Distribution of chromosome breakpoints in benzene-exposed and unexposed AML patients.

Results of laboratory studies and investigations of occupationally exposed healthy individuals have been used to develop a mode of action for benzene-induced leukemia that mirrors disease following treatment with chemotherapeutic agents. Recently we have described series of AML and MDS cases with benzene exposure history, and have provided cytogenetic, molecular, and pathologic evidence that these cases differ significantly in many features from therapy-related disease. Here we have extended this work, and describe chromosome breakpoints across 441 identifiable regions, in terms of gains or losses, in 710 AML cases collected during the Shanghai Health Study, which include 75 with a history of benzene exposure. Using FISH and cytogenetic analysis, we developed prevalence information and risk ratios for benzene exposure across all regions with a lesion in at least one exposed and unexposed case. These results indicate that AML following benzene exposure mirrors de novo disease, and supports a mechanism for development of hematopoietic disease that bears no resemblance to therapy-related disease.

Hospital-Based Case-Control Study of MDS Subtypes and Benzene Exposure in Shanghai.

OBJECTIVE: Due to the sparse data on benzene exposure and myelodysplastic syndrome (MDS) subtypes, we studied this relationship in patients from 29 hospitals in Shanghai, China. METHODS: We recruited 604 cases of MDS and 1193 controls matched on age, sex, and admission date. We interviewed subjects for information on workplace and lifestyle exposures, and developed semi-quantitative exposure estimates. RESULTS: Benzene exposure showed a direct exposure-response pattern with refractory cytopenia with multilineage dysplasia, a less certain association with refractory cytopenia with unilineage dysplasia, and no association with other MDS subtypes. A different pattern was observed with farm residence and smoking, which was primarily related to refractory anemias. CONCLUSIONS: This research demonstrates the importance of MDS subtype specification for more robust etiologic insights. Our data suggests that subtypes with non-erythroid dysplasia are associated with benzene exposure.

Cytogenetics in benzene-associated myelodysplastic syndromes and acute myeloid leukemia: new insights into a disease continuum.

Hematopoiesis in health and disease results from complex interactions between primitive hematopoietic stem cells (HSCs) and the extrinsic influences of other cells in the bone marrow (BM) niche. Advances in stem cell biology, molecular genetics, and computational biology reveal that the immortality, self-renewal, and maintenance of blood homeostasis generally attributed to individual HSCs are functions of the cells' behavior in the normal BM environment. Here we discuss how these advances, together with results of outcomes-based clinical epidemiology studies, provide new insight into the importance of epigenetic events in leukemogenesis. For the chemical benzene (Bz), development of myeloid neoplasms depends predominantly on alterations within the microenvironments in which they arise. The primary persistent disease in Bz myelotoxicity is myelodysplastic syndrome, which precedes cytogenetic injury. Evidence indicates that acute myeloid leukemia arises as a secondary event, subsequent to evolution of the leukemia-initiating cell phenotype within the altered BM microenvironment. Further explorations into the nature of chemical versus de novo disease should consider this mechanism, which is biologically distinct from previous models of clonal cytogenetic injury. Understanding alterations of homeostatic regulation in the BM niche is important for validation of models of leukemogenesis, monitoring at-risk populations, and development of novel treatment and prevention strategies.

Risk of myeloproliferative disease and chronic myeloid leukaemia following exposure to low-level benzene in a nested case-control study of petroleum workers.

BACKGROUND: Benzene exposure has been associated with increased risk of leukaemia and myelodysplastic syndrome. Existing studies are sparse for other lymphohaematopoietic cancer subtypes, such as myeloproliferative disease (MPD) and the related chronic myeloid leukaemia (CML). We pooled data from three petroleum worker nested case-control studies to address this gap. To our knowledge, this is the first study to systematically examine the relationship between MPD and quantitative benzene exposure. METHODS: There were 28 cases and 122 matched controls for CML and 30 MPD cases with 124 matched controls. Two haematopathologists identified each case and provided a diagnosis certainty score. Blinded data-driven assessments estimated benzene exposure for each job held by study participants. Statistical analyses included conditional logistic regression and penalised smoothing splines. RESULTS: Benzene exposures were low, and mean average exposure intensity for CML cases was 0.3 ppm and for MPD cases 0.17 ppm. Categorical analyses showed no increased risk of CML or MPD with benzene exposure. There was no significantly increased risk identified for more highly exposed terminal workers. Some association was seen in spline analyses between increased risk of MPD and benzene exposure experienced in the 2-20 years before diagnosis and with peak exposures considered with cumulative exposure as a continuous variable. CONCLUSIONS: No convincing association was identified between MPD or CML and low exposure to benzene. The greater risk for exposures experienced in the 20 years before diagnosis needs investigating in more powerful studies with a wider range of exposure to benzene, and the biological plausibility further examined from a mechanistic viewpoint.

Acute myeloid leukemia following exposure to benzene more closely resembles de novo than therapy related-disease.

Benzene (Bz) is widely regarded as a prototype environmental leukemogen and individuals chronically exposed are at risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is widely assumed that initiation and pathogenesis of AML following Bz exposure (Bz-AML) is similar or identical to therapy-related AML (t-AML), in which clonal cytogenetic abnormalities, including aneuploidy, are initiating events. However, this assumption is not supported by studies reporting actual disease outcomes together with cytogenetic analyses. Here, using clinically relevant cytogenetic, hematologic, and epidemiological methods, we directly show for 722 consecutive AML cases that the pattern of clonal cytogenetic abnormalities encountered in Bz-exposed cases (n = 78) more closely resembles de novo-AML than t-AML. The prevalence of aneuploidy in Bz-exposed- and de novo-AML cases was identical (23%), and no significant increases in -5/5q- (RR = 0.79) (95% CI: 0.29-2.12) or -7/7q- (RR = 1.27) (95% CI: 0.55-2.92) abnormalities were observed between Bz- vs de novo-AML, respectively. Previous studies have suggested a role for autoimmunity in Bz related MDS including immune mediated inflammatory features and positive responses to immunosuppressive therapy which are indistinguishable from those reported in MDS with low risk of progression to AML. These observations are more consistent with an epigenetic model for initiation of Bz-AML in which altered homeostatic regulation in the bone marrow niche, not direct cytogenetic injury, predominates in the initial development of the leukemic stem cell phenotype, a mechanism biologically distinct from previous models of clonal cytogenetic injury. These findings are important for further understanding the biological basis of AML, particularly in environmental and occupational settings.

Myelodysplastic syndrome and benzene exposure among petroleum workers: an international pooled analysis.

BACKGROUND: Benzene at high concentrations is known to cause acute myeloid leukemia (AML), but its relationship with other lymphohematopoietic (LH) cancers remains uncertain, particularly at low concentrations. In this pooled analysis, we examined the risk of five LH cancers relative to lower levels of benzene exposure in petroleum workers. METHODS: We updated three nested case-control studies from Australia, Canada, and the United Kingdom with new incident LH cancers among petroleum distribution workers through December 31, 2006, and pooled 370 potential case subjects and 1587 matched LH cancer-free control subjects. Quantitative benzene exposure in parts per million (ppm) was blindly reconstructed using historical monitoring data, and exposure certainty was scored as high, medium, or low. Two hematopathologists assigned diagnoses and scored the certainty of diagnosis as high, medium, or low. Dose-response relationships were examined for five LH cancers, including the three most common leukemia cell-types (AML, chronic myeloid leukemia [CML], and chronic lymphoid leukemia [CLL]) and two myeloid tumors (myelodysplastic syndrome [MDS] and myeloproliferative disease [MPD]). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, controlling for age, sex, and time period. RESULTS: Cumulative benzene exposure showed a monotonic dose-response relationship with MDS (highest vs lowest tertile, >2.93 vs ≤0.348 ppm-years, OR = 4.33, 95% CI = 1.31 to 14.3). For peak benezene exposures (>3 ppm), the risk of MDS was increased in high and medium certainty diagnoses (peak exposure vs no peak exposure, OR = 6.32, 95% CI = 1.32 to 30.2) and in workers having the highest exposure certainty (peak exposure vs no peak exposure, OR = 5.74, 95% CI = 1.05 to 31.2). There was little evidence of dose-response relationships for AML, CLL, CML, or MPD. CONCLUSIONS: Relatively low-level exposure to benzene experienced by petroleum distribution workers was associated with an increased risk of MDS, but not AML, suggesting that MDS may be the more relevant health risk for lower exposures.

A case-control study of chronic myelomonocytic leukemia (CMML) in Shanghai, China: evaluation of risk factors for CMML, with special focus on benzene.

The authors report the results of a hospital-based case-control study of all patients diagnosed with chronic myelomonocytic leukemia (CMML) (n = 36) from 28 participating hospitals over a 4-year period. Diagnoses were made by a single laboratory using 2001 World Health Organization (WHO) criteria. Subjects were matched to 2 control patients and interviewed concerning previous diseases, work histories, and exposures to potential etiologic agents. Peripheral blood and bone marrow findings revealed clinical features of both myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (MPNs), consistent with hematopoietic disease category of MDS/MPN. The frequency of clonal cytogenetic abnormalities in all CMML cases was 31%, with no consistent pattern identified. A select number of risk factors associated with occupational exposure, nonoccupational exposure, and prior medical or family history of disease were extracted from the questionnaire. The results were compared between the case and control subjects. A total of 5 study subjects (2 CMML cases and 3 control subjects) were determined to have had some benzene exposure. In addition, none of the highlighted risk factors associated with nonoccupational exposure to etiologic agents was significantly different among the study subjects. These results do not support an increased risk for developing CMML associated with historical exposures to benzene.

Integrating WHO 2001-2008 criteria for the diagnosis of Myelodysplastic Syndrome (MDS): a case-case analysis of benzene exposure.

We characterized the prevalence of hematopoietic and lymphoid disease for 2923 consecutive patients presenting at 29 hospitals from August 2003 to June 2007. Diagnoses were made in our laboratory using WHO criteria based on morphologic, immunophenotypic, cytogenetic, FISH and molecular data. A total of 611 subjects (322 males/289 females) were prospectively diagnosed with MDS using WHO (2001) criteria. Update and re-evaluation of cases using MDS (2008) criteria resulted in 649 MDS cases. Using WHO (2008) criteria, refractory cytopenia with multilineage dysplasia (RCMD) accounted for 68% of total cases, refractory anemia with excess blasts (RAEB), 16.3%; refractory anemia (RA), 6.5%; refractory cytopenia with unilineage dysplasia (RCUD), 4%; and MDS-unclassifiable (MDS-U), 4.5%. Subjects were administered questionnaires and information on previous disease, work histories and exposures to potential etiologic agents such as benzene (BZ) was obtained. A total of 80/649 (13.2%) were determined to have some BZ exposure. The frequency of clonal cytogenetic abnormalities in all MDS was 30%, the most common being +8>del(20)q>del(7q)>del(5q), while the analogous frequency in BZ-exposed cases was only 24%. To further investigate the characteristics of MDS associated with BZ, we identified a subset of cases with high BZ exposure. These BZ signal cases were each matched by age and gender to two cases with no known BZ exposure. When contrasting BZ signal cases vs matched cases with no BZ exposure, we found a high odds ratio (OR) for the WHO subtype MDS-U (OR=11.1), followed by RAEB and RCUD (OR=1), RA (OR=0.7) and RCMD (OR=0.6). Multilineage dysplasia with abnormal eosinophils (MDS-Eo) was strongly associated with BZ exposure, whereas the relative risk of clonal cytogenetic abnormalities was reduced for high BZ-exposed cases (OR=0.5). These findings are strongly indicative that MDS subtypes are influenced by BZ exposure, and taken together with previous studies, the features of MDS-Eo suggest that altered immune regulation plays a major role in the pathogenesis of MDS following chronic exposure to BZ.

A hospital-based case control study of aplastic anemia in Shanghai, China.

We report results of a hospital-based case control study of 137 consecutive patients diagnosed with aplastic anemia (AA) in participating hospitals over a 4-year period. Diagnoses were made by a single laboratory, subjects were age- and gender-matched to two controls and interviewed concerning previous disease, work histories and exposures to potential etiologic agents. Analysis was conducted on two distinct subgroups: severe aplastic anemia (SAA) and moderate aplastic anemia (MAA). In univariate regression models, the strongest associations were observed for exposure to benzene and SAA (OR=3.12, 95% CI=1.12-8.65) and life on a farm and MAA (OR=3.08, 95% CI=1.44-6.56). Benzene exposure did not show a strong dose-response relationship with either subtype. When accounting for all of the potential confounders we considered in conditional regression models, the previous relationships persisted. Other explanatory variables included hair-dye use for MAA and farm exposures, such as livestock for SAA, although most of these additional variables fell just short of statistical significance. Adjusted R-squared values were only 10% for each subtype, leaving 90% of AA occurrence unexplained. Our results suggest that: (a) benzene exposure is more strongly related to SAA than MAA, (b) farm and livestock exposures are related to both forms of AA, confirming some previous results, and (c) a large percentage of AA remains unexplained, which may indicate that individual susceptibility has a major influence on AA occurrence.

Peripheral blood effects in benzene-exposed workers.

The hematotoxic effects of benzene exposure may be important in the occurrence of subsequent health effects. We sought to provide further information on peripheral blood effects by studying 928 workers in five factories in and around Shanghai, China exposed to a wide range of benzene concentrations. Specifically, we sought to investigate which blood indices are more strongly related to benzene exposure and which concentration levels of benzene result in peripheral blood changes. Lifestyle habits and demographic information was obtained via questionnaire, and potentially important genetic influences were determined by assessing single nucleotide polymorphisms in four genes (NQO1, MPO, CYP2E1, GSTT1). Weekly benzene exposure estimated from individual monitoring results ranged from 0.07 to 872 mg/m(3) with a median value of 7.4 mg/m(3). Twelve peripheral blood indices were examined. Stronger effects on peripheral blood were seen for red cell indices such as anemia and macrocytosis, albeit at higher (>10 ppm) exposure levels. The most sensitive parameters to benzene appeared to be neutrophils and the mean platelet volume (MPV), where effects were seen for benzene air concentrations of 7.8-8.2 ppm. Toluene exposure is a potential confounder for some peripheral blood effects, pointing to the need to scrutinize levels of both compounds in the occupational environment.

Prospective analysis of clinical and cytogenetic features of 435 cases of MDS diagnosed using the WHO (2001) classification: a prognostic scoring system for predicting survival in RCMD.

We characterized the prevalence, clinical and cytogenetic characteristics and survival of 435 patients diagnosed with de novo MDS in a single laboratory according to WHO criteria, and compared the utility of different scoring systems to predict survival for individual subtypes of MDS. The mean follow-up period was 25.1 (5.5-53.2) months. Our results confirm major differences in the age-distribution and prevalence of individual subtypes of MDS between Asian and Western patients with a median age of 58 years and a predominance of RCMD (69.9%). Survival rates were similar to those reported in the West: the 3-year survival rate for MDS was 46.7% with a median survival time for RCMD of 38 months and RAEB, 10 months. We found that the IPSS and WPSS scoring systems, which are weighted heavily by blast cell count and karyotype, were not independent predictors for survival in RCMD patients. Multivariate analysis demonstrated that a scoring system based on age (> or =60 years), ANC (<1.0 x 10(9)/L), Hb (<90 g/L), number of cytopenias and complex karyotype is a more useful predictor of survival in RCMD.

Characterization of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Shanghai, China: molecular and cytogenetic characteristics, IgV gene restriction and hypermutation patterns.

The clinical, cytogenetic and molecular features of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a disease previously considered to be rare in Asia, were examined in consecutive series of 70 cases diagnosed by our laboratory over a 30-month period. Clonal abnormalities were observed in 80% of CLL/SLL cases using a combination of conventional cytogenetic and fluorescence in situ hybridization (FISH) analysis. Those involving 14q32/IGH were the most frequent (24 cases), followed by trisomy 12 and 11q abnormalities. IgV(H) gene usage was non-random with over-representation of V(H)4-34, V(H)3-23 and a previously unreported increase in V(H)3-48 gene use. Somatic hypermutation (SHM) of IgV(H) germline sequences was observed in 56.5% of cases with stereotyped patterns of SHM observed in V(H)4-34 heavy chain complimentary-determining (HCDR1) and framework region CFR2 sequences. These findings in a Chinese population suggest subtle geographical differences in IgV(H) gene usage while the remarkably specific pattern of SHM suggest that a relatively limited set of antigens may be involved in the development of this disease worldwide. IgV(H) gene mutation status was a significant predictor of initial survival in CLL/SLL. However, an influence of karyotype on prognosis was not observed.

Adult precursor B lymphoblastic leukemia in Shanghai, China: characterization of phenotype, cytogenetics and outcome for 137 consecutive cases.

Acute lymphoblastic leukemia (ALL) accounts for 20-30% of adult leukemia in the West. However, detailed studies of B-cell-specific ALL in adult Asian populations are lacking. We diagnosed and characterized 137 consecutive cases of precursor B lymphoblastic leukemia (precursor B-cell ALL) presented to our laboratory in Shanghai using the WHO 2001 classification system. Patient clinical, phenotypic and cytogenetic characteristics were correlated with outcome. In contrast to Western studies, females (71) outnumbered males (66) partly due to an increased prevalence of the CD10- pro B-cell phenotype. Females with a CD10- pro B-cell phenotype exhibited significantly better overall survival than males. The most common cytogenetic abnormality was the Philadelphia chromosome (PH/BCR/ABL) which was found in approximately 37% of the cases. Cases of precursor B cell ALL lacking the PH/BCR/ABL genotype exhibited a pronounced age-dependent, gender prevalence with a modal age in the sixth decade for females compared to the second decade for males. These findings suggest significant geographic heterogeneity in precursor B-cell ALL which may be of both etiological and therapeutic significance.

A prospective study of 728 cases of non-Hodgkin lymphoma from a single laboratory in Shanghai, China.

The frequency of subtypes of lymphoid neoplasms was determined in a prospective series of 831 patients presenting at 29 Shanghai hospitals over a 4-year period. Diagnosis and classification was established in a single laboratory according to the 2001 WHO classification system. The frequency of non-Hodgkin lymphoma was 87.6% (n = 728) and Hodgkin lymphoma was 12.4% (n = 103). The most prevalent NHL subtypes diagnosed using WHO criteria were diffuse large B cell lymphoma (DLBCL), precursor B lymphoblastic leukemia/lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Although a low incidence has been reported in some Asian populations, CLL/SLL was commonly encountered, indicating that chronic lymphoid neoplasms are not rare in Shanghai. Consistent with previous reports, our findings indicate a decrease in the frequency of follicular lymphoma and an increase in T cell neoplasms compared to the West. Precursor T lymphoblastic leukemia/lymphoma, anaplastic large T cell lymphoma, aggressive NK cell leukemia, angioimmunoblastic T cell lymphoma and peripheral T cell lymphoma were prominent subtypes of T cell NHL.

Dithiocarbamates and viral IL-10 collaborate in the immortalization and evasion of immune response in EBV-infected human B lymphocytes.

Epstein-Barr virus (EBV) is implicated in the development of a number of human malignancies including several subtypes of non-Hodgkin lymphoma (NHL) [G. Pallesen, S.J. Hamilton-Dutoit, X. Zhou, The association of Epstein-Barr virus (EBV) with T cell lymphoproliferations and Hodgkin's disease: two new developments in the EBV Field, Adv. Cancer Res. 62 (1993) 179-239]. Lymphoproliferative disease and NHL occurring in severely immunosuppressed individuals almost always involve EBV and have been extensively studied and modeled in vitro. EBV has also been causally associated with some cases of NHL occurring in otherwise immunocompetent individuals. However, a direct role for EBV in the pathogenesis of neoplasms developing in the presence of an otherwise competent immune system has not been established. We investigated potential interactions between dithiocarbamates (DTC), an important class of thiono-sulfur compounds, and EBV leading to immortalization of human B lymphocytes and evasion of cell-mediated immune response in culture. Primary lymphocyte cultures employing wild-type and recombinant EBV mutants were used to assess the respective roles of DTC and viral genes in lymphocyte transformation and survival. Pretreatment of EBV-infected human B lymphocytes with DTC directly enhanced transformation in the absence of T cells (5 nM) and independently increased survival of transformed cells in the presence of competent autologous T cells (10 nM). Both DTC-induced transformation and immortalization of EBV-infected B lymphocytes were dependent on the expression of viral IL-10. These results provide a biological basis for studying collaborations between chemical and virus that alter lymphocyte biology, and provide a rationale for further molecular epidemiology studies to better understand the potential influence of these interactions on the development of NHL and perhaps other viral-associated malignancies.

[Cytogenetic and interphase FISH studies in the diagnosis of malignant lymphomas].

OBJECTIVE: To evaluate the role of cytogenetic study and interphase FISH analysis in differential diagnosis of patients with clinical and/or cytological diagnosis as lymphoma or "suspicious for lymphoma". METHODS: Routine histology, immunohistochemistry, cytogenetics and interphase FISH studies were used to assess 223 cases with superficial lymph nodes of not less than 1. 5 cm in diameter. The probe used in the interphase FISH assays is the Vysis' LSI IGH Dual Color, Break Apart Rearrangement Probe. RESULTS: Based on these studies, forty-four patients were diagnosed as Hodgkin's lymphomas ( HL) , 162 as Non-Hodgkin's lymphomas ( NHL) , 11 with benign diseases and 4 as other malignancies, while the remaining 2 cases were discarded due to tissue necrosis. Using interphase FISH, abnormalities of immunoglobulin heavy chain gene (IGH) were detected in 6/44 (13.6%) and 83/162 (51.2%) in the HIL and NHL cases, respectively, while none was observed in 11 cases with a benign disease (P <0. 001). Combining cytogenetics and FISH studies, the detection rates for HL and NHL cases then increased to 15.9% and 77. 8%, respectively, otherwise, 3 of whom could not have made definite diagnosis. CONCLUSION: Interphase FISH assay is a rapid and sensitive tool for detecting IGH abnormalities. Both cytogenetics and interphase FISH analyses may play a significant role in diagnosis of lymphomas.

The TNF-alpha 238A polymorphism is associated with susceptibility to persistent bone marrow dysplasia following chronic exposure to benzene.

Chronic exposure to benzene can result in transient hematotoxicity (benzene poisoning, BP) or persistent bone marrow pathology including dysplasia and/or acute myeloid leukemia. We recently described a persistent bone marrow dysplasia with unique dysplastic and inflammatory features developing in individuals previously exposed to benzene (BID) [Irons RD, Lv L, Gross SA, Ye X, Bao L, Wang XQ, et al. Chronic exposure to benzene results in a unique form of dysplasia. Leuk Res 2005;29:1371-80]. In this study we investigated the association of single nucleotide polymorphisms (SNP) (-863 (C-->A), -857 (C-->T), -308 (G-->A), -238 (G-->A)) in the promoter region of the cytokine, tumor necrosis factor-alpha (TNF-alpha) on the development of BP, persistent BID and de novo myelodysplastic syndrome (MDS) in 394 individuals. Only the -238 (G-->A) polymorphism was significantly associated with the development of BID (odds ratio (OR)=7.4; 95% C.I. 1.23-44.7) and was specific for BID and not de novo MDS or BP. These findings are consistent with a role for inflammation in the development of BID and suggest that cell-specific alterations in TNF-alpha expression may promote clonal selection in the evolution of neoplastic hematopoietic disease.

Aggressive natural killer cell leukemia: report of a Chinese series and review of the literature.

Aggressive natural killer cell leukemia (ANKL) is a rare Epstein-Barr virus (EBV)-associated fulminating disease that is widely disseminated at diagnosis. Because of its typically extranodal presentation, differing degrees of NK cell involvement, and varying bone marrow pathology, ANKL can be confused with a reactive process. These features, coupled with a rapidly fatal course, have hampered systematic study of the pathogenesis of ANKL. Nine cases of ANKL were diagnosed and characterized by a single laboratory over a 2-year period. Constant features at presentation included disseminated disease, high fever, bone marrow involvement, and a high lactate dehydrogenase index. All cases were positive for EBV early region protein and negative for latent membrane protein 1, and all had a germline T-cell receptor gene configuration. Peripheral blood counts were variable, with severe thrombocytopenia being the most frequently encountered abnormality (7 of 9 cases). Hematophagocytosis, dyserythropoiesis, and stromal degeneration were the most frequent findings in the bone marrow. Neoplastic cells in the bone marrow were consistently CD2+, CD56+, CD45+, CD34-, CD117-, CD4-, and surface CD3-. Most cases were HLA-DR+ (8/9) and CD8- (8/9). Complex clonal cytogenetic abnormalities were found in 8 of 9 cases. Because of its aggressive course, rapid and accurate diagnosis of ANKL is essential for a better understanding of the etiology, pathogenesis, and treatment of the disease.

Benzene exposure in the shoemaking industry in China, a literature survey, 1978-2004.

This article presents a summary of benzene exposure levels in the shoemaking industry in China reported in the Chinese medical literature between 1978 and 2004. A comprehensive search identified 182 papers reporting such exposure data. These papers could be classified into two categories: benzene poisoning case reports and industrial hygiene surveys. From each paper, the following information was abstracted whenever available: location and year of occurrence, occupation and/or task involved, benzene content in adhesives/solvents, work environment, working conditions, working hours, diagnosis, and air monitoring data of benzene. A total of 333 benzene measurements (88 averages, 116 minimums, 129 maximums) in the shoemaking industry were reported in the 182 papers identified. The data were analyzed in terms of geographical location, time period, type of ownership (state, township, or foreign), type of report (benzene poisoning reports vs. industrial hygiene surveys), and job title (work activity) or process. The reported data covered a wide range; some measurements were in excess of 4500 mg/m(3). Thirty-five percent of the reported benzene concentrations were below 40 mg/m(3), which was the national occupational exposure limit (OEL) for benzene between 1979 and 2001. The remaining 65% measurements, which exceeded the national OEL in effect at the time, and were distributed as follows: 40-100 mg/m(3), 11%; 100-300 mg/m(3), 21%; 300-500 mg/m(3), 13%; and 500+ mg/m(3), 20%. However, only 24% of the reported measurements after 2002 were below 6 mg/m(3), i.e., Permissible Concentration-Time Weighted Average (PC-TWA) and 10 mg/m(3), i.e., Permissible Concentration-Short Term Exposure Limit (PC-STEL), the newly amended benzene OELs in effect after May 2002. The data demonstrated that the majority of the facilities in the shoemaking industry reported in the literature were not in compliance of the OEL for benzene in effect at the time. Overall, the data show a clear downward trend of benzene exposure levels over the years, particularly after the introduction of the new lower OEL in 2002. Even though substantially lower when compared to levels in the past, current benzene exposure measurements from the literature review suggest that many facilities in the shoemaking industry in China have benzene concentrations that are still above the new OEL. The reported data, stratified by job, year and survey reason, can be used as part of the information and analysis for developing a job-exposure matrix in retrospective exposure assessment and thus may be part of the information used in developing historical exposure estimates in epidemiologic studies of shoe workers.

Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations.

We report a prospective study of 174 unselected adult de novo acute myeloid leukemia (AML) cases diagnosed using the WHO classification. Of those, 57 (33%) were AML with recurrent cytogenetic abnormalities, 41 were (24%) AML with multilineage dysplasia, 74 (42%) were AML not otherwise categorized, and two were acute leukemias of ambiguous lineage. Clonal cytogenetic abnormalities were detected in 64% of the WHO AML cases with t(15;17) (15%), t(8;21) (12%), +8 (11%), -7/del7q (8%) and del9q (5%) being the most common ones. The FLT3/ITD mutations (FMS-like tyrosine kinase 3/internal tandem duplication) were observed in 12% of the WHO AML cases, which is much lower than ones in the literature, while the 6% incidence of the FLT3-activating loop mutations (either FLT3/D835 or FLT3/I836) was comparable with others. Both mutations were associated with leukocytosis. Our study also suggests that the FLT3 mutations are biomarkers independent of cytogenetic characteristics.