Objective response to radiation therapy and long-term survival of patients with WHO grade II astrocytic gliomas with known LOH 1p/19q status

BACKGROUND: WHO grade II gliomas are often approached by radiation therapy (RT). However, little is known about tumor response and its potential impact on long-term survival. PATIENTS AND METHODS: Patients subjected to RT were selected from the own database of WHO grade II gliomas diagnosed between 1991 and 2000. The volumetric tumor response after RT was assessed based on magnetic resonance imaging and graded according to standard criteria as complete, partial (PR, >or= 50%), or minor (MR, 25% to <50%). RESULTS: There were 24 astrocytomas and three oligoastrocytomas. 21 patients (78%) were dead at follow-up (mean survival 74 months). None of the patients had chemotherapy. Objective response occurred in 14 patients (52%, five PR and nine MR) but was not associated with overall survival. The vast majority of the tumors had no loss of heterozygosity (LOH) 1p and/or 19q (86%). CONCLUSION: Approximately 50% of patients with astrocytic WHO grade II gliomas respond to RT despite the absence of LOH for 1p/19q. The potential predictive factors for response and the impact of response on overall survival remain unclear.

Quantitative analysis of O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas

Methylation of the MGMT promoter is supposed to be a predictive and prognostic factor in glioblastoma. Whether MGMT promoter methylation correlates with tumor response to temozolomide in low-grade gliomas is less clear. Therefore, we analyzed MGMT promoter methylation by a quantitative methylation-specific PCR in 22 patients with histologically verified low-grade gliomas (WHO grade II) who were treated with temozolomide (TMZ) for tumor progression. Objective tumor response, toxicity, and LOH of microsatellite markers on chromosomes 1p and 19q were analyzed. Histological classification revealed ten oligodendrogliomas, seven oligoastrocytomas, and five astrocytomas. All patients were treated with TMZ 200 mg/m2 on days 1-5 in a 4 week cycle. The median progression-free survival was 32 months. Combined LOH 1p and 19q was found in 14 patients; one patient had LOH 1p alone and one patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. LOH 1p and/or 19q correlated with longer time to progression but not with radiological response to TMZ. MGMT promoter methylation was detectable in 20 patients by conventional PCR and quantitative analysis revealed the methylation status was between 12 and 100%. The volumetric response to chemotherapy analyzed by MRI and time to progression correlated with the level of MGMT promoter methylation. Therefore, our retrospective case series suggests that quantitative methylation-specific PCR of the MGMT promoter predicts radiological response to chemotherapy with TMZ in WHO grade II gliomas.

Loss of heterozygosity 1p36 and 19q13 is a prognostic factor for overall survival in patients with diffuse WHO grade 2 gliomas treated without chemotherapy

PURPOSE: This study was conducted to elucidate the impact of loss of heterozygosity (LOH) for chromosomes 1p36 and 19q13 on the overall survival of patients with diffusely infiltrating WHO grade 2 gliomas treated without chemotherapy. PATIENTS AND METHODS: We assessed the LOH status of tumors from patients harboring WHO grade 2 gliomas diagnosed between 1991 and 2000. Patients were either followed after initial biopsy or treated by surgery and/or radiation therapy (RT). Overall survival, time to malignant transformation, and progression-free survival were last updated as of March 2005. RESULTS: Of a total of 79 patients, LOH 1p36 and LOH 19q13 could be assessed in 67 and 66 patients, respectively. The median follow-up after diagnosis was 6 years. Loss of either 1p or 19q, in particular codeletion(s) at both loci, was found to positively impact on both overall survival (log-rank P < .01), progression-free survival, and survival without malignant transformation (P < .05). Tumor volume (P < .0001), neurologic deficits at diagnosis (P < .01), involvement of more than one lobe (P < .01), and absence of an oligodendroglial component (P < .05) were also predictors of shorter overall survival. The extent of surgery was similar in patients with or without LOH 1p and/or 19q; RT was more frequently resorted to for patients without than for patients with LOH 1p/19q (30% v 60%). CONCLUSION: The presence of LOH on either 1p36 or 19q13, and in particular codeletion of both loci is a strong, nontreatment-related, prognostic factor for overall survival in patients with diffusely infiltrating WHO grade 2 gliomas.

Age at diagnosis and loss of heterozygosity on chromosome 1p and 19q in oligodendroglial tumors

The age distribution and incidence of loss of heterozygosity (LOH) of 1p and 19q was analyzed in 85 oligodendroglial tumors WHO II and III. The peak of tumor manifestation was in the age group of 35 to 55 years. There was no association between age at diagnosis and LOH incidence. We conclude that the prognostic effect of age on survival is not mediated by LOH 1p/19q.

Origins of Shared Genetic Variation in African Cichlids

Cichlid fishes have evolved tremendous morphological and behavioral diversity in the waters of East Africa. Within each of the Great Lakes Tanganyika, Malawi, and Victoria, the phenomena of hybridization and retention of ancestral polymorphism explain allele sharing across species. Here, we explore the sharing of single nucleotide polymorphisms (SNPs) between the major East African cichlid assemblages. A set of approximately 200 genic and nongenic SNPs was ascertained in five Lake Malawi species and genotyped in a diverse collection of 160 species from across Africa. We observed segregating polymorphism outside of the Malawi lineage for more than 50% of these loci; this holds similarly for genic versus nongenic SNPs, as well as for SNPs at putative CpG versus non-CpG sites. Bayesian and principal component analyses of genetic structure in the data demonstrate that the Lake Malawi endemic flock is not monophyletic and that river species have likely contributed significantly to Malawi genomes. Coalescent simulations support the hypothesis that river cichlids have transported polymorphism between lake assemblages. We observed strong genetic differentiation between Malawi lineages for approximately 8% of loci, with contributions from both genic and nongenic SNPs. Notably, more than half of these outlier loci between Malawi groups are polymorphic outside of the lake. Cichlid fishes have evolved diversity in Lake Malawi as new mutations combined with standing genetic variation shared across East Africa.

Anaplastic oligodendroglioma arising from the brain stem and featuring 1p/19q co-deletion

With respect to localization, oligodendrogliomas are characterized by a marked preponderance of the cerebral hemispheres. Outside these typical sites, any tumor histopathologically reminiscent of oligodendroglioma a priori is likely to represent one of its morphological mimics, including clear cell ependymoma, neurocytoma, pilocytic astrocytoma or glioneuronal tumors. This is particularly relevant as several of the latter are in principle curable by surgery. Among extrahemispherical sites, bona fide oligodendroglioma - as characterized by loss of heterozygosity (LOH) of chromosome arms 1p and 19q - so far has not been documented to occur in the brain stem. Here, we report the case of a 55-year-old female patient with an anaplastic oligodendroglioma (WHO grade III) of the brain stem and cerebellum diagnosed by stereotactic biopsy and featuring combined LOH of 1p and 19q. A morphological peculiarity was a population of interspersed tumor giant cells, a phenomenon that has been referred to as polymorphous oligodendroglioma. Our findings confirm the notion that - although very infrequently - true oligodendrogliomas do occur in the infratentorial compartment.

New generation genomic platforms in investigation of complex diseases and BEN.

(Full text is available at http://www.manu.edu.mk/prilozi). New generation genomic platforms enable us to decipher the complex genetic basis of complex diseases and Balkan Endemic Nephropathy (BEN) at a high-throughput basis. They give valuable information about predisposing Single Nucleotide Polymorphisms (SNPs), Copy Number Variations (CNVs) or Loss of Heterozygosity (LOH) (using SNP-array) and about disease-causing mutations along the whole sequence of candidate-genes (using Next Generation Sequencing). This information could be used for screening of individuals in risk families and moving the main medicine stream to the prevention. They also might have an impact on more effective treatment. Here we discuss these genomic platforms and report some applications of SNP-array technology in a case with familial nephrotic syndrome. Key words: complex diseases, genome wide association studies, SNP, genomic arrays, next generation sequ-encing.

Phylogenetic position of Riemerella anatipestifer based on 16S rRNA gene sequences

Riemerella anatipestifer, the causative agent of septicemia anserum exsudativa (also called new duckling disease), belongs to the family Flavobacteriaceae of gram-negative bacteria. We determined the DNA sequences of the rrs genes encoding the 16S rRNAs of four R. anatipestifer strains by directly sequencing PCR-amplified rrs genes. A sequence similarity analysis confirmed the phylogenetic position of R. anatipestifer in the family Flavobacteriaceae in rRNA superfamily V and allowed fine mapping of R. anatipestifer on a separate rRNA branch comprising the most closely related species, Bergeyella zoohelcum, as well as Chryseobacterium balustinum, Chryseobacterium indologenes, and Chryseobacterium gleum. The sequences of the rrs genes of the four R. anatipestifer strains varied between 0.5 and 1.0%, but all of the strains occupied the same position on the phylogenetic tree. In general, differences in rrs genes were observed among R. anatipestifer strains, even within a given serotype, as shown by restriction fragment length polymorphism of PCR-amplified rrs genes.

Polymorphous oligodendroglioma of Zülch revisited: a genetically heterogeneous group of anaplastic gliomas including tumors of bona fide oligodendroglial differentiation.

A polymorphous variant of oligodendroglioma was described by K.J. Zülch half a century ago, and is only very sporadically referred to in the subsequent literature. In particular, no comprehensive analysis with respect to clinical or genetic features of these tumors is available. From a current perspective, the term polymorphous oligodendroglioma (pO) may appear as contradictory in terms, as nuclear monotony is a histomorphological hallmark of oligodendrogliomas. For the purpose of this study, we defined pO as diffusely infiltrating gliomas felt to be of oligodendroglial rather than astrocytic differentiation and characterized by the presence of multinucleate tumor giant cells and/or nuclear pleomorphism. In a total of nine patients, we identified tumors consistent with this working definition. All tumors were high-grade. We characterized these with respect to clinical, histomorphological and genetic features. Despite clinical and genetic heterogeneity, we identified a subset of tumors of bona fide oligodendroglial differentiation as characterized by combined loss of heterozygosity of chromosome arms 1p and 19q (LOH 1p19q). Those tumors that lacked LOH 1p19q showed a high frequency of IDH1 mutations and loss of alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) immunoreactivity, indicating a possible phenotypic convergence of true oligodendrogliomas and gliomas of the alternative lengthening of telomeres (ALT) pathway. p53 alterations were common irrespective of the 1p19q status. Histomorphologically, the tumors featured interspersed bizarre multinucleate giant tumor cells, while the background population varied from monotonous to significantly pleomorphic. Our findings indicate, that a rare polymorphous - or "giant cell" - variant of oligodendroglioma does indeed exist.

Combined ATRX/IDH1 immunohistochemistry predicts genotype of oligoastrocytomas

AIMS To assess whether in oligoastrocytomas ATRX deficiency - as a surrogate of the alternative lengthening of telomeres (ALT) pathway - has a role in predicting the presence or absence of loss of heterozygosity of 1p and 19q (LOH), the genetic signature of oligodendroglial differentiation and a favourable prognostic marker. METHODS AND RESULTS A series of 54 oligoastrocytomas were investigated by immunohistochemistry as well as microsatellite analysis for LOH 1p19q. Genetic findings were correlated with morphological assessment. CONCLUSIONS ATRX deficiency was mutually exclusive with LOH. Conversely, ATRX-proficient tumours immunoreactive for R132H-mutant isocitrate dehydrogenase 1 (IDH1) showed a high rate (85%) of LOH. A more oligodendroglioma-like morphology was associated with a higher rate of LOH even in the morphologically ambiguous group of oligoastrocytomas. Our findings support the concept that oligoastrocytomas represent a morphological grey zone rather than a group of truly "mixed" or "intermediate" tumours. More precise classification of diffuse gliomas may also improve grading of borderline cases. We propose an immunohistochemical algorithm for classification of morphologically ambiguous diffuse gliomas. This article is protected by copyright. All rights reserved.

Etude des relations entre la pluie, le sol, le relief, la couverture végétale et l'érosion dans la région de Mandraka

Le relief accidenté, le climat agressif favorisé par l’Alizé, ainsi que l’étroite dépendance de la population de l’exploitation forestière et de l’exploitation agricole sans dispositifs de protection antiérosifs, sont les contextes qui permettent de dire que la région de Mandraka est sujette au problème d’érosion. L’étude a pour objectif de déterminer les relations entre les caractéristiques du sol, son mode d’occupation, les précipitations ainsi que l’érosion dans la région de Mandraka et ce en vue d’un aménagement rationnel. Des dispositifs pour la mesure de pertes en terre et de ruissellement ont été matérialisés sur des parcelles d’expérimentation. A cet effet, le choix de ces parcelles a porté sur le mode d’occupation du sol (sous terrains aménagés, sous « tavy », sous « savoka », et sous forêt naturelle), sur la similitude des pentes et sur leur localisation de manière à ce qu’elles soient situées sur les mi-versants. Les résultats ont montré que le sol dans cette région contient un taux de matière organique satisfaisant à élevé (2,41 à 3,74% de MO), lui permettant une bonne stabilité structurale (Is = 0,85 et K = 0,08). Les pertes en terre (0,13 à 20,93t/ha/an) et les ruissellements (0,3 à 5%) obtenus indiquent que l’érosion est faible à accélérée suivant le mode d’occupation du sol. En deux ans d’aménagement, les terrasses se sont stabilisées et les racines de Vetiveria zizanoides peuvent remplacer les fascines initialement installées pour tenir les talus. Toutefois, l’exposition du sol à la battance de la pluie et la mauvaise infiltration d’eau de ruissellement dans le sol accélèrent le phénomène d’érosion. Par ailleurs, il y a l’efficacité de la SCV sans brûlis bien qu’il s’agit de la première année d’expérience. Dans ces conditions, un plan d’aménagement simplifié a été proposé en vue (i) de protéger le sol contre la battance de la pluie, (ii) de réduire les transports solides par l’érosion et (iii) d’améliorer l’infiltration d’eau du sol.

EMAS position statement: Testosterone replacement therapy in the aging male‏.

INTRODUCTION Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate. AIMS The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks. MATERIALS AND METHODS Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.