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Dive into the research topics where Alfred Ian Lee is active.

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Featured researches published by Alfred Ian Lee.


The American Journal of Surgical Pathology | 2010

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma.

Matija Snuderl; Olga K. Kolman; Yi-Bin Chen; Jessie J. Hsu; Adam M. Ackerman; Paola Dal Cin; Judith A. Ferry; Nancy Lee Harris; Robert P. Hasserjian; Lawrence R. Zukerberg; Jeremy S. Abramson; Ephraim P. Hochberg; Hang Lee; Alfred Ian Lee; Christiana E. Toomey; Aliyah R. Sohani

B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements, also known as “double-hit” lymphomas (DHL), are rare neoplasms characterized by highly aggressive clinical behavior, complex karyotypes, and a spectrum of pathologic features overlapping with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and B-lymphoblastic lymphoma/leukemia (B-LBL). The clinical and pathologic spectrum of this rare entity, including comparison to other high-grade B-cell neoplasms, has not been well defined. We conducted a retrospective analysis of clinical and pathologic features of 20 cases of DHL seen at our institution during a 5-year period. In addition, we carried out case-control comparisons of DHL with BL and International Prognostic Index (IPI)-matched DLBCL. The 11 men and 9 women had a median age of 63.5 years (range 32 to 91). Six patients had a history of grade 1 to 2 follicular lymphoma; review of the prior biopsy specimens in 2 of 5 cases revealed blastoid morphology. Eighteen patients had Ann Arbor stage 3 or 4 disease and all had elevated serum lactate dehydrogenase (LDH) levels at presentation. Extranodal disease was present in 17/20 (85%), bone marrow involvement in 10/17 (59%) and central nervous system (CNS) disease in 5/11 (45%). Nineteen patients were treated with combination chemotherapy, of whom 18 received rituximab and 14 received CNS-directed therapy. Fourteen patients (70%) died within 8 months of diagnosis. Median overall survival in the DHL group (4.5 mo) was inferior to both BL (P=0.002) and IPI-matched DLBCL (P=0.04) control patients. Twelve DHL cases (60%) were classified as B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, 7 cases (35%) as DLBCL, not otherwise specified, and 1 case as B-LBL. Distinguishing features from BL included expression of Bcl2 (P<0.0001), Mum1/IRF4 (P=0.006), Ki-67 <95% (P<0.0001), and absence of EBV-EBER (P=0.006). DHL commonly contained the t(8;22) rather than the t(8;14) seen in most BL controls (P=0.001), and exhibited a higher number of chromosomal aberrations (P=0.0009). DHL is a high-grade B-cell neoplasm with a poor prognosis, resistance to multiagent chemotherapy, and clinical and pathologic features distinct from other high-grade B-cell neoplasms. Familiarity with the morphologic and immunophenotypic spectrum of DHL is important in directing testing to detect concurrent IGH-BCL2 and MYC rearrangements when a karyotype is unavailable. The aggressive clinical behavior and combination of genetic abnormalities seen in these cases may warrant categorization as a separate entity in future classifications and call for novel therapeutic approaches.


PLOS Biology | 2003

A Functional Analysis of the Spacer of V(D)J Recombination Signal Sequences

Alfred Ian Lee; Sebastian D. Fugmann; Lindsay G. Cowell; Leon M. Ptaszek; Garnett Kelsoe; David G. Schatz

During lymphocyte development, V(D)J recombination assembles antigen receptor genes from component V, D, and J gene segments. These gene segments are flanked by a recombination signal sequence (RSS), which serves as the binding site for the recombination machinery. The murine Jβ2.6 gene segment is a recombinationally inactive pseudogene, but examination of its RSS reveals no obvious reason for its failure to recombine. Mutagenesis of the Jβ2.6 RSS demonstrates that the sequences of the heptamer, nonamer, and spacer are all important. Strikingly, changes solely in the spacer sequence can result in dramatic differences in the level of recombination. The subsequent analysis of a library of more than 4,000 spacer variants revealed that spacer residues of particular functional importance are correlated with their degree of conservation. Biochemical assays indicate distinct cooperation between the spacer and heptamer/nonamer along each step of the reaction pathway. The results suggest that the spacer serves not only to ensure the appropriate distance between the heptamer and nonamer but also regulates RSS activity by providing additional RAG:RSS interaction surfaces. We conclude that while RSSs are defined by a “digital” requirement for absolutely conserved nucleotides, the quality of RSS function is determined in an “analog” manner by numerous complex interactions between the RAG proteins and the less-well conserved nucleotides in the heptamer, the nonamer, and, importantly, the spacer. Those modulatory effects are accurately predicted by a new computational algorithm for “RSS information content.” The interplay between such binary and multiplicative modes of interactions provides a general model for analyzing protein–DNA interactions in various biological systems.


Oncologist | 2009

Nodular Lymphocyte Predominant Hodgkin Lymphoma

Alfred Ian Lee; Ann S. LaCasce

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of HL with unique clinicopathologic features. The hallmark histologic feature is the presence of malignant LP cells, unusual CD20(+)CD15(-)CD30(-) variants of Reed-Sternberg cells, embedded within a nodular pattern of infiltrating lymphocytes. Compared with classical HL, NLPHL shows a slightly older median age at presentation (30-40 years), greater male predominance (3:1), less mediastinal involvement (<15%), and lower occurrence of classical HL risk factors. The differential diagnosis includes progressive transformation of germinal centers, lymphocyte-rich classical HL, and T-cell/histiocyte-rich large B-cell lymphoma, the latter of which may share a common biologic relationship. The vast majority of patients present with limited stage disease (70%-80%), the standard treatment for which is involved field radiotherapy at 30-36 Gy. Response rates to primary therapy exceed 90%, although relapses are common and may occur years after the initial diagnosis. Secondary malignancies, particularly non-Hodgkin lymphoma, may also occur at a frequency similar to that of relapsed NLPHL. Patients with advanced stage disease may have lower response rates and overall survival times than those with limited stage disease. For relapsed disease, treatment options include the salvage therapies used in classical HL, and rituximab.


Journal of Investigative Dermatology | 2017

Treatment of Hypereosinophilic Syndrome with Cutaneous Involvement with the JAK Inhibitors Tofacitinib and Ruxolitinib

Brett A. King; Alfred Ian Lee; Jaehyuk Choi

Hypereosinophilic syndrome (HES) is a heterogeneous group of disorders characterized by persistent peripheral blood eosinophilia, eosinophil-mediated end-organ damage, and absence of other infectious or allergic causes of eosinophilia.(Gotlib, 2014, Valent et al., 2012) Treatment of HES is challenging and usually relies on corticosteroids, which have significant adverse effects.(Klion, 2015, Klion et al., 2006) There are 3 categories of HES: primary, secondary, and idiopathic. Primary HES is a myeloproliferative disease with clonal eosinophils. In secondary HES and idiopathic HES, other cells produce Th2 cytokines that promote polyclonal expansion and activation of eosinophils.(Roufosse, Cogan and Goldman, 2007) Lymphocytic variant HES (L-HES) is a subtype of secondary HES wherein the source of Th2 cytokines is a phenotypically abnormal CD4+ T cell (typically CD3-CD4+).(Simon, Plotz, Dummer and Blaser, 1999, Walker et al., 2015) We recently demonstrated the importance of Janus kinase-Signal transducer and activation of transcription (JAK-STAT) signaling in L-HES.(Walker, et al., 2015) Specifically, we showed a gain-of-function mutation in STAT3 and overexpression of STAT3 gene targets that were necessary and sufficient for the production of eosinophil-promoting Th2 cytokines. Based on these data, we hypothesized that inhibitors of this pathway, namely the JAK inhibitors tofacitinib (JAK1/3 inhibitor) and ruxolitinib (JAK1/2 inhibitor), would be effective treatment of secondary HES.


Hematology-oncology Clinics of North America | 2011

Transfusion Medicine and the Pregnant Patient

Alfred Ian Lee; Richard M. Kaufman

Alloimmunity in pregnancy is the basis for two of the major complications of pregnancy in transfusion medicine: hemolytic disease of the fetus and newborn (HDFN), and fetal and neonatal alloimmune thrombocytopenia (FNAIT). Use of Rh(D) immune globulin has dramatically reduced the incidence of HDFN in Rh(D)-mismatched pregnancies. Treatment of HDFN may involve intrauterine transfusion, with fetal and neonatal survival rates of 70% to 90%. Treatments for FNAIT include immune globulin, steroids, or in severe cases, intrauterine platelet transfusions. Transfusion medicine is central to the management of pregnancy-associated complications such as postpartum hemorrhage, parvovirus B19 infection, hemoglobinopathies, and aplastic anemia.


Clinical Lymphoma, Myeloma & Leukemia | 2015

Patterns of Venous Thromboembolism Prophylaxis During Treatment of Acute Leukemia: Results of a North American Web-Based Survey

Eun-Ju Lee; B. Douglas Smith; Jessica W. Merrey; Alfred Ian Lee; Nikolai A. Podoltsev; Lisa Barbarotta; Mark R. Litzow; Thomas Prebet; Selina M. Luger; Steven D. Gore; Michael B. Streiff; Amer M. Zeidan

BACKGROUND Venous thromboembolism (VTE) occurs in 2% to 12% of patients with acute leukemia (AL) despite disease- and therapy-associated thrombocytopenia, and it can be associated with significant morbidity and mortality. Because of the few high-quality studies, there are no evidence-based guidelines for VTE prophylaxis in this patient population. We sought to determine the spectrum of practice regarding prevention of VTE in patients with AL during induction and consolidation therapies. METHODS We conducted a 19-question Web-based survey directed at North American providers caring for these patients. One hundred fifty-one of 215 responses received were eligible for analysis, with a response rate of 20.9% among physicians who treated leukemias. RESULTS Overall, 47% and 45% of providers reported using pharmacologic VTE prophylaxis during induction and consolidation phases, respectively. Approximately 15% of providers did not provide any VTE prophylaxis, while 36% used mechanical methods and ambulation. Among providers who did not recommend pharmacologic prophylaxis, the most commonly cited reasons were the perceived high risk of bleeding (51%), absence of data supporting use (38%), and perceived low risk of VTE (11%). CONCLUSION Large, prospective studies are needed to define the safest and most effective approach to VTE prevention in patients with AL.


Transfusion | 2017

Wide variations in blood product transfusion practices among providers who care for patients with acute leukemia in the United States

Alexander B. Pine; Eun-Ju Lee; Mikkael A. Sekeres; David P. Steensma; Daniel Zelterman; Thomas Prebet; Amy E. DeZern; Rami S. Komrokji; Mark R. Litzow; Selina M. Luger; Richard Stone; Harry P. Erba; Guillermo Garcia-Manero; Alfred Ian Lee; Nikolai A. Podoltsev; Lisa Barbarotta; Stephanie Kasberg; Jeanne E. Hendrickson; Steven D. Gore; Amer M. Zeidan

Transfusion of blood products is a key component of the supportive management in patients with acute leukemia (AL). However high‐quality trial evidence and clinical outcome data to support specific transfusion goals for blood products for patients with AL remain limited leading to diverse transfusion practices. The primary objective of this study was to determine the spectrum of transfusion patterns in a variety of care settings among providers who treat AL patients.


The New England Journal of Medicine | 2013

Venting the Spleen

Neal Varughese; Angie Duong; Sukru Emre; Mina L. Xu; Alfred Ian Lee

A 19-year-old woman presented to a community hospital with a 4-day history of abdominal pain, located in the right upper quadrant and epigastrium, with occasional radiation to her back. She described the pain as intermittent and variable in intensity, associated with nausea, and occurring independently of oral intake or body position. A review of systems was notable for profound fatigue and a 13.6-kg (30-lb) weight loss during the preceding months, which she attributed to stress in the wake of her parents’ recent divorce. She reported no fever, sweats, jaundice, dyspnea, vom iting, diarrhea, constipation, urinary abnormalities, joint aches, or rash. An anatomical approach is helpful in formulating the differential diagnosis of abdominal pain. Diseases of the liver and pancreaticobiliary tree are the most common causes of right-upper-quadrant abdominal pain, and in a young person, acute viral hepatitis, autoimmune hepatitis, and hepatic injury due to ingestion of alcohol or another toxic substance should be considered. Cholelithiasis or choledocholithiasis may occur in young adults with predisposing risk factors such as obesity, a family history of gallstones, or an underlying chronic hemolytic disorder. The FitzHugh–Curtis syndrome, or pelvic inflammatory disease with perihepatitis, is man ifested in young women as right-upper-quadrant pain and may mimic hepatobiliary disease. Pancreatitis, gastritis, and peptic ulcer disease are common causes of epigastric and midabdominal pain that may also involve the right upper abdomen. The patient’s recent weight loss, although apparently circumstantial, is of sufficient magnitude to prompt serious consideration of chronic infection, rheumatologic disease, or cancer. The patient had a history of hereditary spherocytosis. Ten years earlier, she had undergone laparoscopic splenectomy and cholecystectomy for chronic hemolytic anemia with symptomatic gallstones, with complete resolution of the hemolytic crises. She had received all requisite vaccinations. Her medications included folic acid and an oral contraceptive. She had smoked one pack of cigarettes per day for 4 years, drank alcohol sparingly, and reported no illicit drug use. She was sexually active with one male partner and reported that she did not have unprotected intercourse. Her most recent menstrual period was 2 weeks earlier. She worked as a waitress, lived in a small town in New England, and had not recently traveled outside the northeastern United States. Her family history was notable for hereditary spherocytosis in her mother and siblings. The patient’s history raises the question of whether hereditary spherocytosis or a complication of splenectomy might explain her abdominal pain. Gallstones, anemia,


British Journal of Haematology | 2012

Clinical significance of coagulation studies in predicting response to activated recombinant Factor VII in cardiac surgery patients

Alfred Ian Lee; Federico Campigotto; James D. Rawn; Donna Neuberg; Richard M. Kaufman; Nancy Berliner

Abdulwahab, J., Al-Tourah, A.J., Savage, K.J., Gill, K.K., Klasa, R.J., Sehn, L., Shenkler, T.N., Gascoyne, R.D. & Connors, J.M. (2007) Addition of rituximab to CHOP chemotherapy significantly improves survival of patients with transformed lymphoma. Blood (ASH Annual Meeting Abstracts), 110, 790. Eide, M.B., Lauritzen, G.F., Kvalheim, G., Kolstad, A., Fagerli, U.M., Maisenholder, M., Ostenstad, B., Fluge, O., Delabie, J., Aarset, H., Liestol, K. & Holte, H. (2011) High dose chemotherapy with autologous stem cell support for patients with histologically transformedB-cellnon-Hodgkin lymphomas. A Norwegian multi centre phase II study. British Journal of Haematology, 152, 600–610. Harris, N.L., Jaffe, E.S., Stein, H., Banks, P.M., Chan, J.K., Cleary, M.L., Delsol, G., de WolfPeeters, C., Falini, B. & Gatter, K.C. (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood, 84, 1361–1392. Krishnan, A., Nademanee, A., Fung, H.C., Raubitschek, A.A., Molina, A., Yamauchi, D., Rodriguez, R., Spielberger, R.T., Falk, P., Palmer, J.M. & Forman, S.J. (2008) Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high-dose chemotherapy in patients with non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 26, 90–95. Robertson, L.E., Redman, J.R., Buter, J.J., Osborne, B.M., Velasquez, W.S., McLaughlin, P., Swan, F., Rodriguez, M.A., Hagemeister, F.B. & Fuller, L.M. (1991) Discordant bone marrow involvement in diffuse large-cell lymphoma: a distinct clinical pathologic entity associated with a continuous risk of relapse. Journal of Clinical Oncology, 9, 236–242. Shimoni, A., Zwas, S.T., Oksman, Y., Hardan, I., Shem-Tov, N., Yerushalmi, R., Ben-Bassat, I. & Nagler, A. (2007) Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin’s lymphoma. Experimental Hematology, 35, 534–540. Stolz, C. & Schuler, M. (2009) Molecular mechanisms of resistance to rituximab and pharmacologic strategies for its circumvention. Leukemia and Lymphoma, 50, 873–885. Vose, J.M., Bierman, P.J., Enke, C., Hankins, J., Bociek, G., Lynch, J.C. & Armitage, J.O. (2005) Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stemcell transplantation for relapsed non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 23, 461– 467.


Blood Advances | 2017

Whole-exome sequencing in evaluation of patients with venous thromboembolism

Eun-Ju Lee; Daniel J. Dykas; Andrew D. Leavitt; Rodney M. Camire; Eduard H.T.M. Ebberink; Pablo García de Frutos; Kavitha Gnanasambandan; Sean X. Gu; James A. Huntington; Steven R. Lentz; Koen Mertens; Christopher R. Parish; Alireza R. Rezaie; Peter P. Sayeski; Caroline Cromwell; Noffar Bar; Stephanie Halene; Natalia Neparidze; Terri L. Parker; Adrienne J Burns; Anne Dumont; Xiaopan Yao; Cassius Iyad Ochoa Chaar; Jean M. Connors; Allen E. Bale; Alfred Ian Lee

Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) (P < .0001). Clinical laboratory-based thrombophilia testing identified a heritable thrombophilia in only 14 of 54 study patients (25.9%). The majority of WES variants were either associated with thrombosis based on prior reports in the literature or predicted to affect protein structure based on protein modeling performed as part of this study. Variants were found in major thrombophilia genes, various SERPIN genes, and highly conserved areas of other genes with established or potential roles in coagulation or fibrinolysis. Ten patients (15.6%) had >1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias.

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