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Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer. TILs can be easily assessed on hematoxylin and eosin stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Since TILs and PD-L1 are parts of an immunological spectrum in breast cancer, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immune-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with breast cancer. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in breast cancer. This article is protected by copyright. All rights reserved., info:eu-repo/semantics/published

Purpose O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation predicts the outcome and response to alkylating chemotherapy in glioblastoma. The aim of this study is to evaluate the prevalence of MGMT methylation in Peruvian glioblastoma cases. Patients and methods We evaluated retrospectively 50 cases of resected glioblastoma during the period 2008-2013 at Instituto Nacional de Enfermedades Neoplasicas in Peru. Samples consisted of paraffin embedded and frozen tumour tissue. MGMT-promoter methylation status and the expression level of MGMT gene were evaluated by methylation-specific PCR and real-time PCR, respectively. Results Unmethylated, methylated and partially methylated statuses were found in 54%, 20% and 26% of paraffin-embedded samples, respectively. Methylation status was confirmed in the Virgen de la Salud Hospital and frozen samples. There was an association between the status of MGMT-promoter methylation and the level of gene expression (p = 0.001). Methylation was associated with increased progression-free survival (p = 0.002) and overall survival (OS) (p < 0.001). Conclusion MGMT-promoter methylation frequency in Peruvian glioblastoma is similar to that reported in other populations and the detection test has been standardised.

In this work a Luenberger observer (LO) for type 1 diabetes is established using the Hovorka?s model (HM). The HM is linearized around an operating point and the eigenvalues are calculated. The LO is designed relocating the HM eigenvalues through the Ackermann?s methodology for linear observers where the proposed LO keeps the nonlinear structure of the model system. The LO is parameterized and tuned with the mean from six virtual patients of HM. Once the observer performance is reliable estimating the state space variables for HM, the virtual patients are changed by patients of Bergman?s model in order to test the observer behavior under unknown dynamics. These estimated variables constitute the ones corresponding to HM. The variables are estimated by the data computational processing which correspond to the insulin (input) and glucose (output) of the virtual patients. The estimated variables by the LO are very similar for virtual patients generated by both models, where the parameter FIT is used to quantify the performance of the observer. The computational implementation of the LO is useful tool to estimate the unmeasured variables in diabetic patients so they can be used in the artificial pancreas.

AIM To investigate the survival impact of clinicopathological factors, including pathological complete response (pCR) and tumor-infiltrating lymphocytes (sTIL) levels according to subtypes, in breast cancer (BC) patients who received neo-adjuvant chemotherapy (NAC). METHODS We evaluated 435 BC patients who presented and received NAC at the Instituto Nacional de Enfermedades Neoplasicas from 2003 to 2014. sTIL was analyzed as the proportion of tumor stroma occupied by lymphocytes, and was prospectively evaluated on hematoxylin and eosin-stained sections of the preNAC core biopsy. pCR was considered in the absence of infiltrating cancer cells in primary tumor and axillary lymph nodes. Analysis of statistical association between clinical pathological features, sTIL, pCR and survival were carried out using SPSSvs19. RESULTS Median age was 49 years (range 24-84 years) and the most frequent clinical stage was III B (58.3%). Luminal A, Luminal B, HER2-enriched and (triple-negative) TN phenotype was found in 24.6%, 37.9%, 17.7% and 19.8%, respectively. pCR was observed in 11% and median percentage of sTIL was 40% (2%-95%) in the whole population. pCR was associated to Ct1-2 ( P = 0.045) and to high sTIL ( P = 0.029) in the whole population. There was a slight trend towards significance for sTIL ( P = 0.054) in Luminal A. sTIL was associated with grade III ( P < 0.001), no-Luminal A subtype ( P < 0.001), RE-negative ( P < 0.001), PgR- negative ( P < 0.001), HER2-positive ( P = 0.002) and pCR ( P = 0.029) in the whole population. Longer disease-free survival was associated with grade I - II ( P = 0.006), cN0 ( P < 0.001), clinical stage II ( P = 0.004), ER-positive ( P < 0.001), PgR-positive ( P < 0.001), luminal A ( P < 0.001) and pCR ( P = 0.002). Longer disease-free survival was associated with grade I - II in Luminal A ( P < 0.001), N0-1 in Luminal A ( P = 0.045) and TNBC ( P = 0.01), clinical stage II in Luminal A ( P = 0.003) and TNBC ( P = 0.038), and pCR in TNBC ( P < 0.001). Longer overall survival was associated with grade I - II ( P < 0.001), ER-positive ( P < 0.001), PgR- positive ( P < 0.001), Luminal A ( P < 0.001), cN0 ( P = 0.002) and pCR ( P = 0.002) in the whole population. Overall survival was associated with clinical stage II ( P = 0.017) in Luminal A, older age ( P = 0.042) in Luminal B, and pCR in TNBC ( P = 0.005). CONCLUSION Predictive and prognostic values of clinicopathological features, like pCR and sTIL, differ depending on the evaluated molecular subtype.

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies., info:eu-repo/semantics/published

Aim: Evaluation of features related to infiltrating immune cell level in glioblastoma. Methods: Tumor- infiltrating lymphocytes (TILs) through H&E staining, and TILs (CD3, CD4, CD8 and CD20) and macrophage (CD68 and CD163) levels through immunohistochemistry were evaluated through digital analysis. Results: CD68 (9.1%), CD163 (2.2%), CD3 (1.6%) and CD8 (1.6%) had the highest density. Higher CD4 + was as- sociated with unmethylated MGMT (p = 0.016). Higher CD8 + was associated with larger tumoral size (p = 0.027). Higher CD163 + was associated with higher age (p = 0.044) and recursive partitioning anal- ysis = 4. Women (p < 0.05), total resection (p < 0.05), MGMT-methylation (p < 0.001), radiotherapy (p < 0.001), chemotherapy (p < 0.001) and lower CD4 + (p < 0.05) were associated with longer overall survival. Conclusion: Macrophages are more frequent than TILs. Some subsets are associated with clinical features.

Este texto discute un problema novedoso sobre el que la bibliografía es escasa: las relaciones entre complejidad –ciencias de la complejidad– y salud. El tema de base es la vida, y la salud constituye una expresión importante de ella. La tesis que se presenta es que para la enfermedad se necesita de mucha y muy buena ciencia, información, educación y tecnología; para la salud se necesita, además, de una pizca de sabiduría. Pensar la enfermedad implica una estructura mental determinista; en efecto, es indispensable determinarla de todas las formas posibles. La salud, en contraste, requiere una estructura mental del todo distinta: la indeterminación.

Purpose: O6 -methylguanine–DNA methyltransferase (MGMT) promoter methylation predicts the outcome and response to alkylating chemotherapy in glioblastoma. The aim of this study is to evaluate the prevalence of MGMT methylation in Peruvian glioblastoma cases. Patients and methods: We evaluated retrospectively 50 cases of resected glioblastoma during the period 2008–2013 at Instituto Nacional de Enfermedades Neoplasicas in Peru. Samples consisted of paraffin embedded and frozen tumour tissue. MGMT-promoter methylation status and the expression level of MGMT gene were evaluated by methylation-specific PCR and real-time PCR, respectively. Results: Unmethylated, methylated and partially methylated statuses were found in 54%, 20% and 26% of paraffin-embedded samples, respectively. Methylation status was confirmed in the Virgen de la Salud Hospital and frozen samples. There was an association between the status of MGMT-promoter methylation and the level of gene expression (p = 0.001). Methylation was associated with increased pro- gression-free survival (p = 0.002) and overall survival (OS) (p < 0.001). Conclusion: MGMT-promoter methylation frequency in Peruvian glioblastoma is similar to that reported in other populations and the detec- tion test has been standardised.

Background Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to BRCA 1 and BRCA 2 germline mutations. Methods We performed a comprehensive analysis of BRCA 1 and BRCA 2 genes by Sanger sequencing and multiplex ligation‐dependent probe amplification (MLPA ) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer. Results In this series, we found four pathogenic mutations, three previously reported (BRCA 1 : c.302‐1G>C and c.815_824dup10; BRCA 2 : c.5946delT) and a duplication of adenines in exon 15 in BRCA 1 gene (c.4647_4648dupAA , ClinVar SCV 000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants. Conclusion This is the first report to determine the spectrum of mutations in the BRCA 1/BRCA 2 genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in BRCA 1/BRCA 2 with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known BRCA 1/BRCA 2 mutations and a BRCA 1 c.4647_4648dupAA as a novel pathogenic mutation.

Este artículo elabora una genealogía del concepto de desarrollo. Formulado originalmente por R. Prebisch (1950), el concepto sufre varias traducciones, extensiones y modificaciones que terminan asimilándolo a una idea perfectamente distinta. El sentido y el contexto originarios terminan transformándose. Así, el desarrollo termina siendo una apología del capitalismo. Después de una introducción histórica y científica, el artículo desarrolla cuatro argumentos, así: el modelo de desarrollo es una idea extraña; esta idea se ve ampliada y extendida en términos de sostenibilidad; varias críticas, sin embargo, emergen y se hacen necesarias; consiguientemente, se hace posible e imperativo un modelo alternativo al desarrollo. Cada una de las secciones mencionadas son justificadas en cada paso. Al final se extraen algunas conclusiones, y el artículo termina con una idea fuerte que vincula bancarización y control ciudadano. This paper carries out a genealogy of the concept of development. Originally stated out by R. Prebisch (1950), the concept suffers a number of translations, extension, and changes that end up with a quite different idea than it was originally thought. Both the meaning and framework end up being radically changed. Thus, development ends as an apology to capitalism. After a short historical and philosophical introduction, this paper develops four arguments, as follows: the model of economic development is a weird idea; such an idea is both extended and widened in terms of sustainability; a number of critiques merge, though, that are necessary and feasible; thereafter, an alternative model of development becomes at the same time possible and compulsory. Each one of the mentioned paragraphs are justified in due time. At the end some conclusions are drawn, and the paper ends with a string idea that links banking and citizen control. Este artigo desenvolve uma genealogia do conceito de desenvolvimento. Originalmente formulado por R. Prebisch (1950), o conceito sofreu várias traduções, extensões e modificações que acabam compreendendo-o como uma ideia diferente. O sentido e o contexto originário acabam se transformando. Assim, o desenvolvimento acaba por ser uma apologia do capitalismo. Depois de uma introdução histórica e científica, o artigo desenvolve quatro argumentos: o modelo de desenvolvimento é uma ideia estranha; esta ideia é ampliada e aumentada em termos de sustentabilidade; vários comentários, no entanto, emergem e se tornam necessários; consequentemente, torna-se possível e imperativo um modelo de desenvolvimento alternativo. Cada uma das seções mencionadas é justificada em cada passo. Ao final algumas conclusões são feitas, e o artigo termina com uma ideia forte que liga a bancarização e o controle do cidadão."

El concepto de hypercomputación (HB) ha sido introducido (Stepney, 2009; Maldonado, Gómez, 2015) como una forma de comprender cómo los sistemas vivos procesan información. Este artículo presenta los desarrollos de la HB pero sostiene la idea que, a partir de la misma, los seres vivos se comunican en forma de estructuras, y no en el modo de signos y símbolos. La química en general y la topología química en particular ofrecen fundamentos para entender esta idea. Lo que está en juego es una comprensión acerca de la lógica de la vida. The concept of biological hypercomputation (BH) has been introduced (Stepney, 2009; Maldonado, Gómez, 2015) as a way to understand how living systems process information. This paper presents the developments of BH but it claims that, accordingly, the living beings communicate via structures rather in the form of signs and symbols. Chemistry in general, and chemical topology in particular set out the ground to understanding this idea. What is at stake is the understanding of the logics of life. O conceito de hipercomputação (HB) foi introduzido (Stepney, 2009; Maldonado Gomez, 2015) como uma forma de entender como os sistemas vivos processam informação. Este artigo apresenta o desenvolvimento do HB, mas apoia a ideia de que, a partir dele, os seres vivos se comunicam em forma de estruturas, e não na forma de sinais e símbolos. A química em geral e a topologia química em particular oferecem fundamentos para entender esta ideia. O que está em jogo é uma compreensão da lógica da vida."

Este artículo argumenta que el futuro de los seres humanos ya se encuentra con nosotros y a título exploratorio y provocativo, reflexiona sobre varias formas de futuro humano: los humanos transgénicos, los humanos transgenómicos, los humanos transexuales, los humanos biónicos y los humanos híbridos. Una revolución cultural y científica, aunadas, están transformando nuestra experiencia del mundo y la cultura. This article argues claims that the future of the human beings is already among us. Exploratorily and as a provocation, the author reflects about various forms of the human future, thus: transgenic humans, trans genomic humans, transsexual humans, bionic humans, and hybrid humans. An authentic both cultural and scientific revolution is currently transforming our experience of the world and culture. Este artigo argumenta que o futuro dos seres humanos já está conosco e provocativo título exploratório reflete sobre várias formas de futuro humano: humano transgênico, transgenómicos humanos, transexuais humanos, biônico humano e híbrido humano. A revolução cultural e científica, combinados, estão transformando a nossa experiência do mundo e da cultura.

En el mundo, cada día son más los estudios y trabajos sobre complejidad; sin embargo, no existe ninguno que explícitamente considere las implicaciones políticas de estudiar los fenómenos complejos no lineales. En esta ocasión, se exploran algunas de las más importantes consecuencias políticas de las ciencias de la complejidad y se propone llenar parcialmente este vacío. Se argumenta que dichas consecuencias incluyen a las políticas públicas que incum­ben sobre todo a la política en sentido amplio. Tres ejes articulan el argumento: a) una presentación de las ciencias dela complejidad y sus derivaciones; b) la consideración de las secuelas políticas de la complejidad, y c) las interrelaciones entre revoluciones científicas y revoluciones políticas. There has been an increasing research and investigation about complexity worldwide. Nevertheless, none of them has explicitly considered the political implications of studying complex, not linear, phenomena. This work explores some of the most important political consequences of Complexity Science and intends to partially fill this gap. It is argued that those consequences include public policies, which mainly consider politics in a broad and strong sense. The argument has three major points: a) a presentation of Complexity Science and its derivations; b) the consideration of political consequences of complexity; and c) the interrelationship between scientific and political revolutions.

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En este texto, se argumenta a favor de un trabajo entre las ciencias de la complejidad y la administración, en particular cuando se trata de problemas de información y de seguridad. Así, la criptografía debe ser vista al mismo tiempo como un campo que ha de ser incorporado en el cuerpo de los estudios sobre administración en general, y como un caso de estudio para la perdurabilidad de las organizaciones. La piedra de toque es, por tanto, la relación entre complejidad y estrategia. This text argues in favor of coordinated work between the sciences of complexity and administration, particularly when it involves problems of information and security. Cryptography must therefore be seen as both a field that must be incorporated within the body of studies on administration in general as well as a case study for the durability of organizations. The touchstone is therefore the relationship between complexity and strategy. Ce texte présente un argument en faveur d'un travail entre les sciences de la complexité et l'administration, s'agissant plus particulièrement de problèmes d'information et de sécurité. La cryptographie doit donc être considérée autant comme un domaine à incorporer dans le corpus d'études de l'administration en général, que comme un cas d'étude pour la durabilité des organisations. En conséquence, la relation entre complexité et stratégie est la pierre de touche. Neste texto argumento a favor de um trabalho entre as ciências da complexidade e a administração, em particular quando se trata de problemas de informação e de segurança. Assim, a criptografia deve ser vista ao mesmo tempo como um campo que deve ser incorporado no corpo dos estudos sobre administração em geral, tanto como um caso de estudo para a perdurabilidade das organizações. A 'pedra de toque' é, por tanto, a relação entre complexidade e estratégia."

Es un lugar común afirmar que la bioética es una ética, y que se integra dentro de las éticas aplicadas. Tal es la idea generalizada acerca de la bioética, que, así, la situaría al interior de, y al mismo nivel con, las éticas aplicadas del tipo: la ética empresarial, la ética del trabajo, la ética del medioambiente. Una comprensión semejante de la bioética se encuentra en Singer (1998) o en Camps (1998), pero son numerosos los autores que argumentan en favor de esta idea. Quiero sostener aquí que esta comprensión de la bioética es equivocada. No solamente desconoce la especificidad misma de la bioética, que se encuentra en el término bios, sino, además, pasa por alto el tema sensible y fundamental de la ética de la bioética: el ethos. En consecuencia, son numerosas las interpretaciones que confunden la bioética, con la ética, e incluso con las éticas deontológicas. En otros lugares me he pronunciado en contra de estas interpretaciones erróneas (por ejemplo en Maldonado, 2004). (1) (PDF) A Reflection about the Epistemological Status of Bioethics The usual understanding of bioethics is in terms o fan applied ethics. Here, I claim that such an approach does not really favour bioethics. I argue that bioethics is to be understood as belonging to the life sciences. Normally, little attention is paid to the relationship between epistemology and bioethics. It is necessary, I claim, to review such a relationship. New insights arise from such a perspective (1) (PDF) A Reflection about the Epistemological Status of Bioethics.

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Este texto discute la posibilidad del desarrollo de una teoría de las extinciones, una teoríainexistente hasta la fecha, y que vendría a ser la contraparte o el complemento de la teoría de laevolución. El problema central es el de la exploración de una teoría general de la complejidad,una tarea que permanece abierta e inconclusa hasta el momento. La paleontología y la biologíaevolutiva pueden verse como las dos caras de una moneda cuyo rasgo distintivo no es el gradua-lismo, sino los equilibrios puntuados y el catastrofismo. El tema de las extinciones se concentraaquí en la importancia y el papel de las extinciones masivas. A partir del diálogo entre biología ypaleontología, evolución y extinciones, varias reflexiones se extrapolan al plano social, cultural yfilosófico. El marco amplio es el de las ciencias de la complejidad. This paper discusses the possibility of reaching a theory of extinctions, a theory nonexistent so farthat can be taken as complementary to the theory of evolution. The core problem is here theexploration of the general theory of complexity, a task that remains open and without a definiteconclusion until now. Paleontology and biology can be grasped as the two faces of one and thesame token whose most salient feature is punctuated equilibria and catastrophism, and notgradualism any longer. Extinctions are viewed here particularly as massive extinctions. After thedialogue between paleontology and biology, evolution and extinctions, a number of reflectionsare extrapolated to the social, cultural and philosophical framework. The general context henceis the one provided by the sciences of complexity.

Hacer filosofía es muy poco, tanto como hacer ciencia es también muy poco, sobre todocuando se llevan a cabo separadamente. Estamos asistiendo a un movimiento asintótico a través delcual ciencia y filosofía tienden a estar unidas. En este artículo se defiende la tesis según la cual el procesode pensar radical no debe ni puede limitarse únicamente a la ciencia o la filosofía. Un proceso semejantede pensar se denomina hoy en día investigación. Pensar es, así, investigar, y la investigación noresponde a reglas ni patrones fijos. A lo largo de la defensa de la tesis mencionada, este artículo frece unpanorama de la investigación de punta en ciencia y en filosofía. Philosophizing, in the traditional sense of the word and practice, as well as doing scienceare, indeed, very little enterprises, if they are isolated. We are facing an asymptotic tendency by whichboth philosophy and science are to be unified, eventually. This paper argues in favor of a radicalprocess of thinking that is not limited to just science or philosophy. Currently, such a process is calledresearch. Thinking thus is to be understood as research, which does not follow rules or norms. Alongwith the defense of this thesis, this paper offers us a fresco of the current spearhead research inphilosophy as well as in science.

Este trabajo tiene el propósito de incursionar en un tema ya bastante controversial pero de suma importancia en la actualidad. Se trata del Rol de la Contabilidad, tal como la hemos conocido prácticamente desde siempre en los negocios versus un entorno empresarial que en los últimos veinte años virtualmente ha desmantelado todas las premisas y condiciones en que la contabilidad ha basado sus prácticas, convenciones y postulados. Esto es algo más que una simple polémica entre profesionales o académicos, y de hecho se convierte en un asunto crucial para el desempeño (performance) de las empresas y sus posibilidades competitivas, pero también en algo que importa al crecimiento o desarrollo nacional. El propósito es reflexionar sobre estos nuevos retos y sobre el rol de la contabilidad ante la "nueva economía"i, particularmente en lo relativo al desafío de medir el verdadero Valor de las empresas que la integran. No se pretende profundizar en las soluciones a los problemas de la contabilidad, aunque ya existen pioneros en ese campo incluyendo quienes procuran una contabilidad del "capital intelectual" y los que están intentando modificar radicalmente la contabilidad de costos. Entre el material consultado destacan el trabajo de Baruch Levii, quien procura encarar los dilemas que enfrenta una contabilidad impotente para registrar el valor de las empresas modernas, sobre todo de aquellas más intensivas en conocimiento o de alta tecnología. Es decir, las firmas que forman parte de la nueva economía. Este profesor de la Stern University, NY, USA expresa los comentarios más agudos y equilibrados escritos recientemente sobre este tema. Asimismo, las obras de Eliyahu Goldtrattiii, escritor sumamente heterodoxo en su estilo, quien ha intentado reconvertir totalmente la contabilidad de costos. Destacan además el pensamiento de Edvinsson y Malone como pioneros de la medición del capital intelectual, así como Shank y Govindarajan que muestran una perspectiva estratégica de costos. El trabajo se divide en cinco capítulos: El primero procura caracterizar el entorno y condiciones; debilidades y desafíos correspondientes a la contabilidad convencional. El segundo hace una relectura, comentarios e interpretación del pensamiento de Baruch Lev, quien caracteriza el más reciente "estado de arte"iv de la contabilidad. El tercero ilustra con un ejemplo numérico la conocida frase de que "los beneficios son una opinión, y el Valor es un hecho"v. El cuarto contiene los comentarios finales y conclusiones más relevantes. Finalmente, el quinto capítulo contiene las pertinentes notas y citas que fundamentan las proposiciones del primero.

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI), Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University., Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance., Funder: The Canadian Cancer Society, Funder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194, Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006, Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.

To examine the relationship between "Quality of Professional Life" and "Perceived Emotional Intelligence" and the relationship of both of these with the level of achievement of occupational objectives in the Costa del Sol Primary Health Care District. Multicentre descriptive cross-sectional observational study. The Costa del Sol Primary Health Care District in the province of Málaga. Sample of Employees of all categories in fixed and contracted employment in the Management Units of the Costa del Sol District. (N=303). Respondents 247 (81.5%) The data collected was that of the percentage of achievement of objectives in 2010 and the socio-demographic data of the participants, using ad hoc designed self-report questionnaires. The TMMS -24 questionnaire was used to measure the "Perceived Emotional Intelligence", with the following dimensions: Perception, comprehension, and emotional control, and the CVP-35 measuring: management support, work demands, and intrinsic motivation. Significant correlationas were observed between Quality of Professional Life and Emotional Intelligence in the Regulation (p The perceived quality of professional life is related to perception and regulation dimensions of Emotional Intelligence. Knowledge of emotion management methods should be promoted by management organisations for all employees.