Intraoperative evaluation of sentinel lymph nodes in patients with breast cancer treated with systemic neoadjuvant therapy.

AIMS: Touch preparation (TP) and frozen section (FS) are the two methods routinely used in the intraoperative evaluation (IOE) of sentinel lymph nodes (SLNs) to detect metastases in patients with breast cancer. Both methods are extremely sensitive and specific in the primary surgery (non-neoadjuvant systemic therapy (non-NST)) setting. Since NST introduces unique challenges in the IOE of SLNs, the aim was to determine the accuracy of TP and FS in the IOE of SLNs in the NST setting and compare the results with the non-NST setting and to examine factors that contribute to any differences. METHODS: We analysed 871 SLNs from 232 patients (615 SLNs from NST and 256 SLNs from non-NST settings) between 2016 through 2019. RESULTS: In the NST group, TP alone (n=366) had a sensitivity of 45.7% and specificity of 99.7%; FS alone (n=90) had a sensitivity of 83.3% and specificity of 100%. When both TP and FS (n=135) were used, the sensitivity was 80.3% and the specificity was 98.6%.In the non-NST group, TP alone (n=193) had a sensitivity of 66.7% and specificity of 100%; FS alone (n=22) had a sensitivity and specificity of 100%; and combined TP and FS (n=34) had a sensitivity and specificity of 100% and 96%, respectively. CONCLUSIONS: Evaluating SLNs intraoperatively in the NST setting can be challenging secondary to therapy-related changes. In the NST setting, FS has higher sensitivity and specificity compared with TP for the IOE of SLNs and should be the preferred method.

SNAT7 regulates mTORC1 via macropinocytosis.

Mammalian target of rapamycin complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Some amino acids signal to mTORC1 through the Rag GTPase, whereas glutamine and asparagine activate mTORC1 through a Rag GTPase-independent pathway. Here, we show that the lysosomal glutamine and asparagine transporter SNAT7 activates mTORC1 after extracellular protein, such as albumin, is macropinocytosed. The N terminus of SNAT7 forms nutrient-sensitive interaction with mTORC1 and regulates mTORC1 activation independently of the Rag GTPases. Depletion of SNAT7 inhibits albumin-induced mTORC1 lysosomal localization and subsequent activation. Moreover, SNAT7 is essential to sustain KRAS-driven pancreatic cancer cell growth through mTORC1. Thus, SNAT7 links glutamine and asparagine signaling from extracellular protein to mTORC1 independently of the Rag GTPases and is required for macropinocytosis-mediated mTORC1 activation and pancreatic cancer cell growth.

Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers.

We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.

¿La medicina científica y el programa Medicina Basada en Evidencia han fracasado? / Has scientific medicine and the EBM program failed?

La medicina científica y el programa de medicina basada en evidencia han fracasado, afirman críticos y detractores. La medicina basad en la evidencia es un programa que busca dar respuesta a la necesidad de sistematizar el conocimiento médico, mejorar el proceso de toma de decisiones en salud y, por ende, mejorar los sistemas de salud. A pesar de su gran difusión no está exenta de críticas, desde cuestionamientos a su enfoque filosófico positivista, a su visión estrictamente biológica y de eficacia y al innegable conflicto de intereses de las investigaciones biomédicas financiadas en su mayoría por la industria farmacéutica. Sin embargo, a pesar de sus limitaciones aún queda un largo camino por desarrollar y sus alcances y beneficios ya se verifican en el ejercicio mismo de las decisiones médicas

According to its critics and detractor, scientific medicine and the Evidence-Based Medicine (EBM) program have failed. EBM is a program that seeks to respond to the need to systematise medical knowledge, improve the decision-making process in health and thus improve health systems. Despite its wide dissemination, it is not without criticism, from the questioning of its positivist philosophical approach, to its strictly biological and of effectiveness vision, and to the undeniable conflict of interests of biomedical research, which is mostly financed by the pharmaceutical industry. However, despite its limitations, there is still a long way to go, and its scope and benefits are already demonstrated in the current making of medical decisions

La importancia de una comunicación de calidad en los servicios de salud. La salud y la teoría de la comunicación desde Pedro Laín Entralgo / The importance of communication quality in health care services. Health and communication theory from Pedro Lain Entralgo

En nuestra época la relación médico paciente se tornado crítica y una de las razones es la falta o inadecuada comunicación. La forma básica de esta relación surge ante el dolor y la búsqueda de su resolución, en esta búsqueda el hombre ha desarrollado una serie de herramientas de acuerdo a su contexto histórico. El hombre es y se ha desarrollado en sociedad y el medio unificador para lograr este desarrollo ha sido la comunicación. Es desde el siglo XX que mediante la teoría lingüística moderna, la informática y la cibernética; la comunicación adquiere una importancia crucial e interés por su estudio, además esto se ha manifestado en su acelerado desarrollo a través de las tecnologías de comunicación e información como el internet. La comunicación permanece como elemento básico y esencial de la relación médico paciente, su comprensión y abordaje podrían favorecer esta relación o de lo contrario perturbarla, con las consecuencias institucionales y personales que esto acarrea.