Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer

BACKGROUND: The risk factors for immune-related adverse events (irAEs) remain undefined. Recently, a correlation between irAEs and clinical benefit was suggested. We examined the risk factors for irAEs and their effect on survival in patients with non-small-cell lung cancer (NSCLC) who had received immunotherapy. PATIENTS AND METHODS: We performed a retrospective review of patients with NSCLC treated with single-agent immunotherapy at our institution. irAEs were determined by treating physician diagnosis. A landmark analysis was performed at 3 months using log-rank tests and the Bonferroni method. RESULTS: irAEs occurred in 27 of 91 patients (30%). The median overall survival (OS) for patients with irAEs was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P \u3c .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without irAEs. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of irAEs or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016). CONCLUSION: The development of irAEs did not significantly correlate with survival when controlling for the duration of therapy in a landmark analysis. We found no increased risk of pneumonitis or irAEs in patients who had received radiotherapy. Radiotherapy before immunotherapy was associated with shorter survival, and radiotherapy after immunotherapy was associated with improved survival

Phase I Study of Veliparib on an Intermittent and Continuous Schedule in Combination with Carboplatin in Metastatic Breast Cancer: A Safety and [18F]-Fluorothymidine Positron Emission Tomography Biomarker Study

Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Further-more, the BROCADE studies demonstrated benefitofadding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay. Materials and Methods: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-30-deoxythymidine (18FLT) positron emission tomography (PET) imaging. Results: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1–36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n =1), and G3 akathisia (n =1).Commongrade3–4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6%achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1–21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax) of target lesions between baseline and early in cycle 1 based on 18FLT-PET (day 7–21; ptrend = .006). Conclusion: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma. METHODS: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario. RESULTS: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity. CONCLUSIONS: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden

Algunas reflexiones a 17 años de la dolarización en El Salvador

El presente artículo analiza la evolución de algunas variables macroeconómicas que se verían afectadas por la dolarización, implementada en El Salvador a partir de 2001, tales como: la tasa de interés, inflación, inversión extranjera, producción nacional y empleo. Asimismo, hace un recuento de las verdaderas razones que el gobierno tuvo para dolarizar y describe el modelo que se generó a partir de entonces. Finalmente, se plantea la posibilidad de la desdolarización, los supuestos peligros de llevarla a cabo y ciertas recomendaciones sobre su conveniencia

La educación intercultural dentro de la educación física

La sociedad en la que vivimos está llena de riqueza cultural, es una sociedad multicultural. Esta multiculturalidad hay que unirla junto con la puesta en práctica de la interculturalidad. Por desgracia hay un porcentaje de personas en el mundo que actúan en contrariedad a lo que el principal objetivo de interculturalidad se refiere. Es necesario trabajar en disminuir ese grupo de personas, y eso empieza en la escuela, desde la enseñanza de la educación intercultural. Esta educación se puede impartir en las escuelas por medio de la educación física, y las herramientas que esta confiere. En este trabajo se quiere facilitar una herramienta de enseñanza, una programación didáctica. Esta se centrará en la enseñanza de la educación intercultural a través de la educación física, más concretamente, desde la expresión corporal, trabajando a través de las danzas. Esta programación estará destinada a los alumnos de tercero de primaria de un colegio. Se realizará durante todo el año escolar, teniendo una sesión por semana, con el objetivo de dar a conocer las diferentes culturas y un método de unión entre ellas, las danzas, así como el aprendizaje del respeto hacia las personas con una cultura diferente a la de uno mismo.Grado en Educación Primari

Métodos iterativos fraccionarios para la resolución de ecuaciones y sistemas no lineales: diseño, análisis y estabilidad

[ES] El cálculo fraccionario es una extensión del cálculo clásico, donde el orden de las derivadas o integrales es un número real. Hoy en día, el cálculo fraccionario tiene numerosas aplicaciones en ciencias e ingeniería. La principal razón es el mayor grado de libertad de las herramientas del cálculo fraccionario en comparación con las herramientas del cálculo clásico. Muchos problemas reales se modelan por medio de ecuaciones diferenciales fraccionarias no lineales cuyo sistema de ecuaciones es no lineal, y por tanto, es conveniente que se adapten procedimientos iterativos para resolver problemas no lineales con el uso de derivadas fraccionarias, y observar cuál es la consecuencia en la convergencia de dicho método. En esta Tesis Doctoral diseñamos nuevos procedimientos iterativos con derivadas fraccionarias (o su aproximación) que al menos igualen a los métodos clásicos en términos de orden de convergencia, mediante la introducción de las derivadas fraccionarias de Riemann-Liouville, de Caputo y conformable (o sus aproximaciones). También, proponemos estudiar la estabilidad de estos esquemas con el uso de planos de convergencia, y planos dinámicos en algunos casos. Finalmente, pretendemos diseñar una técnica que nos permita obtener la versión fraccionaria conformable (o versión con derivada conformable o su aproximación) de cualquier procedimiento iterativo clásico para problemas no lineales. En el Capítulo 2 se exponen los conceptos previos que serán necesarios para el desarrollo de los siguientes capítulos: Se presentan los conceptos básicos relacionados con métodos de punto fijo, se muestran los esquemas clásicos que trataremos en esta memoria, y finalmente se introducen las herramientas del cálculo fraccionario que serán necesarias para el diseño de procedimientos iterativos fraccionarios. En el Capítulo 3 se diseñan métodos fraccionarios (o esquemas con derivadas fraccionarias) de tipo Newton-Raphson escalares con las derivadas de Caputo, de Riemann Liouville y la conformable. También diseñamos esquemas fraccionarios de Newton-Raphson escalares de mayor orden. Finalmente, realizamos el análisis de convergencia de dichos procedimientos y estudiamos su estabilidad. En el Capítulo 4 se diseña la versión vectorial del método de Newton-Raphson conformable visto en el Capítulo 3. Antes, es necesario definir nuevos conceptos y establecer nuevos resultados que serán necesarios para el dersarrollo de este esquema. Finalmente, realizamos el análisis de convergencia y estudiamos su estabilidad. En el Capítulo 5 se diseñan procedimientos fraccionarios de tipo Traub escalares con derivadas de Caputo y de Riemann-Liouville. También se diseña una técnica general para obtener la versión fraccionaria conformable escalar de cualquier método clásico, y se usa esta técnica para diseñar algunos esquemas conformables multipunto escalares: de tipos Traub, Chun-Kim, Ostrowski y Chun. Por último, se realiza el análisis de convergencia y se estudia la estabilidad de tales procedimientos. En el Capítulo 6 se diseñan métodos fraccionarios libres de derivadas escalares de tipos Steffensen y Secante (el cual tiene memoria), donde es necesario la aproximación de derivadas conformables. Aquí se usa la técnica general propuesta en el Capítulo 5 para obtener la versión conformable de cada esquema. Finalmente, realizamos el análisis de convergencia y se estudia la estabilidad de dichos procedimientos. En el Capítulo 7 se presentan las conclusiones y líneas futuras de investigación.[CA] El càlcul fraccionari és una extensió del càlcul clàssic, on l'ordre de les derivades o integrals és un nombre real. Hui dia, el càlcul fraccionari té nombroses aplicacions en ciències i enginyeria. La principal raó és el major grau de llibertat de les eines del càlcul fraccionari en comparació amb les eines del càlcul clàssic. Molts problemes reals es modelen per mitjà d'equacions diferencials fraccionàries no lineals el sistema d'equacions de les quals és no lineal, i per tant, és convenient que s'adapten procediments iteratius per a resoldre problemes no lineals amb l'ús de derivades fraccionàries, i observar quina és la conseqüència en la convergència d'aquest mètode. En aquesta Tesi Doctoral dissenyem nous procediments iteratius amb derivades fraccionàries (o la seua aproximació) que almenys igualen als mètodes clàssics en termes d'ordre de convergència, mitjançant la introducció de les derivades fraccionàries de Riemann-Liouville, de Caputo i conformable (o les seues aproximacions). També, proposem estudiar l'estabilitat d'aquests esquemes amb l'ús de plans de convergència, i plans dinàmics en alguns casos. Finalment, pretenem dissenyar una tècnica que ens permeta obtindre la versió fraccionària conformable (o versió amb derivada conformable o la seua aproximació) de qualsevol procediment iteratiu clàssic per a problemes no lineals. En el Capítol 2 s'exposen els conceptes previs que seran necessaris per al desenvolupament dels següents capítols: Es presenten els conceptes bàsics relacionats amb mètodes de punt fix, es mostren els esquemes clàssics que tractarem en aquesta memòria, i finalment s'introdueixen les eines del càlcul fraccionari que seran necessàries per al disseny de procediments iteratius fraccionaris. En el Capítol 3 es dissenyen mètodes fraccionaris (o esquemes amb derivades fraccionàries) de tipus Newton-Raphson escalars amb les derivades de Caputo, de Riemann Liouville i la conformable. També dissenyem esquemes fraccionaris de Newton-Raphson escalars de major ordre. Finalment, realitzem l'anàlisi de convergència d'aquests procediments i estudiem la seua estabilitat. En el Capítol 4 es dissenya la versió vectorial del mètode de Newton-Raphson conformable vist en el Capítol 3. Abans, és necessari definir nous conceptes i establir nous resultats que seran necessaris per al dersarrollo d'aquest esquema. Finalment, realitzem l'anàlisi de convergència i estudiem la seua estabilitat. En el Capítol 5 es dissenyen procediments fraccionaris de tipus Traub escalars amb derivades de Caputo i de Riemann-Liouville. També es dissenya una tècnica general per a obtindre la versió fraccionària conformable escalar de qualsevol mètode clàssic, i s'usa aquesta tècnica per a dissenyar alguns esquemes conformables multipunt escalars: de tipus Traub, Chun-Kim, Ostrowski i Chun. Finalment, es realitza l'anàlisi de convergència i s'estudia l'estabilitat de tals procediments. En el Capítol 6 es dissenyen mètodes fraccionaris lliures de derivades escalars de tipus Steffensen i Assecant (el qual té memòria), on és necessari l'aproximació de derivades conformables. Ací s'usa la tècnica general proposta en el Capítol 5 per a obtindre la versió conformable de cada esquema. Finalment, realitzem l'anàlisi de convergència i s'estudia l'estabilitat d'aquests procediments. En el Capítol 7 es presenten les conclusions i línies futures d'investigació.[EN] Fractional calculus is an extension of classical calculus, where the order of the derivatives or integrals is a real number. Today, fractional calculus has numerous applications in science and engineering. The main reason is the higher degree of freedom of the fractional calculus tools compared to the classical calculus tools. Many real problems are modeled by means of nonlinear fractional differential equations whose system of equations is nonlinear, and therefore it is convenient that iterative procedures are adapted to solve nonlinear problems with the use of fractional derivatives, and observe what the consequence is in the convergence of said method. In this Doctoral Thesis we design new iterative procedures with fractional derivatives (or their approximation) that are at least equal to the classical methods in terms of convergence order, by introducing the Riemann-Liouville, Caputo and conformable fractional derivatives (or their approximations). Also, we propose to study the stability of these schemes with the use of convergence planes, and dynamic planes in some cases. Finally, we intend to design a technique that allows us to obtain the conformable fractional version (or version with conformable derivative or its approximation) of any classical iterative procedure for nonlinear problems. In Chapter 2 the previous concepts that will be necessary for the development of the following chapters are exposed: The basic concepts related to fixed point methods are presented, the classic schemes that we will deal with in this memory are shown, and finally the tools of the fractional calculus that will be necessary for the design of fractional iterative procedures. In Chapter 3, scalar Newton-Raphson type fractional methods (or schemes with fractional derivatives) are designed with the Caputo, Riemann Liouville and conformable derivatives. We also design higher order scalar Newton-Raphson fractional schemes. Finally, we perform the convergence analysis of these procedures and study their stability. In Chapter 4, the vector version of the conformable Newton-Raphson method seen in Chapter 3 is designed. Before, it is necessary to define new concepts and establish new results that will be necessary for the development of this scheme. Finally, we perform the convergence analysis and study its stability. In Chapter 5, fractional procedures of the scalar Traub type with derivatives of Caputo and Riemann-Liouville are designed. A general technique is also designed to obtain the scalar conformable fractional version of any classical method, and this technique is used to design some scalar multipoint conformable schemes: of Traub, Chun-Kim, Ostrowski and Chun types. Finally, the convergence analysis is carried out and the stability of such procedures is studied. In Chapter 6 free fractional methods of scalar derivatives of Steffensen and Secant types (which has memory) are designed, where the conformable derivatives approximation is necessary. Here we use the general technique proposed in Chapter 5 to obtain the conformable version of each scheme. Finally, we carry out the convergence analysis and the stability of these procedures is studied. In Chapter 7 the conclusions and future lines of research are presented.Candelario Villalona, GG. (2023). Métodos iterativos fraccionarios para la resolución de ecuaciones y sistemas no lineales: diseño, análisis y estabilidad [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/19427

Racial/Ethnic Disparities in HPV-associated Anogenital Cancers Among Males in the United States: A Population-Based Retrospective Cohort Study

Little is known regarding racial/ethnic differences in human papillomavirus (HPV)-associated anogenital cancer among males. We examined age-adjusted incidence, late-stage diagnosis, survival and mortality of anogenital cancers among males in the United States. This population-based retrospective cohort study included 39,601 males diagnosed with HPV-associated invasive penile and anorectal cancers between 2005-2016 from the North American Association of Central Cancer Registries. We evaluated the association of race/ethnicity with outcomes using multivariable logistic regression, adjusted survival curves, and Cox proportional hazard modeling, adjusting for age, insurance, residential characteristics (metropolitan/non-metropolitan, area poverty, and geographic region), stage, and treatment. We also assessed interaction of race/ethnicity with other covariates in our late-stage and mortality models. Hispanic and Non-Hispanic (NH) Black males had highest age-adjusted incidence of penile and anorectal cancer, respectively. Higher odds of late-stage penile cancer was observed among NH Black (adjusted odds ratios [aOR] 1.22, 95% CI 1.07-1.39) and Hispanic males (aOR 1.17, 95% CI 1.04-1.31). Higher odds of late-stage anorectal cancer was observed among NH Black (aOR 1.25, 95% CI 1.14-1.36) and NH Other males (aOR 1.29, 95% CI 1.01-1.66). Compared to all other groups, NH Black males had the lowest cumulative and mean survival of both cancers and higher cancer-specific mortality (penile adjusted hazards ratios [aHR] 1.23, 95% CI 1.01-1.49; anorectal aHR 1.25, 95% CI 1.10-1.42). Racial/ethnic disparities in HPV-associated anogenital cancers differ depending on site. Interventions to increase HPV vaccination rates, early detection, and treatment of anogenital cancers in males are needed, particularly among men of color

MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein)

Review on MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein), with data on DNA, on the protein encoded, and where the gene is implicated

Altered p16INK4 and RB1 Expressions Are Associated with Poor Prognosis in Patients with Nonsmall Cell Lung Cancer

p16INK4 and RB1 are two potent cell cycle regulators to control the G1/S transition by interacting with CDK4/6, E2F, and D-type cyclins, respectively. Depending on the tumour type, genetic alterations resulting in the functional inactivation have frequently been reported in both genes. By contrast, much less is known regarding the overexpression of these proteins in the tumor cells. In this study, expressions of p16INK4 RB1, and CDKN2A copy number variances (CNV) in the tumor cells were assessed by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively, in 73 nonsmall cell lung cancer (NSCLC) with known 5-year survivals. The histologic type (P = 0.01), p16INK4 (P = 0.004), and RB1 (P < 0.001) were predictive of survivals. The CDKN2A CNV (P < 0.05) was also significant when compared to those cases without CNV. Therefore, among the molecular genetic prognostic factors, expressions of RB1 and p16INK4 in the tumor cells were the most strongly predictive of adverse outcomes in stage I and II nonsquamous NSCLC