Class of 2006 Abstract / Objectives: To create, deliver, and evaluate a malignant melanoma continuing education (CE) seminar for pharmacists. Methods: A CE program was developed and presented to educate pharmacists about skin cancer prevention, specifically malignant melanoma, and their role in prevention through patient counseling. All practicing pharmacists who attended the CE program were asked to fill out a knowledge indicator and assess their comfort level in counseling patients about sun safety before and after the program. The participants also answered questions addressing how often they counsel patients on sunscreen use, their personal experience with skin cancer, preferred CE format, previous CE attendance, sex, age, practice site, hours worked per week, and years since graduation from pharmacy school. Results: The survey instrument was completed by 84 pharmacists. The average score on the pre-test knowledge indicator was 4.95 ± 0.39 and the average score on the post-test knowledge indicator was 7.81 ± 0.39. This was a significant improvement (p < 0.01). There was a significant increase in participant comfort level when counseling patients about sun safety after attending the CE program (p < 0.01). Personal experience with skin cancer did not have a significant effect on the pre-test knowledge indicator scores, however it was associated with the knowledge indicator change score (p < 0.01). Completion of previous skin cancer CE programs did not have a significant effect on the pre-test knowledge indicator score or the change score. Conclusions: Pharmacists who attended the CE program improved their knowledge indicator scores when tested about malignant melanoma and sun safety. Many participants felt more comfortable counseling patients about sun safety and felt their counseling on sun safety would change as a result of attending this CE program.

Dysregulation of the chemokine receptor 4 (CXCR4) and its primary ligand CXCL12 (SDF-1, stromal cell-derived factor-1), has been implicated in the progression of melanoma and the mechanisms by which the CXCR4/CXCL12 axis has been shown to activate cell cycle progression is via stimulation of the mitogen-activated protein kinase (MAPK) pathway. Given this, we sought to ascertain the potential cooperativity of CXCR4 with established histopathologic prognosticators including the BRAF status in primary cutaneous melanoma. In this IRB approved study, archived tissue samples with diagnosis of primary cutaneous melanoma were retrieved from the Skin Pathology Laboratory at BUSM, Boston, MA and a total of 107 cases identified as meeting criteria for inclusion. Protein expression of CXCR4 and CXCL12 were assessed using commercially available rabbit polyclonal antibodies (Ab2074 and, ab9797 respectively, Abcam, Cambridge, MA, USA). CXCR4 gene expression (mRNA) was measured by semiquantitative RT-PCR with appropriate controls. For IHC, a semi-quantitative scoring (ranging from 0-3) was used and cases with a score of ≥2 (>10%) were considered positive. Molecular analysis for CXCR4 gene expression and BRAF exon 15 mutation status was performed using mRNA semi-quantitative RT-PCR and DNA Sanger sequencing respectively. Univariate analyses of CXCR4 mRNA expression revealed a statistically significant correlation between elevated CXCR4 expression (low ΔCt value) and presence of the BRAF mutation and absence of a host response (p=0.03 and p=0.0003 respectively). Univariate analyses revealed a significant correlation between elevated CXCR4 mRNA (low ΔCt value) and the following: presence of BRAF mutation and absence of a host response (p=0.03 and 0.0003 respectively). CXCR4 mRNA was significantly higher among both AJCC stage 1 and stage 3 compared to stage 2 (p=0.01). Compared with CXCR4 negative samples, univariate analyses of CXCR4 protein showed that the proportion of CXCR4 positives was significantly greater in melanomas with absence of mitoses (p<0.0001), ulceration (p=0.0008) and regression (p=0.02). Patients presenting at shallower stages (AJCC 1-2) exhibited a larger proportion of CXCR4 positives (76.9%, p<0.0001 and 69.0%, p=0.004), while those at deeper stages (AJCC 3-4) exhibited a larger proportion of negatives (75.0%, p=0.002 and 66.7%, p=0.10). In a multivariable analysis, lower odds of CXCR4 protein expression were associated with AJCC stage-3 (OR=0.16, p=0.01), stage-4 (OR=0.17, p=0.04), and mitoses (OR=0.21, p=0.01). Lack of correlation between CXCR4 mRNA and protein expression suggests that further study is required for a more precise understanding of mRNA-protein interaction for CXCR4 in order to identify factors contributing to the lack of concordance. CXCR4 protein appears to be associated with established prognosticators of good clinical outcome as its expression is less frequently observed in melanomas with mitoses, ulceration and depth >2 mm. The association between CXCR4 mRNA and a brisk host response suggests that it may serve as a biomarker for recruiting melanoma patients for immunotherapy. Higher CXCR4 mRNA in patients with a BRAF mutation suggests its utility as a putative therapeutic target.

Targeting the mutant BRAF and immunotherapy are new approaches to the treatment of metastatic malignant melanoma that has significantly improved survival but is associated with significant toxicity and cost. Potent and specific BRAF inhibitors like vemurafenib and dabrafenib are superior to chemotherapy in treatment of BRAF mutant melanomas which represent nearly 50% of all melanomas. A less toxic approach to treatment of malignant melanoma is hence appealing. Delta-tocotrienol (DT3), an unsaturated vitamin E isoform, and simvastatin, an HMG-CoA reductase inhibitor have been shown to have anti-neoplastic properties. We studied the effects of these chemicals in both BRAF-mutated SK-MEL-28 and BRAF-wild type SK-MEL-2 melanoma cells. MTS assays were used to analyze cytotoxicity. SK-MEL-28 and SK-MEL-2 cells were cultured in MEM media containing 10% serum and plated in 96-well culture plates for 48 hours then treated with DT3 (0-80 µM), simvastatin (0-10 µM), or a combination and dosed again at 72 hours. SK-MEL-28 and SK-MEL-2 cells were grown in 60 mm plates and treated with DT3 at concentrations of 30 µM, simvastatin at concentrations of 10 µM and combination of DT3 and simvastatin at concentrations of 10 µM and 2 µM. Cell were lysed with RIPPA buffer with protease and phosphatase inhibitor after 6 hours of treatment. Protein concentration of cell lysates was measured spectrophotometrically (GLO Max Multi+, Promega), using a BCA protein assay kit. The samples were run in SDS PAGE and blotted onto nitrocellulose membranes. Membranes were incubated with antibodies against Hsp 70 (Enzo Life Sciences, Farmingdale, NY), Hsp 90 (Santa Cruz, Dallas, TX), pS6 and pERK (Cell Signaling, Danvers, MA) and pAKT. Using MTS assay, we found that DT3 (IC50 75.2 μM) and simvastatin (IC50 8.3μM) have cytotoxic effects on melanoma cell line SK-MEL-2, but not on the SK-MEL-28 cells DT3 and simvastatin at the concentrations studied (10-80 μM DT3) and (0.625- 10 μM simvastatin). Further studies determined that simvastatin decreased expression of pS6, pERK on SK-MEL-2 and not DT3. However, these effects are different in SK-MEL-28 cells where there is only decrease in expression of pS6; treated SK-MEL-2 cells also show over-expression of Hsp70 suggestive of a rescue effect leading to lesser cytotoxic activity. The selective cytotoxicity observed in wild type BRAF melanoma cell lines by DT3 and simvastatin warrants further research into the potential therapeutic use of these drugs. A differential cytotoxicity is shown by DT3 and simvastatin in malignant melanoma cells with selective more potency in wild type BRAF melanoma compared to mutant BRAF melanoma cells. Further studies will be undertaken to dissect the mechanistic basis of this differential response.

La mayoría de los reportes realizados en los países con alta incidencias en melanoma de tipo cutáneos, son realizados en pacientes de raza blanca, con predominio del subtipo histológico, melanoma de extensión superficial, pero en países como latinoamericanos, africanos u orientales, existe una alta incidencia de melanomas de tipo lentiginoso acral, en los que predominan en pacientes de raza no blanca. En el Perú, existe pocos estudios relacionados con esta neoplasia, de ahí la realización de este estudio de tipo descriptivo y retrospectivo, con la finalidad de proporcionar información sobre las características histopatológicas, clínicas y la supervivencia asociado a factores pronósticos en pacientes que fueron diagnosticados en el Hospital Nacional Edgardo Rebagliati Martins, Lima-Perú, uno de los centros hospitalarios de referencia para pacientes asegurados, en el periodo comprendido desde el 01 enero del 2002 al 31 de diciembre 2011. Debido a que esta neoplasia representa un problema en el sector de salud por aumento en su incidencia, demora en el diagnóstico, poca respuesta al tratamiento de ciertos tipos histológicos de melanoma, se busca evitar que pacientes con factores de riesgo para desarrollar melanoma de tipo cutáneo o mucoso, progresen a la enfermedad; mediante la adopción de medidas profilácticas adecuadas o mediante las extirpaciones de lesiones premalignas, por tanto es importante el conocimiento y la difusión de información a la población sobre la enfermedad. / Trabajo académico

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / In this research paper, we proposed an extended model for the early detection of skin cancer... The purpose is reduce the waiting time to obtaining a diagnosis, in addition, the function of the dermatoscope has been digitized by using a Smartphone and magnifying lenses as an accessory the mobile device. The proposed model has five phases: 1. The patient is attended by a general practitioner or nurse previously trained in any health center which has WiFi or mobile network connectivity to record their data and capture the skin lesion that will be analyzed. 2) The image will be in the cloud storage, which at the same time feeds an exclusive access website of dermatologists.3) Images are analyzed in real time using an image recognition service provided by IBM, which is integrated into a cloud-hosted web platform and an-Android application. 4)The result of the image processing is visualized by the dermatologist who makes a remote diagnosis.5) This diagnosis is received by the general practitioner or nurse, responsible for transmitting the diagnosis and treatment to the patient. This model was validated in a group of 60 patients, where 28 suffer from skin cancer in the early stage, 12 in the late stage and 20 are healthy patients, in a network of clinics in Lima, Peru. The obtained result was 97.5% of assertiveness on the analyzed skin lesions and 95% in healthy patients. / Revisión por pares

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PURPOSE: Uveal melanoma (UM) is the most common intraocular malignancy in adults with an incidence of six per one million individuals each year. Globe conserving treatments are currently the standard of care, but unfortunately, despite successful local control, a substantial mortality risk exists due to eventual emergence of distant metastasis, which is invariably lethal. There is therefore an unmet need for novel, effective, targeted therapies for metastatic UM. Somatic mutations in the G-protein α subunits, Gαq and Gα, are present in a mutually exclusive pattern in approximately 80% of UMs, and they abolish the GTPase activity, resulting in a constitutively active protein. We have previously demonstrated that GNAQ-mutant (GNAQ^mt) UMs are addicted to the oncogenic effect of the mutant GNAQ protein and dissected the GNAQ pathway in an attempt to identify druggable targets. Our findings that the mutant GNAQ protein activates the PKC/PKD axis, which activates beta-catenin (β-Catenin), prompted us to investigate the role of PKC and β-Catenin in GNAQ^mt UM. EXPERIMENTAL DESIGN: The GNAQ^mt UM cell lines Mel202 and OMM1.3 were treated with either the PKC inhibitor bisindolylmaleimide I (BIM) alone, the Wnt/β-Catenin inhibitors FH535 or cardamonin alone, the Wnt/β-Catenin activator Wnt-3a alone, or siRNAs for β-Catenin in combination with BIM, and their viability was assessed with the MTT assay. Levels of β-Catenin, phosphorylated AKT, ERK1/2, caspase 3 and LC3BII were assessed with western blotting. β-Catenin mRNA levels were assessed with microarray analysis and RT-PCR. RESULTS: GNAQ^mt UM cells are very sensitive to PKC inhibition and respond with a decrease in cell viability that involves autophagy and cleavage and translocation of LC3BII in autophagosomes, but not caspase activation. PKC inhibition results in the upregulation of β-Catenin protein, but not mRNA levels, through a post-translational mechanism that involved the phosphorylation and activation of AKT, but not ERK1/2. β-Catenin inhibition by either small molecule inhibitors or siRNA resulted in a dose-dependent increase of cell proliferation, whereas β-Catenin activation by Wnt-3a had the opposite effects, resulting in a decrease in cell viability. CONCLUTIONS: Our study demonstrates that PKC is a mediator of the oncogenic effect of mutant Gα protein in UM through the Wnt-3/β-Catenin signaling pathway. These results open exciting opportunities for the development of personalized targeted therapies for UM in a genotype-dependent fashion.

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