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Dive into the research topics where James K. Mangan is active.

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Featured researches published by James K. Mangan.


PLOS ONE | 2011

Runx1 Loss Minimally Impacts Long-Term Hematopoietic Stem Cells

Xiongwei Cai; Justin J. Gaudet; James K. Mangan; Michael J. Chen; Maria Elena De Obaldia; Zaw Min Oo; Patricia Ernst; Nancy A. Speck

RUNX1 encodes a DNA binding subunit of the core-binding transcription factors and is frequently mutated in acute leukemia, therapy-related leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Mutations in RUNX1 are thought to confer upon hematopoietic stem cells (HSCs) a pre-leukemic state, but the fundamental properties of Runx1 deficient pre-leukemic HSCs are not well defined. Here we show that Runx1 deficiency decreases both apoptosis and proliferation, but only minimally impacts the frequency of long term repopulating HSCs (LT-HSCs). It has been variously reported that Runx1 loss increases LT-HSC numbers, decreases LT-HSC numbers, or causes age-related HSC exhaustion. We attempt to resolve these discrepancies by showing that Runx1 deficiency alters the expression of several key HSC markers, and that the number of functional LT-HSCs varies depending on the criteria used to score them. Finally, we identify genes and pathways, including the cell cycle and p53 pathways that are dysregulated in Runx1 deficient HSCs.


Journal of Clinical Oncology | 2015

High Graft CD8 Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning

Ran Reshef; Austin P. Huffman; Amy Gao; Marlise R. Luskin; Noelle V. Frey; Saar Gill; Elizabeth O. Hexner; Taku Kambayashi; Alison W. Loren; Selina M. Luger; James K. Mangan; Sunita D. Nasta; Lee P. Richman; Mary Sell; Edward A. Stadtmauer; Robert H. Vonderheide; Rosemarie Mick; David L. Porter

PURPOSE To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies. PATIENTS AND METHODS We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content. RESULTS Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio [aHR], 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 × 10(8) CD8 cells per kilogram optimally segregated patients receiving CD8(hi) and CD8(lo) grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8(hi) graft, whereas approximately half of younger donors provided CD8(hi) grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8(lo) doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8(hi) doses (P = .03), but not for recipients of younger unrelated donor CD8(lo) grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors. CONCLUSION Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT.


Biology of Blood and Marrow Transplantation | 2014

Early Donor Chimerism Levels Predict Relapse and Survival after Allogeneic Stem Cell Transplantation with Reduced-Intensity Conditioning

Ran Reshef; Elizabeth O. Hexner; Alison W. Loren; Noelle V. Frey; Edward A. Stadtmauer; Selina M. Luger; James K. Mangan; Saar Gill; Pavel Vassilev; Kathryn A. Lafferty; Jacqueline Smith; Vivianna M. Van Deerlin; Rosemarie Mick; David L. Porter

The success of hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for preemptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day-30) donor chimerism measurements on disease relapse, graft-versus-host disease, and survival in a cohort of 121 patients allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (hazard ratio [HR] = .90, P < .001), relapse-free survival (HR = .89, P < .001), and overall survival (HR = .94, P = .01). Day-30 T cell chimerism levels were also significantly associated with relapse (HR = .97, P = .002), relapse-free survival (HR = .97, P < .001), and overall survival (HR = .99, P = .05). Multivariate models that included T cell chimerism provided a better prediction for these outcomes compared with whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient before transplant, highlighting the impact of pretransplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT.


Leukemia Research | 2013

Acute myeloid leukemia with translocation t(8;16) presents with features which mimic acute promyelocytic leukemia and is associated with poor prognosis.

Adi Diab; Lynette Zickl; Omar Abdel-Wahab; Suresh C. Jhanwar; Manjit A. Gulam; Katherine S. Panageas; Jay Patel; Joseph G. Jurcic; P. Maslak; Elisabeth Paietta; James K. Mangan; Martin Carroll; Hugo F. Fernandez; Julie Teruya-Feldstein; Selina M. Luger; Dan Douer; Mark R. Litzow; Hillard M. Lazarus; Jacob M. Rowe; Ross L. Levine; Martin S. Tallman

Previous small series have suggested that acute myeloid leukemia with t(8;16) is a distinct morphologic and clinical entity associated with poor prognosis. We describe 18 patients with t(8;16) AML, including their clinical, cytomorphologic, immunophenotypic and cytogenetic features. Half of the patients had extramedullary disease, most commonly leukemia cutis, which often preceded bone marrow involvement and six had therapy-related AML. Patients with t(8;16) AML commonly present with clinical and pathological features that mimic APL, with promyelocytes and promyeloblast-like cells and coagulopathy in most patients. Several patients also presented with marrow histiocytes with hemophagocytosis and erythrophagocytosis. Comprehensive molecular analysis for co-occurring genetic alterations revealed a somatic mutation in RUNX1 in 1 of 6 t(8;16) patients with no known AML mutation in the remaining five t(8;16) patients. This suggests that the t(8;16) translocation could be sufficient to induce hematopoietic cell transformation to AML without acquiring other genetic alteration. These data further support classifying t(8;16) AML as a clinically and molecularly defined subtype of AML marked by characteristic clinical and cytomorphologic features that mimic APL, and is associated with very poor survival.


Therapeutic advances in hematology | 2011

Salvage therapy for relapsed or refractory acute myeloid leukemia

James K. Mangan; Selina M. Luger

There are a significant number of patients diagnosed with acute leukemia who either fail to achieve remission or who relapse thereafter. Challenges in treating this patient population include accurately assessing prognosis of disease and whether remission can be achieved; assessing the ability of patients to tolerate aggressive salvage therapies; choosing a salvage therapy that is most likely to succeed; and identifying suitable patients for hematopoietic stem cell transplantation. Despite the development of a variety of new investigational therapies, relapsed or refractory acute myeloid leukemia remains a difficult clinical problem. Clinicians will need to consider all currently available approaches, including cytotoxic chemotherapy, targeted agents, and allogeneic stem cell transplantation, to optimize outcomes.


Current Opinion in Hematology | 2015

Approach to patients with primary refractory acute myeloid leukemia.

Robert J. Orlowski; James K. Mangan; Selina M. Luger

Purpose of reviewDespite successful remission induction in 60–80% of patients with newly diagnosed acute myeloid leukemia, there remain a significant number of patients who exhibit primary refractory disease. Here we examine the data for predicting likelihood of having refractory disease, available therapeutic options, and how to decide the appropriate treatment option for a patient. Recent findingsRecently identified recurrent molecular mutations and early response to chemotherapy as determined by kinetics of peripheral blast clearance or nadir bone marrow biopsy assist in determining the likelihood of primary refractory disease. Newer cytotoxic agents, used as salvage chemotherapy, or in novel conditioning regimens for hematopoietic stem cell transplant may represent improvement over prior regimens. FMS-like tyrosine kinase 3 gene inhibitors and other targeted therapies currently in clinical trials show promise for select patients. Hypomethylating agents provide benefit to patients who are not candidates for other therapies. SummaryRecent advances in understanding the pathogenesis of acute myeloid leukemia have not yet translated to a significantly improved outlook for patients with refractory disease. While there are several therapeutic options, outcomes remain poor and further studies are needed to identify and validate novel approaches.


Cancer | 2017

Differences in treatment goals and perception of symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists/oncologists in the United States: Findings from the MPN Landmark survey.

Ruben A. Mesa; Carole B. Miller; Maureen Thyne; James K. Mangan; Sara Goldberger; Salman Fazal; Xiaomei Ma; Wendy Wilson; Dilan Paranagama; David G. Dubinski; Ahmad Naim; Shreekant Parasuraman; John Boyle; John Mascarenhas

This analysis of the myeloproliferative neoplasm (MPN) Landmark survey evaluated gaps between patient perceptions of their disease management and physician self‐reported practices.


Biology of Blood and Marrow Transplantation | 2015

Acute Cholecystitis Is a Common Complication after Allogeneic Stem Cell Transplantation and Is Associated with the Use of Total Parenteral Nutrition

Stephen J. Bagley; Alison Sehgal; Saar Gill; Noelle V. Frey; Elizabeth O. Hexner; Alison W. Loren; James K. Mangan; David L. Porter; Edward A. Stadtmauer; Ran Reshef; Selina M. Luger

The incidence and risk factors for acute cholecystitis after allogeneic hematopoietic stem cell transplantation (HSCT) are not well defined. Of 644 consecutive adult transplants performed at our institution between 2001 and 2011, acute cholecystitis occurred in the first year of transplant in 32 patients (5.0%). We conducted 2 retrospective case-control studies of this population to determine risk factors for cholecystitis after HSCT and to evaluate the performance of different methods of imaging to diagnosis cholecystitis in patients undergoing HSCT compared with non-HSCT patients. In the HSCT population, development of cholecystitis was associated with an increased 1-year overall mortality rate (62.5% versus 19.8%, P < .001). The risk of developing cholecystitis was higher in patients who received total parenteral nutrition (TPN) (adjusted odds ratio, 3.41; P = .009). There was a trend toward more equivocal abdominal ultrasound findings in HSCT recipients with acute cholecystitis compared with nontransplant patients (50.0% versus 30.6%, P = .06). However, hepatobiliary iminodiacetic acid (HIDA) scans were definitively positive for acute cholecystitis in most patients in both populations (80.0% of HSCT recipients versus 77.4% of control subjects, P = .82). In conclusion, acute cholecystitis is a common early complication of HSCT, the risk is increased in patients who receive TPN, and it is associated with high 1-year mortality. In HSCT recipients with findings suggestive of acute cholecystitis, especially those receiving TPN, early use of HIDA scan may be considered over ultrasound.


Case reports in hematology | 2012

A Paraneoplastic Syndrome Characterized by Extremity Swelling with Associated Inflammatory Infiltrate Heralds Aggressive Transformation of Myelodysplastic Syndromes/Myeloproliferative Neoplasms to Acute Myeloid Leukemia: A Case Series

James K. Mangan; Selina M. Luger

There has been a long history of reports describing a variety of paraneoplastic phenomena associated with myelodysplastic syndromes, particularly those with autoimmune manifestations. We report here a series of patients with an antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) that underwent aggressive transformation to acute myeloid leukemia (AML). In each case, the transformation to AML was preceded by an inflammatory syndrome characterized by unilateral extremity swelling and an associated inflammatory skin infiltrate, as well as other signs of inflammation, including profound hyperferritinemia without evidence of a hemophagocytic syndrome. We suggest that such an inflammatory syndrome may herald aggressive transformation of MDS/MPN to AML. Patients with known MDS/MPN who present with these features may benefit from early bone marrow examination to assess disease status. Early intervention with corticosteroids in select patients may result in improvement or resolution of the symptoms and permit intensive therapy for AML to be delivered.


American Journal of Hematology | 2016

Infusion of CD3/CD28 costimulated umbilical cord blood T cells at the time of single umbilical cord blood transplantation may enhance engraftment.

Elizabeth O. Hexner; Selina M. Luger; Ran Reshef; Grace R. Jeschke; James K. Mangan; Noelle V. Frey; Dale Frank; Lee P. Richman; Robert H. Vonderheide; Nicole A. Aqui; Misha Rosenbach; Yi Zhang; Anne Chew; Alison W. Loren; Edward A. Stadtmauer; Bruce L. Levine; Carl H. June; Stephen G. Emerson; David L. Porter

Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (105cells/kg). At the 105cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD. Am. J. Hematol. 91:453–460, 2016.

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Selina M. Luger

University of Pennsylvania

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Alison W. Loren

University of Pennsylvania

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David L. Porter

University of Pennsylvania

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Noelle V. Frey

University of Pennsylvania

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Ran Reshef

Columbia University Medical Center

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Saar Gill

University of Pennsylvania

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Martin Carroll

University of Pennsylvania

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Alexander E. Perl

University of Pennsylvania

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