Optimized Cytogenetic Risk-Group Stratification of KMT2A-Rearranged Pediatric Acute Myeloid Leukemia.

Comprehensive international consensus on cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1,256 children with KMT2A-r AML aimed to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs), and secondly, to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared to our previous study, three additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8% to 76.2%; P<0.01). ACAs occurred in 46.8% of 1,200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P<0.01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcome was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate the five adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcome, and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.

Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group.

PURPOSE: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

New highly divergent rRNA sequence among biodiverse genotypes of Enterocytozoon bieneusi strains isolated from humans in Gabon and Cameroon.

Intestinal microsporidiosis due to Enterocytozoon bieneusi is a leading cause of chronic diarrhea in severely immunocompromised human immunodeficiency virus (HIV)-positive patients. It may be a public health problem in Africa due to the magnitude of the HIV pandemic and to poor sanitary conditions. We designed two prevalence studies of E. bieneusi in Central Africa, the first with HIV-positive patients from an urban setting in Gabon and the second with a nonselected rural population in Cameroon. Stool samples were analyzed by an immunofluorescence antibody test and PCR. Twenty-five out of 822 HIV-positive patients from Gabon and 22 out of 758 villagers from Cameroon were found to be positive for E. bieneusi. The prevalence rates of the two studies were surprisingly similar (3.0% and 2.9%). Genotypic analysis of the internal transcribed spacer region of the rRNA gene showed a high degree of diversity in samples from both countries. In Gabon, 15 isolates showed seven different genotypes: the previously reported genotypes A, D, and K along with four new genotypes, referred to as CAF1, CAF2, CAF3, and CAF4. In Cameroon, five genotypes were found in 20 isolates: the known genotypes A, B, D, and K and the new genotype CAF4. Genotypes A and CAF4 predominated in Cameroon, whereas K, CAF4, and CAF1 were more frequent in Gabon, suggesting that different genotypes present differing risks of infection associated with immune status and living conditions. Phylogenetic analysis of the new genotype CAF4, identified in both HIV-negative and HIV-positive subjects, indicates that it represents a highly divergent strain.

Detection of Aspergillus galactomannan antigenemia to determine biological and clinical implications of beta-lactam treatments.

Detection of Aspergillus galactomannan (GM) in serum with the Platelia Aspergillus enzyme immunoassay (EIA) is useful for diagnosing invasive aspergillosis. From May 2003 to November 2004, 65 patients who did not develop aspergillosis had at least two positive sera while receiving a beta-lactam treatment (GM index [GMI], >or=0.5). Of the 69 treatment episodes scored, 41 consisted of a beta-lactam other than piperacillin-tazobactam (n=29), namely, amoxicillin-clavulanate (n=25), amoxicillin (n=10), ampicillin (n=3), or phenoxymethylpenicillin (n=2). In all cases, antigenemia became negative 24 h to 120 h upon stopping the antibiotic. Monitoring of 35 patients, including 26 with hematological malignancies, revealed three antigenemia kinetic patterns: each was observed with any drug regimen and consisted of a persistent GMI of >2.0 (65.7%), >0.5, and

The DNA sequence of chromosome I of an African trypanosome: gene content, chromosome organisation, recombination and polymorphism.

The African trypanosome, Trypanosoma brucei, causes sleeping sickness in humans in sub-Saharan Africa. Here we report the sequence and analysis of the 1.1 Mb chromosome I, which encodes approximately 400 predicted genes organised into directional clusters, of which more than 100 are located in the largest cluster of 250 kb. A 160-kb region consists primarily of three gene families of unknown function, one of which contains a hotspot for retroelement insertion. We also identify five novel gene families. Indeed, almost 20% of predicted genes are members of families. In some cases, tandemly arrayed genes are 99-100% identical, suggesting an active process of amplification and gene conversion. One end of the chromosome consists of a putative bloodstream-form variant surface glycoprotein (VSG) gene expression site that appears truncated and degenerate. The other chromosome end carries VSG and expression site-associated genes and pseudogenes over 50 kb of subtelomeric sequence where, unusually, the telomere-proximal VSG gene is oriented away from the telomere. Our analysis includes the cataloguing of minor genetic variations between the chromosome I homologues and an estimate of crossing-over frequency during genetic exchange. Genetic polymorphisms are exceptionally rare in sequences located within and around the strand-switches between several gene clusters.