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1.  Acute liver failure due to natural killer-like T-cell leukemia/lymphoma: A case report and review of the Literature 
Acute liver failure (ALF) is a medical emergency requiring immediate evaluation for liver transplantation. We describe an unusual case of a patient who presented with ascites, jaundice, and encephalopathy and was found to have ALF due to natural killer (NK)-like T cell leukemia/lymphoma. The key immunophenotype was CD2+, CD3+, CD7+, CD56+. This diagnosis, which was based on findings in the peripheral blood and ascitic fluid, was confirmed with liver biopsy, and was a contraindication to liver transplantation. A review of the literature shows that hematologic malignancies are an uncommon cause of fulminant hepatic failure, and that NK-like T-cell leukemia/lymphoma is a relatively recently recognized entity which is characteristically CD3+ and CD56+. This case demonstrates that liver biopsy is essential in diagnosing unusual causes of acute liver failure, and that infiltration of the liver with NK-like T-cell lymphoma/leukemia can cause acute liver failure.
PMCID: PMC4087729  PMID: 16810767
Liver failure; Liver transplant; Nutaral killer cell
3.  Bone Marrow B cell Precursor Number after Allogeneic Stem Cell Transplantation and GVHD Development 
Patients without chronic graft-versus-host disease (cGVHD) have robust B cell reconstitution and are able to maintain B cell homeostasis after allogeneic hematopoietic stem cell transplantation (HSCT). To determine whether B lymphopoiesis differs before cGVHD develops, we examined bone marrow (BM) biopsies for terminal deoxynucleotidyl transferase (TdT) and PAX5 immunostaining early post-HSCTat day 30 when all patients have been shown to have high B cell activating factor (BAFF) levels. We found significantly greater numbers of BM B cell precursors in patients who did not develop cGVHD compared with those who developed cGVHD (median = 44 vs 2 cells/high powered field [hpf]; respectively; P < .001). Importantly, a significant increase in precursor B cells was maintained when patients receiving high-dose steroid therapy were excluded (median = 49 vs 20 cells/hpf; P =.017). Thus, we demonstrate the association of BM B cell production capacity in human GVHD development. Increased BM precursor B cell number may serve to predict good clinical outcome after HSCT.
PMCID: PMC3693471  PMID: 22446015
Immunology; Graft-versus-host disease; B-cell development; Autoimmunity
4.  The genetic landscape of mutations in Burkitt lymphoma 
Nature genetics  2012;44(12):1321-1325.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
PMCID: PMC3674561  PMID: 23143597
6.  A case-control study of tobacco use and other non-occupational risk factors for lymphoma subtypes defined by t(14;18) translocations and bcl-2 expression 
Cancer causes & control : CCC  2010;21(7):1147-1154.
We re-evaluated reported associations between tobacco use and other factors and non-Hodgkin lymphoma (NHL) t(14;18)-subtypes based on fluorescence in situ hybridization (FISH) assays believed to be more sensitive than polymerase chain reaction (PCR), previously used for detecting t(14;18).
Commercial FISH assays and bcl-2 immunostaining were performed on paraffin sections to determine t(14;18) and bcl-2 case-subtypes. Polytomous logistic regression models estimated associations between NHL case-subtypes (versus 1,245 population-based controls) and tobacco use as well as other factors.
Adjusting for age, state, and proxy status, t(14;18)-negative NHL was associated with any tobacco use (vs. no tobacco use, OR=1.9, 95% CI=1.0-3.5), including current smoking (vs. no cigarette use, OR= 1.9, 95% CI=1.1-3.2). Tobacco exposures were not clearly associated with t(14;18)-positive NHL or bcl-2 case-subtypes. Hair dye use and family history of a hemolymphatic cancer were associated with t(14;18)-negative NHL, but the number of exposed cases was small.
The association between t(14;18)-negative NHL and cigarette smoking was unexpected given previous evidence of associations between smoking and follicular lymphoma (which is largely t(14;18)-positive). Future studies characterizing additional molecular characteristics of t(14;18)-negative NHL may help determine whether the association with smoking may have been causal versus an artifact of chance or bias.
PMCID: PMC3052629  PMID: 20232134
bcl-2; epidemiology; lymphoma; molecular genes; non-Hodgkin; tobacco; translocation (genetics); FISH; t(14;18)
7.  Non-Hodgkin Lymphoma (NHL) subtypes defined by common translocations: utility of fluorescence in situ hybridization (FISH) in a case-control study 
Leukemia research  2009;34(2):190.
We used fluorescence in situ hybridization (FISH) assays to identify t(14;18) translocations in archival paraffin-embedded tumor sections from non-Hodgkin lymphoma (NHL) cases enrolled in a population-based study. t(14;18) was identified in 54% of 152 cases, including 39% of diffuse large cell lymphomas (26 of 66 cases) and 84% of follicular lymphomas (36 of 43 cases). Eighty-seven percent of t(14;18)-positive cases and 57% of t(14;18)-negative cases expressed bcl-2. FISH assays detected twice as many t(14;18)-positive follicular lymphomas as PCR assays. Overall, study findings support the use of FISH assays to detect t(14;18) in archival tumor samples for epidemiologic studies of NHL subtypes.
PMCID: PMC2815151  PMID: 19505720
FISH; translocation; lymphoma; t(14:18); bcl-2
8.  The implication of identifying JAK2V617F in myeloproliferative neoplasms and myelodysplastic syndromes with bone marrow fibrosis 
Journal of Hematopathology  2008;1(2):111-117.
The myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) occasionally demonstrate overlapping morphological features including hypercellularity, mild/nonspecific dysplastic changes and variable bone marrow fibrosis. Thus, when the associated bone marrow fibrosis results in a suboptimal specimen for morphological evaluation, the descriptive diagnosis “fibrotic marrow with features indeterminate for MDS versus MPN” is often applied. The JAK2V617F mutation was recently shown to be frequently identified in MPN, but it is rarely present in other myeloid disorders. However, the diagnostic utility of JAK2V617F screening in hypercellular bone marrow specimens with fibrosis has not been previously investigated. Using a real-time polymerase chain reaction melting-curve assay capable of detecting JAK2V617F in archived fixed materials, we retrospectively studied JAK2V617F in 45 cases with fibrotic hypercellular bone marrow at initial presentation, including 19 cases initially described as “with features indeterminate for MDS versus MPN”. These 19 cases were reclassified into more specific categories of MDS (n = 14) or MPN (n = 5) based on the availability of subsequent clinical data and/or bone marrow examinations. The JAK2V617F allele was identified in 17 out of 18 BCR/ABL gene-negative MPN cases with marrow fibrosis, whereas only wild-type alleles were identified in the remaining non-MPN cases. Importantly, JAK2V617F alleles were seen in all five cases of “with features indeterminate for MDS versus MPN” at initial presentation that were later determined to be MPN, but they were absent in the 14 cases later determined to be MDS. Our results suggest that JAK2V617F allele evaluation can be a useful ancillary test for discriminating MDS from MPN in specimens with bone marrow fibrosis.
PMCID: PMC2713481  PMID: 19669209
Myeloproliferative neoplasm; Myelodysplastic syndrome; Bone marrow fibrosis; JAK2V617F
9.  Primary mediastinal B-cell lymphoma: detection of BCL2 gene rearrangements by PCR analysis and FISH 
Journal of Hematopathology  2008;1(2):77-84.
Primary mediastinal large B-cell lymphoma (PMBCL) has a characteristic clinical presentation, morphology, and immunophenotype, representing a clinically favorable subgroup of diffuse large B-cell lymphoma (DLBCL). By gene expression profiling (GEP), PMBCL shares features with classical Hodgkin lymphoma (cHL). Of further interest, BCL6 gene mutations and BCL6 and/or MUM1 expression in a number of PMBCLs have supported an activated B-cell (ABC) origin. Several studies, including GEP, have failed to detect BCL2 gene rearrangements (GRs) in PMBCL. An index case of t(14; 18)+ PMBCL prompted our study of the incidence of BCL2 GRs in PMBCL by polymerase chain reaction (PCR)/fluorescence in situ hybridization (FISH) analyses and its possible clinical impact. Twenty-five retrospectively identified, well-defined PMBCLs (five with cytogenetics) from three institutions were analyzed for a BCL2 GR by PCR/FISH analyses. The formalin-fixed, paraffin-embedded tissue blocks of 24 available cases were also analyzed by BCL2 immunohistochemistry (IHC). Of the five with cytogenetics, two had a t(14; 18) (q32; q21). Of the 25 analyzed by PCR, 2 had no amplifiable DNA (aDNA), including 1 t(14; 18)+ case. Of those with aDNA, two showed a BCL2 GR; by FISH analysis, three demonstrated a BCL2 GR. BCL2 protein expression by IHC analysis was variably detected in 21 out of 24 (strongly, uniformly expressed: 6, including all with a t(14; 18) or a BCL2 gene rearrangement; moderately weakly expressed in a subset of the malignant cells: 15). Available clinical follow-up of this BCL2+ subset showed a similar course to the other PMBCL cases. Our results imply that a subset of PMBCL [(4 out of 24 analyzed) in our series] may be of GC origin. A larger study is necessary to determine any clinical significance.
PMCID: PMC2713480  PMID: 19669206
Primary mediastinal B-cell lymphoma; BCL2 gene; PCR and FISH analysis

Results 1-9 (9)