Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes

Propósito: Las mutaciones en el oncogén viral del sarcoma de rata de Kirsten (KRAS) constituyen un importante impulsor del adenocarcinoma de pulmón, presente en el 10-40% de los pacientes, que exhiben resultados clínicos heterogéneos, principalmente impulsados por alteraciones genéticas concurrentes. Sin embargo, la caracterización de los subtipos mutacionales de KRAS y su impacto en los resultados clínicos en Latinoamérica es limitada. Métodos: Se realizó un estudio de cohorte en el Instituto Nacional de Cancerología (INCan) de México. Se incluyeron para el análisis individuos con estadios avanzados de adenocarcinoma y mutaciones de KRAS, detectadas por secuenciación de próxima generación, que habían sido sometidos al menos a una línea de terapia. Las características clínicas y patológicas se recuperaron de la base de datos institucional de junio de 2014 a marzo de 2023. Resultados: KRAS fue identificado en cincuenta y cuatro (15,6%) de 346 pacientes, entre los cuales 50 casos fueron incluidos para el análisis. KRASG12D (n = 16, 32%) y KRASG12C (n = 16, 32%) representaron los subtipos más prevalentes. Las mutaciones en KRASG12D se asociaron con el sexo femenino (p = 0,018), con no haber fumado nunca (p = 0,108) y con concurrencias con EGFR (25,0% frente a 17,6%, p = 0,124) y CDKN2A (18,8% frente a 14,7%, p = 0,157). Los pacientes con KRASG12D mostraron una mejor ORR (66,6% vs. 30,0%; OR 4,66; IC 95% 1,23-17,60; p = 0,023) y en el análisis multivariante se asoció significativamente con una mejor SLP (HR 0,36; IC 95% 0,16-0,80; p = 0,012) y SG (HR 0,24; IC 95% 0,08-0,70; p = 0,009). Conclusiones: Hasta donde sabemos, este estudio representa el primer esfuerzo por caracterizar exhaustivamente la heterogeneidad molecular del CPCNP con mutación de KRAS en pacientes latinoamericanos. Nuestros datos refuerzan la opinión actual de que el CPNM con mutación de KRAS no es una enfermedad impulsada por un único oncogén y enfatiza el impacto pronóstico de los diversos perfiles moleculares en este subconjunto genómicamente definido de CPNM. Se justifica una mayor validación en cohortes latinoamericanas multicéntricas más grandes para confirmar nuestros hallazgos. 2023, El Autor (es).Purpose: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10–40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited. Methods: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023. Results: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRASG12D (n = 16, 32%) and KRASG12C (n = 16, 32%) represented the most prevalent subtypes. KRASG12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRASG12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23–17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16–0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08–0.70; p = 0.009). Conclusions: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings. © 2023, The Author(s)

Grupos relacionados por el diagnóstico (GRD) como herramienta de gestión clínica para medir el producto sanitario en la unidad de cuidados intensivos del Hospital Regional Docente de Cajamarca

Es una ardua tarea medir el producto sanitario en el país. La evidente desintegración de información ocasiona entre otros problemas una imprecisa distribución de recursos. Por ello es necesario generar herramientas que permitan asociar la casuística clínica al consumo de recursos optimizando la gestión clínica de los hospitales. Los Grupos relacionados por el diagnóstico (GRD) son un sistema de clasificación de pacientes que se basa en agruparlos por características similares (diagnósticos y tratamientos), permitiendo identificar y reducir la variabilidad clínica, reconocer a los grupos complejos y lograr una mejor estandarización optimizando la calidad de atención en salud al menor costo. Este sistema utilizado en países como EE. UU., Asia y Europa, en los últimos años se viene implementando con éxito en Latinoamérica. Implementar los GRD en hospitales públicos del país generaría una producción eficiente, uso adecuado de recursos, mejora de la estructura de costos, y tarifas más precisas, favoreciendo al intercambio prestacional, y por lo tanto al tarifario referencial nacional, de acuerdo con la eficiencia operativa, categoría y complejidad de cada establecimiento, permitiendo una adecuada toma de decisiones basada en información clara, actualizada, inmediata y acorde al contexto

Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non-small cell lung cancer patients previously treated with radiotherapy

Introduction:Immune checkpoint inhibitor-related pneumonitis (ICIP) is a potentially lifethreatening immune-related adverse event (irAE), especially in non-small cell lung cancer(NSCLC) patients. Currently, the potential for increased irAE in patients who receiveradiotherapy is scarcely known, although a connection between antitumor immuneresponses and irAEs has been suggested. In this study, we evaluated the developmentof ICIP in non-small cell lung cancer patients with prior radiotherapy, treated withimmunotherapy in the second-line.Methods:In this retrospective trial, we included patients treated with second-lineimmunotherapy at the National Cancer Institute in Mexico City from February 2015 toFebruary 2018. Clinical, radiological and treatment variables were evaluated accordingto the presence of ICIP as defined by the Common Terminology Criteria for AdverseEvents (4.0) in patients with or without a previous (≥months) history of radiotherapy.Results:Among 101 NSCLC patients who received treatment with ICIs, 22 patients(21.8%) were diagnosed with ICIP, of which 73% (16/22) had a history of radiotherapy(OR 6.04, 95% CI 2.03−18.0,p<0.001). Median progression free survival and overallsurvival were similar in patients who developed ICIP compared with those who did not,however, patients who presented grade≥2 ICIP had an increased risk of mortality (HR2.54, 95% CI 1.20−5.34,p= 0.014).Conclusion:In this real-world cohort of NSCLC patients treated with ICI, the historyof prior radiotherapy was associated with increased risk for ICIP development. Unlikeother irAEs, grade≥2 ICIP is an independent prognostic factor for decreased survivalin NSCLC patients

Pepsinógenos séricos para detectar cáncer gástrico en Costa Rica

Artículo científico -- Universidad de Costa Rica, Instituto de Investigaciones en Salud. 2003Las concentraciones de pepsinagenos (PG) I y II en suero, reflejan el estado funcional y morfológico de la mucosa gástrica. En este estudio se determinaron los puntos de corte óptimos de los niveles séricos de PGI, PGII y de la razón PGI/PGII, para identificar a las personas con alto riesgo de cáncer gástrico en una población de alto riesgo en Costa Rica. La población en estudio estaba formada por 338 personas sin cáncer gástrico y por 20 pacientes con cáncer gástrico. Los niveles de PGI y el valor de PGI/PGI I fueron significativamente mas bajos en las personas con cáncer gástrico que en los controles, Los puntos de cone Optimos para la detección de cáncer gástrico fueron de PGI 5 60 pg/L junto con el valor de la razón PGI/PGII 5 2,5. Usando estos puntos de corte la sensibilidad y especificidad fueron de 90 y 64%. Las concentraciones bajas de PGI y valores bajos de PGI/PGII indican alto riesgo de presentar un cáncer gástrico. El tamizaje por medio de pepsinegenos es simple y relativamente barato, sin embargo el beneficio real de esta prueba debe determinarse en el impacto sabre las tasas de mortalidad por cáncer gástrico.Serum pepsinogen (PG) concentrations reflect the morphological and functional status of the gastric mucosa. This study was carried out in order to determine the appropiate Cut off point of serum pepsinogen PGI, PGII and the ratio PGI/PGII, for identifying gastric cancer in a high risk population in Costa Rica. The study population was comprised of 338 subjects without gastric cancer and 20 gastric cancer patients. Serum pepsinogen concentrations were assayed. The pepsinogen I level and the ratio PGI/PGII were significantly lower in patients with gastric cancer than in control subjets. The best cut off point was a combination of pepsinogen I concentrations less that 60 pg/L. and a ratio of pepsinogen 1 to pepsinogen 11 less than 2.5 in screening for gastric cancer. Using this cut off point, sensitivity of pepsinogen screening for gastric cancer was 90% and specificity was 64%. Low serum pepsinogen 1 concentrations and a low pepsinogen 1/11 ratio are predictive of gastric cancer in this population. Pepsinogen screening is simple and inexpensive. However, the real benefits of this test need to be defined by determining the impact on gastric cancer mortality rates.Universidad de Costa Rica. Instituto de Investigaciones en SaludUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

Wearables for Engagement Detection in Learning Environments: A Review

Appropriate teaching–learning strategies lead to student engagement during learning activities. Scientific progress and modern technology have made it possible to measure engagement in educational settings by reading and analyzing student physiological signals through sensors attached to wearables. This work is a review of current student engagement detection initiatives in the educational domain. The review highlights existing commercial and non-commercial wearables for student engagement monitoring and identifies key physiological signals involved in engagement detection. Our findings reveal that common physiological signals used to measure student engagement include heart rate, skin temperature, respiratory rate, oxygen saturation, blood pressure, and electrocardiogram (ECG) data. Similarly, stress and surprise are key features of student engagement

Short Daily Exposure to Environmental Enrichment, Fluoxetine, or Their Combination Reverses Deterioration of the Coat and Anhedonia Behaviors with Differential Effects on Hippocampal Neurogenesis in Chronically Stressed Mice

Depression is a neuropsychiatric disorder with a high impact on the worldwide population. To overcome depression, antidepressant drugs are the first line of treatment. However, pre-clinical studies have pointed out that antidepressants are not entirely efficacious and that the quality of the living environment after stress cessation may play a relevant role in increasing their efficacy. As it is unknown whether a short daily exposure to environmental enrichment during chronic stress and antidepressant treatment will be more effective than just the pharmacological treatment, this study analyzed the effects of fluoxetine, environmental enrichment, and their combination on depressive-associated behavior. Additionally, we investigated hippocampal neurogenesis in mice exposed to chronic mild stress. Our results indicate that fluoxetine reversed anhedonia. Besides, fluoxetine reversed the decrement of some events of the hippocampal neurogenic process caused by chronic mild stress. Conversely, short daily exposure to environmental enrichment changed the deterioration of the coat and anhedonia. Although, this environmental intervention did not produce significant changes in the neurogenic process affected by chronic mild stress, fluoxetine plus environmental enrichment showed similar effects to those caused by environmental enrichment to reverse depressive-like behaviors. Like fluoxetine, the combination reversed the declining number of Ki67, doublecortin, calretinin cells and mature newborn neurons. Finally, this study suggests that short daily exposure to environmental enrichment improves the effects of fluoxetine to reverse the deterioration of the coat and anhedonia in chronically stressed mice. In addition, the combination of fluoxetine with environmental enrichment produces more significant effects than those caused by fluoxetine alone on some events of the neurogenic process. Thus, environmental enrichment improves the benefits of pharmacological treatment by mechanisms that need to be clarified

LKB1 Loss Assessed by Immunohistochemistry as a Prognostic Marker to First-Line Therapy in Advanced Non-Small-Cell Lung Cancer

(1) Background: Liver kinase B1 (LKB1) is a tumor suppressor gene involved in cell growth and metabolism. However, its alterations are not routinely assessed for guiding therapy in clinical practice. We assessed LKB1 expression by immunohistochemistry as a potential biomarker. (2) Methods: This bicentric retrospective cohort study analyzed data from patients with advanced NSCLC who initiated platinum-based chemotherapy or epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI) between January 2016 and December 2020. Kaplan–Meier and Cox regression models were used for survival curves and multivariate analysis. (3) Results: 110 patients were evaluated, and the clinical stage IV predominated the lung adenocarcinoma histology. LKB1 loss was observed in 66.3% of cases. LKB1 loss was associated with non-smokers, the absence of wood smoke exposure and an EGFR wild-type status. The median progression-free survival (PFS) and overall survival (OS) in the population were 11.1 and 26.8 months, respectively, in the loss group, compared with cases exhibiting a positive expression. After an adjustment by age, smoking status, Eastern Cooperative Oncology Group Performance Score (ECOG-PS), EGFR status and type of administered therapy, LKB1 loss was significantly associated with worse PFS and OS. (4) Conclusion: Patients with an LKB1 loss had worse clinical outcomes. This study warrants prospective assessments to confirm the prognostic role of the LKB1 expression in advanced NSCLC

Comprehensive Genomic Profile of Heterogeneous Long Follow-Up Triple-Negative Breast Cancer and Its Clinical Characteristics Shows DNA Repair Deficiency Has Better Prognostic

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.This study was funded by grants from UNAM PAPIIT IN219217 and CONACyT Fondo Sectorial 272573.Ye

The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes

In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies

Guía de práctica clínica para el manejo del cáncer de pulmón de células pequeñas: enfermedad extensa

Antecedentes: El cáncer de células pequeñas (CPCP) representa el 13-15% del total de neoplasias primarias de pulmón. Se caracteriza por su rapidez en la tasa de crecimiento y en el desarrollo de metástasis a distancia. Objetivos: Orientar y estandarizar el tratamiento del CPCP enfermedad extensa en México basado en evidencia clínica nacional e internacional. Material y métodos: Este documento se desarrolló como una colaboración del Instituto Nacional de Cancerología y la Sociedad Mexicana de Oncología en cumplimiento con estándares internacionales. Se integró un grupo conformado por oncólogos médicos, cirujanos oncólogos, cirujanos de tórax, radio-oncólogos y metodólogos con experiencia en revisiones sistemáticas de la literatura y guías de práctica clínica. Resultados: Se consensaron, por el método Delphi y en reuniones a distancia, las recomendaciones en CPCP enfermedad extensa, producto de preguntas de trabajo. Se identificó y evaluó la evidencia científica que responde a cada una de dichas preguntas clínicas antes de incorporarla al cuerpo de la guía. Conclusión: Esta guía proporciona recomendaciones clínicas para el manejo de la enfermedad extensa del CPCP y durante el proceso de toma de decisiones de los clínicos involucrados con su manejo en nuestro país para mejorar la calidad de la atención clínica para estos pacientes