Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era.

Owing to recent advances in genomic technologies, personalized oncology is poised to fundamentally alter cancer therapy. In this paradigm, the mutational and transcriptional profiles of tumors are assessed, and personalized treatments are designed based on the specific molecular abnormalities relevant to each patient's cancer. To date, such approaches have yielded impressive clinical responses in some patients. However, a major limitation of this strategy has also been revealed: the vast majority of tumor mutations are not targetable by current pharmacological approaches. Immunotherapy offers a promising alternative to exploit tumor mutations as targets for clinical intervention. Mutated proteins can give rise to novel antigens (called neoantigens) that are recognized with high specificity by patient T cells. Indeed, neoantigen-specific T cells have been shown to underlie clinical responses to many standard treatments and immunotherapeutic interventions. Moreover, studies in mouse models targeting neoantigens, and early results from clinical trials, have established proof of concept for personalized immunotherapies targeting next-generation sequencing identified neoantigens. Here, we review basic immunological principles related to T-cell recognition of neoantigens, and we examine recent studies that use genomic data to design personalized immunotherapies. We discuss the opportunities and challenges that lie ahead on the road to improving patient outcomes by incorporating immunotherapy into the paradigm of personalized oncology.

Aspectos macroeconômicos da reforma da Previdência Social no Brasil: duas análises em equilíbrio geral com restrições ao crédito

Este trabalho utiliza dois modelos de simulação matemática de equilíbrio geral na presença de restrições ao crédito com o propósito de analisar o quadro macroeconômico em estado estacionário resultante de uma reforma previdenciária que substitua o regime de repartição pelo de capitalização, executada sob diversas condições. Embora ambos os modelos adotem o esmo conjunto de hipóteses básicas, eles diferem quanto ao mecanismo de funcionamento da Previdência Social sob o regime de repartição. No primeiro, supõe-se a operação de um sistema de contribuição definida orçamentariamente equilibrado. Já o segundo introduz um regime de repartição com a dupla característica de beneficio definido e de contribuição definida, condição que dá origem a um desequilíbrio orçamentário endógeno.

Orfeu sem travessa: leitura de um poema de José Paulo Paes

Starting from general considerations on the Orpheus myth and its resonance on Brazilian poetry, this essay aims at an interpretative analysis of the prose poem “Orpheus” from José Paulo Paes, published in one of the author’s latest books, A meu esmo (1995).

Genomic alterations in patients showing multiple primary tumors and family history of cancer

Multiple primary tumors (MPT) are a major cause of mortality and morbidity among patients that have survived after the treatment of a first cancer. It has been proposed that after the first primary tumor, high risk of a subsequent tumor could be associated with radiotherapy used as treatment for the first cancer. Other potential risk factors include unhealthy lifestyle, genetic predisposition, aging, environmental determinants or an interaction between these factors. However, an association between the presence of MPT and family history of cancer in cases without clinical and molecular evidence of a known hereditary cancer syndrome is rarely described. Genomic DNA from 12 patients with at least two primary tumors and without mutations on TP53 was evaluated by CytoScan HD Array (Affymetrix). Chromosome Analysis Suite (ChAS) software v.2.0.1 was used considering at least 50 markers for gains; 25 for losses and a minimum of 5Mb for cnLOHs. Data from 1038 phenotypically healthy individuals (Affymetrix) and from Database of Genomic Variants were used as reference. Only alterations found in <1% (rare) or never described (new rare) in the reference population were considered. All cases, except one, presented a family history of cancer. Five cases developed MTP after radiotherapy and only one was located in the same treated area. It was detected 67 rare and 15 new rare genomic alterations encompassing 5.906 genes: 17 losses, 29 gains, and 36 cnLOH. X chromosome presented the higher number of alterations. Two patients with breast cancer presented a large deletion/cnLOH on 7q21. Enrichment analysis revealed 1275 genes associated with breast cancer (p= 0.001), which was diagnosed in 6 patients and their family members (all negative for BRCA1/2 or TP53 mutations). cnLOHs accounted for 44% of all the alterations. A significant proportion of cases (11/12) presented family history of cancer and the patients were not submitted to radiotherapy (7/12). We demonstrated the presence of rare genomic alterations in patients with MPT suggesting their involvement in the MPT development. cnLOH may arise as a new mechanism associated with the risk to develop MPT. All authors have declared no conflicts of interest.

Building a global consensus approach to chordoma: a position paper from the medical and patient community

Chordomas are very rare bone malignant tumours that have had a shortage of effective treatments for a long time. New treatments are now available for both the local and the metastatic phase of the disease, but the degree of uncertainty in selecting the most appropriate treatment remains high and their adoption remains inconsistent across the world, resulting in suboptimum outcomes for many patients. In December, 2013, the European Society for Medical Oncology (ESMO) convened a consensus meeting to update its clinical practice guidelines on sarcomas. ESMO also hosted a parallel consensus meeting on chordoma that included more than 40 chordoma experts from several disciplines and from both sides of the Atlantic, with the contribution and sponsorship of the Chordoma Foundation, a global patient advocacy group. The consensus reached at that meeting is shown in this position paper.

Intensificación terapéutica en adenocarcinoma de recto cT4NxM0. Resultados y factores pronósticos

El cáncer colorrectal es el tercer tumor más frecuente en Occidente (1,2). Dentro de esta entidad el cáncer de recto representa un tercio del total de los pacientes afectos por esta neoplasia (3,4). Los síntomas iniciales de este tumor son anodinos lo que explica porque en casi la mitad de los casos los pacientes presentan una enfermedad localmente avanzada o metastásica al diagnóstico (1). La supervivencia de los pacientes con cáncer de recto localmente avanzado (CRLA) ha experimentado una gran mejoría desde finales del siglo pasado, especialmente por la disminución de las recidivas locales. Sin embargo, la diseminación sistémica es el mayor reto en el tratamiento de esta enfermedad. El CRLA se define como aquel con una extensa afectación de la pared del recto o que presenta adenopatías locorregionales metastásicas, englobándose dentro de los estadios II y III de la AJCC (5). Para su tratamiento es imprescindible un enfoque multimodal, en el que se combinan distintos componentes terapéuticos y especialidades asistenciales (6). El esquema de referencia avalado científicamente por las principales guías clínicas y documentos de consenso disponibles en la actualidad (NCCN (7), ESMO (4), NICE (2) y EURECCA (8), se basa en la administración inicial de quimioradioterapia (QRT) neoadyuvante seguida de la cirugía y posteriormente considerar la opción de un tratamiento quimioterápico adyuvante...

Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study

BACKGROUND: Radium-223 dichloride (radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P).

PATIENTS AND METHODS: Analyses were conducted to determine treatment effects of radium-223 plus standard of care (SOC) versus placebo plus SOC on QOL using FACT-P and EQ-5D. Outcomes assessed were percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores during the study.

RESULTS: Analyses were carried out on the intent-to-treat population of patients randomized to receive radium-223 (n = 614) or placebo (n = 307). The mean baseline EQ-5D utility and FACT-P total scores were similar between treatment groups. A significantly higher percentage of patients receiving radium-223 experienced meaningful improvement in EQ-5D utility score on treatment versus placebo {29.2% versus 18.5%, respectively; P = 0.004; odds ratio (OR) = 1.82 [95% confidence interval (CI) 1.21-2.74]}. Findings were similar for FACT-P total score [24.6% versus 16.1%, respectively; P = 0.020; OR = 1.70 (95% CI 1.08-2.65)]. A lower percentage of patients receiving radium-223 experienced meaningful worsening versus placebo measured by EQ-5D utility score and FACT-P total score. Prior docetaxel use and current bisphosphonate use did not affect these findings. Treatment was a significant predictor of EQ-5D utility score, with radium-223 associated with higher scores versus placebo (0.56 versus 0.50, respectively; P = 0.002). Findings were similar for FACT-P total score (99.08 versus 95.22, respectively; P = 0.004).

CONCLUSIONS: QOL data from ALSYMPCA demonstrated that improved survival with radium-223 is accompanied by significant QOL benefits, including a higher percentage of patients with meaningful QOL improvement and a slower decline in QOL over time in patients with CRPC.

Que técnica usar nos cuidados ao cordão umbilical do recém-nascido

É durante o puerpério que o Enfermeiro ESMO cuida do RN de forma a promover o bem-estar e potenciar a sua saúde, incluindo os cuidados ao coto umbilical. Parece existirem diferentes práticas nos cuidados ao coto umbilical do RN, que se caraterizam pela não uniformização e nem sempre baseadas em evidência científica. Na prestação de cuidados surgem, às vezes, dúvidas. A primeira premissa para sanar estas questões, baseia-se no recurso à evidência, sendo a prática baseada na evidência a mais aceite e deverá ser praticada.

Evidencia sobre la eficacia de cannabinoides en el dolor neuropático oncológico

Contexto: La eficacia de los cannabinoides en el dolor neuropático es desconocida. El control del dolor es determinante en los pacientes ya que genera un impacto negativo en la calidad de vida de los pacientes. Objetivo: El presente trabajo pretende demostrar la evidencia sobre la eficacia de los medicamentos cannabinoides en el control del dolor neuropático oncológico, mediante la evaluación de la literatura disponible. Metodología: Se realizó una revisión sistemática de literatura incluyendo estudios experimentales, observacionales y revisiones sistemáticas en un periodo de 15 años. Se incluyeron todos los estudios desde el años 2000 con evidencia IB según la escala de evidencia de Oxford. Resultados: Cuatro estudios cumplieron criterios para su inclusión, sin embargo la evidencia es baja y no permite recomendar o descartar los cannabinoides como terapia coadyuvante en control del dolor neuropático oncológico. La combinación de THC/CDB (Sativex®) parece ser un medicamento seguro pues no se reportaron muertes asociadas a su uso, sin embargo la presentación de eventos adversos a nivel gastrointestinal y neurológico podría aumentar el riesgo de interacciones medicamentosas y tener un impacto negativo en la calidad de vida de los pacientes oncológicos. Conclusiones: No hay suficiente literatura y la evidencia no es suficiente para recomendar o descartar el uso de los cannabinoides en dolor neuropático oncológico. Futuros estudios deben realizarse para analizar el beneficio de estos medicamentos. Aunque ética y socialmente hay resistencia para el uso de los cannabinoides, actualmente hay una gran discusión política en el mundo y en Colombia para su aceptación como terapia en el control del dolor.

Discovering Hands - México

El modelo de Discovering Hands ha sido reconocido internacionalmente como un proyecto innovador que se ha expandido por diferentes países del mundo, como Austria, y se ha empezado a estudiar la propuesta en países como República Checa, India y Colombia. (Discovering Hands, 2016). Esto se debe a que no solo mejora el tratamiento de cáncer de mama, sino que también reduce los costos totales de tratamiento de la enfermedad y aumenta la fuerza laborar de los países donde esté presente. Al representar una gran oportunidad en diferentes aspectos, se quiso desarrollar un estudio de factibilidad del modelo de negocio en tres países de América Latina, Colombia –donde ya se encuentra en marcha un proyecto piloto liderado por la CAF en Cali - , Argentina y México. El presente trabajo consiste en dicho estudio de factibilidad, focalizado en México; por medio de este se buscaron tres cosas primordiales, conocer y estudiar el contexto del mercado y situación de salud en el país, analizar los datos recogidos, con el fin de proponer soluciones para disminuir una de las principales causas de muerte en el país. Actualmente en México el 52% de casos de cáncer de mama diagnosticados sucede en etapas tardías, aumentando el riesgo de muerte de los pacientes (Colima, 2013). Con el estudio se logró identificar una oportunidad potencial para Discovering Hands siendo su estrategia un recurso adicional para contribuir a mejorar el diagnóstico precoz de cáncer de mama en el país y debido a esto se presenta un modelo de negocio adaptable a las necesidades mexicanas