Our observations suggest that ACh polarizes DC toward a Th2-promoting profile.

Myelodysplastic syndromes (MDS) include a group of heterogeneous hematological disorders with a variable risk of leukemic evolution and short survival. Around 40-50% of patients show abnormal karyotypes that are mostly characterized by monosomies or deletions. Cytogenetic findings are an independent prognostic factor and the International prognostic scoring system (IPSS) differentiates three cytogenetic categories, despite the Intermediate one being heterogeneous. The aim of this study, including 421 Argentinean patients with primary MDS, is to characterize the cytogenetic profile, to test its prognostic value and to compare partial and monosomal karyotypes against other cytogenetic findings. An abnormal karyotype (median survival: 26 months) was observed in 176 patients. The presence of complex karyotypes, number of alterations, and the IPSS cytogenetic groups showed significant differences for predicting outcome. Behavior of patients with isolated deletions (median survival: 49 months) did not differ from those with normal karyotype (56 months, P 5 0.654) or Good prognostic findings (43 months, P 5 0.371). However, a worse prognosis was observed when another alteration was added (31 months, P 5 0.043). Karyotypes with autosomal monosomies (median survival: 16 months) had a prognostic impact similar to other Poor cytogenetic findings (17 months, P 5 0.626). In our population classified according to French-American-British (FAB) or World Health Organization (WHO), this new categorization of cytogenetic abnormalities, recognizing three different risk groups, showed an independent prognostic impact and a better discriminating power than the IPSS categories. It can be concluded that all isolate deletions (excluding 7q-) are good prognostic findings and all monosomies (excluding Y chromosome loss) are bad indicators. Am. J. Hematol. 86:540-545, 2011. V

Specific NRAS oncogene missense mutations have been frequently found in some tumors and several hematological diseases, especially in those of myeloid origin. There is a wide range of PCR-based methods for screening and detection of NRAS exon 1 single-base substitutions. However, there are disadvantages and ambiguities associated with these techniques because all of them require either separate probes, separate PCR amplifications, or complicated post-PCR manipulations. This report describes a new approach for detection of NRAS gene mutations at codon 12 and 13 based on the DNA heteroduplex analysis method. The strategy relies upon differential electrophoretic behavior of induced heteroduplex molecules formed by cross-hybridization of two PCR-amplified species, the sample under analysis and the synthetic universal heteroduplex generator (UHG). The screening of a panel of all codon 12 and 13 NRAS mutant DNA variants indicated that this approach discriminates all 12 relevant mutations. The sensitivity of the method was estimated by a competitive assay where mutant alleles could be detected at a dilution level of 1 to 16 wild-type alleles. This UHG technology was tested on some clinical samples previously studied by PCR-ASO. This methodology is highly specific, sensitive, and achieves an appreciable reduction in workload and time because it requires one PCR amplification followed by polyacrylamide gel electrophoresis in standard conditions. We propose that this new approach may be applied as an alternative strategy for codon 12-13 NRAS mutations and it could be easily incorporated into the range of routine assays performed in oncology laboratories.

The impaired hematopoiesis in acquired aplastic anemia (AA) results from immune-mediated mechanisms. We characterized polymorphisms implicated in controlling type-1 cytokine production in 69 patients with AA. Our data suggest that the studied polymorphisms are not associated with susceptibility in the overall AA population. However, the presence of the higher expressing TNF - 308A allele was associated with younger age (p = 0.0297) and more profound neutropenia (p = 0.0312), and over-represented in patients with very severe AA (p = 0.0168). The higher producing IFNG 12 CA-repeat allele showed strong linkage disequilibrium with the + 874T allele, and was associated with a lower hemoglobin level (p = 0.0351). Also, the presence of at least one higher expressing variant was more frequent among patients responding to immunosuppressive treatment (p = 0.0519). Our findings suggest that the presence of higher expressing variants of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in AA patient genotypes could be related to clinical parameters, disease severity and therapy outcomes.

A small primary or secondary tumor load can occasionally induce more deleterious effects than a histologically identical larger one. In the four murine models studied herein this enhanced tumor aggressiveness could not be attributed to NRAS mutations or other hereditary changes, differential vascularization of live tumor tissues, or necrosis content. Instead, the main tumor feature associated with a more aggressive behavior was the presence of a high number of vessels, sometimes filled with inflammatory cells, inside a tumor area, which we have identified and designated as the transition zone between the live and the necrotic zones. Our experiments suggest that during tumor growth, different cachectic factors are produced within the transition and necrotic zones by dying tumor cells and by tumor infiltrating macrophages only reaching the general circulation through the vessels present in the transition zone. Therefore, a small tumor displaying high vascularization of its transition area could be harmful to its host, while, in contrast, a large tumor could behave as a relatively benign one if its transition zone exhibited little or no vascularization, and in consequence its cachectic factors remained "trapped." Similar histological images to those observed in mice were seen in a significant percentage of human cancer biopsies, raising the possibility that such images might have a prognostic value.

There are previously reported data describing differences between Asian and European patients with Myelodysplastic Syndromes (MDS), few direct comparisons based on cancer registration characteristics or using cohorts to validate scoring systems. This is the first study from South-America, which attempts to describe demographic, clinical features, and outcome of MDS patients. We retrospectively analyzed 1,080 patients with de novo MDS from Argentina (635), Brazil (345), and Chile (100). Chilean patients were younger (P 5 0.001) with female preponderance (P 5 0.071). Brazilian series showed a higher predominance of RARS subtype regarding FAB and WHO classifications (P < 0.001). Hemoglobin levels were significantly lower in Brazilian and Chilean series (P < 0.001), and Chilean series also showed a lower platelet count (P 5 0.028), with no differences concerning the neutrophil count, % BM blast, and the distribution of cytogenetic risk groups (P > 0.05). Chilean series depicted a lower overall survival (OS; 35 months vs. 56 months-Argentine; 55 monthsBrazil, P 5 0.030), which was consistent with a higher predominance of the high-risk group according both to the IPSS and IPSS-R (P 5 0.046 and P < 0.001). The IPSS-R system and its variables showed a good reproducibility to predict clinical outcome for the whole South-American population. Epidemiological and clinical characteristics, distribution among prognostic subgroups, the OS, and the access to disease modifying therapies were more similar between Argentinean and Brazilian compared with Chilean MDS series. This will need further analysis in a larger group of patients. Descriptive and comparative studies are necessary to establish epidemiological features useful for public health attitudes to generate suitable therapeutic schemes.

No abstract

Summary We describe a multiplex polymerase chain reaction (PCR)‐based test that detected all relevant NRAS activating mutations using a single PCR followed directly by electrophoresis. The test uses a Universal Heteroduplex Generator (UHG) to detect exon‐2 (codon 61) NRAS mutations in multiplex with an UHG for exon‐1 (codons 12 and 13). The method differentiated all 19 relevant mutations in these exons and showed a mutation independent sensitivity of approximately 6%. The sensitive, specific detection of all NRAS activating mutations using this single rapid test represents a minimum workload and could be applied readily for large‐scale screening and for routine analysis.