The importance of evaluating specific myeloid malignancies in epidemiological studies of environmental carcinogens.

INTRODUCTION: Although myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN) - including chronic myeloid leukemia (CML) - and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are largely clinically distinct myeloid malignancies, epidemiological studies rarely examine them separately and often combine them with lymphoid malignancies, limiting possible etiological interpretations for specific myeloid malignancies. METHODS: We systematically evaluated the epidemiological literature on the four chemical agents (1,3-butadiene, formaldehyde, benzene, and tobacco smoking, excluding pharmaceutical, microbial and radioactive agents, and pesticides) classified by the International Agency for Research on Cancer as having sufficient epidemiological evidence to conclude that each causes "myeloid malignancies." Literature searches of IARC Monographs and PubMed identified 85 studies that we critically assessed, and for appropriate subsets, summarized results using meta-analysis. RESULTS: Only two epidemiological studies on 1,3-butadiene were identified, but reported findings were inadequate to evaluate specific myeloid malignancies. Studies on formaldehyde reported results for AML and CML - and not for MDS or MPN - but reported no increased risks. For benzene, several specific myeloid malignancies were evaluated, with consistent associations reported with AML and MDS and mixed results for CML. Studies of tobacco smoking examined all major myeloid malignancies, demonstrating consistent relationships with AML, MDS and MPN, but not with CML. CONCLUSIONS: Surprisingly few epidemiological studies present results for specific myeloid malignancies, and those identified were inconsistent across studies of the same exposure, as well as across chemical agents. This exercise illustrates that even for agents classified as having sufficient evidence of causing "myeloid malignancies," the epidemiological evidence for specific myeloid malignancies is generally limited and inconsistent. Future epidemiological studies should report findings for the specific myeloid malignancies, as combining them post hoc - where appropriate - always remains possible, whereas disaggregation may not. Furthermore, combining results across possibly discrete diseases reduces the chances of identifying important malignancy-specific causal associations.

Accumulation of Major Linezolid Metabolites in Patients with Renal Impairment.

In patients with renal impairment (n = 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.

Myeloid malignancies after treatment for solid tumours.

The cure rate for several solid tumour malignancies including breast cancers, head and neck cancers, bone cancers, and sarcoma has improved remarkably with the advent of neoadjuvant and adjuvant therapies. Unfortunately, exposure to chemotherapy or radiation as a part of these treatments exposes patients to the risk of subsequent myeloid malignancies. Therapy related myeloid malignancies have certain characteristic findings. They typically arise within 10 years of treatment exposure, they are seen in younger patients, and the greatest risk is in patients who receive therapy with alkylating agents or topoisomerase II inhibitors. Solid tumours whose therapies utilize these agents at higher doses, namely bone/soft tissue cancers, testicular cancer, anal cancer, and brain tumours, appear to be the groups at highest risk for T-MN. Beyond these patients, emerging populations diagnosed with T-MN include prior platinum exposure, and patients requiring G-CSF support with chemotherapy.

Therapy-related myeloid neoplasms in lymphoma survivors: Reducing risks.

Treatment for Hodgkin (HL) and non-Hodgkin's lymphoma (NHL) has changed dramatically in the last fifty years. While there are increasing numbers of long-term survivors, there has been increasing recognition of the long-term toxicities of treatments, particularly therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). The survival for t-MDS/AML is extremely poor. Multiple heterogeneous retrospective studies have reported risk factors for the development of t-MDS/AML. Chemotherapy and radiation therapy have been most closely examined as possible t-MDS/AML risk factors. In this paper, we will review the risks of t-MDS/AML for HL and NHL patients as reported in the literature and assess for any changes over time. In HL patients, the incidence of t-MDS/AML has decreased with a reduction in alkylating agents. In indolent NHL patients, we anticipate decreased incidence of t-MDS/AML as targeted therapies begin to replace cytotoxic chemotherapy.

Therapy-associated leukemic transformation in myeloproliferative neoplasms - What do we know?

Myeloproliferative Neoplasms (MPNs) are a group of progressive diseases that share a common pathogenesis, clinical and laboratory features, as well as a spontaneous risk of secondary AML. Certain MPN therapies have been associated with an increased risk of leukemic conversion, with robust data highlighting the highest rates with 32P, chlorambucil, and pipobroman. Herein, we review risk factors for leukemic transformation, including therapy-related MPN-BP, with a focus on the debate surrounding the potential leukemogenicity of hydroxyurea. Lastly, we discuss emerging studies on the association between ruxolitinib and high grade B-cell lymphomas. We conclude that statistical associations have not implicated hydroxyurea monotherapy as leukemogenic. However, it is difficult to definitely disprove an association, as large prospective, controlled studies with decades of follow-up would be needed to draw conclusions. Overall, the concept of therapy-related neoplasms remains important to the field, and mandates judicious selection and sequencing of therapies for MPN patients.

Smoking is associated with increased risk of myeloproliferative neoplasms: A general population-based cohort study.

BACKGROUND: Former studies on smoking as a risk factor for Philadelphia-negative myeloproliferative neoplasms (MPNs) have mainly been carried out in women's cohorts and studies with various definitions of MPNs. Herein, we conducted a cohort study with register-based follow-up of a general population from Denmark, to validate and substantiate prior observations. METHODS: In the Danish Health Examination Survey cohort, we used the Cox proportional-hazards model adjusted for age, sex, body mass index, and level of education, to calculate hazard ratios (HRs), to investigate, whether daily smokers or occasional/ex-smokers had an increased risk of MPNs compared to never-smokers. RESULTS: From the time of data collection (September 2007 to October 2008) until 1 January 2015, 70 individuals were diagnosed with MPNs among 75 896 study participants. Similar results were observed in both the age and sex adjusted analysis and the multivariable analysis. The multivariable HR of any MPN diagnosis for daily smokers was 2.5 (95% CI: 1.3-5.0). For essential thrombocytosis, polycythemia vera, myelofibrosis, and MPN-unclassified, the HRs were 1.8 (95% CI: 0.5-5.8), 1.7 (95% CI: 0.5-5.8), 4.3 (95% CI: 0.9-19), and 6.2 (95% CI: 1.5-25), respectively. Among occasional/ex-smokers the corresponding HRs were 1.9 (95% CI: 1.1-3.3), 1.5 (95% CI: 0.6-3.7), 0.8 (95% CI: 0.3-2.4), 0.9 (95% CI: 0.2-4.4), and 6.2 (95% CI: 1.8-21). Participants, who smoked >15 g/day, had an overall HR of 3.4 (95% CI: 1.4-8.2) for any MPN diagnosis, while participants who smoked ≤15 g/day, had an overall HR of 2.1 (95% CI: 0.9-4.7). CONCLUSION: Smoking was associated with MPN development when comparing smokers and never-smokers. Further studies investigating smoking in MPNs are warranted to substantiate our findings.

A monocentric retrospective study of 138 therapy-related myeloid neoplasms.

As diagnosing therapy-related myeloid neoplasms (t-MN) is often challenging, we reviewed clinicopathological features of t-MN patients. Medical records of 138 patients, diagnosed with t-MN between 1995 and 2017, were reviewed. Of 138 patients, 80 had t-MDS, 53 t-AML, and 5 t-MDS/MPN (age, 22-88 years; median 64 years; male/female ratio, 0.8). The median latency time was 6 years and 5 months. Of 115 patients, 56 patients received cytotoxic-/radiotherapy for a solid tumor, 56 for hematological malignancy, and 3 for an auto-immune disorder, respectively. Another 21 patients had a combination of 2 disorders. Moreover, 2 patients had 3 previous malignancies. Breast cancer was the most prevalent tumor, followed by low-grade B non-Hodgkin lymphoma. Immunophenotyping and immunohistochemistry showed aberrant expression of B-, T-, or NK-cell markers in 21% and 6%, respectively. In 90% of the patients, dysplasia in ≥ 1 lineage was found. KMT2A fusion gene transcripts were seen in 5%. Cytogenetic analysis showed complex karyotypes (31%) and chromosome 5 and/or 7 abnormalities (40%). Almost 82% of the patients died and the median overall survival was about 1 year. Our study confirms that previous therapy for breast cancer is the most important cause of t-MN. KMT2A fusion genes are prevalent and complex karyotypes and/or chromosomes 5 and/or 7 abnormalities are common.

Shanghai Health Study (2001-2009): What was learned about benzene health effects?

The Shanghai Health Study (SHS) was a large epidemiology study conducted as a joint effort between the University of Colorado and Fudan University in Shanghai, China. The study was funded by members of the American Petroleum Institute between 2001 and 2009 and was designed to evaluate the human health effects associated with benzene exposure. Two arms of the SHS included: an occupational-based molecular epidemiology study and several hospital-based case control studies. Consistent with historical literature, following sufficient exposure to relatively high airborne concentrations and years of exposure, the SHS concluded that exposure to benzene resulted in an increased risk of various blood and bone marrow abnormalities such as benzene poisoning, aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). Non-Hodgkin lymphoma (NHL) was not significantly increased for the exposures examined in this study. Perhaps the most important contribution of the SHS was furthering our understanding of the mechanism of benzene-induced bone marrow toxicity and the importance of identifying the proper subset of MDS relevant to benzene. Investigators found that benzene-exposed workers exhibited bone marrow morphology consistent with an immune-mediated inflammatory response. Contrary to historic reports, no consistent pattern of cytogenetic abnormalities was identified in these workers. Taken together, findings from SHS provided evidence that the mechanism for benzene-induced bone marrow damage was not initiated by chromosome abnormalities. Instead, chronic inflammation, followed by an immune-mediated response, is likely to play a more significant role in benzene-induced disease initiation and progression than previously thought.

Exposure to benzene in a pooled analysis of petroleum industry case-control studies.

Cases of lymphohematopoietic cancer from three petroleum industry cohorts, matched to controls from the respective cohort, were pooled into single study. Average benzene exposure was quantitatively estimated in ppm for each job based on measured data from the relevant country, adjusted for the specific time period, site and job exposure characteristics and the certainty of the exposure estimate scored. The probability of dermal exposure and of peak exposure was also assessed. Before risk was examined, an exposure estimate comparison and rationalisation exercise was performed across the studies to ensure accuracy and consistency of approach. This article evaluates the final exposure estimates and their use in the risk assessments. Overall benzene exposure estimates were low: 90% of participants accumulated less than 20 ppm-years. Mean cumulative exposure was estimated as 5.15 ppm-years, mean duration was 22 years, and mean exposure intensity was 0.2 ppm. 46% of participants were allocated a peak exposure (>3 ppm at least weekly). 40% of participants had a high probability of dermal exposure (based on the relative probability of at least weekly exposure). There were differences in mean intensity of exposure, probability of peak, and/or dermal exposure associated with job category, job site, and decade of exposure. Terminal Operators handling benzene-containing products were the most highly exposed group, followed by Tanker Drivers carrying gasoline. Exposures were higher around 1940-1950 and lower in more recent decades. Overall confidence in the exposure estimates was highest for recently held jobs and for white-collar jobs. We used sensitivity analyses, which included and excluded case-sets on the basis of exposure certainty scores, to inform the risk assessment. The above analyses demonstrated that the different patterns of exposure across the three studies are largely attributable to differences in jobs, site types, and time frames rather than study. This provides reassurance that the previous rationalisation of exposures achieved inter-study consistency and that the data could be confidently pooled.

Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib.

Mutations of calreticulin (CALR) are detected in 25-30% of patients with essential thrombocythemia (ET) or primary myelofibrosis and cause frameshifts that result in proteins with a novel C-terminal. We demonstrate that CALR mutations activated signal transducer and activator of transcription 5 (STAT5) in 293T cells in the presence of thrombopoietin receptor (MPL). Human megakaryocytic CMK11-5 cells and erythroleukemic F-36P-MPL cells with knocked-in CALR mutations showed increased growth and acquisition of cytokine-independent growth, respectively, accompanied by STAT5 phosphorylation. Transgenic mice expressing a human CALR mutation with a 52 bp deletion (CALRdel52-transgenic mice (TG)) developed ET, with an increase in platelet count, but not hemoglobin level or white blood cell count, in association with an increase in bone marrow (BM) mature megakaryocytes. CALRdel52 BM cells did not drive away wild-type (WT) BM cells in in vivo competitive serial transplantation assays, suggesting that the self-renewal capacity of CALRdel52 hematopoietic stem cells (HSCs) was comparable to that of WT HSCs. Therapy with the Janus kinase (JAK) inhibitor ruxolitinib ameliorated the thrombocytosis in TG mice and attenuated the increase in number of BM megakaryocytes and HSCs. Taken together, our study provides a model showing that the C-terminal of mutant CALR activated JAK-STAT signaling specifically downstream of MPL and may have a central role in CALR-induced myeloproliferative neoplasms.

Working environment and myeloproliferative neoplasm: A population-based case-control study following a cluster investigation.

BACKGROUND: Occupational exposures, including those to polycyclic aromatic hydrocarbons (PAH), are suspected risk factors for myeloproliferative neoplasms (MPN). METHODS: We investigated occupational exposures and MPN risk (54 cases and 472 controls) in a population-based case-control study in three rural Pennsylvania counties. Occupational histories, coded to SIC/SOC 1980, were linked to a previously created PAH job-exposure matrix. Odds ratios for industry (17 categories), occupation (26 categories), and PAH exposure were adjusted using logistic regression. RESULTS: No industries or occupations were strongly or consistently associated with increased MPN risk. Analysis of employment duration found that being employed for 5 or more years in transportation, communications, and other public utilities was associated with MPN risk. There was no indication of an association with cumulative PAH exposure. CONCLUSIONS: These few associations did not appear to have a common exposure. This exploratory study does not support the hypothesis that occupational exposure, including PAH, are strong risk factors for MPNs.

Sole abnormalities of chromosome 7 in myeloid malignancies: spectrum, histopathologic correlates, and prognostic implications.

Among 6,565 consecutive abnormal cytogenetic reports at our institution, 3,192 (49%) constituted sole abnormalities, of which 230 (7%) involved chromosome 7: monosomy 7 (n = 98), 7q- (n = 51), der(1;7)(q10;p10) (n = 44), balanced translocations (n = 15), ring 7 (n = 13), and 7p- (n = 9). The most frequent histopathologic correlates were myelodysplastic syndromes (MDS; 28%), acute myeloid leukemia (AML; 17%), secondary or therapy-related MDS/AML (13%), primary myelofibrosis (PMF; 7%), and chronic myelomonocytic leukemia (6%). Monosomy 7 was the most frequent in each one of these disease categories except PMF where 7q- was more frequent. In primary MDS, patients with der(1;7)(q10;p10) (n = 13), compared to those with monosomy 7 (n = 30) or 7q- (n = 15), were less likely (P = 0.04) to display excess blasts or multilineage dysplasia but overall and leukemia-free survival adjusted for these variables revealed no significant difference between the three groups (P = 0.57 and 0.81, respectively). The current study does not prognostically distinguish monosomy 7 from 7q- or der(1;7), in MDS.

Temozolomide-induced severe myelosuppression: analysis of clinically associated polymorphisms in two patients.

Genotyping of putative determinants of temozolomide (TMZ)-induced life-threatening bone marrow suppression was performed in two patients with glioma treated with adjuvant TMZ and radiation therapy. DNA was extracted from the patients' mononuclear cells and genotyping of O-methylguanine-DNA-methyltransferase (MGMT), multidrug resistance (MDR1; also known as ABCB1), NQO1, and GSTP1 genes and analysis for the epigenetic silencing of specific MGMT gene promoters were carried out to evaluate the possible genetic determinants of increased risk of severe TMZ-induced myelosuppression. Although both patients were heterozygous for all ABCB1 single nucleotide polymorphisms and for rs12917 and rs1803965 in the MGMT gene, patient 1 was heterozygous for rs1695 in GSTP1 and rs2308327 in the MGMT gene. This patient also exhibited GG genotype for the MGMT single nucleotide polymorphisms, rs2308321, which is noteworthy for its 0.7% frequency globally. Epigenetic silencing of MGMT gene was not detected in either patient. Two single nucleotide polymorphisms identified in patient 1 (missense I143V and K178R polymorphisms; rs2308321 and rs2308327, respectively) have recently been shown to correlate with an increased risk of severe TMZ-induced myelosuppression. The polymorphisms identified in patient 2 have not been associated with an increased risk of severe TMZ-induced myelosuppression. Genotyping analyses of larger patient populations administered TMZ are required to validate the genetic determinants of severe TMZ-induced myelosuppression.

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output.

The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.

[Practice of recognizing benzene-caused occupational diseases in 2006]. / Beurteilung myeloischer und lymphatischer Neoplasien bei beruflicher Benzolexposition. Anerkennungspraxis benzolbedingter Erkrankungen im Jahr 2006.

BACKGROUND AND PURPOSE: Benzene-caused hematologic diseases can be recognized as occupational diseases (ODs) if they fulfill the legal requirements specified under No. 1303 of the appendix of the German ordinance on ODs. The aim of this study is to analyze the most important criteria that determined whether these diseases were recognized or rejected as ODs according to No. 1303 in 2006. METHODS: In 2006, 70 suspected cases of OD No. 1303 reported in North Rhine-Westphalia were examined in terms of diagnosis, notifiers, cumulative benzene exposures, professions, coexposures, delays in notification, latency periods, interim periods, and recognition criteria. RESULTS: 70 benign and malignant diseases of myeloid and lymphoid origin were reported as suspected ODs, among them 41 B-cell non-Hodgkin's lymphomas (B-cell NHL). Latency periods ranged between 14 and 57 years (median 37; mean 36.3+/-11.4; n=45), estimated cumulative benzene exposures varied from 0 to 144 ppm-years (median 12; mean 11.4+/-22.8; n=59). Four of 70 suspected cases were recognized as OD No. 1303. In 37 cases (52.9%), the nature of the disease was assessed as being nontypical of OD No. 1303, in 50 cases (71.4%), no sufficient benzene exposure could be found. Mature-cell NHL and Hodgkin's lymphoma were not recognized as OD. Cumulative benzene exposures

Delayed effects of long-term administration of granulocyte colony-stimulating factor to mice.

We studied the effects of chronic administration of granulocyte colony-stimulating factor in nonmobilizing doses to mice. Over 18 months of the study, 55% animals of the treatment group died of unknown cause, blood diseases and tumors were found in 20% mice, and in 5% animals pathological changes were absent. Control mice had no diseases (normal values of total and differential leukocyte count). The diagnoses made over the first 7 months mainly included myeloproliferative diseases. Solid tumors were found at later terms. Suppurative inflammation at the site of injection was observed in all mice after 3-month treatment with granulocyte colony-stimulating factor. Our results indicate that chronic administration of granulocyte colony-stimulating factor in low doses leads to the development of etiologically different tumors and sharply reduced animal life span. The use of granulocyte colony-stimulating factor during allogeneic transplantation of hemopoietic stem cells can be hazardous for donors.