[Immune checkpoint inhibitors. A breakthrough in cancer therapy]. / La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018.

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.

[The contribution of omic sciences for the management of cancer in Chile]. / Planificación sanitaria a partir de los datos ómicos: ¿es posible esta idea para Chile?

With or without a COVID19 pandemic, cancer is and will continue to be one of the greatest health challenges on the planet. In Chile, during 2016, this disease was the second cause of death in the country and during 2019, it was the first cause in seven Chilean regions, surpassing cardiovascular diseases. With the advent of precision medicine as a powerful tool for cancer control, it is necessary to have genomic, proteomic, and molecular data in general, ideally on a population scale. This is essential for decision-making, for example in public and private oncology, to be as cost-effective as possible. Chile has a mass of high-quality researchers in cancer. However, until today the investment in research and development is far below the peers in the OECD. In this work we put into perspective the role of precision medicine and omic sciences as essential tools for public health. We offer a brief national diagnosis of the knowledge collected to date by the local scientific community regarding onco-genomic data from our own population. We finally discuss the potential behind the strengthening of this scientific knowledge, aiming to optimize the comprehensive management of cancer.

[Molecular diagnosis of human papillomavirus infection. The Chilean experience]. / Implementación del diagnóstico molecular del VPH: experiencia chilena en curso.

Cervical Cancer (CaCu) has a heterogeneous epidemiological behavior throughout the planet, depending on regional socioeconomic development level. Some developed countries predict a potential eradication of this cancer in the next 100 years, while in Chile it still constitutes a pending challenge. Incidence rates show a slow but sustained downward prob, however, mortality has continued to fluctuate between 500-600 cases per year. A few years ago, vaccination against Human Papillomavirus (HPV), the main causal agent for this tumor, was consolidated as a public policy, both in girls and in boys. However, the technological leap in the screening prob was pending, from cytology to molecular diagnosis of the agent (HPV). In this report, we update our most recent data (2018) regarding CaCu mortality, then review global guidelines and experiences in HPV screening. Finally, we offer an account of the strategies that our health system is promoting to address the screening of the disease and whose molecular approach generates the widest worldwide scientific consensus. We also recognize the main barriers and future challenges, which, if overcome, would allow us to be in line with the mandate of WHO to control this women's health problema.

Radiotherapy for cervical cancer: Chilean consensus of the Society of Radiation Oncology.

BACKGROUND: Cervical cancer is a public health problem in Latin America. Radiotherapy plays a fundamental role both as definitive or adjuvant treatment. There are important intra and inter-country differences regarding access and availability of radiotherapy facilities in this region. The aim of a study was to standardize the basic clinical and technical criteria for the radiation treatment of patients with CC in Chile and provide a guide for Latin American Radiation Oncologists. MATERIALS AND METHODS: Forty-one expert radiation oncologists from the Chilean Radiation Oncology Society made a consensus using the Delphi methodology. RESULTS: There was a high degree of agreement for each of the recommendations. Those with the lowest percentage were related to the definition of the conformal 3D technique as the standard for definitive external radiotherapy (81%) and the criteria for extended nodal irradiation (85%). CONCLUSIONS: These recommendations present an updated guide for radiotherapy treatment of patients with cervical cancer for Latin America. Those should be implemented according to local resources of each institution.

[An analysis of scientific formation in medical schools]. / Formación científica en el pregrado de medicina en Chile: ¿dónde estamos? y ¿hacia dónde vamos?

For more than a century the training of medical professionals has been organized according to the Flexnerian model, which comprises three cycles: basic, clinical and clerkship. On the other hand, the accelerated development of biomedical sciences modified the competences of the first cycle. Additionally, new skills required for medical practice, such as teamwork and innovation as a tool to solve health problems, challenged in recent years the classic paradigm of medical education. Therefore, the medical schools have developed multiple strategies to deal with it, such as curricular integration using competency-based education models, incorporating basic and clinical sciences in parallel during the curriculum, ensuring a relevant and applicable scientific knowledge throughout the training process. Although in Chile the Flexner prototype is still followed, the basic sciences are taught as single or integrated courses or using a systems approach. In this article we report a diagnosis about the local integration of fundamental sciences in medical training. We also compare our schools with those of Canada, Europe and Latin America. Recommendations aimed at modernizing medical school curricula are made.

[The cardiovascular impact of cancer control therapy]. / Impacto cardiovascular secundario a la terapia para el control del cáncer.

Cardiovascular diseases and cancer account for 27 and 25% of mortality in Chile, respectively. In the last decades, survival of people with cancer has improved due to preventive programs, early detection strategies, advances in technology and development of new antineoplastic therapies. Consequently, a progressive number of cancer-surviving patients have been generated, who may develop cardiovascular diseases, secondary to the same cancer therapy. Cardio-Oncology has emerged as the necessary link between both specialties to promote the prevention and early detection of cardiac complications, in patients undergoing oncological therapies. The aim is to curb cardiovascular complications. Also, to acquire knowledge about the mechanisms and effects of drugs that lead to heart damage aiming to develop efficient cardioprotective therapies. In this article we review and propose a didactic organization and classification of the main cardiovascular effects of cancer control therapy. We recognize that there is still a knowledge gap in basic sciences about the mechanisms that underlie these alterations.

[The present situation of colorectal cancer in Chile]. / Situación actual del cáncer de colon en Chile: una mirada traslacional.

Colorectal (CRC) is one of the most common types of cancer worldwide. Most tumors develop from an adenoma in a period of 10 to 15 years, but some may appear without previous adenomatous lesions. Seventy-five percent of colorectal cancers are sporadic, 20% have a family component (first or second-degree relatives with CRC) and 5% have a hereditary predisposition with a Mendelian pattern. The epidemiological evolution in the recent years in Chile has a worrisome evolution and the treatment costs of advanced stages are a burden for the healthcare system. We herein highlight the main Chilean medical and scientific contributions on the pathogenesis, early diagnosis, and treatment of CRC, which lead to its better understanding, and therefore better management, based on local evidence.

[Digital health services as a means to control dementia]. / Oportunidad en la salud digital: una respuesta al control de las demencias.

The increase of the elderly population with a significant load of non-communicable diseases, accelerates pathological aging and increases the risk of dementia, generating a huge health, social and economic cost for any country. Dementia does not have an effective treatment yet, therefore, the focus must remain on prevention and early diagnosis. The early stages of dementia are known as mild cognitive impairment; at this stage is still possible to mitigate the progression of the disease, however, health systems worldwide face difficulties to provide universal access to health services, due to a lack of specialists and geographical distances, interfering with the access to healthcare centers. In this scenario, WHO urged countries to implement strategies to democratize and to expand the reach of health institutions. In this document, we briefly review the global and local situation of dementias and discuss some attempts to control their progression by using revolutionary digital tools. We believe the focus should be on the population that is just beginning to show cognitive impairment.

[The implementation of a Biobank network for Chile]. / Una red de biobancos para Chile: investigar hoy, para curar mañana.

The concept "Biobank" is relatively new in the scientific literature, and is not yet consensually defined, even for the World Health Organization (WHO). However, the use of human samples in biomedical research is a very old activity. The organized development of Biobanks in different places has grown in the last decade. The experience in different countries and continents has been diverse. In this special article we intend to summarize, organize and communicate to the national medical and scientific community, (i) the concept of Biobank, (ii) the international experience and a map of the Research Biobanks working in Chile, (iii) the basic biomedical and essential operational aspects to manage a Biobank for Research and (iv) the impact of a National Network of Biobanks implementation in the Chilean Health System. Ethical and regulatory aspects will not be included, given their intrinsic complexity, which should be discussed elsewhere.

Wnt3a ligand facilitates autophagy in hippocampal neurons by modulating a novel GSK-3ß-AMPK axis.

BACKGROUND: In the adult central nervous system (CNS), Wnt signaling regulates dendritic structure and synaptic plasticity. The Wnt signaling pathway can be divided into the canonical (ß-catenin-dependent) and non-canonical pathways. In the canonical pathway, the binding of canonical ligands such as Wnt3a to the Frizzled receptor induces inactivation of glycogen synthase kinase-3ß (GSK-3ß), which stabilizes ß-catenin and allows its translocation to the nucleus. However, to date, few studies have focused on ß-catenin-independent Wnt signaling or explained the underlying mechanisms connecting Wnt signaling to cellular energy metabolism. A recent study demonstrated negative regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a major target of GSK-3ß that regulates cellular metabolism under diverse conditions. Mainly based on these observations, we evaluated whether Wnt3a ligand modulates autophagy by regulating the GSK-3ß/AMPK axis. METHODS: Cultured primary hippocampal neurons and slices of the CA1 region of rat hippocampus were used. GSK-3ß inhibition, AMPK activation, PP2Ac expression, and LC3 processing were examined by western blotting. Autophagic compartments were studied using the CYTO-ID® fluorescent probe, and mature autophagosomes were observed via transmission electron microscopy (TEM). RESULTS: Wnt3a ligand, acting through the Frizzled receptor, promotes the rapid activation of AMPK by inactivating GSK-3ß. Biochemical analysis of downstream targets indicated that Wnt3a ligand modulates autophagy in hippocampal neurons. CONCLUSIONS: Our results revealed new aspects of Wnt signaling in neuronal metabolism. First, AMPK is an additional target downstream of the Wnt cascade, suggesting a molecular mechanism for the metabolic effects previously observed for Wnt signaling. Second, this mechanism is independent of ß-catenin, suggesting a relevant role for non-genomic activity of the Wnt pathway in cellular metabolism. Finally, these results have new implications regarding the role of Wnt signaling in the modulation of autophagy in neurons, with a possible role in the removal of accumulated intracellular proteins.

[The impact of tap water fluoridation on human health]. / Consecuencias de la fluoración del agua potable en la salud humana.

The purpose of this review is to describe the osteological, neurological, endocrine and dermatological effects of fluoride ingestion. Additional aims are to evaluate whether the Chilean tap water fluoridation program has had any impact on dental health, and analyze the basis for the Chilean elementary school milk fluoridation program, which is targeted at children living in places where tap water has a fluoride concentration less than 0.3 mg/L, without any artificial fluoridation process. We discuss the finding that both public measures have no direct or remarkable effect on dental health, since topical dental hygiene products are the main and most effective contributors to the prevention of dental decay. We also suggest that the permanent and systematic ingestion of fluorides imposes health risks on the population. Therefore, we recommend reevaluating the national fluoridation program for public tap water and the elementary school milk program.

Signaling pathway cross talk in Alzheimer's disease.

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-ß aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.

Model for managing scientific research in a public hospital: case study: Chilean National Cancer Institute, from 2015-2022.

Research is an essential element in the practice of healthcare, and hospitals play a fundamental role in its promotion. Research in hospitals can improve the quality of care, knowledge of diseases and the discovery of new therapies. Hospitals can conduct research in various fields, including basic research, clinical research, population-based research and even hospital management research. The findings of hospital research can be directly applied to clinical practice and management, thereby enhancing the quality of patient care, a central paradigm in translational health. This article details the experience of the National Cancer Institute of Chile over the past 8 years in its role as a high-complexity public hospital, specialised institute, healthcare centre, teaching institution, and research facility. It reviews the work of generating and strengthening its institutional research model since its redesign in 2018, the key elements that underpin it, and discusses the challenges the institute faces in its growth amidst the increasing cancer epidemiology in Chile, the recent enactment of a National Cancer Law, the post-pandemic scenario that has left a significant waiting list of oncology patients, and the initiation of the design and construction process for the new institute building.

Proteogenomic analysis in an early onset diffuse gastric cancer patient revealed alterations in PIK3R1, TP53, SMAD4 and a potential role of the PI3K-AKT and EGFR pathways: a case report.

Background: Early-onset gastric cancers (EOGC) are poor prognosis hard-to treat malignancies that affect young individuals (<45 years old). Case Description: Herein we describe the case of a 26-year-old female EOGC patient that initially displayed stable disease after first-line CAPOX plus immunotherapy. However, patient eventually developed progressive disease and was consecutively switched to paclitaxel plus ramucirumab, and palliative irinotecan. In search for therapeutic alternatives a proteo-genomic analysis was performed in a tissue biopsy taken after the first progression. Our analyses found a total of 18 somatic mutations, including TP53 and PIK3R1, and a previously unreported germline alteration in the tumor suppressor SMAD4. Also, our proteomic analysis found 62 proteins previously documented as "enriched in stomach cancer" and AKT/mTOR and EGFR as pathways with therapeutic potential. Unfortunately, the clinical utility of AKT/mTOR inhibitors or EGFR targeted therapies could not be assessed. Conclusions: As explained above EOGC is a growing health concern that affects young individuals. Furthermore, the reported case displayed a poor response to standard therapy including checkpoint inhibitors and chemotherapy despite the presence of biomarkers that predict a favorable outcome. Future studies should adopt alternative approaches to find novel, more effective therapies.

Mutational Landscape and Actionable Target Rates on Advanced Stage Refractory Cancer Patients: A Multicenter Chilean Experience.

Major advances in sequencing technologies and targeted therapies have accelerated the incorporation of oncology into the era of precision medicine and "biomarker-driven" treatments. However, the impact of this approach on the everyday clinic has yet to be determined. Most precision oncology reports are based on developed countries and usually involve metastatic, hard-to-treat or incurable cancer patients. Moreover, in many cases race and ethnicity in these studies is commonly unreported and real-world evidence in this topic is scarce. Herein, we report data from a total of 202 Chilean advanced stage refractory cancer patients. Retrospectively, we collected patient data from NGS tests and IHC in order to determine the proportion of patients that would benefit from targeted treatments. Overall >20 tumor types were included in our cohort and 37% of patients (n = 74) displayed potentially actionable alterations, including on-label, off-label and immune checkpoint inhibitor recommendations. Our findings were in-line with previous reports such as the cancer genome atlas (TCGA). To our knowledge, this is the first report of its kind in Latin America delivering real-world evidence to estimate the percentage of refractory tumor patients that might benefit from precision oncology. Although this approach is still in its infancy in Chile, we strongly encourage the implementation of mutational tumor boards in our country in order to provide more therapeutic options for advanced stage refractory patients.

Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration.

Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.

Pruebas no invasivas para el tamizaje del cáncer colon: fundamentos básico-clínicos y recientes avances biotecnológicos / Non-invasive tests for colorectal cancer screening: basic-clinical fundamentals and recent biotechnological advances

Colorectal Cancer (CRC) is the third most frequent neoplasia worldwide. Despite the significant advances in surgical techniques and the development of new targeted antineoplastic therapies for this type of tumor, primary prevention and early diagnosis of malignant precursor lesions will continue to be the best strategies to reduce their incidence, morbidity, and mortality. Technologies for CRC screening can be classified into two groups, those of an invasive nature, such as colonoscopy and all its different modalities of use, and those of a non-invasive nature, such as laboratory tests and imaging. This review, will focus exclusively on non-invasive screening tests, excluding imaging. Specifically, it will address those that use depositions as a sample. This review will approach the latest international recommendations, regarding the age at which they should be used, their technical-biological bases, the two main types currently used (biochemical and immunological), and we will put into perspective their advantages and their possible disadvantages. Towards the end of this article, the most recent biotechnological developments in relation to molecular tests based on the study of blood samples, will be discussed. Although these tests are not yet in routine clinical use given their high costs, they are promising for the early detection of CRC.

El cáncer colorrectal (CCR) es la tercera neoplasia más común en todo el mundo. A pesar de los avances significativos en las técnicas quirúrgicas y en el desarrollo de nuevas terapias antineoplásicas para este tipo de tumor, la prevención primaria y el diagnóstico precoz de lesiones precursoras malignas siguen siendo las mejores estrategias para reducir la incidencia, morbilidad y mortalidad asociadas al CCR. Existen dos tipos de tecnologías para el tamizaje del CCR: las invasivas, como la colonoscopia, y las no invasivas, como los ensayos de laboratorio y la imagenología. Esta revisión, se centrará exclusivamente en las pruebas de tamizaje no invasivas que utilizan muestras de deposiciones, excluyendo las imágenes. Se abordarán las últimas recomendaciones internacionales sobre el momento etario en que se deben utilizar, sus bases técnico-biológicas, los dos principales tipos utilizados en la actualidad (bioquímico e inmunológico) y pondremos en perspectiva sus ventajas y posibles desventajas. Al final de esta revisión, se discutirá brevemente los últimos avances biotecnológicos relacionados con pruebas moleculares basadas en el estudio de muestras sanguíneas. Aunque estas pruebas aún no son de uso clínico habitual debido a sus altos costos, representan una prometedora innovación para la detección temprana del CCR.

Caracterización de la incidencia del cáncer de mama en un servicio público de salud chileno en el período 2006-2015 / Characterization of incidence rates of breast cancer in public health service, period 2006-2015

OBJETIVO: El cáncer de mama constituye la primera causa de muerte oncológica en mujeres chilenas. Las tasas de incidencia solo han sido estimadas según el registro 2003-2007. Nuestro objetivo fue estimar las tasas de incidencia en un período de 10 años en un servicio de salud y caracterizar dicha población. MÉTODO: Se calcularon las tasas de incidencia del período 2006-2015, por método directo, y se analizó la tendencia por Prais-Winsten. Se caracterizó la población según la edad y la etapa al diagnóstico. RESULTADOS: De 2862 casos, la tasa de incidencia estandarizada promedio fue de 66,6 por 100.000 mujeres. En el período hubo una tendencia al alza del diagnóstico de 0,63/100.000 anualmente (p = 0,5; intervalo de confianza del 95%: −1,73 a 2,99). La mayor tasa de incidencia bruta fue en el grupo de 70 y más años (154,8/100.000). El 49% correspondieron a casos diagnosticados de 50 a 69 años. El 56% se diagnosticó precozmente; la etapa I tuvo la más alta tasa (15,8/100.000). CONCLUSIONES: En este estudio, las tasas de incidencia son mayores que las reportadas en informes nacionales previos. El diagnóstico es mayoritariamente en etapas precoces, lo que difiere del resto de los países de la región. Nuestros datos pueden aportar a mejorar las políticas públicas.

OBJECTIVE: Breast cancer is the leading cause of cancer death in Chilean women. Incidence rates have only been estimated based on population records (2003-2007). Our objective was to estimate the incidence rates in a 10-year period in a health service and portray in words this cohort. METHOD: Incidence rates were calculated between 2006-2015 by direct method and trends were analyzed with the Prais-Winsten model. The population was defined according to age and stage at diagnosis. RESULTS: Of a total of 2862 cases, the average incidence rate was 66.6 out of 100,000 women. Between 2006-2015, the trend rose in breast cancer diagnosis of 0.63/100,000 annually (p = 0.5; 95% confidence interval: −1.73, 2.99). The highest crude rate of incidence was in the group aged 70 and over (154.8/100,000). 49% correspond to cases diagnosed between 50 and 69 years. 56% were in early stages, stage I, being the most frequent (15.8/100,000). CONCLUSIONS: On this research the incidence rates were higher than the ones reported on previous national reports. Diagnosis is mostly in early stages which differs from other countries in the region, our data can help improve public health policies.

La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018 / Immune checkpoint inhibitors: a breakthrough in cancer therapy

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.