Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 31
Filter
1.
Adv Hematol ; 2022: 1182384, 2022.
Article in English | MEDLINE | ID: mdl-35096069

ABSTRACT

Of the variety of immunoglobulin related amyloidosis (AL), immunoglobulin M (IgM) related AL represents only 6 to 10% of affected patients, and the majority of these cases are associated with underlying non-Hodgkin's Lymphoma including Waldenström's macroglobulinemia (WM). Ibrutinib, acalabrutinib, and zanubrutinib are Bruton tyrosine kinase (BTK) inhibitors approved for certain indolent B cell non-Hodgkin's lymphoma (NHL). BTK is a nonreceptor kinase involved in B-cell survival, proliferation, and interaction with the microenvironment. We retrospectively evaluated the tolerability and effectiveness of BTK inhibitors ibrutinib and acalabrutinib therapy in (n = 4) patients with IgM-related AL amyloidosis with underlying WM. Treatment was well tolerated with both hematologic and organ response in patients with AL amyloidosis in the setting of WM. Atrial fibrillation led to the discontinuation of ibrutinib in one patient, and acalabrutinib caused significant thumb hematoma needing dose reduction in another patient. All patients evaluated had the MYD88 mutation. This may explain the good response to BTK inhibitors therapy in our series. BTK inhibitors should be further investigated in larger prospective studies for treatment of AL amyloidosis in patients with lymphoplasmacytic lymphoma/WM.

2.
Arch Pathol Lab Med ; 146(7): 894-902, 2022 07 01.
Article in English | MEDLINE | ID: mdl-34619751

ABSTRACT

CONTEXT.­: Clinical laboratories and the training of pathology residents are tightly regulated environments. Compliance with regulatory requirements must be addressed when developing entrustable professional activities (EPAs) for pathology residents. OBJECTIVE.­: To describe the development of EPAs for peripheral blood and body fluid review in compliance with Clinical Laboratory Improvement Amendments and College of American Pathologists personnel and testing requirements. To examine the impact of EPA implementation on the workflow in a busy hematology laboratory. DESIGN.­: A training program was designed to prepare pathology residents to function as independent testing personnel in compliance with Clinical Laboratory Improvement Amendments. After a series of lectures, hands-on microscopy sessions, self-assessment quizzes, and achievement of a passing score on a training assessment exam, residents were deemed competent to release certain results independently. The volume and the turnaround time of hematology tests were compared before and after residents were integrated into the laboratory workflow. Faculty and residents were surveyed to assess satisfaction with the training. RESULTS.­: Empowering residents to independently release noncritical results from peripheral blood and body fluid reviews had no adverse impact on test turnaround time. The resident contribution to workflow resulted in a corresponding decrease in the number of cases that required attending pathologist review. Faculty and residents viewed the EPAs as beneficial to service and education. CONCLUSIONS.­: The implementation of the EPAs had a beneficial effect on the laboratory, the trainees, and faculty. Our experience may be helpful to other training programs as EPAs become more widely implemented in residency training.


Subject(s)
Hematology , Internship and Residency , Clinical Competence , Humans , Surveys and Questionnaires
3.
J Cutan Pathol ; 47(11): 1003-1009, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32356378

ABSTRACT

BACKGROUND: Purpura fulminans, an uncommon syndrome of intravascular thrombosis with hemorrhagic infarction of the skin, is often accompanied by disseminated intravascular coagulation (DIC) and multi-organ failure, and may ultimately lead to death. METHODS: Herein, we document 13 skin biopsies from 11 adult patients with the clinical diagnosis of sepsis and confirmed histopathologic diagnosis of intravascular thrombosis and/or DIC, compatible with acute infectious purpura fulminans (AIPF). Detailed history and clinical examination were performed, and the lesions were correlated with histopathologic findings. Any underlying medical disease was taken into consideration. RESULTS: There were 5 males and 6 females with lower extremity or peri-incisional purpuric skin lesions. The most important comorbidities identified were a history of surgical procedure or neoplasm, although 4 patients had no relevant underlying history. Most skin biopsies revealed focal epidermal ischemia or necrosis and 3 showed full-thickness epidermal necrosis. In the underlying dermis, there were fibrin thrombi in superficial and deep blood vessels with acute inflammation. Changes of an inflammatory destructive vasculitis were identified in 5 cases. No bacteria or fungi were identified on histopathology. CONCLUSIONS: AIPF is a rapidly-progressing medical emergency which may be identified by histopathology in culture-negative cases. Biopsies may show neutrophilic infiltrate without infective organisms.


Subject(s)
Purpura Fulminans/pathology , Skin/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Necrosis/etiology , Necrosis/pathology
5.
Acad Pathol ; 5: 2374289518781575, 2018.
Article in English | MEDLINE | ID: mdl-30014036

ABSTRACT

This study describes a quantitative tool in the assessment of residency programs, in which national ranking of residents after the resident in-service examination in postgraduate year 4 is compared to that in postgraduate year 1. The relationship between training and changes in ranking, resident in-service examination results before and after training in specific areas are also compared. To illustrate the use of this novel approach, data from a large residency program were analyzed. The 70 residents were ranked as a postgraduate year 1 group at the 50th national percentile. As postgraduate year 4 residents, they were ranked at the 59th percentile, a significant (P < .003) improvement. There was moderate correlation between performance in postgraduate year 1 and that in postgraduate year 4 (0.61); however, initial ranking was no indication of the final (R2 = .34), with the exception of high performers. Training in specific areas improved ranking, demonstrating association between training and performance. In conclusion, the effectiveness of training provided by a residency program can be quantified using the resident in-service examination. This should provide a quantitative tool in the assessment of postgraduate programs.

6.
Arch Pathol Lab Med ; 141(10): 1342-1393, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28225303

ABSTRACT

CONTEXT: - A complete diagnosis of acute leukemia requires knowledge of clinical information combined with morphologic evaluation, immunophenotyping and karyotype analysis, and often, molecular genetic testing. Although many aspects of the workup for acute leukemia are well accepted, few guidelines have addressed the different aspects of the diagnostic evaluation of samples from patients suspected to have acute leukemia. OBJECTIVE: - To develop a guideline for treating physicians and pathologists involved in the diagnostic and prognostic evaluation of new acute leukemia samples, including acute lymphoblastic leukemia, acute myeloid leukemia, and acute leukemias of ambiguous lineage. DESIGN: - The College of American Pathologists and the American Society of Hematology convened a panel of experts in hematology and hematopathology to develop recommendations. A systematic evidence review was conducted to address 6 key questions. Recommendations were derived from strength of evidence, feedback received during the public comment period, and expert panel consensus. RESULTS: - Twenty-seven guideline statements were established, which ranged from recommendations on what clinical and laboratory information should be available as part of the diagnostic and prognostic evaluation of acute leukemia samples to what types of testing should be performed routinely, with recommendations on where such testing should be performed and how the results should be reported. CONCLUSIONS: - The guideline provides a framework for the multiple steps, including laboratory testing, in the evaluation of acute leukemia samples. Some aspects of the guideline, especially molecular genetic testing in acute leukemia, are rapidly changing with new supportive literature, which will require on-going updates for the guideline to remain relevant.


Subject(s)
Leukemia , Pathology, Clinical , Humans , Acute Disease , Leukemia/diagnosis , Pathology, Clinical/standards , Systematic Reviews as Topic
8.
J Clin Pathol ; 69(8): 713-9, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26754830

ABSTRACT

AIMS: Marked thrombocytosis is uncommon in chronic myelogenous leukaemia (CML) but may be associated with mutation of JAK2 V617F, calreticulin (CALR) and/or phospho-STAT5 (p-STAT5) activation in other myeloproliferative neoplasms (MPNs), particularly essential thrombocythaemia (ET). We investigated the JAK2 V617F, CALR and STAT5 activation status in patients with CML and thrombocytosis (CML-T) that mimicked ET, trying to identify a common mechanism for thrombocytosis in MPN. METHODS: Blood and bone marrow morphological findings were reviewed from seven CML-T, four otherwise typical CML and one CML in blast phase. All cases were analysed for BCR-ABL1, JAK2 V617F and CALR exon 9 mutation and p-STAT5 expression. RESULTS: Four of seven cases of CML-T had marked thrombocytosis (>1000×10(9)/L). Eleven of 12 cases had megakaryocyte morphology typical for CML. All cases were BCR-ABL1 positive. Eleven of 12 cases were negative for JAK2 V617F, while STAT5 was activated in six of seven CML-T and in four of five CML cases. No case had a detectable CALR exon 9 mutation. One case of CML developed ET-like morphology and had JAK2 V617F detected while in molecular remission for CML. CONCLUSIONS: Detection of BCR-ABL1 is critical in the distinction of ET from CML. Thrombocytosis and STAT5 activation in CML-T are not consistently associated with CALR exon 9 or JAK2 V617F mutation.


Subject(s)
Calreticulin/genetics , Janus Kinase 2/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Mutation , STAT5 Transcription Factor/metabolism , Thrombocythemia, Essential/diagnosis , Thrombocytosis/diagnosis , Adult , Aged , Aged, 80 and over , Calreticulin/metabolism , Diagnosis, Differential , Exons , Female , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Humans , Janus Kinase 2/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Male , Middle Aged , Phosphorylation , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/metabolism , Thrombocytosis/complications , Thrombocytosis/genetics , Thrombocytosis/metabolism
9.
Cancer Genet ; 207(5): 171-6, 2014 May.
Article in English | MEDLINE | ID: mdl-25027637

ABSTRACT

In chronic myelogenous leukemia, BCR-ABL1 positive detection of cytogenetic abnormalities in addition to the t(9;22) is thought to portend a poor prognosis; however, not all abnormalities associated with the t(9;22) have the same impact. Inv(3) defines a group of aggressive neoplasms with poor response to conventional treatment options. In this study, four cases with the t(9;22) and inv(3) treated with tyrosine kinase inhibitors (TKI) were investigated. In three cases, the inv(3) was not detected at the initial diagnosis and the patients initially responded to TKI therapy; the inv(3) was detected at blast crisis in all three cases, and one case had both abnormalities at the initial presentation, but this case presented as acute myeloid leukemia. In all cases, detection of an inv(3) was associated with a high blast count and a lack of response to treatment regimens including TKI. All patients died within months from the detection of inv(3). This indicates that cases with the t(9;22) and inv(3) have a clinical course similar to that of cases with an inv(3) and no other therapeutically targetable abnormality.


Subject(s)
Chromosome Inversion/genetics , Chromosomes, Human, Pair 3/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Philadelphia Chromosome , Protein Kinase Inhibitors/therapeutic use , Aged , Blast Crisis/drug therapy , Blast Crisis/genetics , Blast Crisis/pathology , Fatal Outcome , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Middle Aged , Translocation, Genetic
10.
Pediatr Blood Cancer ; 61(5): 946-8, 2014 May.
Article in English | MEDLINE | ID: mdl-24610751

ABSTRACT

Single cases of B- and T-lymphoblastic leukemia/lymphoma occurring after remission of JMML, and JMML occurring after remission of B-lymphoblastic leukemia have been reported in the literature. We present a unique case of a child with concurrent JMML and T-lymphoblastic lymphoma in which an identical missense mutation in NRAS was found in both the neoplastic JMML and T-LBL cells. JMML has been considered a stem cell disorder, and our case provides additional molecular evidence for a stem cell lesion underlying the two different disease phenotypes.


Subject(s)
GTP Phosphohydrolases/genetics , Leukemia, Myelomonocytic, Juvenile/genetics , Membrane Proteins/genetics , Mutation, Missense/genetics , Neoplasms, Multiple Primary/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Bone Marrow Transplantation , Child, Preschool , Cytogenetic Analysis , Humans , Leukemia, Myelomonocytic, Juvenile/diagnosis , Leukemia, Myelomonocytic, Juvenile/therapy , Male , Neoplasms, Multiple Primary/diagnosis , Neoplasms, Multiple Primary/therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prognosis , Transplantation Conditioning
11.
Arch Pathol Lab Med ; 136(1): 47-52, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22208487

ABSTRACT

CONTEXT: Fluorescence in situ hybridization (FISH) is a molecular cytogenetic assay that is commonly used in laboratory medicine. Most FISH assays are not approved by the US Food and Drug Administration but instead are laboratory-developed tests that use analyte-specific reagents. Although several guidelines exist for validation of FISH assays, few specific examples of FISH test validations are available in the literature. OBJECTIVE: To provide an example of how a FISH assay, using an analyte-specific reagent probe, may be validated in a clinical laboratory. DESIGN: We describe the approach used by an individual laboratory for validation of a FISH assay for mixed lineage leukemia (MLL) gene. RESULTS: Specific validation data are provided illustrating how initial assay performance characteristics in a FISH assay for MLL may be established. CONCLUSIONS: Protocols for initial validation of FISH assays may vary between laboratories. However, all laboratories must establish several defined performance specifications prior to implementation of FISH assays for clinical use. We describe an approach used for assessing performance specifications and validation of an analyte-specific reagent FISH assay using probes for MLL rearrangement in interphase nuclei.


Subject(s)
Fluorescent Dyes , In Situ Hybridization, Fluorescence/methods , Leukemia, Biphenotypic, Acute/diagnosis , Leukemia, Biphenotypic, Acute/genetics , Molecular Diagnostic Techniques/standards , Myeloid-Lymphoid Leukemia Protein/genetics , Cell Nucleus/pathology , Humans , Interphase , Leukemia, Biphenotypic, Acute/pathology , Reproducibility of Results , Sensitivity and Specificity , United States , United States Food and Drug Administration
12.
Mol Cytogenet ; 4: 25, 2011 Nov 16.
Article in English | MEDLINE | ID: mdl-22087757

ABSTRACT

BACKGROUND: Cytogenetic evaluation is a key component of the diagnosis and prognosis of chronic lymphocytic leukemia (CLL). We performed oligonucleotide-based comparative genomic hybridization microarray analysis on 34 samples with CLL and known abnormal karyotypes previously determined by cytogenetics and/or fluorescence in situ hybridization (FISH). RESULTS: Using a custom designed microarray that targets >1800 genes involved in hematologic disease and other malignancies, we identified additional cryptic aberrations and novel findings in 59% of cases. These included gains and losses of genes associated with cell cycle regulation, apoptosis and susceptibility loci on 3p21.31, 5q35.2q35.3, 10q23.31q23.33, 11q22.3, and 22q11.23. CONCLUSIONS: Our results show that microarray analysis will detect known aberrations, including microscopic and cryptic alterations. In addition, novel genomic changes will be uncovered that may become important prognostic predictors or treatment targets for CLL in the future.

13.
Genet Med ; 13(9): 765-9, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21633292

ABSTRACT

PURPOSE: To evaluate the feasibility of administering a newly established proficiency test offered through the College of American Pathologists and the American College of Medical Genetics for genomic copy number assessment by microarray analysis, and to determine the reproducibility and concordance among laboratory results from this test. METHODS: Surveys were designed through the Cytogenetic Resource Committee of the two colleges to assess the ability of testing laboratories to process DNA samples provided and interpret results. Supplemental questions were asked with each Survey to determine laboratory practice trends. RESULTS: Twelve DNA specimens, representing 2 pilot and 10 Survey challenges, were distributed to as many as 74 different laboratories, yielding 493 individual responses. The mean consensus for matching result interpretations was 95.7%. Responses to supplemental questions indicate that the number of laboratories offering this testing is increasing, methods for analysis and evaluation are becoming standardized, and array platforms used are increasing in probe density. CONCLUSION: The College of American Pathologists/American College of Medical Genetics proficiency testing program for copy number assessment by cytogenomic microarray is a successful and efficient mechanism for assessing interlaboratory reproducibility. This will provide laboratories the opportunity to evaluate their performance and assure overall accuracy of patient results. The high level of concordance in laboratory responses across all testing platforms by multiple facilities highlights the robustness of this technology.


Subject(s)
Cytogenetic Analysis/standards , Laboratory Proficiency Testing/standards , Microarray Analysis/standards , Cytogenetic Analysis/methods , Data Collection , Humans , Laboratories/standards , Microarray Analysis/methods , Societies, Medical , United States
14.
Am J Clin Pathol ; 135(6): 915-20, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21571964

ABSTRACT

It is unclear how often and in what setting fluorescence in situ hybridization (FISH) panels for myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) provide additional information over metaphase cytogenetics alone. Furthermore, the usefulness of peripheral blood vs bone marrow FISH has also not been directly compared. We prospectively compared metaphase cytogenetics and FISH for -5/5q-, -7/7q-, +8, and 20q- in 433 cases of suspected MDS/AML. FISH testing was abnormal in 6 (14%) of 43 and 10 (19%) of 54 cases with fewer than 20 normal metaphases or no growth, respectively. FISH was only rarely abnormal in cases with 20 normal metaphases obtained (6/222 [2.7%]). Comparison of peripheral blood and bone marrow results in 48 cases showed abnormal peripheral blood FISH results in 18 (69%) of 26 cases with abnormal bone marrow FISH results and in 5 (23%) of 22 cases with normal bone marrow FISH results. These findings, the largest published comparison of FISH vs metaphase cytogenetics in MDS/AML, provide a rational strategy for FISH testing in peripheral blood and bone marrow.


Subject(s)
Bone Marrow/metabolism , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/metabolism , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/metabolism , Cytogenetic Analysis , Humans , Karyotyping , Leukemia, Myeloid, Acute/blood , Metaphase , Myelodysplastic Syndromes/blood , Prospective Studies
15.
Blood ; 117(13): 3485-93, 2011 Mar 31.
Article in English | MEDLINE | ID: mdl-21258008

ABSTRACT

Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34(+)CD133(+) proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34(+)CD133(+) progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/physiology , Bone Marrow Diseases/etiology , Hypoxia-Inducible Factor 1/physiology , Hypoxia/metabolism , AC133 Antigen , Adult , Antigens, CD/blood , Antigens, CD/metabolism , Antigens, CD34/blood , Antigens, CD34/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Bone Marrow Diseases/metabolism , Bone Marrow Diseases/pathology , Cell Count , Cells, Cultured , Familial Primary Pulmonary Hypertension , Female , Glycoproteins/blood , Glycoproteins/metabolism , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Humans , Hypertension, Pulmonary/blood , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Hypoxia/blood , Hypoxia/complications , Hypoxia/pathology , Hypoxia-Inducible Factor 1/metabolism , Male , Middle Aged , Myeloid Cells/metabolism , Myeloid Cells/pathology , Peptides/blood , Peptides/metabolism , Up-Regulation/physiology
16.
Rheumatol Int ; 31(3): 405-7, 2011 Mar.
Article in English | MEDLINE | ID: mdl-19834709

ABSTRACT

Macrophage activation syndrome (MAS) is a disorder characterized by increased activation of mononuclear cells leading to phagocytosis of blood cell precursors in the bone marrow. We describe a case of MAS triggered by disseminated histoplasmosis occurring in a patient with Still's disease on long-term treatment with adalimumab.


Subject(s)
Antibodies, Monoclonal/adverse effects , Antirheumatic Agents/adverse effects , Histoplasmosis/complications , Macrophage Activation Syndrome/etiology , Still's Disease, Adult-Onset/complications , Still's Disease, Adult-Onset/therapy , Adalimumab , Antibodies, Monoclonal, Humanized , Humans , Phagocytosis , Young Adult
17.
Genes Chromosomes Cancer ; 49(4): 390-9, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20095039

ABSTRACT

Deletion of the long arm of chromosome 20 is a common abnormality associated with myeloid malignancies. We characterized abnormalities of chromosome 20 as defined by metaphase cytogenetics (MC) in patients with myeloid neoplasms to define commonly deleted regions (CDR) and commonly retained regions (CRR) using genome-wide, high resolution single nucleotide polymorphism array (SNP-A) analysis. We reviewed the MC results of a cohort of 1,162 patients with myeloid malignancies, including myelodysplastic syndromes (MDS), MDS/myeloproliferative neoplasia (MDS/MPN), and acute myeloid leukemia (AML). We further analyzed a subcohort of 532 patients by SNP-A using the Affymetrix Genome-Wide Human SNP Array 6.0 and GeneChip Human Mapping 250K Nsp arrays. By MC, 5% (54/1,162) harbored a deletion of 20q; in 30% (16/54), del(20q) was the sole cytogenetic abnormality. By SNP-A analysis, we identified del(20q) in 23 patients, 3 not detected by MC. In four cases, monosomy 20 with a marker chromosome by MC was proven to be an interstitial deletion of 20q by SNP-A. We defined 2 CDR and 2 CRR on chromosome arm 20q: CDR1 spanned 2.5 Mb between bands 20q11.23 and 20q12, while CDR2 encompassed 1.8 Mb within 20q13.12. CRR1 spanned 1.9 Mb within 20q11.21 and CRR2 encompassed 2.5 Mb within 20q13.33. In contrast to other chromosomes frequently affected by deletions, no somatic copy neutral loss of heterozygosity (CN-LOH) was detected. Our data suggest that SNP-A is useful for the detection of cryptic aberrations of chromosome 20q and allows for a more precise characterization of complex karyotypes. Furthermore, SNP-A allowed definition of a CDR on 20q.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 20 , Myelodysplastic Syndromes/genetics , Myeloproliferative Disorders/genetics , Adult , Aged , Aged, 80 and over , Cohort Studies , Cytogenetic Analysis , Female , Gene Deletion , Gene Dosage , Genome-Wide Association Study/methods , Humans , Loss of Heterozygosity , Male , Markov Chains , Middle Aged , Oligonucleotide Array Sequence Analysis/methods , Polymorphism, Single Nucleotide
18.
Leuk Res ; 34(4): 447-53, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19758696

ABSTRACT

Cytogenetic aberrations identified by metaphase cytogenetics (MC) have important diagnostic, prognostic and therapeutic roles in myelodysplastic syndromes (MDS). Fluorescence in situ hybridization (FISH) complements MC by the ability to evaluate large numbers of both interphase and metaphase nuclei. However, clinically practical FISH strategies are limited to detection of known lesions. Single nucleotide polymorphism array (SNP-A)-based karyotyping can reveal unbalanced defects with superior resolution over MC and FISH and identify segmental uniparental disomy (UPD) undetectable by either method. Using a standardized approach, we focused our investigation on detection of -5/del(5q), -7/del(7q), trisomy 8 and del(20q) in patients with MDS (N=52), MDS/myeloproliferative overlap syndromes (N=7) and acute myeloid leukemia (N=15) using MC, FISH and SNP-A karyotyping. The detection rate for del(5q) was 30, 32 and 32% by MC, FISH, and SNP-A, respectively. No single method detected all defects, and detection rates improved when all methods were used. The rate for detection of del(5q) increased incrementally to 35% (MC+FISH), 38% (MC+SNP-A), 38% (FISH+SNP-A) and 39% (all three methods). Similar findings were observed for -7/del(7q), trisomy 8 and -20/del(20q). We conclude that MC, FISH and SNP-A are complementary techniques that, when applied and interpreted together, can improve the diagnostic yield for identifying genetic lesions in MDS and contribute to the better description of abnormal karyotypes.


Subject(s)
DNA Mutational Analysis/methods , In Situ Hybridization, Fluorescence , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Chromosome Deletion , Chromosomes, Human, Pair 20 , Chromosomes, Human, Pair 5 , Chromosomes, Human, Pair 7 , Chromosomes, Human, Pair 8 , Female , Humans , Karyotyping/methods , Male , Middle Aged , Monosomy/diagnosis , Polymorphism, Single Nucleotide , Trisomy/diagnosis , Young Adult
19.
Leuk Lymphoma ; 49(8): 1560-6, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18766970

ABSTRACT

We evaluated patients with newly diagnosed ALL treated at the Cleveland Clinic during the years 1996 through 2005. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of complete remission, overall survival and progression-free survival. On univariate analysis, significant prognostic factors included: age at diagnosis (per 10-year increase), poor risk cytogenetics, time to white blood count recovery, and time from induction chemotherapy (IC) to post-remission therapy (PRT). In patients age <60 years without poor risk cytogenetics, time from IC to PRT (per week increase) was a significant prognostic factor by multivariate analysis and was associated with a decreased progression-free survival [HR 1.27, CI (1.04-1.55), p = 0.019] and decreased overall survival [HR 1.34, CI (1.08-1.67), p = 0.009]. Delayed time from IC to PRT (> or =6.6 weeks) was associated with a statistically worse progression-free and overall survival.


Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Adolescent , Adult , Age Factors , Aged , Cytogenetic Analysis , Humans , Middle Aged , Prognosis , Proportional Hazards Models , Remission Induction , Retrospective Studies , Survival Analysis , Time Factors , Treatment Outcome
20.
Blood ; 111(3): 1534-42, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-17954704

ABSTRACT

Using metaphase cytogenetics (MC), chromosomal abnormalities are found in only a proportion of patients with myelodysplastic syndrome (MDS). We hypothesized that with new precise methods more cryptic karyotypic lesions can be uncovered that may show important clinical implications. We have applied 250K single nucleotide polymorphisms (SNP) arrays (SNP-A) to study chromosomal lesions in samples from 174 patients (94 MDS, 33 secondary acute myeloid leukemia [sAML], and 47 myelodysplastic/myeloproliferative disease [MDS/MPD]) and 76 controls. Using SNP-A, aberrations were found in around three-fourths of MDS, MDS/MPD, and sAML (vs 59%, 37%, 53% by MC; in 8% of patients MC was unsuccessful). Previously unrecognized lesions were detected in patients with normal MC and in those with known lesions. Moreover, segmental uniparental disomy (UPD) was found in 20% of MDS, 23% of sAML, and 35% of MDS/MPD patients, a lesion resulting in copy-neutral loss of heterozygosity undetectable by MC. The potential clinical significance of abnormalities detected by SNP-A, but not seen on MC, was demonstrated by their impact on overall survival. UPD involving chromosomes frequently affected by deletions may have prognostic implications similar to the deletions visible by MC. SNP-A-based karyotyping shows superior resolution for chromosomal defects, including UPD. This technique further complements MC to improve clinical prognosis and targeted therapies.


Subject(s)
Chromosomes, Human/genetics , Leukemia, Myeloid, Acute/genetics , Myelodysplastic Syndromes/genetics , Myeloproliferative Disorders/genetics , Polymorphism, Single Nucleotide/genetics , Uniparental Disomy/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Cytogenetics , Humans , Karyotyping , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/pathology , Middle Aged , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/pathology , Myeloproliferative Disorders/pathology , Oligonucleotide Array Sequence Analysis , Prognosis
SELECTION OF CITATIONS
SEARCH DETAIL
...