Athena Cherry
Member, Stanford Cancer Institute
Professional Education
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Ph.D., Indiana University, Medical Genetics (1990)
Current Research and Scholarly Interests
The use of molecular and molecular cytogenetic methods to identify chromosomal abnormalities in acquired and congenital disorders.
Clinical Trials
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Phase 2 Fludarabine, Cytoxan and FCCAM <Alemtuzumab> in Untreated B-Cell Chronic Lymphocytic Leukemia
Not Recruiting
The primary objective of this study was to evaluate the safety and efficacy of the combination of fludarabine and cyclophosphamide in previously untreated CLL patients. Participants will receive fludarabine and cyclophosphamide on days 1, 2, and 3 of six 28-day cycles.
Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.
2022-23 Courses
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Independent Studies (5)
- Directed Reading in Pathology
PATH 299 (Aut, Win, Spr, Sum) - Early Clinical Experience in Pathology
PATH 280 (Aut, Win, Spr, Sum) - Graduate Research
PATH 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
PATH 370 (Aut, Win, Spr, Sum) - Undergraduate Research
PATH 199 (Aut, Win, Spr, Sum)
- Directed Reading in Pathology
All Publications
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An analysis of blastic plasmacytoid dendritic cell neoplasm with translocations involving the MYC locus identifies t(6;8)(p21;q24) as a recurrent cytogenetic abnormality
HISTOPATHOLOGY
2018; 73 (5): 767–76
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm with leukaemic features and frequent skin involvement. Translocations involving the MYC locus have been recently identified as recurrent cytogenetic abnormalities in this entity. The aim of this study was to assess the clinicopathological, immunophenotypic and genetic features in MYC-rearranged BPDCN cases.Pathology archives from six major institutes were queried for cases of BPDCN with 8q24 MYC translocations, and two cases were identified. A literature review identified 14 cases. Clinicopathological features, immunophenotype and cytogenetic and molecular data were reviewed. In these 16 MYC-rearranged cases, the median age at diagnosis was 70.5 years, and there was a male predominance. Whereas all cases showed marrow involvement, skin lesions (62.5%) and lymphadenopathy (50%) were variably seen. The median survival was 11 months. The median percentage of blasts in peripheral blood was 9%. All cases showed expression of CD4, with 10 of 16 being positive for CD56. HLA-DR, CD123, TCL1 and CD303 were positive in all cases tested. Cytogenetic analysis revealed a single recurrent translocation partner of MYC at 6p21 in 11 cases (69%), whereas four cases showed different MYC translocation partners (2p12, Xq24, 3p25, and 14q32). Interestingly, the group of patients with t(6;8)(p21;q24) showed an older median age at diagnosis (74 years) and a remarkably shorter median survival (3 months).Translocations involving the 8q24 MYC locus more frequently manifest as t(6;8)(p21;q24), and, given its association with specific clinicopathological features suggesting even more aggressive behaviour, t(6;8)(p21;q24) indicate a genetically defined subgroup within BPDCN.
View details for PubMedID 29884995
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A Clinicopathologic and Molecular Analysis of 34 Mediastinal Germ Cell Tumors Suggesting Different Modes of Teratoma Development.
The American journal of surgical pathology
2018
Abstract
Mediastinal teratomas are enigmatic; those in children and women are almost invariably benign but in men they may be benign or malignant. There are few data on the chromosome 12p status of mediastinal germ cell tumors (GCT), whereas increased 12p copy number is virtually uniform in malignant testicular GCTs. We therefore studied chromosome 12p copy number in 34 diverse mediastinal GCTs and correlated the results with morphology and follow-up to gain insight into possible pathogenesis. Four prepubertal (below 12y) children (3 females and 1 male), 7 postpubertal females (14 to 52y) and 6 postpubertal males (12 to 40y old) had pure, previously untreated teratomas; 15 were mature and 2 had low-grade immaturity. All lacked 12p copy number increase and cytologic atypia, and most (14/17) showed organoid morphology. On follow-up of 16, 1 died of postoperative complications and the remaining 15 were disease free (1 to 119mo, mean: 39mo). Eight postpubertal males (19 to 44y old) had pure teratomas in postchemotherapy resections; 5/8 showed 12p copy number increase. All 8 had distinct cytologic atypia, with organoid morphology in 3. On follow-up, 6 were disease free after surgical resection (1.5 to 94mo, mean 38mo); 1 died of disease at 14.5 months, and 1 was alive with metastases at 176 months. Two postpubertal patients, 1 male (29y) and 1 female (31y), had teratoma with secondary somatic-type malignancies, with positive 12p copy number increase in the former but not the latter. The man's tumor occurred after chemotherapy and was a nonorganoid teratoma with primitive neuroectodermal tumor and malignant glioma; the woman's was a previously untreated organoid teratoma with an undifferentiated carcinoma component. The man died of disease (16mo) and the woman was alive with metastases (27mo). Seven patients had resections for mixed GCTs (4) or pure nonteratomatous tumors, all after chemotherapy; 5/7 had positive 12p copy number increase. The teratoma component of the 2 cases having one showed distinct cytologic atypia and lacked organoid morphology. On follow-up, 1 died of disease (5mo), 2 were alive with disease (1, 1.5mo), 3 were disease free (1 to 43mo; mean: 18mo), and 1 was alive with unknown status (31mo). Our results support that mediastinal teratomas likely develop from 2 separate pathways. Those in children, women and some men arise as pure neoplasms from a nontransformed precursor cell and, therefore, lack 12p copy number increase, show no cytologic atypia, often have organoid morphology and are benign. Common 12p copy number increase, uniform atypia, infrequent organoid structures and malignant behavior support that pure teratomas after chemotherapy in postpubertal males derive from a malignantly transformed precursor cell. Interestingly, we identified organoid pancreatic differentiation only in the benign group and neuroglia more commonly in the malignant teratomas.
View details for PubMedID 30256256
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Investigating human placentation and pregnancy using first trimester chorionic villi.
Placenta
2018; 65: 65–75
Abstract
Chorionic villus sampling (CVS), routinely used for prenatal diagnosis of cytogenetic disorders, also possesses great potential for the study of placentation. To better understand villus biology, human placentation, and how these relate to pregnancy outcomes, we examined the morphology and transcriptomes of villi obtained via CVS from 10 to 14 weeks of pregnancy and correlated these with pregnancy attributes and clinical outcomes. First, we established a morphological scoring system based on three main villus features: branching, budding and vascularization. We then tested whether morphology scores were predictive of pregnancy attributes and clinical outcomes. Finally, we used RNA sequencing to assess the transcriptional basis of villus morphology and tested the hypothesis that gene expression may predict pregnancy outcomes. We demonstrate that villus morphology varies tremendously between patients, irrespective of gestational age, and that transcriptional differences are highly predictive of villus morphology. We show that pre-eclampsia markers are associated with villi with low morphology scores. Additionally, we identify SVEP1 as a possible biomarker for defining gestational age. Overall, chorionic villi in the first trimester remain one of the few means to correlate placental function with pregnancy outcome and these samples are a valuable and increasingly rare resource.
View details for PubMedID 29908643
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Validation of CD274/PD-L1 FISH as a Predictive Biomarker for the Use of Immune Check Point Therapies in Undifferentiated Malignancies
ELSEVIER SCIENCE INC. 2017: 1024
View details for Web of Science ID 000414275900349
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A novel TRIP11-FLT3 fusion in a patient with a myeloid/lymphoid neoplasm with eosinophilia
CANCER GENETICS
2017; 216: 10–15
Abstract
FLT3 fusions are associated with myeloid and lymphoid neoplasms with eosinophilia. We describe a patient presenting with clinicopathologic features of both chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) and systemic mastocytosis (SM). The bone marrow demonstrated a myeloproliferative neoplasm with eosinophilia and aggregates of atypical mast cells. Cytogenetic analysis revealed a t(13;14)(q12;q32), which was subsequently molecularly characterized as a novel TRIP11-FLT3 rearrangement. A KIT D816V mutation was also identified. The patient rapidly transformed to T-lymphoblastic leukemia/lymphoma and expired shortly after diagnosis. This is the fifth FLT3 fusion gene described in the literature; the presence of both myeloid and lymphoid neoplasms implicates involvement of an early hematopoietic progenitor by rearranged FLT3. We suggest that leukemias and lymphomas with FLT3 fusion genes exhibit similar clinicopathologic features to, and should be included in, the WHO category of "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2."
View details for PubMedID 29025582
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Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG)
GENETICS IN MEDICINE
2017; 19 (8): 845–50
Abstract
Disclaimer: ACMG Clinical Laboratory Practice Resources are developed primarily as an educational tool for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these practice resources is voluntary and does not necessarily assure a successful medical outcome. This Clinical Laboratory Practice Resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this Clinical Laboratory Practice Resource. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening (NIPS) using cell-free DNA has been rapidly adopted into prenatal care. Since NIPS is a screening test, diagnostic testing is recommended to confirm all cases of screen-positive NIPS results. For cytogenetics laboratories performing confirmatory testing on prenatal diagnostic samples, a standardized testing algorithm is needed to ensure that the appropriate testing takes place. This algorithm includes diagnostic testing by either chorionic villi sampling or amniocentesis samples and encompasses chromosome analysis, fluorescence in situ hybridization, and chromosomal microarray.
View details for PubMedID 28726804
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Independent Prognostic Significance of Monosomy 17 and Impact of Karyotype Complexity in Monosomal Karyotype/Complex Karyotype Acute Myeloid Leukemia: Results from Four ECOG-ACRIN Prospective Therapeutic Trials.
Leukemia research
2017; 59: 55-64
Abstract
The presence of a monosomal karyotype (MK+) and/or a complex karyotype (CK+) identifies subcategories of AML with poor prognosis. The prognostic significance of the most common monosomies (monosomy 5, monosomy 7, and monosomy 17) within MK+/CK+AML is not well defined. We analyzed data from 1,592 AML patients age 17-93 years enrolled on ECOG-ACRIN therapeutic trials. The majority of MK+ patients (182/195; 93%) were MK+/CK+ with 87% (158/182) having ≥5 clonal abnormalities (CK≥5). MK+ patients with karyotype complexity ≤4 had a median overall survival (OS) of 0.4y compared to 1.0y for MK- with complexity ≤4 (p<0.001), whereas no OS difference was seen in MK+vs. MK- patients with CK≥5 (p=0.82). Monosomy 5 (93%; 50/54) typically occurred within a highly complex karyotype and had no impact on OS (0.4y; p=0.95). Monosomy 7 demonstrated no impact on OS in patients with CK≥5 (p=0.39) or CK≤4 (p=0.44). Monosomy 17 appeared in 43% (68/158) of CK≥5 patients and demonstrated statistically significant worse OS (0.4y) compared to CK≥5 patients without monosomy 17 (0.5y; p=0.012). Our data suggest that the prognostic impact of MK+is limited to those with less complex karyotypes and that monosomy 17 may independently predict for worse survival in patients with AML.
View details for DOI 10.1016/j.leukres.2017.05.010
View details for PubMedID 28551161
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Commentary on the decision of the American Board of Medical Genetics and Genomics to create a 24-month specialty of Laboratory Genetics and Genomics (vol 19, pg 294, 2016)
GENETICS IN MEDICINE
2017; 19 (4): 483
View details for Web of Science ID 000399067600014
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Immune Check-Point Blockade as a Potential Therapeutic Strategy for Undifferentiated Malignancies
NATURE PUBLISHING GROUP. 2017: 456A
View details for Web of Science ID 000394467302405
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Analysis of Blastic Plasmacytoid Dendritic Cell Neoplasm with Translocations Involving the MYC Locus Identifies t(6;8)(p21;q24) as a Recurrent Cytogenetic Abnormality: A Multi-Institutional Study with Review of the Literature
NATURE PUBLISHING GROUP. 2017: 340A
View details for Web of Science ID 000394467301641
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The Significance of CD56 Expression and the RAM Immunophenotype, a Recurrent Immunophenotype Seen in Children, in Adult Acute Myeloid Leukemia
NATURE PUBLISHING GROUP. 2017: 358A–359A
View details for Web of Science ID 000394467302016
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The Significance of CD56 Expression and the RAM Immunophenotype, a Recurrent Immunophenotype Seen in Children, in Adult Acute Myeloid Leukemia
NATURE PUBLISHING GROUP. 2017: 358A–359A
View details for Web of Science ID 000393724401713
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Analysis of Blastic Plasmacytoid Dendritic Cell Neoplasm with Translocations Involving the MYC Locus Identifies t(6;8)(p21;q24) as a Recurrent Cytogenetic Abnormality: A Multi-Institutional Study with Review of the Literature
NATURE PUBLISHING GROUP. 2017: 340A
View details for Web of Science ID 000393724401641
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Immune Check-Point Blockade as a Potential Therapeutic Strategy for Undifferentiated Malignancies
NATURE PUBLISHING GROUP. 2017: 456A
View details for Web of Science ID 000393724402313
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Two cases of histiocytic sarcoma with BCL2 translocations and occult or subsequent follicular lymphoma.
Human pathology
2016; 55: 39-43
Abstract
Histiocytic sarcoma is rare and difficult to distinguish from histologic mimics such as myeloid sarcoma due to its relatively nonspecific immunoprofile. A subset of histiocytic sarcomas are clonally related to synchronous or metachronous follicular lymphomas. Interestingly, the histiocytic tumor component has been shown to harbor BCL2 gene translocations that are identical to those found in the lymphoma. We present one case of histiocytic sarcoma and initially occult follicular lymphoma in which detection of a BCL2 gene translocation helped support the diagnosis. We also provide follow up regarding a previously published case of histiocytic sarcoma with IGH/BCL2 fusion gene in which the patient subsequently developed follicular lymphoma and, later, diffuse large B-cell lymphoma. Our findings suggest that BCL2 gene translocations are a recurrent feature of a distinct subset of histiocytic sarcomas that are associated with follicular lymphoma; the follicular lymphoma component may be clinically occult at the time of diagnosis. Testing for an IGH/BCL2 translocation should be considered in the diagnostic workup of difficult to characterize neoplasms with histiocytic/monocytic morphology and immunoprofile.
View details for DOI 10.1016/j.humpath.2016.04.004
View details for PubMedID 27134111
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Section E6.1-6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow-acquired chromosomal abnormalities
GENETICS IN MEDICINE
2016; 18 (6): 635-642
Abstract
These American College of Medical Genetics and Genomics standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these standards and guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cytogenetic analyses of hematological neoplasms are performed to detect and characterize clonal chromosomal abnormalities that have important diagnostic, prognostic, and therapeutic implications. At the time of diagnosis, cytogenetic abnormalities assist in the diagnosis of such disorders and can provide important prognostic information. At the time of relapse, cytogenetic analysis can be used to confirm recurrence of the original neoplasm, detect clonal disease evolution, or uncover a new unrelated neoplastic process. This section deals specifically with the standards and guidelines applicable to chromosome studies of neoplastic blood and bone marrow-acquired chromosomal abnormalities. This updated Section E6.1-6.4 has been incorporated into and supersedes the previous Section E6 in Section E: Clinical Cytogenetics of the 2009 Edition (Revised 01/2010), American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories.Genet Med 18 6, 635-642.
View details for DOI 10.1038/gim.2016.50
View details for Web of Science ID 000378184300013
View details for PubMedID 27124785
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Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia.
Leukemia
2016; 30 (4): 947-950
View details for DOI 10.1038/leu.2015.136
View details for PubMedID 26055304
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Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications
PLOS ONE
2016; 11 (3)
Abstract
We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.
View details for DOI 10.1371/journal.pone.0151735
View details for Web of Science ID 000372582800093
View details for PubMedCentralID PMC4798531
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An analysis of MYC and EBV in diffuse large B-cell lymphomas associated with angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified.
Human pathology
2016; 48: 9-17
Abstract
Composite diffuse large B-cell lymphomas (DLBCLs) with peripheral T-cell lymphomas (PTCLs) are rare co-occurrences with poorly understood pathologic features. Herein, we describe 15 distinct cases of DLBCL occurring in association with PTCL, including angioimmunoblastic T-cell lymphoma (AITL; n = 12) and PTCL, not otherwise specified (n = 3). Sheets of large B cells were seen in all cases, with Hodgkin/Reed-Sternberg-like (HRS-L) cells present in 6 cases. When compared to cases of AITL without DLBCL, HRS-L cells were more frequently seen in cases of AITL with DLBCL (P = .02). Epstein-Barr virus (EBV) expression was seen in 10 of 15 cases, and in those with HRS-L cells, EBV expression was detected invariably in at least a subset of the HRS-L cells. MYC gene rearrangements were consistently absent, although 6 of the 10 cases showed MYC overexpression by immunohistochemistry in the neoplastic B cells; a frequency significantly increased compared to other cases of DLBCL not associated with a T-cell lymphoma: 29 of 166 (P = .005). In addition, when MYC was overexpressed in DLBCL, it was also weakly present in the HRS-L cells. The increased and frequent morphologic presence of HRS-L cells in association with this composite lymphoma raises a possible link between their occurrence and DLBCLs in PTCLs; furthermore, the frequent detection of MYC protein expression and EBV infection in these cases suggests a possible role of these pathways in B-cell lymphomagenesis.
View details for DOI 10.1016/j.humpath.2015.09.033
View details for PubMedID 26772393
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Double-Hit Diffuse Large B-Cell Lymphomas with MYC Gene Rearrangements More Commonly Involve BCL2 Than BCL6 Gene Rearrangements as the Second Hit: A Large Scale Single Institution Study
NATURE PUBLISHING GROUP. 2016: 362A
View details for Web of Science ID 000369270702171
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Double-Hit Diffuse Large B-Cell Lymphomas with MYC Gene Rearrangements More Commonly Involve BCL2 Than BCL6 Gene Rearrangements as the Second Hit: A Large Scale Single Institution Study
NATURE PUBLISHING GROUP. 2016: 362A
View details for Web of Science ID 000370302502438
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An analysis of MYC and EBV in diffuse large B-cell lymphomas associated with angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified
HUMAN PATHOLOGY
2016; 48: 9-17
Abstract
Composite diffuse large B-cell lymphomas (DLBCLs) with peripheral T-cell lymphomas (PTCLs) are rare co-occurrences with poorly understood pathologic features. Herein, we describe 15 distinct cases of DLBCL occurring in association with PTCL, including angioimmunoblastic T-cell lymphoma (AITL; n = 12) and PTCL, not otherwise specified (n = 3). Sheets of large B cells were seen in all cases, with Hodgkin/Reed-Sternberg-like (HRS-L) cells present in 6 cases. When compared to cases of AITL without DLBCL, HRS-L cells were more frequently seen in cases of AITL with DLBCL (P = .02). Epstein-Barr virus (EBV) expression was seen in 10 of 15 cases, and in those with HRS-L cells, EBV expression was detected invariably in at least a subset of the HRS-L cells. MYC gene rearrangements were consistently absent, although 6 of the 10 cases showed MYC overexpression by immunohistochemistry in the neoplastic B cells; a frequency significantly increased compared to other cases of DLBCL not associated with a T-cell lymphoma: 29 of 166 (P = .005). In addition, when MYC was overexpressed in DLBCL, it was also weakly present in the HRS-L cells. The increased and frequent morphologic presence of HRS-L cells in association with this composite lymphoma raises a possible link between their occurrence and DLBCLs in PTCLs; furthermore, the frequent detection of MYC protein expression and EBV infection in these cases suggests a possible role of these pathways in B-cell lymphomagenesis.
View details for DOI 10.1016/j.humpath.2015.09.033
View details for Web of Science ID 000368319200002
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Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications.
PloS one
2016; 11 (3)
Abstract
We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.
View details for DOI 10.1371/journal.pone.0151735
View details for PubMedID 26991267
View details for PubMedCentralID PMC4798531
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The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients Implications for Molecular Diagnostic Testing
JOURNAL OF MOLECULAR DIAGNOSTICS
2016; 18 (1): 39-50
Abstract
Despite the implementation of cystic fibrosis (CF) newborn screening programs across the United States, the identification of CFTR gene variants in nonwhite populations compared with whites remains suboptimal. Our objective was to establish the spectrum of CFTR variants and their frequencies in CF patients in the United States with African, Native American, Asian, East Indian, or Middle Eastern backgrounds. By using direct DNA sequencing, we identified two CFTR variants in 89 of 140 affected nonwhite individuals with uncharacterized genotypes. Seven variants were novel. Multiplex ligation-dependent probe amplification detected 14 rearrangements in the remaining 51 patients, 6 of which were novel. Deletions and duplications accounted for 17% of unidentified alleles. A cross-sectional analysis of genotyping data from the CF Foundation Patient Registry was performed, comparing 3496 nonwhite patients with 22,206 white CF patients. Patients of Hispanic, black, or Asian ancestry were less likely to have two identified CFTR variants (P < 0.0001 for Hispanics and blacks, P = 0.003 for Asians), and more likely to carry no mutations on the commonly used 23 mutation carrier screening panel (P < 0.0001). We analyzed the mutations recorded for each ancestry and summarized the most frequent ones. This research could facilitate equity in mutation detection between white and nonwhite or mixed-ethnicity CF patients, enabling an earlier diagnosis improving their quality of life.
View details for DOI 10.1016/j.jmoldx.2015.07.005
View details for Web of Science ID 000368211300006
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Reply: To PMID 25843063.
American journal of obstetrics and gynecology
2015; 213 (4): 596-?
View details for DOI 10.1016/j.ajog.2015.06.007
View details for PubMedID 26070704
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Noninvasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2015; 213 (2)
Abstract
We sought to determine the positive predictive value (PPV) of noninvasive prenatal screening (NIPS) for various aneuploidies based on cases referred for follow-up cytogenetic testing. Secondarily, we wanted to determine the false-negative (FN) rate for those cases with a negative NIPS result.We compared the cytogenetic findings (primarily from chromosome analysis) from 216 cases referred to our laboratories with either a positive or negative NIPS result, and classified NIPS results as true positive, false positive, true negative, or FN. Diagnostic cytogenetic testing was performed on the following tissue types: amniotic fluid (n = 137), chorionic villi (n = 69), neonatal blood (n = 6), and products of conception (n = 4).The PPV for NIPS were as follows: 93% for trisomy (T)21 (n = 99; 95% confidence interval [CI], 86-97.1%), 58% for T18 (n = 24; 95% CI, 36.6-77.9%), 45% for T13 (n = 11; 95% CI, 16.7-76.6%), 23% for monosomy X (n = 26; 95% CI, 9-43.6%), and 67% for XXY (n = 6; 95% CI, 22.3-95.7%). Of the 26 cases referred for follow-up cytogenetics after a negative NIPS result, 1 (4%) was FN (T13). Two cases of triploidy, a very serious condition but one not claimed to be detectable by the test providers, were among those classified as true negatives.T21, which has the highest prevalence of all aneuploidies, demonstrated a high true-positive rate, resulting in a high PPV. However, the other aneuploidies, with their lower prevalence, displayed relatively high false-positive rates and, therefore, lower PPV. Patients and physicians must fully understand the limitations of this screening test and the need in many cases to follow up with appropriate diagnostic testing to obtain an accurate diagnosis.
View details for DOI 10.1016/j.ajog.2015.04.001
View details for Web of Science ID 000358550900024
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Noninvasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings.
American journal of obstetrics and gynecology
2015; 213 (2): 214 e1-5
Abstract
We sought to determine the positive predictive value (PPV) of noninvasive prenatal screening (NIPS) for various aneuploidies based on cases referred for follow-up cytogenetic testing. Secondarily, we wanted to determine the false-negative (FN) rate for those cases with a negative NIPS result.We compared the cytogenetic findings (primarily from chromosome analysis) from 216 cases referred to our laboratories with either a positive or negative NIPS result, and classified NIPS results as true positive, false positive, true negative, or FN. Diagnostic cytogenetic testing was performed on the following tissue types: amniotic fluid (n = 137), chorionic villi (n = 69), neonatal blood (n = 6), and products of conception (n = 4).The PPV for NIPS were as follows: 93% for trisomy (T)21 (n = 99; 95% confidence interval [CI], 86-97.1%), 58% for T18 (n = 24; 95% CI, 36.6-77.9%), 45% for T13 (n = 11; 95% CI, 16.7-76.6%), 23% for monosomy X (n = 26; 95% CI, 9-43.6%), and 67% for XXY (n = 6; 95% CI, 22.3-95.7%). Of the 26 cases referred for follow-up cytogenetics after a negative NIPS result, 1 (4%) was FN (T13). Two cases of triploidy, a very serious condition but one not claimed to be detectable by the test providers, were among those classified as true negatives.T21, which has the highest prevalence of all aneuploidies, demonstrated a high true-positive rate, resulting in a high PPV. However, the other aneuploidies, with their lower prevalence, displayed relatively high false-positive rates and, therefore, lower PPV. Patients and physicians must fully understand the limitations of this screening test and the need in many cases to follow up with appropriate diagnostic testing to obtain an accurate diagnosis.
View details for DOI 10.1016/j.ajog.2015.04.001
View details for PubMedID 25843063
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Cytogenetic Variation of B-Lymphoblastic Leukemia With Infrachromosomal Amplification of Chromosome 21 (iAMP21) A Multi-Institutional Series Review
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
2015; 144 (1): 103-112
Abstract
B-lymphoblastic leukemia (B-ALL) with intrachromosomal amplification of chromosome 21 (iAMP21) is a relatively uncommon manifestation of acute leukemia and limited predominantly to the pediatric population. Case-specific information regarding flow cytometric, morphologic, and laboratory findings of this subtype of leukemia is currently lacking.We searched the databases of three large institutions for lymphoblastic leukemia with iAMP21 from 2005 through 2012 and analyzed the clinicopathologic features.We identified 17 cases with five or more RUNX1 signals on interphase nuclei, 14 of which were consistent with the Children's Oncology Group (COG) definition for iAMP21—namely, the presence of three or more RUNX1 signals on one marker chromosome. These cases showed a statistically significant lower peripheral WBC count and older age at diagnosis compared with all pediatric cases of B-ALL. We also identified three cases with increased RUNX1 signals scattered on multiple marker chromosomes that did not meet the COG definition of iAMP21 but showed similar 21q instability and older age at presentation.Our findings not only demonstrate that B-ALL with iAMP21 is truly a distinct clinicopathologic entity but also suggest that a subset of cases of B-ALL with iAMP21 can show variable cytogenetic features.
View details for DOI 10.1309/AJCPLUYF11HQBYRB
View details for PubMedID 26071468
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Expression Profiles of MYC Protein and MYC Gene Rearrangement in Lymphomas
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2015; 39 (3): 294-303
Abstract
MYC translocations are a defining feature of Burkitt lymphoma and a group of diffuse large B-cell lymphoma (DLBCL) with inferior outcome. However, the clinical relevance of MYC gene rearrangement and its relationship with MYC protein expression has not been well characterized in lymphomas. Tissue microarrays containing 1214 lymphomas were successfully evaluated by immunohistochemistry using anti-MYC clone Y69 and a dual-color break-apart fluorescence in situ hybridization probe to detect MYC gene rearrangements. Aggressive B-cell lymphomas including Burkitt lymphoma and DLBCL showed the highest level of MYC protein staining defined as staining in >50% of lymphoma cells. A significant proportion of plasmablastic, B-lymphoblastic and T-lymphoblastic, and extranodal NK/T-cell lymphomas also showed staining in >50% of cells, whereas only occasional plasma cell myeloma, mantle cell lymphoma, and classical Hodgkin lymphoma showed a high level of staining. Small B-cell lymphomas, when positive, showed MYC protein in <50% of cells. In aggressive B-cell lymphomas, MYC rearrangement and MYC immunohistochemistry showed a high concordance rate; however, some DLBCL and all T-cell and NK-cell lymphomas with MYC protein expression lacked MYC gene rearrangements. Our results provide a baseline for MYC protein expression in lymphomas and indicate that its expression is not specific to lymphoma subtypes, cell lineage, or expected clinical behavior and is highly variable. In addition, MYC protein expression is not necessarily correlated with MYC gene rearrangements and suggests the need for caution in the interpretation of MYC immunohistochemistry in the differential diagnosis of lymphomas.
View details for Web of Science ID 000349803400002
View details for PubMedID 25581730
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Acute myeloid leukemia with monosomal karyotype: morphologic, immunophenotypic, and molecular findings.
American journal of clinical pathology
2014; 142 (2): 190-195
Abstract
Acute myeloid leukemia (AML) with monosomal karyotype (MK) recently has been reported to be associated with worse outcome than the traditional complex karyotype.In this retrospective study of 111 patients with AML, we identified 14 patients with MK (13% of all patients with AML) using the definition proposed by Breems et al.Five (36%) of these 14 patients had a loss of a single chromosome in the presence of other structural abnormalities, and nine (64%) had a loss of two or more autosomal chromosomes. Patients with AML-MK presented at an older age, with lower bone marrow blasts, and their blasts less frequently expressed CD34. Most patients with AML-MK had morphologic multilineage dysplasia and were predominantly subclassified as having AML with myelodysplasia-related changes (AML-MRC). Molecular analysis showed a significant absence of NPM1 and FLT3 in patients with AML-MK.Outcome data showed that patients with AML-MK had significantly worse overall survival, disease-free survival, and complete response compared with the rest of the patients with AML as well as within the AML-MRC group.
View details for DOI 10.1309/AJCPMLO84JDNVLNK
View details for PubMedID 25015859
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Reply: To PMID 23529082.
American journal of obstetrics and gynecology
2014; 211 (1): 81-?
View details for DOI 10.1016/j.ajog.2014.01.015
View details for PubMedID 24418226
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Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study
HAEMATOLOGICA
2014; 99 (5): 821-829
Abstract
Acute myeloid leukemia and myelodysplastic syndrome with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) have a poor prognosis. Indeed, the inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has been recognized as a poor risk karyotype in the revised International Prognostic Scoring System. However, inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is not among the cytogenetic abnormalities pathognomonic for diagnosis of acute myeloid leukemia irrespective of blast percentage in the 2008 WHO classification. This multicenter study evaluated the clinico-pathological features of acute myeloid leukemia/myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and applied the revised International Prognostic Scoring System to myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2). A total of 103 inv(3)(q21q26.2)/t(3;3)(q21;q26.2) patients were reviewed and had a median bone marrow blast count of 4% in myelodysplastic syndrome (n=40) and 52% in acute myeloid leukemia (n=63) (P<0.001). Ninety-one percent of patients showed characteristic dysmegakaryopoiesis. There was no difference in overall survival between acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) (12.9 vs. 7.9 months; P=0.16). Eighty-three percent of patients died (median follow up 7.9 months). Complex karyotype, monosomal karyotype and dysgranulopoiesis (but not blast percentage) were independent poor prognostic factors in the entire cohort on multivariable analysis. The revised International Prognostic Scoring System better reflected overall survival of inv(3)(q21q26.2)/t(3;3)(q21;q26.2) than the International Prognostic Scoring System but did not fully reflect the generally dismal prognosis. Our data support consideration of myelodysplastic syndrome with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) as an acute myeloid leukemia with recurrent genetic abnormalities, irrespective of blast percentage.
View details for DOI 10.3324/haematol.2013.096420
View details for Web of Science ID 000336257500009
View details for PubMedID 24463215
View details for PubMedCentralID PMC4008101
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Is It Time to Sound an Alarm About False-Positive Cell-Free DNA Testing for Fetal Aneuploidy?
OBSTETRICAL & GYNECOLOGICAL SURVEY
2014; 69 (3): 135-136
View details for DOI 10.1097/01.ogx.0000445775.75414.e7
View details for Web of Science ID 000333251400008
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Acute Lymphoblastic Leukemia with Intrachromosomal Amplification of Chromosome #21-A Single Institutional Review
NATURE PUBLISHING GROUP. 2014: 354A
View details for Web of Science ID 000331155802015
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Acute Lymphoblastic Leukemia with Intrachromosomal Amplification of Chromosome #21-A Single Institutional Review
NATURE PUBLISHING GROUP. 2014: 354A
View details for Web of Science ID 000331502202015
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Accuracy of Non-Invasive Prenatal Screening for Trisomies 13, 18 and 21 and Sex Chromosome Aneuploidy
KARGER. 2014
View details for Web of Science ID 000336054700020
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Chromosomal Alterations/Genomic Imbalances in Chronic Lymphocytic Leukemia (CLL) Using Array Comparative Genomic Hybridization (aCGH) and Comparison with Interphase Fluorescence in situ Hybridization (FISH)
KARGER. 2014
View details for Web of Science ID 000336054700027
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Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes.
Haematologica
2013; 98 (11): 1689-1696
Abstract
In order to identify novel somatic mutations associated with classic BCR/ABL1-negative myeloproliferative neoplasms, we performed high-coverage genome sequencing of DNA from peripheral blood granulocytes and cultured skin fibroblasts from a patient with MPL W515K-positive primary myelofibrosis. The primary myelofibrosis genome had a low somatic mutation rate, consistent with that observed in similar hematopoietic tumor genomes. Interfacing of whole-genome DNA sequence data with RNA expression data identified three somatic mutations of potential functional significance: a nonsense mutation in CARD6, implicated in modulation of NF-kappaB activation; a 19-base pair deletion involving a potential regulatory region in the 5'-untranslated region of BRD2, implicated in transcriptional regulation and cell cycle control; and a non-synonymous point mutation in KIAA0355, an uncharacterized protein. Additional mutations in three genes (CAP2, SOX30, and MFRP) were also evident, albeit with no support for expression at the RNA level. Re-sequencing of these six genes in 178 patients with polycythemia vera, essential thrombocythemia, and myelofibrosis did not identify recurrent somatic mutations in these genes. Finally, we describe methods for reducing false-positive variant calls in the analysis of hematologic malignancies with a low somatic mutation rate. This trial is registered with ClinicalTrials.gov (NCT01108159).
View details for DOI 10.3324/haematol.2013.092379
View details for PubMedID 23872309
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Is it time to sound an alarm about false-positive cell-free DNA testing for fetal aneuploidy?
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2013; 209 (5): 415–19
Abstract
Testing cell-free DNA (cfDNA) in maternal blood samples has been shown to have very high sensitivity for the detection of fetal aneuploidy with very low false-positive results in high-risk patients who undergo invasive prenatal diagnosis. Recent observation in clinical practice of several cases of positive cfDNA tests for trisomy 18 and trisomy 13, which were not confirmed by cytogenetic testing of the pregnancy, may reflect a limitation of the positive predictive value of this quantitative testing, particularly when it is used to detect rare aneuploidies. Analysis of a larger number of false-positive cases is needed to evaluate whether these observations reflect the positive predictive value that should be expected. Infrequently, mechanisms (such as low percentage mosaicism or confined placental mosaicism) might also lead to positive cfDNA testing that is not concordant with standard prenatal cytogenetic diagnosis. The need to explore these and other possible causes of false-positive cfDNA testing is exemplified by 2 of these cases. Additional evaluation of cfDNA testing in clinical practice and a mechanism for the systematic reporting of false-positive and false-negative cases will be important before this test is offered widely to the general population of low-risk obstetric patients. In the meantime, incorporating information about the positive predictive value in pretest counseling and in clinical laboratory reports is recommended. These experiences reinforce the importance of offering invasive testing to confirm cfDNA results before parental decision-making.
View details for DOI 10.1016/j.ajog.2013.03.027
View details for Web of Science ID 000326243700006
View details for PubMedID 23529082
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Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes.
Haematologica
2013; 98 (11): 1689-1696
Abstract
In order to identify novel somatic mutations associated with classic BCR/ABL1-negative myeloproliferative neoplasms, we performed high-coverage genome sequencing of DNA from peripheral blood granulocytes and cultured skin fibroblasts from a patient with MPL W515K-positive primary myelofibrosis. The primary myelofibrosis genome had a low somatic mutation rate, consistent with that observed in similar hematopoietic tumor genomes. Interfacing of whole-genome DNA sequence data with RNA expression data identified three somatic mutations of potential functional significance: a nonsense mutation in CARD6, implicated in modulation of NF-kappaB activation; a 19-base pair deletion involving a potential regulatory region in the 5'-untranslated region of BRD2, implicated in transcriptional regulation and cell cycle control; and a non-synonymous point mutation in KIAA0355, an uncharacterized protein. Additional mutations in three genes (CAP2, SOX30, and MFRP) were also evident, albeit with no support for expression at the RNA level. Re-sequencing of these six genes in 178 patients with polycythemia vera, essential thrombocythemia, and myelofibrosis did not identify recurrent somatic mutations in these genes. Finally, we describe methods for reducing false-positive variant calls in the analysis of hematologic malignancies with a low somatic mutation rate. This trial is registered with ClinicalTrials.gov (NCT01108159).
View details for DOI 10.3324/haematol.2013.092379
View details for PubMedID 23872309
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Hidden Mastocytosis in Acute Myeloid Leukemia With t(8;21)(q22;q22).
American journal of clinical pathology
2013; 140 (4): 525-535
Abstract
Objectives: To assess the frequency of systemic mastocytosis (SM) in a large series of acute myeloid leukemia (AML) with t(8;21)(q22;q22). Methods: We retrospectively characterized 40 bone marrow aspirate smears and biopsy specimens from patients with AML with t(8;21) for the presence of SM. Cases were assessed for mast cell morphology and immunohistochemistry, as well as KIT exon 8 and 17 mutational assessment by reverse transcription polymerase chain reaction. Results: Four patients met criteria for SM, 1 met criteria for myelomastocytic leukemia, and 8 demonstrated the benign finding of mast cell hyperplasia. Conclusions: We recommend examining all cases of AML with t(8;21) for the presence of SM via morphology, immunophenotyping, and KIT mutational analysis studies.
View details for DOI 10.1309/AJCP1Q0YSXEAHNKK
View details for PubMedID 24045550
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Activating HRAS mutation in agminated Spitz nevi arising in a nevus spilus.
JAMA dermatology
2013; 149 (9): 1077-1081
Abstract
IMPORTANCE Spitz nevi are benign melanocytic proliferations that can sometimes be clinically and histopathologically difficult to distinguish from melanoma. Agminated Spitz nevi have been reported to arise spontaneously, in association with an underlying nevus spilus, or after radiation or chemotherapy. However, to our knowledge, the genetic mechanism for this eruption has not been described. OBSERVATIONS We report a case of agminated Spitz nevi arising in a nevus spilus and use exome sequencing to identify a clonal activating point mutation in HRAS (GenBank 3265) (c.37G→C) in the Spitz nevi and underlying nevus spilus. We also identify a secondary copy number increase involving HRAS on chromosome 11p, which occurs during the development of the Spitz nevi. CONCLUSIONS AND RELEVANCE Our results reveal an activating HRAS mutation in a nevus spilus that predisposes to the formation of Spitz nevi. In addition, we demonstrate a copy number increase in HRAS as a "second hit" during the formation of agminated Spitz nevi, which suggests that both multiple Spitz nevi and solitary Spitz nevi may arise through similar molecular pathways. In addition, we describe a unique investigative approach for the discovery of genetic alterations in Spitz nevi.
View details for DOI 10.1001/jamadermatol.2013.4745
View details for PubMedID 23884457
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Activating HRAS Mutation in Agminated Spitz Nevi Arising in a Nevus Spilus.
JAMA dermatology
2013; 149 (9): 1077-1081
Abstract
IMPORTANCE Spitz nevi are benign melanocytic proliferations that can sometimes be clinically and histopathologically difficult to distinguish from melanoma. Agminated Spitz nevi have been reported to arise spontaneously, in association with an underlying nevus spilus, or after radiation or chemotherapy. However, to our knowledge, the genetic mechanism for this eruption has not been described. OBSERVATIONS We report a case of agminated Spitz nevi arising in a nevus spilus and use exome sequencing to identify a clonal activating point mutation in HRAS (GenBank 3265) (c.37G→C) in the Spitz nevi and underlying nevus spilus. We also identify a secondary copy number increase involving HRAS on chromosome 11p, which occurs during the development of the Spitz nevi. CONCLUSIONS AND RELEVANCE Our results reveal an activating HRAS mutation in a nevus spilus that predisposes to the formation of Spitz nevi. In addition, we demonstrate a copy number increase in HRAS as a "second hit" during the formation of agminated Spitz nevi, which suggests that both multiple Spitz nevi and solitary Spitz nevi may arise through similar molecular pathways. In addition, we describe a unique investigative approach for the discovery of genetic alterations in Spitz nevi.
View details for DOI 10.1001/jamadermatol.2013.4745
View details for PubMedID 23884457
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B-Cell Transcription Factor Expression and Immunoglobulin Gene Rearrangement Frequency in Acute Myeloid Leukemia With t(8;21)(q22;q22)
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
2013; 140 (3): 355-362
Abstract
Objectives: To assess a large series of patients with acute myeloid leukemia (AML) with t(8;21) for both IGH@ and IGK@ B-cell gene rearrangements and for expression of PAX5, OCT2, and Bob.1 by immunohistochemistry and expression of CD19, CD79a, CD20, and CD22 by flow cytometry immunophenotyping. Methods: A total of 48 cases of AML with t(8;21)(q22;q22) were evaluated by immunohistochemistry and/or heavy chain and light chain immunoglobulin rearrangement studies where paraffin-embedded and/or fresh frozen material was available for study; previously performed flow cytometry studies were also reviewed in available cases. Results: Our study yielded 1 of 19 cases of AML with t(8;21) with an IGH@ gene rearrangement; blasts were associated with weak PAX5 expression. In addition, expression of antigens CD79a by flow cytometry and OCT2 by immunohistochemistry were highly associated with PAX5 expression, and CD19 was expressed in most cases assessed. Conclusions: Although B-cell antigen and B-cell transcription factor expression is seen in the majority of AMLs with t(8;21)(q22;q22) and correlates with PAX5 expression, immunoglobulin gene rearrangements are an uncommon event in this group of leukemias.
View details for DOI 10.1309/AJCPFBCFXP94AKWJ
View details for PubMedID 23955454
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A Case Series of Lengthy Progression-Free Survival With Pemetrexed-Containing Therapy in Metastatic Non-Small-Cell Lung Cancer Patients Harboring ROS1 Gene Rearrangements.
Clinical lung cancer
2013; 14 (5): 592-595
View details for DOI 10.1016/j.cllc.2013.04.008
View details for PubMedID 23810364
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Still a screening test: more attention needed to noninvasive prenatal test false-positive rates
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
2013; 209 (2): 160–61
View details for DOI 10.1016/j.ajog.2013.04.021
View details for Web of Science ID 000322657000036
View details for PubMedID 23583784
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Pediatric Acute Myeloid Leukemia as Classified Using 2008 WHO Criteria: A Single-Center Experience.
American journal of clinical pathology
2013; 139 (6): 818-825
Abstract
The classification of acute myeloid leukemia (AML) has evolved to the most recent World Health Organization (WHO) schema, which integrates genetic, morphologic, and prognostic data into a single system. However, this system was devised using adult data and how this system applies to a pediatric cohort is unknown. Performing a retrospective chart review, we examined our single-center experience with AML in 115 children and classified their leukemia using the WHO 2008 schema. We examined patient samples for mutations of FLT3, NPM1, and CEBPA. Overall survival was calculated within categories. In our pediatric population, most cases of AML had recurrent genetic abnormalities of favorable prognosis. More than 10% of patients in our series were categorized as AML, with myelodysplasia-related changes, an entity not well-described in pediatric patients. In addition, a large proportion of patients were categorized with secondary, therapy-related AML. To our knowledge, this is the first application of the WHO 2008 classification to a pediatric cohort. In comparison to adult studies, AML in the pediatric population shows a distinct distribution within the WHO 2008 classification.
View details for DOI 10.1309/AJCP59WKRZVNHETN
View details for PubMedID 23690127
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HER2 Status in Breast Cancer as Determined by Three ASCO/CAP Recognized Reporting Techniques Reveals Testing Discordance, and Emphasizes the Utility of Co-Testing with FISH and IHC
NATURE PUBLISHING GROUP. 2013: 34A
View details for Web of Science ID 000314444400134
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Complex Karyotype but Not Blast Percentage Is Associated with Poor Survival in Acute Myeloid Leukemia and Myelodysplastic Syndrome with Inv(3)(q21q26.2)/t(3;3)(q21;q26.2); a Bone Marrow Pathology Group Study
NATURE PUBLISHING GROUP. 2013: 358A
View details for Web of Science ID 000314444402125
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HER2 Status in Breast Cancer as Determined by Three ASCO/CAP Recognized Reporting Techniques RevealsTesting Discordance, and Emphasizes the Utility of Co-Testing with FISH and IHC
NATURE PUBLISHING GROUP. 2013: 34A
View details for Web of Science ID 000314789300134
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Complex Karyotype but Not Blast Percentage Is Associated with Poor Survival in Acute Myeloid Leukemia and Myelodysplastic Syndrome with Inv(3)(q21q26.2)/t(3;3)(q21;q26.2); a Bone Marrow Pathology Group Study
102nd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP)
NATURE PUBLISHING GROUP. 2013: 358A–358A
View details for Web of Science ID 000314789302115
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Clinicopathologic Characteristics of HER2 FISH-ambiguous Breast Cancer at a Single Institution
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2013; 37 (1): 120-127
Abstract
: The typical algorithm for human epidermal growth factor-2 (HER2) testing is immunohistochemistry (IHC), followed by reflex HER2 fluorescence in situ hybridization (FISH) for HER2 IHC-ambiguous (2+) cases. At our institution, HER2 FISH testing is initially performed as part of routine breast cancer testing, with HER2 FISH-ambiguous (HER2:CEP17 ratio, 1.8 to 2.2) cases reflexed to HER2 IHC. This provides a unique dataset for lesions that may not routinely undergo FISH testing. The clinicopathologic characteristics of HER2 FISH-ambiguous cases are described.: The electronic pathology database in our institution was searched for HER2 FISH-ambiguous cases from 2007 to December 2011. Review of clinical and pathologic characteristics was performed.: Sixty cases from 60 patients were reported as HER2 FISH ambiguous. Reflex HER2 IHC testing was performed on all 60 cases, of which 26 were HER2 IHC negative (0 to 1+), 18 were HER2 IHC ambiguous (2+), and 16 were HER2 IHC positive (3+). Of the 46 HER2 FISH-ambiguous patients with available clinical records, 13 (32%) pursued anti-HER2 treatment (10 IHC 3+, 1 IHC 2+, 2 IHC 0 to 1+). All were grade II or III ductal carcinomas, with 1 grade III metaplastic carcinoma.: Reflex HER2 IHC testing after initially ambiguous HER2 FISH testing provides definitive HER2 status in a majority of cases (70%). However, a substantial percentage (30%) of HER2 FISH-ambiguous cases is also HER2 IHC ambiguous, suggesting an intermediate HER2 biology. Most HER2 FISH-ambiguous patients who received trastuzumab were HER2 IHC 3+, grade III, and had associated high-grade ductal carcinoma in situ. Although not statistically significant and with only minimal follow-up, no recurrences have occurred in those patients treated with trastuzumab (P=0.5754).
View details for DOI 10.1097/PAS.0b013e31826ab19d
View details for Web of Science ID 000312486700015
View details for PubMedID 23108020
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Report of Two Patients and Further Characterization of Interstitial 9p13 Deletion-A Rare But Recurrent Microdeletion Syndrome?
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2012; 158A (9): 2328-2335
Abstract
To date, an interstitial deletion of 9p13 has been described only two times in the medical literature. These reports were based on routine chromosomal analysis. We report on two additional patients with an interstitial deletion of 9p13 further defined on array CGH who share clinical features with the other two patients previously described. Our first patient is a 16-year-old girl with a 5.9 Mb deletion at 9p13.3-9p13.1, initially detected on routine karyotype analysis and further characterized on array CGH. Our second patient is a 7½-year-old boy with a 4.8 Mb deletion also at 9p13.3-9p13.1. Patients with 9p13 deletion appear to have mild to moderate developmental delay, social and interactive personality, behavior issues such as attention deficit-hyperactivity disorder, short stature, prominent antihelices, hypoplastic nails, and precocious/early puberty. Our 16-year-old patient is the oldest patient described thus far. This report further characterizes this condition and helps to delineate the long-term prognosis in these patients.
View details for DOI 10.1002/ajmg.a.35536
View details for Web of Science ID 000310068700037
View details for PubMedID 22887577
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Will a peripheral blood (PB) sample yield the same diagnostic and prognostic cytogenetic data as the concomitant bone marrow (BM) in myelodysplasia?
LEUKEMIA RESEARCH
2012; 36 (7): 832-840
Abstract
In patients with myelodysplastic syndromes (MDS), chromosome anomalies are detected by conventional cytogenetic studies (CCS) and/or interphase fluorescence in situ hybridization (FISH) of bone marrow (BM) samples and provide prognostic and diagnostic information, which can direct therapy. Whether peripheral blood (PB) can be substituted for bone marrow in these cases and can provide the same information remains unknown. Concurrent BM and PB specimens collected from 100 patients with recently diagnosed MDS were studied using both CCS and FISH. While 68% of BM samples showed an abnormal karyotype by CCS, only 31% of PB samples were abnormal by CCS. In 12% of patients, FISH and CCS were discordant due to the inability of the FISH panel to detect all possible abnormalities. However, only one case (1%) had a cryptic abnormality detected by FISH. BM and PB FISH were discordant in 3% of cases, most likely due to the smaller clone size in PB vs. BM. While PB should not be substituted for BM at diagnosis, it is a viable alternative for monitoring patients using the appropriate FISH probe(s).
View details for DOI 10.1016/j.leukres.2012.03.013
View details for Web of Science ID 000304353400018
View details for PubMedID 22537394
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Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia
NEW ENGLAND JOURNAL OF MEDICINE
2012; 366 (12): 1079-1089
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML.We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients.We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67).We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).
View details for DOI 10.1056/NEJMoa1112304
View details for Web of Science ID 000301769700007
View details for PubMedID 22417203
View details for PubMedCentralID PMC3545649
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HER2 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma in a US Population: Clinicopathologic Analysis With Proposed Approach to HER2 Assessment
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
2012; 20 (1): 13-24
Abstract
Recent evidence suggests that trastuzumab, a monoclonal antibody which targets HER2, in combination with chemotherapy is a therapeutic option in patients with HER2-positive gastric or gastroesophageal junction cancer. Widely accepted guidelines for HER2 testing in gastric and gastroesophageal junction cancer have not been established. The purpose of this study was to analyze the incidence and patterns of HER2 expression in gastric and gastroesophageal junction cancer using a tissue microarray approach, which closely simulates small biopsies routinely tested for HER2. One hundred sixty-nine patients, including 99 primary gastric adenocarcinomas and 70 primary gastroesophageal junction carcinomas were analyzed for HER2 overexpression by immunohistochemistry and HER2 gene amplification by fluorescence in situ hybridization using scoring schemes proposed by both American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the results of the recently published Trastuzumab for Gastric Cancer (ToGA) trial. In our analysis, 19 adenocarcinomas were HER2 positive, defined as either a HER2/CEP17 ratio >2.2 and/or a 3+ HER2 immunohistochemistry score with either the ASCO/CAP or ToGA scoring schemes. Of the 19 HER2-positive adenocarcinomas, 8 (42%) exhibited a characteristic strongly intense basolateral membranous staining pattern which would be interpreted as negative (1+) using the accepted ASCO/CAP scoring scheme for HER2 assessment in breast carcinoma, but were correctly labeled as 3+ positive using the proposed ToGA scoring scheme. Of the 19 HER2-positive adenocarcinomas, 8 (42%) demonstrated heterogeneous HER2 protein expression by immunohistochemistry. Twelve of 99 (12%) gastric carcinomas were positive for HER2. Of these, HER2 was more often identified in intestinal-type adenocarcinomas (10 of 52, 19%) compared with diffuse (2 of 34, 6%) adenocarcinoma. Seven of 70 (10%) gastroesophageal junction carcinomas were positive for HER2 of which all were intestinal type (7 of 58, 12%). HER2 status or primary tumor site did not correlate with patient survival. Gastric and gastroesophageal junction adenocarcinomas typically display a characteristic basolateral membranous pattern of HER2 expression which is often heterogeneous rendering routine evaluation of HER2 status on small tissue samples challenging.
View details for DOI 10.1097/PAI.0b013e31821c821c
View details for PubMedID 21617522
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CHROMOSOMAL MOSAICISM IDENTIFIED BY ACGH: A CASE OF TETRASOMY 12P
LIPPINCOTT WILLIAMS & WILKINS. 2012: 202
View details for Web of Science ID 000298634401272
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Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells
NATURE
2011; 474 (7351): 399-?
Abstract
The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of dyskeratosis congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of dyskeratosis congenita. Here we show that even in the undifferentiated state, iPSCs from dyskeratosis congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. These findings in iPSCs from dyskeratosis congenita patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell-culture-based system for the development of targeted therapeutics.
View details for DOI 10.1038/nature10084
View details for Web of Science ID 000291647100050
View details for PubMedID 21602826
View details for PubMedCentralID PMC3155806
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Short tandem repeat and human leukocyte antigen mutations or losses confound engraftment and typing analysis in hematopoietic stem cell transplants
HUMAN IMMUNOLOGY
2011; 72 (6): 503-509
Abstract
Clonal chromosomal abnormalities are often found in the tumor cells of patients with malignancies. These abnormalities can cause downregulation of human leukocyte antigen (HLA) and instability of short tandem repeat (STR) DNA sequences, confounding HLA typing and/or engraftment analysis in hematopoietic stem cell transplants (HSCT). We describe here the abnormalities observed during testing of 600 HSCT patients. HLA molecular typing was performed by reference strand conformational analyses and/or sequence-based typing. STR testing was performed with 10 to 16 STR primer sets, following 1 to 4 informative loci in each patient. Eight patients exhibited either loss of heterozygosity (4 STR, 3 HLA) or STR length mutation (n = 1), and 5 of the 8 exhibited correlative cytogenetic abnormalities. Diagnoses were acute myelogenous leukemia (AML; n = 7) or myelofibrosis (MFIB: n = 1), yielding an 11% incidence of these chromosomal abnormalities among the subset of 72 AML/MFIB HSCT patients. These results highlight some of the problems encountered and the possibility for interpretive errors that can arise when analyzing molecular typing and engraftment data, particularly among AML/MFIB patients.
View details for DOI 10.1016/j.humimm.2011.03.003
View details for Web of Science ID 000291138900007
View details for PubMedID 21463659
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A Pediatric B Lineage Leukemia With Coincident MYC and MLL Translocations
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2011; 33 (2): 158-160
Abstract
Translocations are key oncogenic events, and many rearrangements are characteristic for a specific malignancy. We present here a case of phenotypic precursor-B acute lymphoblastic leukemia (ALL), subsequently found to have both MYC and MLL translocations. Owing to the potential prognostic impact of these translocations, a novel treatment strategy was applied which merged precursor-B ALL, Burkitt-ALL, and "MLL-adapted" rationales. With the advent of expanding diagnostic panels and molecular therapeutic options, use of such adapted therapies for individualized treatment will undoubtedly continue to increase as we move toward pharmacogenomic-based approaches.
View details for DOI 10.1097/MPH.0b013e3181e65c39
View details for Web of Science ID 000287648800031
View details for PubMedID 20829716
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Replication-compromised cells require the mitotic checkpoint to prevent tetraploidization
CHROMOSOMA
2011; 120 (1): 73-82
Abstract
Replication stress often induces chromosome instability. In this study, we explore which factors in replication-compromised cells promote abnormal chromosome ploidy. We expressed mutant forms of either polymerase α (Polα) or polymerase δ (Polδ) in normal human fibroblasts to compromise DNA replication. Cells expressing the mutant Polα-protein failed to sustain mitotic arrest and, when propagated progressively, down-regulated Mad2 and BubR1 and accumulated 4N-DNA from the 2N-DNA cells. Significantly, a population of these cells became tetraploids. The Polα mutant expressing cells also exhibited elevated cellular senescence markers, suggesting as a mechanism to limit proliferation of the tetraploids. Expression of the Polδ mutant also caused cells to accumulate 4N-DNA. In contrast to the Polα mutant expressing cells, the Polδ mutant expressing cells expressed sufficient levels of Mad2, BubR1, and cyclin B1 to sustain mitotic arrest, and these cells had normal chromosome ploidy. Together, these results suggest that replication-compromised cells depend on the mitotic checkpoint to prevent mitotic slippage that could result in tetraploidization.
View details for DOI 10.1007/s00412-010-0292-7
View details for Web of Science ID 000286628800006
View details for PubMedID 20827484
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MITOCHONDRIAL PATHOLOGY IN ANGELMAN SYNDROME
Western Regional Meeting of the American-Federation-for-Medical-Research
LIPPINCOTT WILLIAMS & WILKINS. 2011: 165–66
View details for Web of Science ID 000285542500293
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Effects of Long-Term Culture on Human Embryonic Stem Cell Aging
STEM CELLS AND DEVELOPMENT
2011; 20 (1): 127-138
Abstract
In recent years, human embryonic stem (hES) cells have become a promising cell source for regenerative medicine. Although hES cells have the ability for unlimited self-renewal, potential adverse effects of long-term cell culture upon hES cells must be investigated before therapeutic applications of hES cells can be realized. Here we investigated changes in molecular profiles associated with young (<60 passages) and old (>120 passages) cells of the H9 hES cell line as well as young (<85 passages) and old (>120 passages) cells of the PKU1 hES cell line. Our results show that morphology, stem cell markers, and telomerase activity do not differ significantly between young and old passage cells. Cells from both age groups were also shown to differentiate into derivatives of all 3 germ layers upon spontaneous differentiation in vitro. Interestingly, mitochondrial dysfunction was found to occur with prolonged culture. Old passage cells of both the H9 and PKU1 lines were characterized by higher mitochondrial membrane potential, larger mitochondrial morphology, and higher reactive oxygen species content than their younger counterparts. Teratomas derived from higher passage cells were also found to have an uneven preference for differentiation compared with tumors derived from younger cells. These findings suggest that prolonged culture of hES cells may negatively impact mitochondrial function and possibly affect long-term pluripotency.
View details for DOI 10.1089/scd.2009.0475
View details for PubMedID 20629482
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Loss of SMARCB1/INI1 expression in poorly differentiated chordomas
ACTA NEUROPATHOLOGICA
2010; 120 (6): 745-753
Abstract
Chordomas are malignant neoplasms that typically arise in the axial spine and primarily affect adults. When chordomas arise in pediatric patients they are more likely to display unusual histological features and aggressive behavior. We noted the absence of SMARCB1/INI1 expression by immunohistochemistry in an index case of poorly differentiated chordoma of the sacrum, leading us to further examine SMARCB1/INI1 expression as well as that of brachyury, a highly specific marker of notochordal differentiation, in 3 additional poorly differentiated chordomas of the clivus, 10 typical chordomas, and 8 atypical teratoid/rhabdoid tumors (AT/RTs). All 4 poorly differentiated chordomas and all AT/RTs lacked nuclear expression of SMARCB1/INI1, while the 10 typical chordomas maintained strong nuclear SMARCB1/INI1 immunoreactivity. All 10 typical and 4 poorly differentiated chordomas expressed brachyury; all 8 AT/RTs were brachyury immunonegative. Cytogenetic evaluation utilizing FISH probes near the SMARCB1/INI1 locus on chromosome 22q was also performed in all of the poorly differentiated chordomas in this series. Three of the four poorly differentiated chordomas had evidence for deletion of this region by FISH. Analysis of the SMARCB1/INI1 gene sequence was performed using formalin-fixed paraffin-embedded tissue in all cases and no point mutations were observed. In summary, all poorly differentiated chordomas in this series showed the absence of SMARCB1/INI1 expression, and were reliably distinguished from AT/RTs, clinically by their characteristic primary sites of origin and pathologically by strong nuclear brachyury expression. Our findings reveal a likely role for SMARCB1/INI1 in a subset of chordomas with aggressive features.
View details for DOI 10.1007/s00401-010-0767-x
View details for PubMedID 21057957
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Clinical and Pathological Features of Non-Hodgkin Lymphomas Harboring Concurrent t(14;18) and 8q24 Anomalies
52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH)
AMER SOC HEMATOLOGY. 2010: 1291–92
View details for Web of Science ID 000289662203465
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Will a Peripheral Blood (PB) Sample Yield the Same Diagnostic and Prognostic Cytogenetic Data as the Concomitant Bone Marrow (BM) In Myelodysplasia? An International Study Comparing Cytogenetics and Interphase FISH Using Parallel PB and BM Samples
AMER SOC HEMATOLOGY. 2010: 1204
View details for Web of Science ID 000289662203254
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Monosomal Karyotype (MK) In Older Patients with Acute Myeloid Leukemia (AML) on Eastern Cooperative Oncology Group (ECOG) Therapeutic Trials: Poor Prognostic Impact of MK, but Not Monosomy
AMER SOC HEMATOLOGY. 2010: 256
View details for Web of Science ID 000289662200580
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BCL6 Expression in B-Cell Lymphoblastic Leukemia Correlates Strongly With the t(1;19) Translocation
AMER SOC CLINICAL PATHOLOGY. 2010: 671–72
View details for Web of Science ID 000282013900047
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Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: A diagnostic challenge
AMERICAN JOURNAL OF HEMATOLOGY
2010; 85 (8): 600-606
View details for DOI 10.1002/ajh.21713
View details for PubMedID 20658589
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Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2)
LEUKEMIA RESEARCH
2010; 34 (5): 594-597
Abstract
Immunophenotypic identification of myeloid specific antigens is an important diagnostic tool in the management of patients with acute myeloid leukemia (AML). These antigens allow determination of cell of origin and degree of differentiation of leukemia blasts. AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a relatively rare subtype of AML. The immunophenotypic characteristics of inv(3) AML patients are somewhat limited. We identified 14 new cases of hematological disorders with increased myeloid blasts carrying inv(3)(q21q26.2)/t(3;3)(q21;q26.2). Also, we identified another 13 cases previously published in the literature, where the immunophenotype of inv(3)(q21q26.2) was documented. As a group, patients with AML with inv(3)(q21q26.2) had high levels of early myeloid (CD13, CD33, CD117 and MPO) and uncommitted markers (CD34, HLA-DR and CD56) and a high rate of monosomy 7 in addition to the inv(3)(q21q26.2). Differential karyotype and expression of certain antigens were noted in patients with de novo AML with inv(3)(q21q26.2) vs. those with inv(3)(q21q26.2)-containing blasts.
View details for DOI 10.1016/j.leukres.2009.08.029
View details for Web of Science ID 000276945300009
View details for PubMedID 19781775
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Characterization of D-cyclin proteins in hematolymphoid neoplasms: lack of specificity of cyclin-D2 and D3 expression in lymphoma subtypes
MODERN PATHOLOGY
2010; 23 (3): 420-433
Abstract
D-cyclin proteins play a central role in cell-cycle regulation and are involved in the pathogenesis of lymphomas. In mantle-cell lymphoma, the t(11;14) translocation leads to overexpression of cyclin-D1, in addition to which cyclin-D1-negative mantle-cell lymphoma that overexpress cyclin-D2 or D3 have also been described. Although cyclin-D2 and D3 have been implicated in the prognosis of specific lymphoma subtypes, a thorough characterization of D-cyclin protein expression in human hematolymphoid neoplasia has not been reported. To evaluate the tissue expression patterns of D-cyclins, particularly D2 and D3, in normal and neoplastic hematolymphoid tissues, we optimized the commercially available antibodies for D-cyclins for use on paraffin-embedded tissue and stained tissue microarrays of over 700 patient samples. Our results show that cyclin-D2 and D3 proteins are expressed in many more lymphoma subtypes than cyclin-D1. Cyclin-D1, D2 and D3 were expressed in 100, 22 and 6% of mantle-cell lymphomas and 2, 49 and 20% of diffuse large B-cell lymphomas. Fluorescence in situ hybridization studies confirmed the presence of the CCND1/IGH translocation in the majority of mantle-cell lymphoma, but not in diffuse large B-cell lymphoma that expressed cyclin-D1 protein. In addition, a subset of follicular, marginal zone, lymphoplasmacytic, lymphoblastic, classical Hodgkin, mature T-cell and natural killer cell lymphomas and acute myeloid leukemias also expressed cyclin-D2 and D3. These data support the hypothesis that dysregulation of cell-cycle control by D-cyclins contribute to the pathogenesis of hematolymphoid neoplasia, and suggest a potential role for these proteins in the prognostic and therapeutic aspects of these diseases. For diagnostic purposes, however, the expression of D-cyclin proteins should be interpreted with caution in the subclassification of lymphoma types.
View details for DOI 10.1038/modpathol.2009.173
View details for Web of Science ID 000275108600009
View details for PubMedID 20062012
View details for PubMedCentralID PMC2831151
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Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009; 106 (37): 15720-15725
Abstract
Ectopic expression of transcription factors can reprogram somatic cells to a pluripotent state. However, most of the studies used skin fibroblasts as the starting population for reprogramming, which usually take weeks for expansion from a single biopsy. We show here that induced pluripotent stem (iPS) cells can be generated from adult human adipose stem cells (hASCs) freshly isolated from patients. Furthermore, iPS cells can be readily derived from adult hASCs in a feeder-free condition, thereby eliminating potential variability caused by using feeder cells. hASCs can be safely and readily isolated from adult humans in large quantities without extended time for expansion, are easy to maintain in culture, and therefore represent an ideal autologous source of cells for generating individual-specific iPS cells.
View details for DOI 10.1073/pnas.0908450106
View details for Web of Science ID 000269806600040
View details for PubMedID 19805220
View details for PubMedCentralID PMC2739869
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Complete remission of primary plasma cell leukemia with bortezomib, doxorubicin, and dexamethasone: a case report.
Cases journal
2009; 2 (1): 121-?
Abstract
Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder considered to be a variant of multiple myeloma. It is an aggressive disease with a poor clinical response to standard chemotherapeutic agents.A novel regimen consisting of bortezomib, doxorubicin, and dexamethasone is currently under active evaluation for the treatment of multiple myeloma. We employed this combination as front-line chemoinduction therapy for a case of primary PCL.Complete remission was achieved with rapid normalization of hematologic parameters. The combination of bortezomib, doxorubicin and dexamethasone demonstrates promise in the treatment of PCL.
View details for DOI 10.1186/1757-1626-2-121
View details for PubMedID 19192311
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Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen
BLOOD
2008; 112 (3): 903-909
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only known curative modality for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). Sixty-seven patients with HLA-matched sibling donors received fractionated total body irradiation (FTBI) and high-dose VP16, whereas 11 patients received FTBI/VP16/cyclophosphamide, and 1 patient received FTBI/VP16/busulfan. The median age was 36 years. At the time of HCT, 49 patients (62%) were in first complete remission (CR1) and 30 patients (38%) were beyond CR1 (> CR1). The median follow-up was 75 months (range, 14-245 months). The 10-year overall survival for the CR1 and beyond CR1 patients was 54% and 29% (P = .01), respectively, and event-free survival was 48% and 26% (P = .02), respectively. There was no significant difference in relapse incidence (28% vs 41%, P = .28), but nonrelapse mortality was significantly higher in the beyond CR1 patients, (31% vs 54%, P = .03, respectively). By univariate analysis, factors affecting event-free and overall survival were white blood cell count at diagnosis (< 30 x 10(9)/L vs > 30 x 10(9)/L) and disease status (CR1 vs > CR1). The median time to relapse for CR1 and for beyond CR1 patients was 12 months and 9 months, respectively. Our results indicate that FTBI/VP16 with or without cyclophosphamide confers long-term survival in Ph(+) ALL patients and that disease status at the time of HCT is an important predictor of outcome.
View details for DOI 10.1182/blood-2008-03-143115
View details for PubMedID 18519812
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Chromosomal aberrations in a case of synchronous extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type and bronchogenic adenocarcinoma
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
2008; 16 (3): 296-300
Abstract
We present the chromosomal aberrations in a case of synchronous extranodal marginal zone B-cell lymphoma and bronchogenic adenocarcinoma with bronchioloalveolar features. Using fluorescence in situ hybridization, we identified deletion of the immunoglobulin heavy chain gene in the lymphomatous component, but not the carcinomatous component. The presence of differing genetic compositions suggests a biclonal environment composed of 2 distinct neoplastic processes.
View details for PubMedID 18301237
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Gliosarcoma with melanocytic differentiation
ACTA NEUROPATHOLOGICA
2008; 115 (3): 357-361
Abstract
We present an unusual case of gliosarcoma containing numerous islands of well-differentiated melanocytes in a 65 year-old man. Melanocytic differentiation of medulloblastomas is well described, and it has also rarely been reported in low-grade glial neoplasms. Histologic features and immunophenotyping are helpful in differentiating divergent differentiation in a gliosarcoma from melanoma. To our knowledge, this is the first description of a gliosarcoma with melanocytic differentiation. Awareness of the phenomenon of melanocytic differentiation within primary neuroepithelial and glial neoplasms is important to prevent the misdiagnosis of these tumors such as metastatic melanoma or primary melanocytic neoplasms of the CNS.
View details for DOI 10.1007/s00401-007-0232-7
View details for Web of Science ID 000253346000009
View details for PubMedID 17641902
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LONG TERM REMISSION IN PHILADELPHIA-POSITIVE ACUTE LYMPHO-BLASTIC LEUKEMIA (Ph plus ALL) PATIENTS AFTER ALLOGENEIC MYELOABLATIVE HEMATOPOIETIC CELL TRANSPLANTATION (HCT) USING MATCHED RELATED DONORS: THE 20 YEAR EXPERIENCE AT STANFORD UNIVERSITY AND CITY OF HOPE NATIONAL MEDICAL CENTER
ELSEVIER SCIENCE INC. 2008: 57–58
View details for DOI 10.1016/j.bbmt.2007.12.161
View details for Web of Science ID 000260330100153
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Fetus-in-Fetu: Twinning or highly-differentiated teratoma?
Western Regional Meeting of the American-Federation-for-Medical-Research
LIPPINCOTT WILLIAMS & WILKINS. 2008: 195–95
View details for Web of Science ID 000252793300287
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Fetus in fetu: An unusual case
40th Biennial American Cytogenetics Conference
KARGER. 2008
View details for Web of Science ID 000256880200066
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Array-based comparative genomic hybridization: clinical contexts for targeted and whole-genome designs
GENETICS IN MEDICINE
2007; 9 (9): 553-559
Abstract
Array-based comparative genomic hybridization is ushering in a new standard for analyzing the genome, overcoming the limits of resolution associated with conventional G-banded karyotyping. The first genomic arrays were based on bacterial artificial chromosome clones mapped during the initial phases of the Human Genome Project. These arrays essentially represented multiple fluorescence in situ hybridization assays performed simultaneously. The first arrays featured a targeted design, consisting of hundreds of bacterial artificial chromosome clones limited mostly to genomic regions of known medical significance. Then came whole-genome arrays, which contained bacterial artificial chromosome clones from across the entire genome. More recently, alternative designs based on oligonucleotide probes have been developed, and all these are high-density whole-genome arrays with resolutions between 3 and 35 kb. Certain clinical circumstances are well suited for investigation by targeted arrays, and there are others in which high-resolution whole-genome arrays are necessary. Here we review the differences between the two types of arrays and the clinical contexts for which they are best suited. As array-based comparative genomic hybridization is integrated into diagnostic laboratories and different array designs are used in appropriate clinical contexts, this novel technology will invariably alter the testing paradigm in medical genetics and will lead to the discovery of novel genetic conditions caused by chromosomal anomalies.
View details for DOI 10.1097/GIM.0b013e318149e354
View details for Web of Science ID 000249640800001
View details for PubMedID 17873642
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Whole-genome array-CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2007; 143A (13): 1431-1441
Abstract
Cytogenetic imbalances are the most frequently identified cause of developmental delay or mental retardation, which affect 1-3% of children and are often seen in conjunction with growth retardation, dysmorphic features, and various congenital anomalies. A substantial number of patients with developmental delay or mental retardation are predicted to have cytogenetic imbalances, but conventional methods for identifying these imbalances yield positive results in only a small fraction of these patients. We used microarray-based comparative genomic hybridization (aCGH) to study a panel of 20 patients predicted to have chromosomal aberrations based on clinical presentation of developmental delay or mental retardation, growth delay, dysmorphic features, and/or congenital anomalies. Previous G-banded karyotypes and fluorescence in situ hybridization results were normal for all of these patients. Using both oligonucleotide-based and bacterial artificial chromosome (BAC)-based arrays on the same panel of patients, we identified 10 unique deletions and duplications ranging in size from 280 kb to 8.3 Mb. The whole-genome oligonucleotide arrays identified nearly twice as many imbalances as did the lower-resolution whole-genome BAC arrays. This has implications for using aCGH in a clinical setting. Analysis of parental DNA samples indicated that most of the imbalances had occurred de novo. Moreover, seven of the 10 imbalances represented novel disorders, adding to an increasing number of conditions caused by large-scale deletions or duplications. These results underscore the strength of high-resolution genomic arrays in diagnosing cases of unknown genetic etiology and suggest that contiguous genomic alterations are the underlying pathogenic cause of a significant number of cases of developmental delay.
View details for DOI 10.1002/ajmg.a.31773
View details for Web of Science ID 000247760600005
View details for PubMedID 17568414
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Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia
FERRATA STORTI FOUNDATION. 2007: 139
View details for Web of Science ID 000247176900383
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Utility of interphase FISH to stratify patients into cytogenetic risk categories at diagnosis of AML in an Eastern Cooperative Oncology Group (ECOG) clinical trial (E1900)
LEUKEMIA RESEARCH
2007; 31 (5): 605-609
Abstract
We evaluated the efficacy of FISH to detect chromosome anomalies in the evaluation of young (<60 years) patients with AML. Patients were enrolled in E1900, an ECOG clinical trial for AML. The protocol was designed to collect bone marrow or blood for both cytogenetic and FISH studies at study entry (diagnosis). FISH for each patient was performed and utilized eight probe sets to detect t(8;21), t(9;22), t(11;var), t(15;17), inv(16), +8, -5/5q, and -7/7q. We analyzed 237 specimens with complete cytogenetic and FISH results. Results for each specimen were classified by probe set into one of six categories. The concordance rate between cytogenetic and FISH results ranged from 98 to 100% for all probe sets and kappa analysis for concordance had a p-value of <0.0001. The high level of agreement between cytogenetic and FISH results demonstrate the accuracy of a panel of eight FISH probe sets for the detection of significant abnormalities in AML. Data from this investigation support the use of FISH as an adjunct method to increase the yield of useful cytogenetic results in large cooperative trials and demonstrate the potential of FISH as a follow-up study of minimal residual disease in ECOG trials.
View details for DOI 10.1016/j.leukres.2006.07.026
View details for Web of Science ID 000246672000005
View details for PubMedID 16996130
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Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial
BLOOD
2007; 109 (8): 3189-3197
Abstract
Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.
View details for DOI 10.1182/blood-2006-10-051912
View details for Web of Science ID 000245658500020
View details for PubMedID 17170120
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Karyotype is an independent prognostic factor in adult acute lymphoblastic leukaemia
BLACKWELL PUBLISHING. 2007: 1
View details for Web of Science ID 000246902100002
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Duplication 22q11.2: Clinically heterogeneous new syndrome or genetic polymorphism?
B C DECKER INC. 2007: S125–S126
View details for DOI 10.1097/00042871-200701010-00309
View details for Web of Science ID 000247692400311
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A case of concurrent relapsed ALL and secondary AML
39th Biennial American Cytogenetics Conference
KARGER. 2007
View details for Web of Science ID 000245885400016
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Novel cytogenetic alterations detected by array CGH in patients with developmental delay, dysmorphology, and mental retardation
KARGER. 2007
View details for Web of Science ID 000245885400029
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Molecular analysis of chromosomal rearrangements in mammalian cells after phi C31-mediated integration
HUMAN GENE THERAPY
2006; 17 (11): 1077-1094
Abstract
Reports on insertional mutagenesis due to integration of gene therapy vectors into the host genome have raised concerns about the genetic manipulation of somatic cells. Previously, it was demonstrated that integrase phiC31 derived from a Streptomyces phage mediates site-specific integration into the host genome of mammalian cells in vitro and in vivo by recombining the attB recognition site in an episomal plasmid and one or more pseudoattP sites in the host chromosomes. In the present study we investigated whether cryptic phiC31 recognition sites in the host genome may result in chromosomal rearrangements. Of 69 independent integration events analyzed in human cells, 6 (8.7%) integrated into human chromosome 19 (19q13.31) and 10 (14.49%) integrated into human chromosome 12 (12q22). Most importantly, of all integration sites analyzed, 15% were found to contain an integrated transgene that was flanked by DNA sequences originating from two different chromosomes. To confirm chromosomal translocations we performed a polymerase chain reaction analysis of chromosomal DNA flanking the transgene and also performed limited studies to determine the genotype of single-cell clones. Although the mechanism responsible for chromosomal translocations needs to be further characterized, we speculate that cryptic phiC31 attachment sites flanking the transgene and cryptic phiC31 attachment sites in the host genome recombine with each other.
View details for Web of Science ID 000242211300003
View details for PubMedID 17069535
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Evaluation of Her-2/neu status in carcinomas with amplified chromosome 17 centromere locus
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
2006; 126 (5): 709-716
Abstract
Accurate assessment of Her-2/neu (erb-b2) status in breast carcinoma is essential for therapy planning. Clinical assays are targeted at protein overexpression (immunohistochemical analysis) or gene amplification (fluorescence in situ hybridization [FISH]). Cases with aberrant FISH signal patterns are problematic and may lead to underreporting of Her-2/neu amplification. We performed FISH with additional chromosome 17 probes, SMS (Smith-Magenis syndrome critical region) and RARA (retinoic acid receptor), on 7 cases with unusual Her-2/CEP17 (chromosome 17 centromere control probe) results to assess whether different measurements of chromosome 17 copy number might clarify the Her-2/neu amplicon status. Although the Her-2/CEP17 ratio scores were within normal range (<2.0), the Her-2/SMS or Her-2/RARA ratio revealed amplification of Her-2/neu in 5 of 7 cases. Immunohistochemical analysis demonstrated Her-2/neu protein overexpression in the same 5 cases only. We describe novel application of SMS/RARA FISH probes for assessing cases with complex Her-2/CEP17 FISH patterns. Such additional data, correlated with immunohistochemical analysis, may help guide therapy in patients with breast carcinoma.
View details for DOI 10.1309/9EYM6VE58F2YCD9F
View details for PubMedID 17050068
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Identification of novel RUNXI (AMLI) translocation partner genes SH3D19, YTHDF2, and ZNF687 in acute myeloid leukemia
GENES CHROMOSOMES & CANCER
2006; 45 (10): 918-932
Abstract
Three patients diagnosed with acute myeloid leukemia (AML) with reciprocal 21q22/RUNX1(AML1) translocations involving chromosomes 1 and 4 were studied. Three novel RUNX1 translocation partner genes on 1q21.2 (ZNF687), 1p35 (YTHDF2), and 4q31.3 (SH3D19) were identified using a panhandle polymerase chain reaction and the 3' rapid amplification of cDNA ends method. The translocation events occurred between exons 3 and 7 of the RUNX1 gene. The partner gene breakpoints localized to the region in the partner gene with the highest Alu density, suggesting that Alus may contribute to the recombination events. Two out of three of the cases retained RUNX1's entire RUNT domain in the translocation, and RUNX1 mutations were absent in the fusion transcripts, confirmed by reverse transcription-polymerase chain reaction and sequencing analysis. SH3D19 encodes a cytoplasmic protein EBP known to suppress RAS-induced cellular transformation, which can be inhibited by nuclear recruitment. The t(4;21) created a hybrid RUNX1-EBP protein retaining RUNX1's DNA binding domain, which may result in nuclear localization of the chimeric protein and inhibition of EBP's RAS-suppressive functions. Future studies would be useful to further characterize these novel fusion protein products.
View details for DOI 10.1002/gcc.20355
View details for PubMedID 16858696
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Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells
CELL CYCLE
2006; 5 (14): 1569-1573
Abstract
The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that controls the cell cycle by directing the ubiquitin-dependent proteolysis of S-phase and mitosis promoting factors. Emi1 is an E2F transcriptional target that drives cell cycle progression from G1/S through early mitosis by inhibiting the APC/C's ubiquitin ligase activity, and thus facilitates accumulation of APC/C substrates. Using cell culture model systems, we found that Emi1 overexpression leads to proliferation, tetraploidy and genome instability of cells deficient for p53. We propose that loss of pRb repression of E2F-mediated transcription causing misregulation of Emi1 and APC/C substrates results in the generation of tetraploidy and proliferation of genomically unstable cells in the absence of normal p53 function. This represents a potentially important mechanism by which pRb and p53 dysfunction may contribute to tumorigenesis through the generation of genomic instability.
View details for Web of Science ID 000240697800017
View details for PubMedID 16861914
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Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization.
American journal of medical genetics. Part A
2006; 140 (12): 1267-1273
Abstract
In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.
View details for PubMedID 16691576
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Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2006; 140A (12): 1267-1273
Abstract
In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.
View details for DOI 10.1002/ajmg.a.31262
View details for Web of Science ID 000237990400003
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Chromosomal Rearrangements in Mammalian Cells Are Induced at High Frequency by the Bacteriophage Derived Integrase phiC31
NATURE PUBLISHING GROUP. 2006: S148
View details for DOI 10.1016/j.ymthe.2006.08.449
View details for Web of Science ID 000208933501312
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CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1
SCIENCE
2006; 312 (5771): 269-272
Abstract
Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture (3C) and fluorescence in situ hybridization, we found that one allele of the insulin-like growth factor 2 (Igf2)/H19 imprinting control region (ICR) on chromosome 7 colocalized with one allele of Wsb1/Nf1 on chromosome 11. Omission of CCCTC-binding factor (CTCF) or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. These findings demonstrate that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provide a model for long-range allele-specific associations between gene regions on different chromosomes that suggest a framework for DNA recombination and RNA trans-splicing.
View details for DOI 10.1126/science.1123191
View details for PubMedID 16614224
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Triplication of 8p22-8p23 in a patient with features similar to Kabuki syndrome.
American journal of medical genetics. Part A
2006; 140 (2): 170-173
Abstract
Kabuki syndrome (KS) comprises multiple congenital anomalies and distinctive facial appearance. Although a number of chromosome abnormalities have been described in patients with KS-like phenotypes, no consensus has been reached regarding the genetic basis underlying the classic Kabuki phenotype. A recent study reported on 8p22-8p23.1 duplication in patients diagnosed with KS; however, a number of other studies have not found this duplication in patients with classic KS. We report on a girl with triplication of 8p22-8p23 who has mental retardation and some features suggestive of KS, including growth retardation, left-sided obstructive heart lesion, long-appearing palpebral fissures, hypertelorism, sparse lateral eyebrows, prominent ears, and persistent fetal fingertip pads. She does not have the typical facial gestalt of KS, nor does she have other more specific findings of KS. We propose that abnormal copy number of genes in the 8p22-8p23 region results in a syndrome of multiple congenital anomalies with many features that overlap with classic KS. However, data from this patient and others with similar duplications in the literature suggest that duplication or triplication of 8p22-8p23 represents a recognizable pattern of malformation distinct from classic KS. The exact genetic abnormality underlying KS currently remains unknown.
View details for PubMedID 16353235
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Triplication of 8p22-8p23 in a patient with features similar to Kabuki syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2006; 140A (2): 170-173
Abstract
Kabuki syndrome (KS) comprises multiple congenital anomalies and distinctive facial appearance. Although a number of chromosome abnormalities have been described in patients with KS-like phenotypes, no consensus has been reached regarding the genetic basis underlying the classic Kabuki phenotype. A recent study reported on 8p22-8p23.1 duplication in patients diagnosed with KS; however, a number of other studies have not found this duplication in patients with classic KS. We report on a girl with triplication of 8p22-8p23 who has mental retardation and some features suggestive of KS, including growth retardation, left-sided obstructive heart lesion, long-appearing palpebral fissures, hypertelorism, sparse lateral eyebrows, prominent ears, and persistent fetal fingertip pads. She does not have the typical facial gestalt of KS, nor does she have other more specific findings of KS. We propose that abnormal copy number of genes in the 8p22-8p23 region results in a syndrome of multiple congenital anomalies with many features that overlap with classic KS. However, data from this patient and others with similar duplications in the literature suggest that duplication or triplication of 8p22-8p23 represents a recognizable pattern of malformation distinct from classic KS. The exact genetic abnormality underlying KS currently remains unknown.
View details for DOI 10.1002/ajmg.a.31036
View details for Web of Science ID 000234491600012
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Identification of novel RUNX1 (AML1) translocation partner genes in acute myeloid leukemia
95th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology
NATURE PUBLISHING GROUP. 2006: 240A–240A
View details for Web of Science ID 000234207601546
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Nablus mask-like facial syndrome is caused by deletion in 8q21-8q22 detected by array-based comparative genomic hybridiztion.
B C DECKER INC. 2006: S138
View details for Web of Science ID 000235301500352
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Identification of novel RUNX1 (AML1) translocation partner genes in acute myeloid leukemia
NATURE PUBLISHING GROUP. 2006: 240A
View details for Web of Science ID 000234094502055
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Fluorescence in situ hybridization investigation of cutaneous lesions in acute promyelocytic leukemia
MODERN PATHOLOGY
2005; 18 (12): 1569-1576
Abstract
Cutaneous manifestations of acute promyelocytic leukemia are rare but well documented. Skin biopsies of leukemia can be difficult to confirm using morphology alone, and paraffin section immunophenotyping is not specific in separating acute promyelocytic leukemia from other acute myeloid leukemias involving the skin or inflammatory conditions, such as Sweet's syndrome and all-trans retinoic acid-associated genital ulcers, which may mimic leukemia cutis. Fluorescence in situ hybridization has been shown to be a fast and effective method of detecting the PML/RARA fusion gene characteristic of acute promyelocytic leukemia in fresh blood and bone marrow samples. Fluorescence in situ hybridization has also been demonstrated to be effective in detecting other chromosomal rearrangements in paraffin-embedded tissue. This retrospective study of cutaneous lesions from four patients with acute promyelocytic leukemia evaluates the utility of performing fluorescence in situ hybridization to confirm the presence of cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed, paraffin-embedded skin biopsies. All patients had previous bone marrow findings of acute promyelocytic leukemia with characteristic morphology, immunophenotype, and cytogenetic studies, which detailed the presence of the t(15;17)(q22;q12) rearrangement. Two skin biopsies showed an infiltrate of blastic cells involving the dermis in a diffuse pattern and one biopsy had a perivascular/periadnexal pattern. The fourth case, involving the scrotum, showed a predominant neutrophilic infiltrate diffusely involving the dermis and epidermis with a subset of blastic cells. Nuclei were extracted from core biopsies of the formalin-fixed paraffin-embedded tissue and fluorescence in situ hybridization was performed using a dual color, dual fusion PML / RARA probe. All cases showed evidence of the t(15;17) rearrangement, with 90, 79, 51 and 16% positive signal patterns, each well above background limits. Fluorescence in situ hybridization appears to be a robust technique to detect cutaneous manifestations of acute promyelocytic leukemia in formalin-fixed paraffin-embedded skin biopsies.
View details for DOI 10.1038/modpathol.3800465
View details for PubMedID 16056248
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Utility of interphase FISH to stratify patients into cytogenetic risk categories at diagnosis of AML in an ECOG clinical trial (E1900).
AMER SOC HEMATOLOGY. 2005: 669A
View details for Web of Science ID 000233426004224
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Cytologic diagnosis of Burkitt lymphoma.
Cancer
2005; 105 (5): 310-318
Abstract
The diagnosis and classification of lymphoma require correlation of morphologic, immunophenotypic, and molecular-cytogenetic studies. Fine-needle aspiration biopsy (FNAB) is a valuable diagnostic technique that allows material to be collected for these ancillary studies, and for morphologic evaluation.The authors report a series of seven cases clinically or morphologically suspicious for Burkitt lymphoma. Fluorescence in situ hybridization studies (FISH) for c-myc were performed on FNAB material and correlated with cytologic and immunophenotypic data.Six of seven specimens were positive for c-myc rearrangement by FISH. However, only three of these cases represented Burkitt lymphoma, with one additional case of atypical Burkitt lymphoma. The other cases included diffuse large B-cell lymphoma, monomorphic posttransplant B-cell lymphoma, and an aggressive B-cell lymphoma, with the latter case negative for c-myc rearrangement by FISH. Of 2 non-Burkitt lymphoma specimens tested, 1 was positive for the immunoglobulin H/bcl-2 rearrangement, in addition to the c-myc rearrangement, suggesting transformation from a lower grade lymphoma.These cases illustrated the value of FNAB in the diagnosis of Burkitt lymphoma, as well as the importance of obtaining material for, and integrating results of, ancillary studies for the final diagnosis.
View details for PubMedID 15986398
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Cytologic diagnosis of Burkitt lymphoma - Role of ancillary studies
94th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology
JOHN WILEY & SONS INC. 2005: 310–18
Abstract
The diagnosis and classification of lymphoma require correlation of morphologic, immunophenotypic, and molecular-cytogenetic studies. Fine-needle aspiration biopsy (FNAB) is a valuable diagnostic technique that allows material to be collected for these ancillary studies, and for morphologic evaluation.The authors report a series of seven cases clinically or morphologically suspicious for Burkitt lymphoma. Fluorescence in situ hybridization studies (FISH) for c-myc were performed on FNAB material and correlated with cytologic and immunophenotypic data.Six of seven specimens were positive for c-myc rearrangement by FISH. However, only three of these cases represented Burkitt lymphoma, with one additional case of atypical Burkitt lymphoma. The other cases included diffuse large B-cell lymphoma, monomorphic posttransplant B-cell lymphoma, and an aggressive B-cell lymphoma, with the latter case negative for c-myc rearrangement by FISH. Of 2 non-Burkitt lymphoma specimens tested, 1 was positive for the immunoglobulin H/bcl-2 rearrangement, in addition to the c-myc rearrangement, suggesting transformation from a lower grade lymphoma.These cases illustrated the value of FNAB in the diagnosis of Burkitt lymphoma, as well as the importance of obtaining material for, and integrating results of, ancillary studies for the final diagnosis.
View details for DOI 10.1002/cncr.21307
View details for Web of Science ID 000232474300009
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A report of three patients with an interstitial deletion of chromosome 15q24.
American journal of medical genetics. Part A
2005; 137 (1): 65-71
Abstract
Partial monosomy of the q2 region of chromosome 15 has been infrequently reported. Moreover, interstitial deletions involving 15q22-q24 have been described in only nine patients to date. The phenotype of these reported individuals is subject to the extent of the deletion but typically includes altered muscle tone and significant developmental delays. In addition, eye abnormalities, such as strabismus, microphthalmia, or colobomas, ear abnormalities including cleft earlobe and preauricular tags, and urogenital defects are common features. Congenital heart defects, diaphragmatic hernia, abnormalities of the central nervous system, and skeletal anomalies have been reported but appear to be less frequent clinical manifestations. In this report, we describe three new patients with interstitial deletions involving 15q24, two with cryptic deletions identified by fluorescence in situ hybridization (FISH) with a probe for the PML gene and one with a cytogenetically visible deletion of 15q22.3-q24. The clinical presentation of these individuals is similar to those previously described and includes global developmental delays, hypotonia, and genital abnormalities in the males. The identification of these three cases demonstrates that the above clinical features are associated with a new cytogenetic deletion syndrome. Furthermore, we suggest that FISH analysis with a probe for the PML gene be performed in patients with these physical findings.
View details for PubMedID 16007617
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A report of three patients with an interstitial deletion of chromosome 15q24
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2005; 137A (1): 65-71
Abstract
Partial monosomy of the q2 region of chromosome 15 has been infrequently reported. Moreover, interstitial deletions involving 15q22-q24 have been described in only nine patients to date. The phenotype of these reported individuals is subject to the extent of the deletion but typically includes altered muscle tone and significant developmental delays. In addition, eye abnormalities, such as strabismus, microphthalmia, or colobomas, ear abnormalities including cleft earlobe and preauricular tags, and urogenital defects are common features. Congenital heart defects, diaphragmatic hernia, abnormalities of the central nervous system, and skeletal anomalies have been reported but appear to be less frequent clinical manifestations. In this report, we describe three new patients with interstitial deletions involving 15q24, two with cryptic deletions identified by fluorescence in situ hybridization (FISH) with a probe for the PML gene and one with a cytogenetically visible deletion of 15q22.3-q24. The clinical presentation of these individuals is similar to those previously described and includes global developmental delays, hypotonia, and genital abnormalities in the males. The identification of these three cases demonstrates that the above clinical features are associated with a new cytogenetic deletion syndrome. Furthermore, we suggest that FISH analysis with a probe for the PML gene be performed in patients with these physical findings.
View details for DOI 10.1002/ajmg.a.30836
View details for Web of Science ID 000231009900012
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Low-grade B-cell lymphomas with plasmacytic differentiation lack PAX5 gene rearrangements
JOURNAL OF MOLECULAR DIAGNOSTICS
2005; 7 (3): 346-351
Abstract
The chromosomal translocation t(9;14)(p13;q32) has been reported in association with lymphoplasmacytic lymphoma (LPL). Although this translocation involving the paired homeobox-5 (PAX5) gene at chromosome band 9p13 and the immunoglobulin heavy chain (IgH) gene at 14q32 has been described in approximately 50% of LPL cases, the actual number of cases studied is quite small. Many of the initial cases associated with t(9;14)(p13;q32) were actually low-grade B-cell lymphomas with plasmacytic differentiation other than LPL. Thus, we analyzed a series of low-grade B-cell lymphomas for PAX5 gene rearrangements. We searched records from the Department of Pathology, Stanford University Medical Center for low-grade B-cell lymphomas, with an emphasis on plasmacytic differentiation, that had available paraffin blocks or frozen tissue. We identified 37 cases, including 13 LPL, 18 marginal zone lymphomas (nodal, extranodal, splenic, and alpha-heavy chain disease), and 6 small lymphocytic lymphomas. A novel dual-color break-apart bacterial artificial chromosome probe was designed to flank the PAX5 gene, spanning previously described PAX5 breakpoints, and samples were analyzed by interphase fluorescence in situ hybridization. All cases failed to demonstrate a PAX5 translocation, indicating that t(9;14)(p13;q32) and other PAX5 translocations are uncommon events in low-grade B-cell lymphomas with plasmacytic differentiation. This study also confirms recent reports that found an absence of PAX5 rearrangements in LPL, suggesting the reassessment of PAX5 rearrangements in LPL.
View details for PubMedID 16049306
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Terminal deletion of 6p results in a recognizable phenotype.
American journal of medical genetics. Part A
2005; 136 (2): 162-168
Abstract
With improved cytogenetic techniques, small deletions and duplications are being identified with increased frequency. We report four cases with terminal deletions involving the 6p24- and 6p25-pter chromosomal segment who exhibit a distinct, recognizable pattern of malformations including hypertelorism, downslanting palpebral fissures, flat nasal bridge, Dandy-Walker malformation/variant, congenital heart defects, anterior eye-chamber abnormalities, hearing loss, and developmental delay. We also compare the clinical aspects of these patients to those of previously reported cases in the literature with similar terminal deletions of chromosome 6p. Routine chromosome analysis can miss this deletion, therefore, high-resolution chromosome analysis is indicated for individuals who exhibit these distinct features. Furthermore, individuals with this deletion should have an ophthalmologic exam, cardiac evaluation, head imaging, renal ultrasound, and formal hearing evaluation.
View details for PubMedID 15940702
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Terminal deletion of 6p results in a recognizable phenotype
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2005; 136A (2): 162-168
Abstract
With improved cytogenetic techniques, small deletions and duplications are being identified with increased frequency. We report four cases with terminal deletions involving the 6p24- and 6p25-pter chromosomal segment who exhibit a distinct, recognizable pattern of malformations including hypertelorism, downslanting palpebral fissures, flat nasal bridge, Dandy-Walker malformation/variant, congenital heart defects, anterior eye-chamber abnormalities, hearing loss, and developmental delay. We also compare the clinical aspects of these patients to those of previously reported cases in the literature with similar terminal deletions of chromosome 6p. Routine chromosome analysis can miss this deletion, therefore, high-resolution chromosome analysis is indicated for individuals who exhibit these distinct features. Furthermore, individuals with this deletion should have an ophthalmologic exam, cardiac evaluation, head imaging, renal ultrasound, and formal hearing evaluation.
View details for DOI 10.1002/ajmg.a.30784
View details for Web of Science ID 000230229100009
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Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: Case report and review of the literature
PEDIATRIC BLOOD & CANCER
2005; 44 (3): 270-276
Abstract
Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplantation. The vast majority of PTLD are Epstein-Barr virus (EBV)-related infections that manifest as B-cell malignancies. We report an unusual case of an EBV-associated T-cell lymphoma in a 10-year-old boy who had previously undergone liver transplantation at age 4 years. He presented with hemophagocytic syndrome (HPS) and active EBV infection, with positive serum titers and polymerase chain reaction (PCR) for EBV in blood, colon, and antral samples.
View details for DOI 10.1002/pbc.20231
View details for PubMedID 15468305
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Fluorescence in-situ hybridization confirmation of cutaneous acute promyelocytic leukemia
NATURE PUBLISHING GROUP. 2005: 88A
View details for Web of Science ID 000226117900397
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Primary CNS low-grade B-cell lymphoma: A case series with FISH analysis
NATURE PUBLISHING GROUP. 2005: 239A
View details for Web of Science ID 000226117901263
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Fluorescence in-situ hybridization confirmation of cutaneous acute promyelocytic leukemia
NATURE PUBLISHING GROUP. 2005: 88A
View details for Web of Science ID 000226238600397
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Cytologic diagnosis of Burkitt lymphoma
NATURE PUBLISHING GROUP. 2005: 79A
View details for Web of Science ID 000226238600354
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Cytologic diagnosis of Burkitt lymphoma
NATURE PUBLISHING GROUP. 2005: 79A
View details for Web of Science ID 000226117900354
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Primary CNS low-grade B-cell lymphoma: A case series with FISH analysis
NATURE PUBLISHING GROUP. 2005: 239A
View details for Web of Science ID 000226238601283
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Mild developmental delay in terminal chromosome 6p deletion
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2004; 129A (2): 201-205
Abstract
Deletions involving the short arm of chromosome 6 are relatively rare. Although features of this condition are variable, common findings include developmental delay, ocular abnormalities, hearing loss, and cardiac defects. In an effort to define further the clinical variability of this condition, we report a 6-year-old female with a de novo terminal deletion of chromosome 6 at band 6p24, with mild gross motor delays and normal cognition.
View details for DOI 10.1002/ajmg.a.30127
View details for PubMedID 15316977
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Terminal 22q deletion syndrome: A newly recognized cause of speech and language disability in the autism spectrum
PEDIATRICS
2004; 114 (2): 451-457
Abstract
Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.
View details for PubMedID 15286229
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Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an Eastern Cooperative Oncology Group (ECOG) study
LEUKEMIA RESEARCH
2003; 27 (12): 1085-1090
Abstract
Cytogenetic analysis can be important in determining the prognosis and diagnosis of a number of hematological disorders, including myelodysplastic syndromes (MDS). Here, we compared metaphase chromosomal analyses on bone marrow aspirates from MDS patients with interphase fluorescence in situ hybridization (FISH) using probes specific for chromosomes nos. 5, 7, 8, 11, 13 and 20. Forty-three patients enrolled in ECOG protocol E1996 for low risk MDS and five patients enrolled in ECOG protocol E3996 for high risk MDS were studied by both metaphase chromosomal analysis and interphase FISH. Excluding those with a clonal loss of the Y chromosome, an abnormal clone was detected by cytogenetic analysis in 18 of 48 samples (37.5%). In comparison, our FISH panel detected an abnormal clone in 17 of 48 samples (35.4%). Twenty-nine of 30 samples with apparently normal karyotypes, including those with a missing Y chromosome, were also normal by our FISH panel. One patient had an occult deletion of chromosome 11 that was detected by FISH. These results indicate that around 60% of patients with MDS do not have abnormalities that are detectable by either chromosomal or FISH studies. In addition, it appears that interphase FISH studies are nearly as sensitive as cytogenetic analyses and can be a useful tool in studying bone marrow aspirates where cytogenetic analysis is not possible.
View details for DOI 10.1016/S0145-2126(03)00104-8
View details for Web of Science ID 000185431400004
View details for PubMedID 12921944
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ATR-16 syndrome: Further delineation of the phenotype.
UNIV CHICAGO PRESS. 2003: 277
View details for Web of Science ID 000185599700631
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Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2003; 100 (17): 9974-9979
Abstract
DNA repair mechanisms are essential for the maintenance of genomic integrity. Disruption of gene products responsible for DNA repair can result in chromosomal damage. Improperly repaired chromosomal damage can result in the loss of chromosomes or the generation of chromosomal deletions or translocations, which can lead to tumorigenesis. The MYC protooncogene is a transcription factor whose overexpression is frequently associated with human neoplasia. MYC has not been previously implicated in a role in DNA repair. Here we report that the overexpression of MYC disrupts the repair of double-strand DNA breaks, resulting in a several-magnitude increase in chromosomal breaks and translocations. We found that MYC inhibited the repair of gamma irradiation DNA breaks in normal human cells and blocked the repair of a single double-strand break engineered to occur in an immortal cell line. By spectral karyotypic analysis, we found that MYC even within one cell division cycle resulted in a several-magnitude increase in the frequency of chromosomal breaks and translocations in normal human cells. Hence, MYC overexpression may be a previously undescribed example of a dominant mutator that may fuel tumorigenesis by inducing chromosomal damage.
View details for DOI 10.1073/pnas.1732638100
View details for PubMedID 12909717
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Preferential expression of a mutant allele of the amplified MDR1 (ABCB1) gene in drug-resistant variants of a human sarcoma
GENES CHROMOSOMES & CANCER
2002; 34 (4): 372-383
Abstract
Activation of the MDR1 (ABCB1) gene is a common event conferring multidrug resistance (MDR) in human cancers. We investigated MDR1 activation in MDR variants of a human sarcoma line, some of which express a mutant MDR1, which facilitated the study of allelic gene expression. Structural alterations of MDR1, gene copy numbers, and allelic expression were analyzed by cytogenetic karyotyping, oligonucleotide hybridization, Southern blotting, polymerase chain reaction, and DNA heteroduplex assays. Both chromosome 7 alterations and several cytogenetic changes involving the 7q21 locus are associated with the development of MDR in these sarcoma cells. Multistep-selected cells and their revertants contain three- to six-fold MDR1 gene amplification compared with that of the drug-sensitive parental cell line MES-SA and single-step doxorubicin-selected mutants. MDR1 gene amplification precedes the emergence of a mutant allele in cells that were coselected with doxorubicin and a cyclosporin inhibitor of P-glycoprotein (P-gp). Allele-specific oligonucleotide hybridization showed that the endogenous mutant allele was present as a single copy, with multiple copies of the normal allele. Reselection of revertant cells with doxorubicin in either the presence or the absence of the P-gp inhibitor resulted in exclusive reexpression of the mutant MDR1 allele, regardless of the presence of multiple wild-type MDR1 alleles. These data provide new insights into how multiple alleles are regulated in the amplicon of drug-resistant cancer cells and indicate that increased expression of an amplified gene can result from selective transcription of a single mutant allele of the gene.
View details for DOI 10.1002/gcc.10067
View details for PubMedID 12112526
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FISHing for answers: the use of molecular cytogenetic techniques in adolescent medicine practice.
Adolescent medicine (Philadelphia, Pa.)
2002; 13 (2): 305-?
Abstract
Chromosomal abnormalities are common causes of a variety of diseases, cancers, and malformation syndromes. Identification of chromosomal aberrations is important for counseling families about prognosis and reproductive risks with future pregnancies. However, limited resolution leads to the inability to detect small deletions, small insertions or duplications, and complex chromosomal rearrangements. Fluorescence-based assays, which have become possible because of sophisticated cloning technologies and improved sensitivity of antibody conjugates, enable the detection of subtle chromosomal changes beyond the resolution of classic cytogenetics. Such techniques have greatly expanded the diagnostic armamentarium available in the investigation of adolescents with mental retardation, malformations and many other disorders.
View details for PubMedID 11986038
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Modified cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone therapy for posttransplantation lymphoproliferative disease in pediatric patients undergoing solid organ transplantation
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2001; 23 (7): 452-455
Abstract
The authors report the use of a cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP)-based chemotherapy regimen in treating six children with posttransplantation lymphoproliferative disorder (PTLD) that developed after solid organ transplantation.The chemotherapy regimen consisted of a 29-day induction with CHOP and then as many as 15 cycles of maintenance therapy using methotrexate and cytarabine alternating with vincristine, adriamycin, mercaptopurine, and prednisone.All patients attained remission. One patient died of sepsis while in remission. Four of the five remaining patients have been followed-up in remission for as long as 8 years without losing the graft. One of the patients experienced relapse after completing therapy and subsequently died with disease.The authors conclude that pediatric patients with PTLD after solid organ transplantation that fails conservative management can be treated successfully with CHOP-based chemotherapy.
View details for Web of Science ID 000171516000011
View details for PubMedID 11878581
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Further delineation of the 7q36 terminal deletion syndrome.
UNIV CHICAGO PRESS. 2001: 289
View details for Web of Science ID 000171648900618
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A unique AML1 (CBF2A) rearrangement, t(1;21)(p32;q22), observed in a patient with acute myelomonocytic leukemia
CANCER GENETICS AND CYTOGENETICS
2001; 129 (2): 155-160
Abstract
The AML1 (CBFA2) gene is the most frequent target of chromosomal rearrangements observed in human acute leukemia. These rearrangements include the commonly reported t(8;21)(q22;q22) or AML1/ETO fusion in AML-M2, the t(3;21)(q26;q22) or AML1 fusion with one of three genes, MDS1, EAP or EVI1, in therapy-related AML and MDS, as well as in blast crisis in CML and the t(12;21)(p13;q22) or TEL/AML1 fusion in B-cell ALL. In addition to the t(3;21), other AML1 translocations have also been reported in therapy-related MDS and AML, particularly after treatment with topoisomerase II inhibitors. AML1 gene rearrangements have also been observed less frequently with numerous other chromosomal partners. Here, we describe a patient with AML-M4 and a previously unreported rearrangement involving the AML1 locus and an unknown locus on the short arm of chromosome 1 at 1p32.
View details for Web of Science ID 000171105500011
View details for PubMedID 11566347
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Natural killer cell precursor acute lymphoma/leukemia presenting in an infant
ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE
2001; 125 (3): 413-418
Abstract
Lymphoma/leukemia derived from immature natural killer (NK) cells occur most commonly in adults and are characterized by blastic cytologic features and an aggressive outcome. Predilection for extranodal sites and absence of the Epstein-Barr virus associated with mature NK cell malignancies further distinguish this entity. We present a NK precursor acute lymphoma presenting with multiple masses in an infant without circulating blasts or marrow replacement by disease. The diagnostic difficulty arose from several factors, including young age, presentation with multiple masses, blastic cytologic features mistaken for a small, round, blue cell tumor, and the absence of lineage-specific markers. The CD56+, CD34+, CD33+, MPO-, cytoplasmic CD3+, CD45-, CD7-, HLA-DR-, and TdT- immunophenotype of this neoplasm overlaps with previously reported cases of myeloid/NK precursor acute leukemia and blastic NK cell lymphoma/leukemia. This case emphasizes the need for a strong index of suspicion to recognize this rare entity and to distinguish it from solid tumors and other hematolymphoid neoplasms that occur in infancy.
View details for Web of Science ID 000167405000023
View details for PubMedID 11231495
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Serial assessment of marrow cytogenetics after autologous transplantation of follicular lymphoma.
AMER SOC HEMATOLOGY. 2000: 406A
View details for Web of Science ID 000165256101749
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Spindle cell lipoma of the foot and the application of CD34 immunohistochemistry to atypical lipomatous tumors in unusual locations
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
2000; 8 (3): 222-227
Abstract
Spindle cell lipoma demonstrates a distinctive histologic appearance and characteristic clinical presentation. We recently observed two cases of solitary subcutaneous neoplasm of the foot with histologic features of spindle cell lipoma that in one case includes a minor component of the overlapping tumor, pleomorphic lipoma. Because the foot is an unusual location for these neoplasms, immunoperoxidase and cytogenetic studies were performed. In both cases, staining was strongly positive for CD34 and negative for smooth muscle actin. Cytogenetic studies from the tumor with a pleomorphic component revealed features consistent with a lipomatous neoplasm, but are otherwise diagnostically nonspecific. An analysis of the literature reveals that although CD34 immunoreactivity is characteristic of spindle cell lipoma and helps exclude nonlipomatous neoplasms, it does not clearly eliminate other well-differentiated lipomatous tumors. Accordingly, without the aid of classic tumor location, the diagnosis of the spindle cell/pleomorphic lipoma group relies primarily on histologic features, with supportive but not definitive information provided by immunoperoxidase and cytogenetic studies. Obscuring this issue, however, are the imprecise histologic distinction between these tumors and those of the atypical lipoma/atypical lipomatous tumor/ well-differentiated liposarcoma group and the nomenclature controversy that surrounds the latter group of neoplasms. Despite these obstacles, both groups of well-differentiated lipomatous tumors are clinically benign when subcutaneously located.
View details for Web of Science ID 000089041100009
View details for PubMedID 10981875
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Blastic/blastoid transformation of follicular lymphoma - Immunohistologic and molecular analyses of five cases
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2000; 24 (4): 525-534
Abstract
Progression of follicular lymphoma to a higher-grade malignancy frequently heralds a poor prognosis. Clinical transformation is variably accompanied by a spectrum of histologic changes characterized by alteration in growth and cytology. Although several cytogenetic events and potential oncogenes have been documented in this progression, the underlying molecular mechanisms are largely unknown. We present five patients with an unusual histologic transformation of follicular lymphoma manifested by blastic/blastoid morphology. This transformation is histologically distinct from other types of transformation of follicular lymphoma. All five cases exhibited the t(14;18) translocation and expressed the BCL-2 protein. In addition, two of the five patients showed increased levels of the p53 protein within neoplastic cells implicating a possible role for this oncogene in blastic/blastoid transformation. The lack of BCL-1 and myeloid antigens by immunohistochemistry and flow cytometry studies served to distinguish blastic/blastoid transformation of follicular lymphoma from its morphologic mimics. This distinction is clinically important because lymphoblastic and myeloid leukemias require significantly different therapeutic modalities and show better prognosis. Moreover, the lack of Epstein-Barr virus-specific mRNA suggests that this virus is unlikely to participate in blastic/blastoid transformation of follicular lymphoma.
View details for Web of Science ID 000086211700006
View details for PubMedID 10757399
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Compound genetic factors as a cause of male infertility
HUMAN REPRODUCTION
2000; 15 (2): 449-451
Abstract
A 40 year old healthy Chinese male with primary infertility was seen in a university male infertility and genetic counselling clinic. He presented with congenital bilateral absence of the vas deferens (CBAVD) and the finding of testis atrophy. Fine needle aspiration mapping of the testis identified and localized sperm production within the testicles for in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Careful evaluation of testicular cytology revealed late maturation arrest of spermatogenesis. Cystic fibrosis gene mutation analysis revealed heterozygosity for the 5T variant within the polypyrimidine tract of intron 8. Cytogenetic analysis revealed a pericentric inversion of chromosome 6 with break points at p12 and q21 [46,XY,inv(6)(p12q21)]. This case illustrates that spermatogenesis is not necessarily normal with congenital bilateral absence of the vas deferens. Compound genetic defects may coexist and underlie male infertility.
View details for Web of Science ID 000085154200035
View details for PubMedID 10655321
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Human endothelial cell life extension by telomerase expression
JOURNAL OF BIOLOGICAL CHEMISTRY
1999; 274 (37): 26141-26148
Abstract
Normal human endothelial cells, like other somatic cells in culture, divide a limited number of times before entering a nondividing state called replicative senescence. Expression of the catalytic component of human telomerase, human telomerase reverse transcriptase (hTERT), extends the life span of human fibroblasts and retinal pigment epithelial cells beyond senescence without causing neoplastic transformation (Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C. P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., and Wright, W. E. (1998) Science 279, 349-352; Jiang, X., Jimenez, G., Chang, E., Frolkis, M., Kusler, B., Sage, M., Beeche, M., Bodnar, A., Wahl, G., Tlsty, T., and Chiu, C.-P. (1999) Nat. Genet. 21, 111-114). Here, we show that both human large vessel and microvascular endothelial cells also bypass replicative senescence after introduction of hTERT. For the first time, we report that hTERT expression in these life-extended vascular cells does not affect their differentiated and functional phenotype and that these cells maintain their angiogenic potential in vitro. Furthermore, hTERT(+) microvascular endothelial cells have normal karyotype, and hTERT(+) endothelial cell strains do not exhibit a transformed phenotype. Relative to parental cells at senescence, hTERT-expressing endothelial cells exhibit resistance to induction of apoptosis by a variety of different conditions. Such characteristics are highly desirable for designing vascular transplantation and gene therapy delivery systems in vivo.
View details for Web of Science ID 000082469700031
View details for PubMedID 10473565
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Telomerase expression affects apoptosis in dermal microvascular endothelial cells
BLACKWELL SCIENCE INC. 1999: 546
View details for Web of Science ID 000079495800162
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Blinded comparison demonstrates that BCL-2 real-time PCR assay provides more sensitive and quantitative assessment of residual disease than nested PCR.
W B SAUNDERS CO. 1998: 238A
View details for Web of Science ID 000077121300966
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Partial trisomy 1q with growth hormone deficiency and normal intelligence
AMERICAN JOURNAL OF MEDICAL GENETICS
1998; 77 (4): 257-260
Abstract
We present two sibs with partial trisomy 1 (q31.1-q32.1) due to a familial insertion. Patient 1 is a girl who presented at age 9 months with minor anomalies, short stature, and normal psychomotor development. Karyotype was 46,XX,der(4)ins(4;1) (p14;q31.1q32.1)pat. The father had a balanced inverted insertion of 1q into 4p, with karyotype 46,XY,ins(4;1)(p14;q31.1q32.1). At age 5 years, patient 1 was found to have short stature with documented growth hormone deficiency and ectopic pituitary. Her growth velocity responded well to treatment with growth hormone. Cognitive testing at 5 9/12 years showed normal intelligence with an IQ of 90. Patient 2, the brother of patient 1, presented with intrauterine growth retardation. He has the same chromosomal insertion as his sister, with partial trisomy 1q. We suggest that there is a recognizable phenotype of trisomy 1(q31.1-q32.1) which includes prenatal and postnatal growth retardation, narrow palpebral fissures, microphthalmia, microstomia, pituitary abnormalities, and normal intelligence in some individuals.
View details for Web of Science ID 000073422100001
View details for PubMedID 9600731
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Complex, variant translocations involving chromosomes 11 and 22 in two Ewing sarcomas: identification by cytogenetics and FISH.
UNIV CHICAGO PRESS. 1997: A362
View details for Web of Science ID 000071446002117