MDM2 309 polymorphism predicts outcome in platinum-treated locally advanced head and neck cancer

Chemo-radiotherapy (CRT) with cisplatin-based regimens is curative in a subset of patients with locally advanced (stage III and IV) squamous carcinomas of the head and neck (LAHNSCC), but causes considerable toxicity. To seek predictive biomarkers, we analysed single nucleotide polymorphisms (SNPs) in the p53 and MDM2 genes in LAHNSCC patients treated with cisplatin-based CRT. We analysed germ-line p53 72 Arg/Pro (R/P) and MDM2 309 SNPs and somatic p53 mutational status in 140 LAHNSCC and determined their utility as predictive biomarkers. In cases with wild-type p53, overall survival (OS) was longest in 72RR (median OS=60.8 months) and less favourable in 72PP (median OS=6.7 months, p<0.0001). OS in individuals with 72RP was intermediate between 72RR and 72PP, while in patients with missense p53 mutations, median OS did not reach statistical significance. Median OS was significantly shorter in patients with MDM2 309 SNP genotypes GG or GT, compared to TT (15 vs. 86 months; p<0.0001). The predictive effect of the G allele was maintained independent of age, gender, stage, primary site, nodal status, performance status, EGFR grade, HPV status, p53 mutation and p53 SNP (HR for death 3.241; 95% CI 1.90-5.52, p<0.001). The predictive utility of the MDM2 germ-line 309 SNP, which can be easily determined from peripheral blood, implies that it may be of value in the objective selection of patients for radical CRT. In contrast, the predictive utility of the 72 Arg/Pro SNP in p53 requires mutational analysis of p53, limiting its routine clinical use.     

Porokeratosis of Mibelli: Successful treatment with 5 percent topical imiquimod and topical 5 percent 5-fluorouracil

Porokeratosis of Mibelli (PM) is a clonal disorder of keratinization. It clinically presents with one or more annular plaques with central atrophy and elevated keratotic borders. With a 7.5 percent risk of malignancy, PM should be treated to prevent transformation into squamous cell carcinoma, Bowen disease, or basal cell carcinoma. Multiple treatment options are available, however, there is not one universally effective treatment. We describe the successful treatment of porokeratosis of Mibelli of the left calf in an 83-year-old man with topical 5 percent imiquimod and topical 5 percent 5-fluorouracil.     

Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake

BACKGROUND:

The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring.

METHODS:

The authors used a case‐control study design to examine the association between retinoblastoma risk and maternal variations in the folate‐metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine‐to‐thymine substitution at nucleotide 677 [MTHFR677C→T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19‐base‐pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board‐approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction‐based genotyping of rs1801133 and rs70991108.

RESULTS:

The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89‐7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32‐5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel‐associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma.

CONCLUSIONS:

Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population. Cancer 2012. © 2012 American Cancer Society.     

Effect of asthma compliance enhancement training on asthma control in patients on combination therapy with salmeterol/fluticasone propionate: a randomised controlled trial

Objective: We investigated if a higher proportion of adults with previously uncontrolled asthma can achieve total control when given salmeterol/fluticasone propionate (50/250 µg) bid and compliance enhancement training (CET) compared to those given medication alone. Methods: Open comparison of stable, but uncontrolled, adult asthmatics. After a 12‐week treatment period on salmeterol/fluticasone propionate (period 1), patients who failed to achieve control were randomised to continuing treatment with or without CET for 12 weeks (period 2). The primary end point was the proportion achieving total control of their asthma in 7 of the last 8 consecutive weeks of period 2. Results: A total of 361 subjects (50.4% males, mean age 40.0 ± 14.4 years) in 29 centres were included, of whom 75.9% were randomised into treatment period 2 (n = 140 in the intervention group). The proportion of subjects achieving total asthma control was 8.8% and 7.6%, respectively, in the intervention and control group [not significant (NS)]. Mean morning peak flow, forced expiratory volume in one second (FEV₁), asthma symptom score and quality of life improved significantly over the study period in both treatment groups. Furthermore, proportion of days with use of rescue medication declined from 59.7% ± 34.6% (55.7% ± 35.3%) during screening to 20.3% ± 29.2% (19.4% ± 30.9%) during treatment period 2 (NS). Conclusion: CET failed to increase the likelihood of achieving total control in asthmatics on salmeterol/fluticasone propionate compared to subjects receiving medication only. However, both groups had a significant improvement in asthma control. (Clinical Trials.gov number, NCT00351143) Please cite this paper as: Ulrik CS, Claudius BK, Tamm M, Harving H, Siersted HC, Backer V, Hellquist B, Dahl R, Høgholm A and Jøhnk IK. Effect of asthma compliance enhancement training on asthma control in patients on combination therapy with salmeterol/fluticasone propionate: a randomised controlled trial. The Clinical Respiratory Journal 2009; 3: 161–168.     

Differential vascular endothelial growth factor A protein expression between small hepatocellular carcinoma and cirrhosis correlates with serum vascular endothelial growth factor A and α‐fetoprotein

Background/Aims: Drugs with antivascular endothelial growth factor A (anti‐VEGF‐A) action are under clinical evaluation with encouraging results in advanced hepatocellular carcinoma (HCC). The relative VEGF‐A protein expression in non‐advanced HCC and in the cirrhotic non‐tumoral tissue in the same patient, a variable that could be important for treatment efficacy, has been investigated with conflicting results, only using the cirrhotic tissue surrounding the neoplasm (CS). Methods: We measured, for the first time, VEGF‐A expression in non‐advanced HCC and in the respective CS and cirrhotic tissue at a distance from the tumour (CD), in 24 patients who underwent liver transplantation. Results: VEGF‐A protein was more expressed (P<0.05) in HCC than in CD, while no difference was found between HCC and CS. In HCC patients with a serum α‐fetoprotein (AFP) higher than 20 ng/ml, VEGF‐A protein expression in HCC was higher than in the corresponding CD in 83% of cases and AFP and serum VEGF‐A corrected for the platelet count positively correlated with the differential VEGF‐A protein expression between HCC and CD. Conclusion: Our data provide a rationale for clinical trials involving anti‐VEGF‐A treatments in patients with non‐advanced HCC, and suggest that serum AFP and VEGF‐A are variables to be taken into account in these studies.     

Neural response to the visual familiarity of faces

Recognizing personally familiar faces is the result of a spatially distributed process that involves visual perceptual areas and areas that play a role in other cognitive and social functions, such as the anterior paracingulate cortex, the precuneus and the amygdala [M.I. Gobbini, E. Leibenluft, N. Santiago, J.V. Haxby, Social and emotional attachment in the neural representation of faces, Neuroimage 22 (2004) 1628-1635; M.I. Gobbini, J.V. Haxby, Neural systems for recognition of familiar faces, Neuropsychologia, in press; E. Leibenluft, M.I. Gobbini, T. Harrison, J.V. Haxby, Mothers' neural activation in response to pictures of their, and other, children, Biol. Psychiatry 56 (2004) 225-232]. In order to isolate the role of visual familiarity in face recognition, we used fMRI to measure the response to faces characterized by experimentally induced visual familiarity that carried no biographical information or emotional content. The fMRI results showed a stronger response in the precuneus to the visually familiar faces consistent with studies that implicate this region in the retrieval of information from long-term memory and imagery. Moreover, this finding supports the hypothesis of a key role for the precuneus in the acquisition of familiarity with faces [H. Kosaka, M. Omori, T. Iidaka, T. Murata, T. Shimoyama, T. Okada, N. Sadato, Y. Yonekura, Y. Wada, Neural substrates participating in acquisition of facial familiarity: an fMRI study, Neuroimage 20 (2003) 1734-1742]. By contrast, the visually familiar faces evoked a weaker response in the fusiform gyrus, which may reflect the development of a sparser encoding or a reduced attentional load when processing stimuli that are familiar. The visually familiar faces also evoked a weaker response in the amygdala, supporting the proposed role of this structure in mediating the guarded attitude when meeting someone new.