Prognostic role of BRAF in human cutaneous melanoma : gene versus protein expression

Melanoma is the deadliest type of skin cancer with an increasing incidence for past two decades. Once melanoma is metastasized (cancer cells are spread out through the body) there is no effective treatment available and 84% of the patients die within 5 years. However, the discovery of braf mutation in melanoma increased the hope for developing new treatments. We first evaluated the effect of braf V600E mutation on melanoma patient survival. In a systematic review we revealed that patients with braf V600E mutation have almost two times more risk of death compared with patients with wild type braf. Next we evaluated the correlation of brafV600E mutation with protein expression. We found that compared with nevi samples, BRAF protein expression was remarkably increased in primary melanomas and further increased in metastatic melanoma patients. Higher BRAF protein expression was significantly correlated with other poor prognosis factors and lead to a significant worse five-year survival. However, we did not find a significant correlation between BRAF protein expression and braf V600E mutation. In our attempt to investigate the cause of induced BRAF protein, we found novel expression of BRAF splice variants (BRAFsv) in both melanoma patients and cell lines. We identified new kinase-dead BRAFsv, which have a dominant negative effect on full-length BRAF and are able to suppress downstream signaling and reduce melanoma cell proliferation. These variants were highly expressed in primary melanoma compared to normal samples, while the expression was decreased in metastatic and more aggressive types of melanoma. In addition, kinase-dead BRAFsv showed a protective effect on patient survival, which remained significant at the presence of full-length BRAF. Thus, patients who expressed the kinase-dead variant and had lower levels of full-length BRAF expression showed the best survival rate in 5 years. Our invitro analysis also indicates that over expression of kinase-dead BRAFsv in melanoma cell lines enhances the effect of BRAF inhibitor treatment. All in all, the data presented in this thesis elucidated a new era in the evaluation of melanoma patient prognosis and revealed new possibilities for more effective melanoma treatments.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat

Topical Immunotherapy With Diphenylcyclopropenone in Vitiligo: A Preliminary Experience

Background: Despite recent significant therapeutic advances, vitiligo remains a clinical conundrum. Topical immunotherapy has been extensively tested in the treatment of various dermatologic disorders, especially those believed to have an immunologic basis. Aim: To evaluate the role of topical diphenylcyclopropenone (DPCP) in the treatment of vitiligo. Methods: Nineteen patients with limited vitiligo lesions were enrolled in this study. After sensitization with 2% lotion of DPCP in acetone, progressively higher concentrations beginning at 0.001% up to 2% were applied weekly for 6 months to the depigmented skin lesions. Results: Thirteen of the 19 patients were evaluated at the end of 6 months. Four patients with focal vitiligo, one patient with vitiligo vulgaris, and three patients with segmental vitiligo showed marked (grade 3) repigmentation. Conclusion: Marginal and central repigmentation with hyperpigmented borders was seen in the majority of lesions. Further controlled trials should be undertaken to evaluate the use of topical DPCP in vitiligo

Impact of psoriasis on quality of life in Iran

Background: The Psoriasis Disability Index (PDI) questionnaire is a widely used instrument to measure psychological morbidity in plaque-type psoriasis patients. Aims: This study aimed to validate the Persian version of the PDI and to evaluate the impact of psoriasis on quality of life (QOL). Methods: The English language version of the PDI was translated into Persian (Iranian official language) and was used in this study. The questionnaire was administered to a consecutive sample of 125 chronic plaque-type psoriasis patients and statistical analysis was performed to evaluate the impact of psoriasis on QOL. The other health-related QOL assessment tool included the Persian version of the Dermatology Life Quality Index (DLQI). Results: Overall, 125 patients who had received the PDI and DLQI completed all the questions. Reliability analysis showed a satisfactory result (Cronbach′s a coefficient = 0.92 and 0.79 for PDI and DLQI, respectively). There was a strong statistical correlation between mean PDI and DLQI scores, with mean Psoriasis Area and Severity Index (PASI) (P = 0.005 and 0.02). Also, a significant correlation coefficient existed between DLQI and PDI (r = 0.94). The higher the PASI index, the higher the PDI and DLQI scores, which indicated greater impact on QOL. In the patients with lesions on visible exposed skin areas, the correlation was statistically significant (P = 0.002 and 0.01). Conclusion: The Persian PDI is an acceptable, reliable and valid measure of psychological distress, with more suitable content validity than DLQI for assessment of impact of psoriasis on QOL among psoriasis patients. Data provided may improve the physicians′ awareness of the importance of the patients′ QOL

The Prognostic Value of <em>BRAF</em> Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-Analysis

<div><h3>Background</h3><p>Mutation of <em>BRAF</em> is a predominant event in cancers with poor prognosis such as melanoma and colorectal cancer. <em>BRAF</em> mutation leads to a constitutive activation of mitogen activated protein kinase pathway which is essential for cell proliferation and tumor progression. Despite tremendous efforts made to target BRAF for cancer treatment, the correlation between <em>BRAF</em> mutation and patient survival is still a matter of controversy.</p> <h3>Methods/Principal Findings</h3><p>Clinical studies on the correlation between <em>BRAF</em> mutation and patient survival were retrieved from MEDLINE and EMBASE databases between June 2002 and December 2011. One hundred twenty relevant full text studies were categorized based on study design and cancer type. Publication bias was evaluated for each category and pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated using random or fixed effect meta-analysis based on the percentage of heterogeneity. Twenty six studies on colorectal cancer (11,773 patients) and four studies on melanoma (674 patients) were included in our final meta-analysis. The average prevalence of <em>BRAF</em> mutation was 9.6% in colorectal cancer, and 47.8% in melanoma reports. We found that <em>BRAF</em> mutation increases the risk of mortality in colorectal cancer patients for more than two times; HR = 2.25 (95% CI, 1.82–2.83). In addition, we revealed that <em>BRAF</em> mutation also increases the risk of mortality in melanoma patients by 1.7 times (95% CI, 1.37–2.12).</p> <h3>Conclusions</h3><p>We revealed that <em>BRAF</em> mutation is an absolute risk factor for patient survival in colorectal cancer and melanoma.</p> </div

Summary of studies that reported the status of <i>BRAF</i> mutation in papillary thyroid carcinoma with information on patient survival.

<p>DFS, Disease free survival; OR, Odds Ratio; SBiPTC, Synchronous bilateral papillary thyroid carcinoma; UiPTC, Unilateral papillary thyroid carcinoma.</p

Random effect model of Log hazard ratio (LogHR) with 95% confidence interval for studies comparing the effect of <i>BRAF-</i>V600E mutation on overall survival in melanoma patients.

<p>A LogHR <0 implies a survival benefit for patients with <i>BRAF</i> mutation. The square size indicates the power of each study in meta-analysis based on the number of patients in that study. The center of diamond shape at the lowest part indicates the combined LogHR for meta-analysis and its extremities the 95% confidence interval.</p

Random effect model of Log hazard ratio (LogHR) with 95% confidence interval for studies comparing the effect of <i>BRAF-</i>V600E mutation on overall survival of colorectal cancer patients.

<p>A LogHR <0 implies a survival benefit for patients with <i>BRAF</i> mutation. The square size indicates the power of each study in meta-analysis based on the number of patients in that study. The center of diamond shape at the lowest part indicates the combined LogHR for meta-analysis and its extremities the 95% confidence interval.</p