Jean-Yves Cahn

Dioxin emissions from a solid waste incinerator and risk of non-Hodgkin lymphoma.

Background It is not clear whether low environmental doses of dioxin affect the general population. We previously detected a cluster of patients with non-Hodgkin lymphoma around a French municipal solid waste incinerator with high dioxin emissions. To explore the environmental route suggested by these findings, we carried out a population-based case-control study in the same area. Methods We compared 222 incident cases of non-Hodgkin lymphoma diagnosed between 1980 and 1995 and controls randomly selected from the 1990 population census, using a 10-to-1 match. Dioxin ground-level concentrations were modeled with a second-generation Gaussian-type dispersion model, yielding four dioxin exposure categories. The latter were linked to individual places of residence, using Geographic Information System technology. Results The risk of developing non-Hodgkin lymphoma was 2.3 times higher (95% confidence interval = 1.4–3.8) among individuals living in the area with the highest dioxin concentration than among those living in the area with the lowest dioxin concentration. No increased risk was found for the intermediate dioxin exposure categories. Adjustment for a wide range of socioeconomic characteristics at the block group level did not alter the results. Conclusion Although emissions from incinerators are usually not regarded as an important source of exposure to dioxins compared with other background sources, our findings support the hypothesis that environmental dioxins increase the risk of non-Hodgkin lymphoma among the population living in the vicinity of a municipal solid waste incinerator.

Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Allogeneic haematopoietic stem‐cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM‐TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non‐relapse mortality (NRM), overall survival (OS) and progression‐free survival (PFS) were analysed. One hundred and forty‐seven patients, aged 20–68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre‐transplant thrombocytopenia. Four‐year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31–50), 32% (95%CI: 24–43) and 39% (95%CI 30–48), respectively. Multivariate analysis indicated that HLA‐identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS.

Increased risk of non-Hodgkin lymphoma and serum organochlorine concentrations among neighbors of a municipal solid waste incinerator

Organochlorine chemicals may contribute to an increased risk of non-Hodgkin lymphoma (NHL) within non-occupationally exposed populations. Among these chemicals, dioxins and furans were mainly released by municipal solid waste incinerators (MSWIs) until a recent past in France, a source of exposure that is of public concern. We investigated organochlorines and the risk of NHL among neighbors of a French MSWI with high levels of dioxin emissions (Besançon, France), using serum concentrations to assess exposure. The study area consisted of three electoral wards, containing or surrounding the MSWI. Pesticides, dioxins, furans, and polychlorinated biphenyls (PCBs) were measured in the serum of 34 newly diagnosed NHL cases (2003-2005) and 34 controls. Risks of NHL associated with each lipid-corrected serum concentration were estimated using exact logistic regression. The pesticides β-hexachlorocyclohexane (odds ratio [OR]=1.05, 95% confidence interval [CI]=1.00-1.12, per 10 ng/g lipid) and p,p dichloro-diphenyl-trichloroethane (DDT) (OR=1.20, 95% CI=1.01-1.45, per 10 ng/g lipid) were associated with NHL risk. Evidence indicated an increased NHL risk associated with cumulative WHO(1998)-toxic equivalency factor (TEQ) concentrations (dioxins, OR=1.12, 95% CI=1.03-1.26; furans, OR=1.16, 95% CI=1.03-1.35; dioxin-like PCBs, OR=1.04, 95% CI=1.00-1.07; and total TEQ, OR=1.04, 95% CI=1.01-1.05), as well as with non dioxin-like PCBs (OR=1.02, 95% CI=1.01-1.05, per 10 ng/g lipid). Most congener-specific associations were statistically significant. This study provides strong and consistent support for an association between serum cumulative WHO(1998)-TEQ concentrations, at levels experienced by people residing in the vicinity of a polluting MSWI, and risk of NHL.

Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B(low)) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B(low) in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B(low) and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.

Epidemiology of invasive fungal infections during induction therapy in adults with acute lymphoblastic leukemia: a GRAALL-2005 study.

Abstract Little data have been published concerning invasive fungal infections during treatment of acute lymphoblastic leukemia (ALL). Patients included between May 2006 and October 2012 in the multicenter phase III trial for newly diagnosed ALL (GRAALL-2005) were retrospectively reviewed for the occurrence of IFI using the EORTC modified criteria. These patients did not routinely receive antifungal prophylaxis. Among 969 patients included (median age 47 years), 65 (6.7%) developed IFI during induction chemotherapy: 26 (3.3%) invasive aspergillosis (IA), 33 (3.4%) invasive candidiasis (IC) and six other IFI. For IA, the median time between induction therapy and IA diagnosis was 20 days. Diagnosis was probable in 22 cases and proven in four. Aspergillus antigen in serum was tested in all cases and positive in 24. Overall 12-week mortality after diagnosis of IA was 5/26 and attributable mortality related to the infection was 4/26 (15.4%). For IC, the median time between induction therapy and diagnosis was 19 days. Diagnosis was proven in 29 episodes. Candida albicans was the major pathogen in yeast infections (16/27). Overall 12-week mortality after diagnosis of IC was 8/33 (24.2%) and attributable mortality related to the infection was 7/33. The median delay between induction chemotherapy initiation and attributable death related to IC was 15 days. These findings may help to optimize the future management of ALL patients, and as in AML advocate systematic monitoring and the development of prophylactic or preemptive antifungal treatments.

Genetic polymorphisms in ARID5B, CEBPE, IKZF1 and CDKN2A in relation with risk of acute lymphoblastic leukaemia in adults: a Group for Research on Adult Acute Lymphoblastic Leukaemia (GRAALL) study.

The incidence of acute lymphoblastic leukaemia (ALL) in adults is approximately one per 200 000, with a peak after 50 years of age. It is a highly heterogeneous disease with inferior long-term disease-free survival rates of 40% compared to 80% in paediatric ALL. Improvements in outcome are largely due to the application of paediatric ALL regimens (Faderl et al, 2010). Paediatric ALL, with a peak incidence between 2 and 5 years of ages, has been recognised to have an inheritable component, based on familial cancer registry studies. However, even if genetic markers of ALL can be detected inutero (i.e., ETV6-RUNX1 gene) this does not inevitably lead to ALL. A two-hit model was therefore proposed. Additional leukaemogenic factors include other environmental factors, the immune system, exposure to pathogens and additional genetic mutations (Pui et al, 2008). Genetics have been proposed to play a role in adult cancer susceptibility, although this has been difficult to evaluate because of confounding factors. To our knowledge, no predisposing genetic marker has been proven for adult ALL. In children, ALL accounts for about 25% of all cancers, compared to 1% in adults. Most strikingly is the different frequency of specific subtypes as a function of age. Specifically, adult patients present with higher frequency ALL of T-lineage and the unfavourable BCR-ABL1 translocation; and with lower frequency ALL with favourable biological characteristics (i.e. hyperdiploidy and ETV6-RUNX1 translocation). Furthermore, the higher incidence of ALL in children may reflect the combination of a susceptible stem cell population in early and mid-development, and the necessity of only few mutations to induce the disease (Downing & Shannon, 2002). Recent independent genome-wide association studies showed that ARID5B (AT-rich interactive domain 5B), CEBPE (CCAAT/enhancer-binding protein epsilon) and IKZF1 (Ikaros family zinc finger 1) germline single nucleotide polymorphisms (SNPs) were associated with an inherited risk of paediatric ALL (Papaemmanuil et al, 2009; Trevino et al, 2009; Yang et al, 2010; Xu et al, 2012). This was later verified in a third independent cohort (Prasad et al, 2010). The risk allele of the IKZF1 SNP rs4132601 has been shown to decrease mRNA expression in Epstein–Barr virustransformed lymphocytes, indicating a potential mechanism of the variant to reduce efficiency in B-cell differentiation. Chromosomal deletions of IKZF1 are common and linked to high-risk B-lineage paediatric ALL (Papaemmanuil et al, 2009). The rs10821936 and rs7089424 SNPs in ARID5B are significantly associated with the development of childhood hyperdiploid B-lineage ALL (Papaemmanuil et al, 2009; Trevino et al, 2009). CEBPE is a suppressor of myeloid leukemogenesis and may be involved in translocations of the IGH@ (immunoglobulin heavy chain locus) in B-cell precursor ALL (Papaemmanuil et al, 2009). More recently, the region encoding CDKN2A, CDKN2B (cyclin-dependent kinase inhibitor 2A and 2B) and CDKN2BAS (CDKN2B antisense RNA 1) has been reported to influence ALL risk in children, independently of other previously reported SNPs. Furthermore, this SNP has been significantly associated with both Band T-lineage ALL incidence (Sherborne et al, 2010). Because all these genes are involved in the regulation and differentiation of haematopoietic progenitors, we aimed to validate whether these low-penetrance susceptibility alleles contribute to the risk of developing ALL in adults. A total of 150 adult patients with newly diagnosed ALL were included in this study. Patients were enrolled on Group for Research on Adult Acute Lymphoblastic Leukaemia (GRAALL) prospective multi-centric clinical trials GRAALL03 (16–60 years), GRAALL05 (18–60 years) and GRAAPH (18– 60 years) between 2006 and 2010 (Huguet et al, 2009). Due to the inclusion criteria, this study contained relatively few Philadelphia chromosome positive t(9:22) cases. Patients who achieved complete remission and who did not receive bone marrow transplantation before completing remission induction treatment were included. Complete remission rate was 93 5% for the GRAALL03 (similar to GRAALL05, which is not yet completed). Informed consent was obtained according to the Declaration of Helsinki. Protocols were approved by the local Review and Ethics Committees. Immunophenotyping was assessed according to the guidelines of the European Group for the Immunological Characterization of Leukaemias (EGIL, Table I) (Huguet et al, 2009). Unfortunately, data regarding ethnicity was not available; however, data from the French population statistics suggests <10% were not of European descent. DNA was extracted from EDTA venous blood samples using the QIAamp DNA Blood Mini Kit (Qiagen, Les Ulis,

Iron for proliferation of cell lines and hematopoietic progenitors: Nailing down the intracellular functional iron concentration.

Iron is an essential nutrient which must be provided in sufficient amounts to support growth of eukaryotic cells. All organisms devote specialized pathways to ensure proper delivery. Yet, a quantitative assessment of the intra-cellular iron concentration needed to allow the cell cycle to proceed in mammalian cells is missing. Starting from iron-depleted cell lines or primary hematopoietic progenitors prepared with clinically implemented iron chelators, replenishment via transferrin and other iron sources has been quantitatively monitored through the main endogenous markers of the cellular iron status, namely proteins involved in the uptake (transferrin receptor), the storage (ferritin), and the sensing (Iron Regulatory Proteins) of iron. When correlated with measurements of iron concentrations and indicators of growth, this minimally intrusive approach provided an unprecedented estimate of the intracellular iron concentration acting upon iron-centered regulatory pathways. The data were analyzed with the help of a previously developed theoretical treatment of cellular iron regulation. The minimal cellular iron concentration required for cell division was named functional iron concentration (FIC) to distinguish it from previous estimates of the cellular labile iron. The FIC falls in the low nanomolar range for all studied cells, including hematopoietic progenitors. These data shed new light on basic aspects of cellular iron homeostasis by demonstrating that sensing and regulation of iron occur well below the concentrations requiring storage or becoming noxious in pathological conditions. The quantitative assessment provided here is relevant for monitoring treatments of conditions in which iron provision must be controlled to avoid unwanted cellular proliferation.

Dispersion Modelling as a Dioxin Exposure Indicator in the Vicinity of a Municipal Solid Waste Incinerator: a Validation Study

Whether low environmental doses of dioxin affect the general population is the matter of intense debate and controversy. In a previous study, we found a 2.3-fold risk for non-Hodgkin lymphoma associated with residence in areas classified as highly exposed to dioxin emitted from a municipal solid waste incinerator (MSWI) (Besançon, France). The main limitation lay within the use of a first-generation Gaussian-type dispersion model as a proxy for dioxin exposure, since its accuracy had not been assessed before. The aim of this study was to validate this geographic-based exposure through PCDD/F measurements from soil samples. PCDD/F concentration, pH, organic carbon concentration, cation exchange capacity, and geomorphology and ecology features were assessed for 75 sampling points. In simple terrain (i.e. northeast of the MSWI), a significant association was highlighted between modeled dioxin ground-level air concentrations and log-transformed measured dioxin soil concentrations with a strong gradient across exposure categories. Conversely, in a complex topography situation (i.e. southwest of the MSWI), the model overpredicted ground-level air concentrations, particularly in the high exposure zone. First-generation modeling provided a reliable proxy for dioxin exposure in simple terrain, reinforcing the results of our case-control study. However, a more advanced atmospheric diffusion model should have been used for refined assessment in complex terrain.

Endogenous megakaryocytic colonies underline association between megakaryocytes and calreticulin mutations in essential thrombocythemia

Calreticulin ( CALR ) mutations occur in 20%–25% of myeloproliferative neoplasms (MPN).[1][1],[2][2] At least 40 CALR mutations have been reported to date, all located in exon 9. The most frequent CALR mutations are a 52-bp deletion (type 1) and a 5-bp insertion (type 2). Expression of type 1 CALR

Inflammation is the main risk factor of voriconazole overdose in hematological patients

Aim: Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Methods: Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/l; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using non-parametric or Chi-square tests followed by multivariable analysis. Results: VRC overdoses were significantly associated with high CRP and bilirubin levels, intra-venous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a genetic score1) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/l) was the sole independent risk factor of VRC overdose (p < 0.01). Patients with CRP levels > 96 mg/l had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/l. Conclusion: This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.