in Jak2V617F Knock-in Mice
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Akada, Hajime, primary, Akada, Saeko, additional, Yan, Dongqing, additional, Hutchison, Robert, additional, and Mohi, Golam, additional
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- 2012
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48. Loss of Wild-Type Jak2 Allele Enhances Myeloid Cell Expansion and Accelerates Myelofibrosis in Jak2V617F Knock-in Mice
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Hajime Akada, Robert E. Hutchison, Saeko Akada, Golam Mohi, and Dongqing Yan
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Myeloid ,Essential thrombocythemia ,Immunology ,Wild type ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Philadelphia chromosome ,Biochemistry ,Molecular biology ,Loss of heterozygosity ,Polycythemia vera ,medicine.anatomical_structure ,hemic and lymphatic diseases ,medicine ,Allele ,Myelofibrosis - Abstract
Abstract 809 The activating JAK2V617F mutation is the most common mutation found in Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), which include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p involving JAK2 has been observed in ∼30% of patients with MPNs particularly in PV and PMF. JAK2V617F homozygosity through 9pLOH has been linked to more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the role of wild-type JAK2 in MPNs induced by JAK2V617F, we have utilized conditional Jak2 knock-out and Jak2V617F knock-in alleles and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like disease in mice, loss of wild-type Jak2 allele in hemizygous or homozygous Jak2V617F mice results in a significantly greater increase in reticulocytes, white blood cells, neutrophils and platelets in the peripheral blood and larger spleen size. We also have found that hemizygous or homozygous Jak2V617F expression significantly increased megakaryocyte-erythroid progenitors in the bone marrow and spleens and marked infiltration of neutrophils in the liver compared with heterozygous Jak2V617F. More importantly, hemizygous or homozygous Jak2V617F mice show accelerated myelofibrosis compared with heterozygous Jak2V617F-expressing mice. Thus, loss of wild type Jak2 allele increases myeloid cell expansion and enhances the severity of the MPN. Together, these results suggest that wild-type Jak2 serves as a negative regulator of MPN induced by Jak2V617F. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2012
49. Hmga2 promotes the development of myelofibrosis in Jak2V617Fknockin mice by enhancing TGF-β1 and Cxcl12 pathways
- Author
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Dutta, Avik, Hutchison, Robert E., and Mohi, Golam
- Abstract
Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617Fmutation has been detected in ∼50% cases of MF. Elevated expression of high-mobility group AT hook 2 (HMGA2) has also been frequently observed in patients with MF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617Fmutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617Fmutation in hematopoiesis, we transduced bone marrow cells from Jak2V617Fknockin mice with lentivirus expressing Hmga2 and performed bone marrow transplantation. Expression of Hmga2 enhanced megakaryopoiesis, increased extramedullary hematopoiesis, and accelerated the development of MF in mice expressing Jak2V617F. Mechanistically, the data show that expression of Hmga2 enhances the activation of transforming growth factor-β1 (TGF-β1) and Cxcl12 pathways in mice expressing Jak2V617F. In addition, expression of Hmga2 causes upregulation of Fzd2, Ifi27l2a, and TGF-β receptor 2. Forced expression of Cxcl12, Fzd2, or Ifi27l2a increases megakaryocytic differentiation and proliferation in the bone marrow of Jak2V617Fmice, whereas TGF-β1 or Cxcl12 stimulation induces collagen deposition in the bone marrow mesenchymal stromal cells. Together, these findings demonstrate that expression of Hmga2 cooperates with Jak2V617Fin the pathogenesis of MF.
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- 2017
- Full Text
- View/download PDF
50. An International Study of High Cut-off Hemodialysis for the Management of Myeloma Kidney,
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Hutchison, Colin A, primary, Bevins, Anne, additional, Mead, Graham, additional, and Cook, Mark, additional
- Published
- 2011
- Full Text
- View/download PDF
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