ABSTRACT
Wilms' tumour (WT) is the most common solid tumour of childhood. The molecular signalling pathways determining the origin and behaviour of WT are very complex and several genes in several loci may participate. This review tries to briefly compile recent works on the histology and on the molecular alterations that promote the genesis, development and behaviour of WT. Some molecular alterations seem to be associated with specific histological types and particular clinical outcomes, suggesting that they might be utilised to determine the prognosis and to identify poor prognostic subgroups that can be targeted for more individualised treatments (AU)
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Subject(s)
Humans , Male , Female , Abnormalities, Multiple/genetics , Chromosome Aberrations , Genes, Wilms Tumor , Kidney Neoplasms/genetics , Wilms Tumor/diagnosis , Wilms Tumor/genetics , Kidney Neoplasms/pathology , Wilms Tumor/pathologyABSTRACT
The efficacy of temozolomide strongly depends on O(6)-alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days until disease progression. O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31-71) with a median KPS of 90 (range 60-100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18-51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/drug therapy , Dacarbazine/analogs & derivatives , Glioblastoma/drug therapy , Adult , Aged , Anemia/chemically induced , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/adverse effects , Brain Neoplasms/genetics , Constipation/chemically induced , DNA Methylation , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Dacarbazine/therapeutic use , Disease Progression , Drug Administration Schedule , Female , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Lymphopenia/chemically induced , Male , Middle Aged , Neoplasm Recurrence, Local , O(6)-Methylguanine-DNA Methyltransferase/genetics , Survival Analysis , Temozolomide , Treatment OutcomeABSTRACT
The enzyme serum paraoxonase plays an important role in antioxidant defences and prevention of atherosclerosis. Metabolic syndrome (MS) is a clinical condition associated with increased oxidant stress and cardiovascular mortality. Two common polymorphisms of serum paraoxonase, PON1 Leu(55)Met and Gln(192)Arg, have been postulated to modulate the cardiovascular risk. We studied 915 subjects with angiographic documentation: 642 subjects with coronary atherosclerosis and 273 with normal coronary arteries. Two hundred and twenty-four subjects met the diagnostic criteria of MS. We found a significant interaction between MS and both the PON1 polymorphisms in determining the risk of coronary artery disease (P<0.05 by likelihood-ratio test). The 55Leu and the 192Arg alleles, associated with reduced protection against lipid peroxidation, were associated with coronary artery disease only in the MS subgroup. Subjects with MS and both 55Leu and 192Arg alleles had significantly increased risk (OR=9.38 with 95% CI=3.02-29.13 after adjustment by multiple logistic regression) as compared to subjects without MS and with 55Met/Met-192Gln/Gln genotype. No increased risk was found for subjects with MS and the 55Met/Met-192Gln/Gln genotype. This study highlights a potential example of genetic (paraoxonase polymorphisms)-clinical (MS) interaction influencing cardiovascular risk.
