BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer.

INTRODUCTION: BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates. AREAS COVERED: This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented. EXPERT OPINION: Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.

Análise dos fatores associados à decisão familiar sobre a doação de córneas / Analysis of factors associated with family decision on corneal donation

Resumo Objetivo: analisar a influência da escolaridade e do grau de parentesco na decisão familiar pela doação de córneas para transplantes. Método: desenho quantitativo, transversal e retrospectivo com amostra composta por 291 fichas das entrevistas realizadas com familiares de potenciais doadores de córneas de janeiro de 2015 a dezembro de 2017 de um hospital público, geral e de grande porte localizado no município de Porto Alegre, Rio Grande do Sul, Brasil. Resultados: entre os potenciais doadores deste tecido, 53,3% são do sexo masculino com idade média de 57 anos (57±11); 55,7% são casados e o turno mais frequente da ocorrência do óbito é o noturno com 29,6% dos casos. Em relação à decisão familiar, 60,8% dos entrevistados decidiram favoravelmente à doação. Existe associação entre doação e turno da entrevista, sendo a madrugada o menos favorável (p=0,04). O tempo médio entre o óbito e a realização da entrevista é de 1:39 (±1:20) e não influenciou na decisão familiar (p=0,63). Dos familiares entrevistados, 58,8% são do sexo feminino e 53,3% são descendentes do potencial doador. O parentesco descendente decide sobre a doação com maior frequência do que ascendentes, laterais ou cônjuges. A faixa etária do familiar entrevistado (41±13) tem diferença estatística em relação a do potencial doador. Há diferença entre decisão de doação e nível de escolaridade (p=0,03) sendo que familiares com maior escolaridade decidem com maior frequência favoravelmente a doação. Conclusões: escolaridade do familiar, grau de parentesco e turno da entrevista influenciam na decisão positiva para a doação de córneas para transplantes.

Abstract Objective: analyzing the influence of schooling and kinship on families' decision to donate corneas for transplants. Method: quantitative, cross-sectional and retrospective study whose sample comprised 291 records of interviews conducted with family members of potential corneal donors from January 2015 to December 2017, who were treated in a public, general and large-sized hospital in Porto Alegre City, Rio Grande do Sul State, Brazil. Results: 53.3% of the potential corneal donors were male at mean age of 57 years (57 ± 11); 55.7% were married and 29.6% of them died during the night shift, which was the shift when death took place more often. With respect to families' decision, 60.8% of interviewees decided for donation. There was association between donation and interview shift; dawn was the least favorable time (p = 0.04). The mean time between patients' death and the interview with family members was 1:39 (± 1: 20) and it did not influence families' decision (p = 0.63). Among the interviewed family members, 58.8% were women and 53.3% were descendants of the potential donor. Descendants decide about the donation more often than ascendants, siblings or spouses. The age group of the interviewed family members (41 ± 13) was statistically different from that of potential donors. There was association between schooling and decision to donate (p = 0.03); family members with higher schooling were more often favorable towards donation. Conclusions: Family members' schooling, degree of kinship and interview shift had positive influence on individuals' decision to donate corneal tissue for transplants.

Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer: an update.

INTRODUCTION: Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (mCRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status, and new biomarkers such as HER2 amplification and NTRK fusions have emerged more recently in refractory CRC, supported by overwhelming clinical relevance. These biomarkers can guide treatment management to improve clinical outcomes in these patients. AREAS COVERED: Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory CRC. Molecular alterations are described for classic and novel biomarkers, and data for completed and ongoing studies with targeted and immunotherapies are presented. EXPERT OPINION: Use of targeted therapies based on biomarker testing in CRC has enabled impressive improvements in clinical outcomes in refractory patients. BRAF, MSI, NRAS and KRAS should be tested upfront in all patients given their indisputable therapeutic implications. Other molecular alterations such as HER2 and NTRK are emerging. Testing for these alterations may further improve outcomes for refractory CRC patients. Nonetheless, many key aspects remain to be defined including the optimal timing and technique for testing, the most adequate panel, and whether all patients should be tested for all alterations.

Neoadjuvant cisplatin plus temozolomide versus standard treatment in patients with unresectable glioblastoma or anaplastic astrocytoma: a differential effect of MGMT methylation.

Patients with unresectable glioblastoma or anaplastic astrocytoma have a dismal prognosis. The role of neoadjuvant chemotherapy prior to irradiation in these patients has been studied primarily in non-randomized studies. We have compared the effect of neoadjuvant chemotherapy plus radiotherapy versus concomitant radiotherapy plus temozolomide in a retrospective analysis of two consecutive series of patients in whom surgery consisted of biopsy only. From 2003 to 2005, 23 patients received two cycles of temozolomide plus cisplatin followed by radiotherapy (Cohort 1), and from 2006 to 2010, 23 additional patients received concomitant radiotherapy and temozolomide followed by adjuvant temozolomide (Cohort 2). In Cohort 1, 91.3 % of patients received all planned chemotherapy cycles. Progression-free and overall survival were 3.3 and 8.5 months, respectively. In Cohort 2, progression-free and overall survival were 5.1 and 11.2 months, respectively. No differences between the two groups were observed in rate of completion of radiotherapy, progression-free or overall survival. MGMT methylation was assessed in 91.3 % of patients. In Cohort 1, patients without MGMT methylation showed a trend towards shorter progression-free survival (P = 0.09), while in Cohort 2, patients without MGMT methylation had longer progression-free survival (P = 0.04). In the overall patient population, neoadjuvant temozolomide plus cisplatin had neither a positive nor negative influence on outcome. However, our findings indicate that patients with methylated MGMT may derive greater benefit from neoadjuvant temozolomide than those with unmethylated MGMT.

Validity, reproducibility, and responsiveness of a twelve-joint simplified power doppler ultrasonographic assessment of joint inflammation in rheumatoid arthritis.

OBJECTIVE: To investigate the validity, reproducibility, and responsiveness of a simplified power Doppler ultrasound (PDUS) assessment of joint inflammation compared with a comprehensive 44-joint PDUS assessment in patients with rheumatoid arthritis (RA) who started therapy with a biologic agent. METHODS: A total of 160 patients with active RA who started a biologic agent were prospectively recruited in 18 Spanish centers. The patients underwent clinical and laboratory assessment and blinded PDUS examination at baseline and 6 months. A PDUS examination of 128 synovial sites in 44 joints was performed. US synovitis and PD signal were semiquantitatively graded from 1 to 3 in all synovial sites. US count and index for synovitis and PD signal were obtained. PDUS intraobserver and interobserver reliability were evaluated. A process of data reduction based on the frequency of involvement of synovial sites by both synovitis and PD signal was conducted. Construct and discriminant validity of a simplified PDUS assessment was investigated. RESULTS: A PDUS simplified assessment including 24 synovial sites from 12 joints detected 100% of patients with synovitis and 91% of patients with PD signal. There was a highly significant correlation between the 44-joint count and index for synovitis and PD signal and the 12-joint count and index for synovitis and PD signal at baseline and 6 months (r = 0.84-0.90, P < 0.0005). The smallest detectable difference was lower than the mean change in simplified PDUS variables. CONCLUSION: A 12-joint PDUS assessment of RA joint inflammation may be a valid, feasible method for multicenter monitoring of therapeutic response to biologic agents.

¿Tienen adolescentes y jóvenes que consumen drogas no inyectadas mayor probabilidad de transmisión sexual del VIH? / Have adolescents and young people who take non-injected drugs a greater probability of HIV sexual transmission?

El objetivo de este artículo es analizar la relación entre el consumo de drogas no inyectadas y las conductas sexuales que incrementan el riesgo de infección por VIH u otras Enfermedades de Transmisión Sexual en adolescentes y jóvenes. Para ello se ha realizado una revisión bibliográfica de investigaciones publicadas en revistas científicas entre 1998 y 2003. Éstas han sido descritas considerando el tipo de droga consumida, el tipo de población, la posición social y el sexo/género de las personas participantes. Algo más de la mitad de los artículos analizados asocian el consumo de alcohol o marihuana con prácticas sexuales de riesgo. Sobre el consumo de otras drogas no inyectadas como cocaína, anfetaminas, etc. y su mezcla con alcohol no hay acuerdo. No aparecen grandes diferencias entre varones y mujeres, según pertenencia poblacional o por posición social. La mayoría de los trabajos analizados encuentran relación entre el consumo de algunas drogas y las prácticas sexuales que incrementan el riesgo de infección por VIH. No obstante, la escasa comparabilidad y otros problemas metodológicos dan pie a la controversia. Se identificaron limitaciones en los artículos revisados y recomendaciones para futuras investigaciones

The objective of this article is to analyse the relationship between the use of non-injected drugs and the sexual risks of HIV infection or another STD in adolescents and young people. A bibliographical review was made of articles published in scientific journals between 1998 and 2003. These studies were described considering type of drug, type of population (population minorities), social position and sex/gender of the participants. Slightly more than a half of the articles analysed associate the use of alcohol or marijuana with risky sexual behaviour. There is no agreement on the use of other non-injected drugs such as cocaine, amphetamines, etc. or their combination with alcohol. No major differences were found between men and women, by population group or by social position. Most of the studies find some relationship between the use of certain drugs and sexual behaviours that increase the risk of HIV infection. However, the lack of comparability and other methodological problems are conducive to controversy. Limitations in reviewed articles were identified and recommendations made for future research