1.Systematic Classification of Mixed-Lineage Leukemia Fusion Partners Predicts Additional Cancer Pathways.
Annals of Laboratory Medicine 2016;36(2):85-100
Chromosomal translocations of the human mixed-lineage leukemia (MLL) gene have been analyzed for more than 20 yr at the molecular level. So far, we have collected about 80 direct MLL fusions (MLL-X alleles) and about 120 reciprocal MLL fusions (X-MLL alleles). The reason for the higher amount of reciprocal MLL fusions is that the excess is caused by 3-way translocations with known direct fusion partners. This review is aiming to propose a solution for an obvious problem, namely why so many and completely different MLL fusion alleles are always leading to the same leukemia phenotypes (ALL, AML, or MLL). This review is aiming to explain the molecular consequences of MLL translocations, and secondly, the contribution of the different fusion partners. A new hypothesis will be posed that can be used for future research, aiming to find new avenues for the treatment of this particular leukemia entity.
Alleles
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Chromosomes, Human, X
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Epigenesis, Genetic
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Humans
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Leukemia/classification/*genetics/pathology
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Myeloid-Lymphoid Leukemia Protein/chemistry/genetics
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Protein Structure, Tertiary
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Translocation, Genetic
2.Pax5 expression in Non-Hodgkin's Lymphomas and Acute Leukemias.
Xianglan ZHANG ; Zhenhua LIN ; Insun KIM
Journal of Korean Medical Science 2003;18(6):804-808
The Pax5 gene encodes the B-cell-specific activator protein which is a key regulator in development and differentiation of B-cell. We studied the expression of Pax5 in hematologic malignancies to evaluate the diagnostic utility as a B cell marker. Materials included 70 B cell lymphomas, 26 T cell lymphomas, 53 acute leukemias, and 6 multiple myelomas (MMs). Representative areas from the paraffinembedded tissues were selected for tissue microarray, and the expressions of Pax5 was immunohistochemically evaluated. Pax5 was strongly expressed in most of the B cell lymphomas; 44 of 47 diffuse large B cell lymphomas (93.6%), 15 of 16 marginal zone B cell lymphomas (93.8%), all 3 mantle cell lymphomas, 2 follicular lymphomas, and 2 Burkitt's lymphomas (100%). However, Pax5 was expressed in only one of 26 T cell lymphomas. Among leukemias, it was expressed in 10 of the 14 B acute lymphocytic leukemias (ALLs) (72.4%), but also in 3 of the 6 T ALLs (50%), 13 of the 26 acute myelogenous leukemias (AMLs) (50%) and in all 3 ALL arising in chronic myelogenous leukemias and 4 mixed B ALL and AML. In MMs, Pax5 was negative in all cases. We concluded that Pax5 is very useful B cell marker in classification of lymphomas, but not of acute leukemias.
B-Lymphocytes/pathology/physiology
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DNA-Binding Proteins/genetics/*metabolism
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Human
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Leukemia/classification/*metabolism/pathology
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Lymphoma, Non-Hodgkin/classification/*metabolism/pathology
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Support, Non-U.S. Gov't
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Tonsil/cytology/metabolism/pathology
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Transcription Factors/genetics/*metabolism
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Tumor Markers, Biological/*metabolism
3.Combined analysis on morphology, immunology, cytogenetics and molecular biology (MICM) classification of 55 patients with acute promyelocytic leukemia.
Journal of Experimental Hematology 2004;12(2):147-150
To investigate the value of bone marrow morphology, immunology, cytogenetics and molecular biology (MICM) examination in the diagnosis of acute promyelocytic leukemia (APL) and their relations of each other, the MICM data of 55 APL patients were analyzed retrospectively. The result showed that the accuracy rate of morphological diagnosis based on FAB classification could reach 96.4%; CD33 and CD13 antigen were co-expressed the highest in immunophenotyping (CD33(+)CD13(+) occupied 96.4%); cytogenetic abnormality containing t (15; 17)(q22; 21) accounted for 87.3%, translocation of chromosomes (simple type) of 100% t (15; 17)(q22; 21) occupied 75%, other involved chromosomes included 1, 8, 9, 11, 12, 21; the positive rate of PML/RARalpha gene also reached 96.4%; the accuracy rate of APL diagnosis by combining MICM measure was 100%. In conclusion, the bone marrow morphology still remains to be base for diagnosis of APL, but the combined analysis of MICM could obviously enhance the accuracy of diagnosis for APL. The MICM examination may provide a new approach to find subtype of APL.
Adolescent
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Adult
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Chromosome Aberrations
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Female
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Humans
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Immunophenotyping
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Leukemia, Promyelocytic, Acute
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classification
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genetics
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pathology
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Male
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Middle Aged
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Neoplasm Proteins
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genetics
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Oncogene Proteins, Fusion
;
genetics
4.Clonality analysis and mutational status of IgVH gene in Hodgkin variant of Richter syndrome.
Zheng-rong MAO ; Andreas ROSENWALD ; Suo-jiang ZHANG ; Ren ZHOU ; Hans Konrad MUELLER-HERMELINK
Chinese Journal of Pathology 2008;37(8):523-528
OBJECTIVETo detect the clonal relationship, the rearrangement, and the mutational status of IgVH gene; the influence of these molecular characteristics on the clinical outcome in Hodgkin variant of Richter syndrome; and the possible molecular pathogenesis in this transformation.
METHODSThe clonal rearrangements and mutational status of IgVH genes were analyzed in Hodgkin variant of Richter syndrome and B-CLL with Reed-Stemberg (R-S)-like cells by GeneScan analysis and sequencing. Semi-nest PCR based on laser capture microdissection was utilized to compare the clonal relationship between B-CLL and R-S/R-Slike cells. Immunohistochemical staining was used to detect the different expressions of ZAP70, p53, IRF-4 and LMP1 in the two components.
RESULTS(1) 5/6 B-CLL cases transformed to Hodgkin lymphoma (HL)/R-S-like cells carried the mutated IgVH genes; (2) 2 cases of R-S cells and 1 case of R-S-like cells were clonally distinct from B-CLL clone and express LMP1, whereas 1 case of R-S-like cells was relating to the surrounding B-CLL cells and did not express LMP1; (3) 2/6 B-CLL cases transformed to HL convey VH4-34 and VH3-48 respectively.
CONCLUSIONS(1) Richter transformation to HL/R-S-like cells evolves from the B-CLL which originates from the germinal center or post germinal center B cells, indicating that different lymphoma cells of different subtypes in Richter syndrome come from different B cell lineage and possibly involve a different pathogenesis and pathway; (2) HL and R-S-like cells evolve from either the B-CLL clone or may develop as a clonally unrelated lymphoma, the independent secondary malignancies are appear to be EBV-positive, possibly as a consequence of the underlying immunodeficiency; (3) The biased usage of IgVH genes suggested a role of antigens involved in the HL variant of Richter syndrome.
Aged ; Aged, 80 and over ; Clone Cells ; pathology ; Female ; Herpesvirus 4, Human ; Hodgkin Disease ; classification ; genetics ; pathology ; virology ; Humans ; Immunoglobulin Variable Region ; genetics ; Leukemia, Lymphocytic, Chronic, B-Cell ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; Reed-Sternberg Cells ; pathology ; Syndrome
5.Chromosomal translocation and malignant tumor.
Chinese Journal of Pathology 2011;40(2):138-140
Diagnosis, Differential
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Female
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Humans
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Immunohistochemistry
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In Situ Hybridization, Fluorescence
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Leukemia, Myeloid, Chronic-Phase
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genetics
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Lymphoma
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classification
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diagnosis
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pathology
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Male
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Neoplasms
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genetics
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metabolism
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pathology
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Oncogene Proteins
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metabolism
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Prognosis
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Prostatic Neoplasms
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genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Translocation, Genetic
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Tumor Suppressor Proteins
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metabolism
6.Expression of Sox11 transcription factor in different types of B-cell lymphomas.
Wei-ming ZHANG ; Cong WANG ; Bai-zhou LI
Chinese Journal of Pathology 2011;40(10):698-699
Burkitt Lymphoma
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metabolism
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pathology
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Cell Nucleus
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metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell
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metabolism
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pathology
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Lymphoma, B-Cell
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classification
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metabolism
;
pathology
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Lymphoma, Follicular
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metabolism
;
pathology
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Lymphoma, Large B-Cell, Diffuse
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metabolism
;
pathology
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Lymphoma, Mantle-Cell
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metabolism
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pathology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
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metabolism
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pathology
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SOXC Transcription Factors
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genetics
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metabolism
7.Application of interphase fluorescence in situ hybridization in the diagnosis of lymphoma.
Rui BI ; Dong-mei LIN ; Ya-ling HAN ; Jun LU ; Li-yan XUE ; Shan ZHENG ; Ming-rong WANG ; Ning LÜ
Chinese Journal of Pathology 2009;38(11):733-738
OBJECTIVETo investigate the feasibility of interphase FISH in the routine clinicopathological practice and its values in the differential diagnosis of lymphomas.
METHODSA total of 74 fresh tissue samples clinically suspicious of lymphoma were investigated by FISH using three probes including IgH/bcl-2, IgH/CCND1 and API2/MALT1, corresponding the translocation t(14;18), t(11;14) and t(11;18) respectively. The results of FISH were analyzed and compared with the histopathologic diagnosis.
RESULTSHistological evaluation eventually confirmed that there were 62 cases of lymphoma and 12 cases of reactive lymphoid processes. The translocations were detected in 7 cases in 62 cases of lymphoma: 3 demonstrated t(14;18) including 2 cases of follicular lymphomas and 1 nodular sclerosing Hodgkin lymphoma. Four cases had t(11;14) including mantle cell lymphoma (2 cases), follicular lymphoma (1 case) and small cell lymphoma (1 case). A lymphoid hyperplasia case showed detectable t(14;18). All 25 cases of DLBCL showed no evidence of t(14;18). Amplification or loss of regional genes was seen more often in malignant than in the benign cases.
CONCLUSIONInterphase FISH offers useful ancillary technology that plays an important role in differential diagnosis and classification of lymphoma.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Chromosomes, Human, Pair 11 ; Chromosomes, Human, Pair 14 ; Chromosomes, Human, Pair 18 ; Diagnosis, Differential ; Female ; Hodgkin Disease ; diagnosis ; genetics ; pathology ; Humans ; In Situ Hybridization, Fluorescence ; methods ; Leukemia, Lymphocytic, Chronic, B-Cell ; diagnosis ; genetics ; pathology ; Lymphoma ; classification ; diagnosis ; genetics ; pathology ; Lymphoma, Follicular ; diagnosis ; genetics ; pathology ; Lymphoma, Large B-Cell, Diffuse ; diagnosis ; genetics ; pathology ; Lymphoma, Mantle-Cell ; diagnosis ; genetics ; pathology ; Lymphoma, Non-Hodgkin ; diagnosis ; genetics ; pathology ; Male ; Middle Aged ; Translocation, Genetic ; Young Adult
8.Correlation between karyotypic characteristics and treatment outcome in childhood acute lymphoblastic leukemia.
Li-jun TIE ; Long-jun GU ; Jing CHEN ; Lu DONG ; Jing CHEN ; Ci PAN ; Hui YE ; Hui-liang XUE ; Jing-yan TANG ; Yao-ping WANG
Chinese Journal of Hematology 2006;27(5):339-343
OBJECTIVETo analyze the relationship between karyotypic characteristics and treatment outcome of childhood acute lymphoblastic leukemia (ALL) and compare the difference in karyotypic aberration between ALL patients in China and in western countries.
METHODSFrom January 1998 to May 2003, 193 patients with newly diagnosed ALL were enrolled on protocol ALL-XH-99. The patients were classified into 4 groups according to the karyotype of the leukemia cells: normal karyotype, hypodiploid, hyperdiploid and pseudodiploid. Event-free survival (EFS) was estimated by Kaplan-Meier analysis and the distributions of EFS were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors.
RESULTS(1) Of 193 ALL patients, 115 had cytogenetic data. There were 53 (46.09%) with normal karyotype, 29 (25.22%) hyperdiploid, 9 (7.83%) hypodiploid, 4 coexpression of hypodiploid/hyperdiploid and 20 (17.39%) pseudodiploid. The probability of 5-year EFS for the four subgroups were (78.28 +/- 6.34)%, (86.07 +/- 6.47)%, (53.85 +/- 13.83)% and (40.10 +/- 12.17)%, respectively (P = 0.0041). (2) The clinical presentation and early response to treatment had no difference among the four groups, but the events are significantly different. (3) The probability of 5-year EFS for the combined hypodiploid group and the non-hypodiploid group was (53.85 +/- 13.83)% and (69.98 +/- 5.94)%, respectively (P = 0.1281). (4) The probability of 4-year EFS was significantly worse for patients with Philadelphia chromosome than for no Philadelphia chromosome patients [(28.57 +/- 17.07)% vs (70.85 +/- 5.60)%, P = 0.0009]. (5) Multivariate analysis suggested that the karyotypic characteristics, Philadelphia chromosome, age < 1-year or > 12-year, and white blood cell counts were independent prognostic factors.
CONCLUSIONSThe cytogenetic pattern of Chinese childhood ALL patients was similar to that of western countries. Cytogenetic findings especially Philadelphia chromosome had important prognostic significance.
Adolescent ; Child ; Child, Preschool ; Chromosome Aberrations ; statistics & numerical data ; Diploidy ; Female ; Humans ; Infant ; Kaplan-Meier Estimate ; Karyotyping ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; classification ; genetics ; pathology ; Prognosis ; Proportional Hazards Models
9.Pathologic diagnosis and subtyping of lymphoma in bone marrow biopsies using histologic examination, immunohistochemistry and gene rearrangement studies.
Jia-cheng XIAO ; Xiao-long JIN ; Fei YUAN
Chinese Journal of Pathology 2004;33(2):120-124
OBJECTIVETo assess the value of histologic examination, immunohistochemistry and gene rearrangement studies in the diagnosis and subtyping of lymphoma with bone marrow involvement (BMI).
METHODSSixty-two formalin fixed, paraffin embedded bone marrow biopsy specimens were studied. Immunohistochemical and immunoglobulin heavy chain (IgH) and T-cell receptor gene rearrangement studies were performed in each case.
RESULTSChronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrated mainly and interstitial infiltration by dysplastic lymphocytes, with intertrabecular nodular arrangement or in dispersion. Sometimes, pseudofollicles may be noted. A predominantly para- or intertrabecular infiltration by nodules of lymphoma cells was characteristic of follicle center cell lymphoma (FCL) cases. In most lymphoplasmacytoid lymphoma (LPL) cases, there was infiltration by small lymphocytes and plasma cells between bony trabeculae. In marginal zone cell lymphoma (MZL), vague inter- or para-trabecular nodules of polymorphic lymphoma cells with clear cytoplasm might be noted. Small to medium-sized dysplastic lymphocytes, with absence of paraimmunoblasts or pseudofollicles, were the most frequent findings in mantle cell lymphoma (MCL). Hairy cell leukemia (HCL) might be identified by the presence of distinct cell membrane and abundant clear cytoplasm, resulting in a "fried-egg" appearance. Tumor cells with large nuclei and eosinophilic nucleoli were characteristically seen in lymphomatosis diffusa (Hodgkin's disease, HD). In T-cell non-Hodgkin lymphoma with BMI, dispersed or clusters of intertrabecular neoplastic lymphoid cells with clear cytoplasm and gyriform nuclei were often observed. In diffuse large B-cell lymphoma (DLBL), the tumor cells were large and isolated or arranged in diffuse pattern. Immunohistochemically, a panel of markers, including CD3 CD20, and CD79 are valuable for the differential diagnosis of T- and B-cell lymphomas. The neoplastic cells in MCL were cyclin D1- and CD5-positive, while BCL2- and CD10-positivity was characteristic for FCL. CLL/SLL cells might be stained with CD5 and CD23, in addition to CD20 and CD79. CD25 expression might be noted in HCL: the positivity for CD15, CD30 and fascin suggests HD. There was a higher positivity rate for IgH gene rearrangement in CLL/SLL, LPL MZL and DLBL (80%, 60%, 66.7%, 70% respectively) and for T- cell receptor gamma gene rearrangement in T-cell lymphoma (66.7%).
CONCLUSIONA combination of histopathology, immunohistochemistry and IgH / T-cell receptor gamma gene rearrangement studies may be of aid to the diagnosis and subtyping of lymphoma with BMI, especially if there is only a small number of tumor cells present in the specimen.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bone Marrow ; chemistry ; pathology ; Diagnosis, Differential ; Female ; Gene Rearrangement ; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor ; Humans ; Immunoglobulin Heavy Chains ; genetics ; Leukemia, Lymphocytic, Chronic, B-Cell ; pathology ; Lymphoma ; classification ; immunology ; pathology ; Lymphoma, Follicular ; pathology ; Male ; Middle Aged
10.The First Korean Case of Sphingobacterium spiritivorum Bacteremia in a Patient with Acute Myeloid Leukemia.
Young Rae KOH ; Shine Young KIM ; Chulhun L CHANG ; Ho Jin SHIN ; Kye Hyung KIM ; Jongyoun YI
Annals of Laboratory Medicine 2013;33(4):283-287
Sphingobacterium spiritivorum has been rarely isolated from clinical specimens of immunocompromised patients, and there have been no case reports of S. spiritivorum infection in Korea to our knowledge. We report a case of S. spiritivorum bacteremia in a 68-yr-old woman, who was diagnosed with acute myeloid leukemia and subsequently received chemotherapy. One day after chemotherapy ended, her body temperature increased to 38.3degrees C. A gram-negative bacillus was isolated in aerobic blood cultures and identified as S. spiritivorum by an automated biochemical system. A 16S rRNA sequencing analysis confirmed that the isolate was S. spiritivorum. The patient received antibiotic therapy for 11 days but died of septic shock. This is the first reported case of human S. spiritivorum infection in Korea. Although human infection is rare, S. spiritivorum can be a fatal opportunistic pathogen in immunocompromised patients.
Aged
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Anti-Bacterial Agents/therapeutic use
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Bacteremia/*complications/drug therapy/*microbiology
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Bone Marrow Cells/pathology
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Fatal Outcome
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Female
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Humans
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Immunocompromised Host
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Leukemia, Myeloid, Acute/*complications
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Phylogeny
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RNA, Ribosomal, 16S/genetics
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Sequence Analysis, DNA
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Shock, Septic/etiology/microbiology
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Sphingobacterium/classification/genetics/isolation & purification/*physiology