A new der(1;7)(q10;p10) leading to a singular 1p loss in a case of glioblastoma with oligodendroglioma component

The combined 1p‐/19q‐ deletions in oligodendrogliomas originate from translocation between both chromosomes. In the few cases of oligoastrocytomas and glioblastomas with an oligodendroglioma component (GBMO) where only 1p deletion was described, the origin remains unknown. We report the first case of GBMO, in which a single 1p deletion was detected and was linked to a translocation between chromosomes 1 and 7. Fresh surgical specimens were collected during surgery and the samples were used for cell culture, touch preparation smear slides (TP slides) and DNA extraction. Peripheral venous blood was also collected from the patient. G‐banding using Trypsin and stained with Giemsa (GTG) banding and karyotyping were performed and 1p‐/19q‐, TP53, PTEN and c‐MYC were analyzed by fluorescent in situ hybridization (FISH). Multicolor FISH (mFISH) and microsatellites analyses were also performed to complete the investigation. Three‐dimensional quantitative FISH (3D‐QFISH) of telomeres was performed on nuclei from TP slides and analyzed using TeloView^TM to determine whether the 3D telomere profile as an assessment of telomere dysfunction and a characterization of genomic instability could predict the disease aggressiveness. An unbalanced chromosomal translocation was found in all metaphases and confirmed by mFISH. The karyotype of the case is: 50～99,XXX, +der(1;7)(q10;p10),inc[47] The derivative chromosome was found in all 47 analyzed cells, but the number of derivatives varied from one to four. There was neither imbalance in copy number for genes TP53 and PTEN, nor amplification of c‐MYC gene. We did not find loss of heterozygosity with analysis of microsatellite markers for chromosomes 1p and 19q in tumor cells. The 3D‐telomere profile predicted a very poor prognostic and short‐term survival of the patient and highlights the potential clinical power of telomere signatures as a solid biomarker of GBMO. Furthermore, this translocation between chromosomes 1 and 7 led to a singular 1p deletion in this GBMO and may generate the 1p and 7q deletions.     

Three-dimensional Nuclear Telomere Architecture Is Associated with Differential Time to Progression and Overall Survival in Glioblastoma Patients

The absence of biological markers allowing for the assessment of the evolution and prognosis of glioblastoma (GBM) is a major impediment to the clinical management of GBM patients. The observed variability in patients'' treatment responses and in outcomes implies biological heterogeneity and the existence of unidentified patient categories. Here, we define for the first time three GBM patient categories with distinct and clinically predictive three-dimensional nuclear-telomeric architecture defined by telomere number, size, and frequency of telomeric aggregates. GBM patient samples were examined by three-dimensional fluorescent in situ hybridization of telomeres using two independent three-dimensional telomere-measurement tools (TeloView program [P₁] and SpotScan system [P₂]). These measurements identified three patients categories (categories 1–3), displaying significant differences in telomere numbers/nucleus (P₁ = .0275; P₂ ≤ .0001), telomere length (P₁ and P₂ = .0275), and number of telomeric aggregates (P₁ = .0464; P₂ ≤ .0001). These categories corresponded to patients with long-term, intermediate, and short-term survival, respectively (P = .0393). The time to progression analyses showed significant differences between the three categories (P = .0167). There was a correlation between time to progression, median survival, and nuclear telomere architecture. Our study suggests a link between patient outcome and three-dimensional nuclear-telomere organization and highlights the potential clinical power of telomere signatures as a new prognostic, predictive, and potentially pharmacodynamic biomarker in GBM. Furthermore, novel automated three-dimensional high-throughput scanning as developed here permits to obtain data from 300 nuclei in 20 minutes. This method is applicable to any cell type and scanning application.     

Mechanisms of postoperative prolonged plasma volume expansion with low molecular weight hydroxethy starch (HES 200/0.62, 6%)

Objective To define the mechanisms of the stable and prolonged post-operative plasma volume expansion observed with Hydroxyethyl Starches (HES) and to determine whether a partial intravascular hydrolysis of large molecules contribute to reinforce the colloid-osmotic effect.Design Prospective, pharmacologic study using single dose of drug.Setting University-based, post-anesthesia care unit.Patients The protocol was performed during the post-operative period, in 10 patients after stable recovery from general anesthesia for carotid endarterectomy.Interventions HES 200/0.62 (500 ml) was infused over 30 min. Standard hemodynamic and biological variables, HES concentration and colloid osmotic pressure were obtained at each measurement. Plasma volume was calculated using⁵¹Cr-labelled RBCs. Patterns of changes in number average molecular weight (MWn) and weight average MW (MWw) were measured using gel permeation chromatography. Measurements were obtained at control, end of infusion, 1 h, 3 h, 6 h and 24 h after infusion.Measurements and main results Plasma volume increased by 693 ml (+21%) after the infusion of HES and remained constant over 24 h. HES concentration progressively decreased to reach a value of 35% of the peak at 24 h. MWn and MWw, initially decreased when compared with the dose solution and changed little in the 24 h study period. Diuresis significantly decreased at 3 h up to 24 h. Plasma albumin decreased after infusion and then progressively increased to reach a significantly higher value at 24 h than after infusion.Conclusion Initial plasma volume expansion and decrease in HES concentration agree with previously-published data. Maintenance of plasma volume expansion over 24 h was not related to a partial intravascular hydrolysis. Low elimination rate of HES, extravascular mobilization of albumin and post-operative renal adaptations were possibly the 3 main mechanisms to explain a prolonged plasma volume expansion with HES 200/0.62, 6%.     

Quantification of fetal nucleated cells in maternal blood of pregnant women with a male trisomy 21 fetus using molecular cytogenetic techniques

BACKGROUND: Prenatal diagnosis of trisomy 21 is based on fetal karyotyping generally obtained using invasive methods. During pregnancy, the circulating fetal cells in maternal blood constitute a potential source for development of a noninvasive prenatal diagnosis. The objective of this study was the identification and quantification of all fetal nucleated cells per unit volume of peripheral blood of pregnant women carrying male fetuses with trisomy 21 using molecular cytogenetic techniques. METHODS: Peripheral blood samples were obtained from 16 women carrying male fetuses with trisomy 21. We used a simple and rapid method of harvesting blood without recourse to any enrichment procedures or cell-separation techniques. To evaluate the potential of this method, 16 specimens were analyzed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH) and primed in situ labeling (PRINS) using specific probes to chromosomes X, Y and 21. RESULTS: The number of fetal cells varied between 6 and 32 per mL of maternal blood. This number is 3-5 times higher than that from normal pregnancies. CONCLUSIONS: Our current results are in agreement with the results previously reported by other groups showing that the number of fetal cells in maternal blood in trisomic 21 pregnancies is higher than in normal pregnancies. This high number of fetal cells is regarded as an advantage for the development of a noninvasive prenatal diagnostic test.     

From cellular morphology to molecular and epigenetic anomalies of myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) are a myeloid neoplasm with a propensity for natural evolution or transformation to acute leukemias (AL) over time. Mechanisms for MDS transformation to AL remain poorly understood but are related to genomic instability, which affects the production of the different cell lineages. Genomic instability is also generated by dysfunctional telomeres. Indeed telomeres, the protective ends of chromosomes are the backbone of genome stability. Nuclear telomere remodeling is an early indicator of nuclear remodeling preceding the onset of genomic instability and MDS. This review aims to revisit the pathogenesis and pathophysiology of MDS from morphology and cytogenetics to molecular and epigenetic mechanisms. Furthermore, this review will highlight and discuss recent breakthroughs in dysfunctional telomeres and nuclear telomere architecture roles in the pathogenesis and physiopathology of MDS in the global context of genomic instability.