Enfermedad mínima residual y cáncer de mama en estadios iniciales: valor pronóstico de la detección de células tumorales diseminadas en médula ósea al diagnóstico y tras quimioterapia

Introducción: La enfermedad mínima residual y en concreto la presencia de células tumorales diseminadas (CTD) en médula ósea constituye una variable con potencial valor pronóstico en cáncer de mama. Aunque existen estudios que evalúan el papel de la afectación de médula ósea por CTD en el momento del diagnóstico, el papel de esta determinación tras tratamiento con quimioterapia (QT) adyuvante es más controvertido. Hipótesis: La EMR tiene un impacto en supervivencia determinada al diagnóstico y tras quimioterapia en pacientes con cáncer de mama en estadios iniciales Objetivos: Los objetivos principales de nuestro estudio fueron: 1) identificar la proporción de afectación de médula ósea por células tumorales, 2)evaluar la relación con otras variables pronósticas, 3) analizar si la presencia de dicha afectación tenía un impacto en supervivencia libre de recaída (SLR). Entre los objetivos secundarios estaban: 1) valorar el impacto con la supervivencia libre de recaída a distancia (SLRD) y la supervivencia global (SG), 2) analizar si la evolución de uno a otro aspirado impactaba en SLR y 3) el impacto de la obesidad en la supervivencia y la enfermedad mínima residual. Material y métodos: Se realizó un estudio prospectivo en pacientes con diagnóstico histológico de carcinoma de mama estadios I-III y consideradas candidatas a tratamiento con quimioterapia neo/adyuvante a las que se les realizó determinación de enfermedad mínima residual en médula ósea en dos tiempos, al diagnóstico y tras finalizar quimioterapia complementaria. Tras la realización de los aspirados, se procedió a la identificación de las células tumorales diseminadas mediante la inmunotinción con el anticuerpo anticitoqueratina A45B/B3. Resultados: Se incluyeron 288 pacientes de las cuales a 286 se les practicó un primer aspirado en el momento del diagnóstico y a 215 un aspirado tras finalizar QT complementaria. Se identificó presencia de CTD en médula ósea en el 26.57% y el 20.47% de los aspirados realizados al diagnóstico y tras finalizar QT respectivamente. Los resultados de afectación de MO al diagnóstico no mostraron impacto alguno en términos de SLR (p=0.275), SLRD o SG. La edad ≥ de 55 años (Riesgo relativo (RR) 1,96; IC95% 1,14-3,38 p=0,015) y el diagnóstico de carcinoma ductal (RR 0,35; IC95% 0,13-0,93 p=0,036) se relacionó con la presencia de enfermedad mínima residual en médula óseo al diagnóstico. Sin embargo la evaluación de enfermedad mínima residual tras QT si se mostró como un factor pronóstico independiente de SLR estadísticamente significativo (RR 2,13; IC95% 1,13-4,02; p=0,02) con una tendencia en SLRD. En este caso ninguna de las variables pronósticas habituales mostró relación con la presencia de CTD en médula ósea. Respecto a los objetivos secundarios, la persistencia de ambos aspirados positivos se mostró como un factor de riesgo para SLR estadísticamente significativo . La obesidad o el sobrepeso no demostraron relación con enfermedad mínima residual ni con supervivencia, aunque en el subgrupo de ≥ de 55 años si se evidenció una tendencia de la obesidad a presentar una SLR inferior (log rango p=0.051) Conclusiones: 1) La detección de CTD en médula ósea es un hecho frecuente tanto al diagnóstico como tras QT complementaria. 2) No se ha encontrado relación entre enfermedad mínima residual y factores pronósticos clásicos 3) Aunque la presencia de enfermedad mínima residual en médula ósea al diagnóstico no impacta en supervivencia, su detección tras el tratamiento supone un factor pronóstico independiente de SLR en cáncer de mama en estadios iniciale

Immunotherapy combined with standard therapies in head and neck squamous cell carcinoma - a meta-analysis

Head and neck squamous cell carcinoma (HNSCC) is a deadly disease with a poor prognosis due to late diagnosis and limited treatment options. Immunotherapy (IT) is emerging as a promising approach, especially after the failure of standard of care therapies (STs). The objective of this systematic review and meta-analysis was to evaluate whether the addition of IT to STs improves outcomes for patients with HNSCC, including overall survival (OS), progression-free survival (PFS), and quality of life (QoL). This review employed the Population Intervention Comparison and Outcome (PICO) framework to identify relevant search terms in electronic databases, and also included supplementary hand searches. Six primary research articles were selected using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) flow chart, and were critically appraised. Data extraction from these studies was conducted, and a meta-analysis was performed to aid in the generation of forest plots. The addition of IT to standard anticancer therapies was found to enhance patient outcomes, such as OS, PFS, and QoL. The toxicity profile of IT was acceptable, with minimal treatment-related deaths. The most frequently observed adverse events (AE) were related to the skin, followed by hematological toxicities. Based on our analysis, the addition of IT to STs is a suitable treatment option and is supported by current research. However, further studies are needed to investigate factors that influence treatment effectiveness and to develop optimal therapies. To achieve this, we recommend a comprehensive treatment approach that involves the multidisciplinary team (MDT) and patient assessment tools. [Abstract copyright: Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Mujeres con cáncer de mama: evaluación del afecto positivo y negativo y valoración de un programa de Intervención psicológica en el ámbito hospitalario

[email protected] la actualidad hay numerosos estudios que demuestran que la intervención psicológica es benefi ciosa para los pacientes con cáncer. Nuestro objetivo es investigar el efecto intra- sujetos de la intervención psicológica sobre el afecto positivo y negativo durante los ciclos de tratamiento de quimioterapia adyuvante en mujeres con cáncer de mama. Además estudiamos el efecto de la interacción entre la psicoterapia y la resistencia/vulnerabilidad psicológica de las pacientes en las mismas variables dependientes. Método: La muestra está formada por 119 pacientes diagnosticadas de un cáncer de mama localizado que recibieron tratamiento adyuvante con quimioterapia. Todas las pacientes fueron evaluadas y recibieron intervención psicológica a lo largo del tratamiento. Las variables dependientes: el afecto positivo y negativo fueron evaluadas en cinco intervalos: previamente al tratamiento quimioterápico, 2º, 4º, 6º ciclo de quimioterapia y a los dos meses post-tratamiento. El factor entresujetos resistencia/vulnerabilidad psicológica se derivó de un Análisis de Cluster a partir de cuatro medidas, pre y post, de ansiedad y depresión. Los instrumentos de evaluación utilizados fueron la Escala de Afecto Positivo y Negativo (Sánchez-Cánovas, 1994), y la Escala Hospitalaria de Ansiedad y Depresión (HADS) de Zigmond y Snaith (1983). Se realizó análisis descriptivo de los datos, Análisis Múltiple de la Varianza (MANOVA) de medias repetidas para la comparación intra-sujetos y el diseño factorial mixto para la comparación entre-sujetos (resistentes /vulnerables) Resultados: muestran el efecto principal intra-sujetos de la intervención psicológica en el afecto positivo (p<0.05), no existiendo efecto de la interacción entre la intervención psicológica y la resistencia/vulnerabilidad psicológica. Respecto del afecto negativo, el efecto de la intervención psicológica intra-sujetos y la interacción de ésta con los grupos de pacientes resistentes/vulnerables es signifi cativo en ambos casos (p<0.05). Los contrastes intrasujetos entre los 5 intervalos muestran diferencias signifi cativas entre el intervalo del pretratamiento (1ª evaluación) y el 2º ciclo de quimioterapia (2ª evaluación) en el afecto positivo y negativo. Conclusiones: La ganancia más importante se obtiene en la primera intervención psicológica y ésta es crucial para el mantenimiento del estado de ánimo positivo y la disminución del afecto negativo de las pacientes. Hay ganancia en los dos grupos, las pacientes vulnerables son las que más mejoría experimentan. Es importante señalar la importancia de esta primera intervención y la repercusión que tiene frente a las contingencias aversivas que supone los sucesivos ciclos de quimioterapia.Currently there are numerous publications demonstrating that psychological intervention in patients with cancer is benefi cial. Our objective is to study the within-subjects effect of the psychological intervention on the positive and negative affect during adjuvant chemotherapy cycles in women with breast cancer. In addition, we study the effect of the interaction between psychotherapy and psychological resistance/ vulnerability of patients on the same dependent variables. Method: The sample consists of 119 patients diagnosed with a localized breast cancer that received adjuvant chemotherapy treatment. All the patients were evaluated and received psychological intervention throughout the treatment. Dependent variables: positive and negative affect were evaluated in fi ve intervals: chemotherapy pre-treatment, second, fourth, sixth cycle of chemotherapy and two month post-treatment. The two groups of resistant and vulnerable patients were divided by Cluster Analysis of two measures of anxiety and depression before and after of chemotherapy. Measures used were the Positive and Negative Affect Scale (Sánchez- Cánovas, 1994) and the Hospital Anxiety and Depression Scale (HADS) of Zigmond and Snaith (1983). Descriptive analysis of data and a multivariate analysis of variance with repeated-measures (MANOVA-RM) were performed to compare within-subjects and the mixed factorial design to compare betweensubjects (resistant/vulnerable). Results: demonstrate the main within-subjects effect of the psychological intervention in the positive affect (p<0.05), existing no effect between psychological intervention and psychological resistance /vulnerability interaction. In relation to the negative affect, the effect of the within-subjects psychological intervention and its interaction with the resistant/vulnerable group of patients is signifi cant in both cases (p<0.05). Within-subjects contrasts among the fi ve intervals show signifi cant differences between the pre-treatment interval (fi rst evaluation) and the second cycle of chemotherapy (second evaluation) in the negative and positive affect. Conclusions: The most important benefi t is obtained in the fi rst psychological intervention which is crucial to maintain a positive mood state and diminish the negative affect of patients. There is benefi t in both groups; however, the vulnerable patients present more improvement. Moreover, it is worth mentioning the importance of this fi rst intervention and its repercussion in response to aversive contingencies of chemotherapy cycles

Women with breast cancer: positive and negative affect assessment and psychological intervention program in the hospital area

En la actualidad hay numerosos estudios que demuestran que la intervención psicológica es beneficiosa para los pacientes con cáncer. Nuestro objetivo es investigar el efecto intra-sujetos de la intervención psicológica sobre el afecto positivo y negativo durante los ciclos de tratamiento de quimioterapia adyuvante en mujeres con cáncer de mama. Además estudiamos el efecto de la interacción entre la psicoterapia y la resistencia/vulnerabilidad psicológica de las pacientes en las mismas variables dependientes. Método: La muestra está formada por 119 pacientes diagnosticadas de un cáncer de mama localizado que recibieron tratamiento adyuvante con quimioterapia. Todas las pacientes fueron evaluadas y recibieron intervención psicológica a lo largo del tratamiento. Las variables dependientes: el afecto positivo y negativo fueron evaluadas en cinco intervalos: previamente al tratamiento quimioterápico, 2º, 4º, 6º ciclo de quimioterapia y a los dos meses post-tratamiento. El factor entresujetos resistencia/vulnerabilidad psicológica se derivó de un Análisis de Cluster a partir de cuatro medidas, pre y post, de ansiedad y depresión. Los instrumentos de evaluación utilizados fueron la Escala de Afecto Positivo y Negativo (Sánchez-Cánovas, 1994), y la Escala Hospitalaria de Ansiedad y Depresión (HADS) de Zigmond y Snaith (1983). Se realizó análisis descriptivo de los datos, Análisis Múltiple de la Varianza (MANOVA) de medias repetidas para la comparación intra-sujetos y el diseño factorial mixto para la comparación entre-sujetos (resistentes /vulnerables) Resultados: muestran el efecto principal intra-sujetos de la intervención psicológica en el afecto positivo (p&lt;0.05), no existiendo efecto de la interacción entre la intervención psicológica y la resistencia/vulnerabilidad psicológica. Respecto del afecto negativo, el efecto de la intervención psicológica intra-sujetos y la interacción de ésta con los grupos de pacientes resistentes/vulnerables es significativo en ambos casos (p&lt;0.05). Los contrastes intra-sujetos entre los 5 intervalos muestran diferencias significativas entre el intervalo del pre-tratamiento (1ª evaluación) y el 2º ciclo de quimioterapia (2ª evaluación) en el afecto positivo y negativo. Conclusiones: La ganancia más importante se obtiene en la primera intervención psicológica y ésta es crucial para el mantenimiento del estado de ánimo positivo y la disminución del afecto negativo de las pacientes. Hay ganancia en los dos grupos, las pacientes vulnerables son las que más mejoría experimentan. Es importante señalar la importancia de esta primera intervención y la repercusión que tiene frente a las contingencias aversivas que supone los sucesivos ciclos de quimioterapia.Currently there are numerous publications demonstrating that psychological intervention in patients with cancer is beneficial. Our objective is to study the within-subjects effect of the psychological intervention on the positive and negative affect during adjuvant chemotherapy cycles in women with breast cancer. In addition, we study the effect of the interaction between psychotherapy and psychological resistance/ vulnerability of patients on the same dependent variables. Method: The sample consists of 119 patients diagnosed with a localized breast cancer that received adjuvant chemotherapy treatment. All the patients were evaluated and received psychological intervention throughout the treatment. Dependent variables: positive and negative affect were evaluated in five intervals: chemotherapy pre-treatment, second, fourth, sixth cycle of chemotherapy and two-month post-treatment. The two groups of resistant and vulnerable patients were divided by Cluster Analysis of two measures of anxiety and depression before and after of chemotherapy. Measures used were the Positive and Negative Affect Scale (Sánchez-Cánovas, 1994) and the Hospital Anxiety and Depression Scale (HADS) of Zigmond and Snaith (1983). Descriptive analysis of data and a multivariate analysis of variance with repeated-measures (MANOVA-RM) were performed to compare within-subjects and the mixed factorial design to compare betweensubjects (resistant/vulnerable). Results: demonstrate the main within-subjects effect of the psychological intervention in the positive affect (p&lt;0.05), existing no effect between psychological intervention and psychological resistance /vulnerability interaction. In relation to the negative affect, the effect of the within-subjects psychological intervention and its interaction with the resistant/vulnerable group of patients is significant in both cases (p&lt;0.05). Within-subjects contrasts among the five intervals show significant differences between the pre-treatment interval (first evaluation) and the second cycle of chemotherapy (second evaluation) in the negative and positive affect. Conclusions: The most important benefit is obtained in the first psychological intervention which is crucial to maintain a positive mood state and diminish the negative affect of patients. There is benefit in both groups; however, the vulnerable patients present more improvement. Moreover, it is worth mentioning the importance of this first intervention and its repercussion in response to aversive contingencies of chemotherapy cycles

A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients

Background: pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature. Methods: epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an independent cohort of TN patients and in TN cell lines. Results: twenty-four and 30 patients were included in the discovery and validation cohorts, respectively. In the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under the ROC curve (AUC) = 0.905 (95% CI = 0.805-1.000). Patients with a positive epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if signature were negative. Conclusions: these results suggest that pCR in TNBC could be accurately predicted with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective validation of these findings is warranted

Chronological age interacts with the circadian melatonin receptor 1b gene variation, determining fasting glucose concentrations in mediterranean populations. Additional analyses on type-2 diabetes risk

Gene-age interactions have not been systematically investigated on metabolic phenotypes and this modulation will be key for a better understanding of the temporal regulation in nutrigenomics. Taking into account that aging is typically associated with both impairment of the circadian system and a decrease in melatonin secretion, we focused on the melatonin receptor 1B (MTNR1B)-rs10830963 C>G variant that has been associated with fasting glucose concentrations, gestational diabetes, and type-2 diabetes. Therefore, our main aim was to investigate whether the association between the MTNR1B-rs10830963 polymorphism and fasting glucose is age dependent. Our secondary aims were to analyze the polymorphism association with type-2 diabetes and explore the gene-pregnancies interactions on the later type-2 diabetes risk. Three Mediterranean cohorts (n = 2823) were analyzed. First, a cross-sectional study in the discovery cohort consisting of 1378 participants (aged 18 to 80 years; mean age 41 years) from the general population was carried out. To validate and extend the results, two replication cohorts consisting of elderly individuals were studied. In the discovery cohort, we observed a strong gene-age interaction (p = 0.001), determining fasting glucose in such a way that the increasing effect of the risk G-allele was much greater in young (p = 5.9 × 10−10) than in elderly participants (p = 0.805). Consistently, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose concentrations in the two replication cohorts (mean age over 65 years) did not reach statistical significance (p > 0.05 for both). However, in the elderly cohorts, significant associations between the polymorphism and type-2 diabetes at baseline were found. Moreover, in one of the cohorts, we obtained a statistically significant interaction between the MTNR1B polymorphism and the number of pregnancies, retrospectively assessed, on the type-2 diabetes risk. In conclusion, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose is age-dependent, having a greater effect in younger people. However, in elderly subjects, associations of the polymorphism with type-2 diabetes were observed and our exploratory analysis suggested a modulatory effect of the number of past pregnancies on the future type-2 diabetes genetic risk

Candidate Gene and Genome-Wide Association Studies for Circulating Leptin Levels Reveal Population and Sex-Specific Associations in High Cardiovascular Risk Mediterranean Subjects

Leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its plasma levels are still not well known. Results of studies investigating polymorphisms in candidate genes have been inconsistent, and, in addition, very few genome-wide association studies (GWAS) have been undertaken. Our aim was to investigate the genes and gene variants most associated with plasma leptin concentrations in a high-cardiovascular-risk Mediterranean population. We measured plasma leptin in 1011 men and women, and analyzed the genetic factors associated using three approaches: (1) Analyzing the single nucleotide polymorphisms (SNPs) reported in a GWAS meta-analysis in other populations (including an SNP in/near each of these LEP, SLC32A1, GCKR, CCNL, COBLL1, and FTO genes); (2) Investigating additional SNPs in/near those genes, also including the RLEP gene; and (3) Undertaking a GWAS to discover new genes. We did not find any statistically significant associations between the previously published SNPs and plasma leptin (Ln) in the whole population adjusting for sex and age. However, on undertaking an extensive screening of other gene variants in those genes to capture a more complete set of SNPs, we found more associations. Outstanding among the findings was the heterogeneity per sex. We detected several statistically significant interaction terms with sex for these SNPs in the candidate genes. The gene most associated with plasma leptin levels was the FTO gene in men (specifically the rs1075440 SNP) and the LEPR in women (specifically the rs12145690 SNP). In the GWAS on the whole population, we found several new associations at the p < 1 × 10-5 level, among them with the rs245908-CHN2 SNP (p = 1.6 × 10-6). We also detected a SNP*sex interaction at the GWAS significance level (p < 5 × 10-8), involving the SLIT3 gene, a gene regulated by estrogens. In conclusion, our study shows that the SNPs selected as relevant for plasma leptin levels in other populations, are not good markers for this Mediterranean population, so supporting those studies claiming a bias when generalizing GWAS results to different populations. These population-specific differences may include not only genetic characteristics, but also age, health status, and the influence of other environmental variables. In addition, we have detected several sex-specific effects. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations

Chronological Age Interacts with the Circadian Melatonin Receptor 1B Gene Variation, Determining Fasting Glucose Concentrations in Mediterranean Populations. Additional Analyses on Type-2 Diabetes Risk

Gene-age interactions have not been systematically investigated on metabolic phenotypes and this modulation will be key for a better understanding of the temporal regulation in nutrigenomics. Taking into account that aging is typically associated with both impairment of the circadian system and a decrease in melatonin secretion, we focused on the melatonin receptor 1B (MTNR1B)-rs10830963 C>G variant that has been associated with fasting glucose concentrations, gestational diabetes, and type-2 diabetes. Therefore, our main aim was to investigate whether the association between the MTNR1B-rs10830963 polymorphism and fasting glucose is age dependent. Our secondary aims were to analyze the polymorphism association with type-2 diabetes and explore the gene-pregnancies interactions on the later type-2 diabetes risk. Three Mediterranean cohorts (n = 2823) were analyzed. First, a cross-sectional study in the discovery cohort consisting of 1378 participants (aged 18 to 80 years; mean age 41 years) from the general population was carried out. To validate and extend the results, two replication cohorts consisting of elderly individuals were studied. In the discovery cohort, we observed a strong gene-age interaction (p = 0.001), determining fasting glucose in such a way that the increasing effect of the risk G-allele was much greater in young (p = 5.9 × 10-10) than in elderly participants (p = 0.805). Consistently, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose concentrations in the two replication cohorts (mean age over 65 years) did not reach statistical significance (p > 0.05 for both). However, in the elderly cohorts, significant associations between the polymorphism and type-2 diabetes at baseline were found. Moreover, in one of the cohorts, we obtained a statistically significant interaction between the MTNR1B polymorphism and the number of pregnancies, retrospectively assessed, on the type-2 diabetes risk. In conclusion, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose is age-dependent, having a greater effect in younger people. However, in elderly subjects, associations of the polymorphism with type-2 diabetes were observed and our exploratory analysis suggested a modulatory effect of the number of past pregnancies on the future type-2 diabetes genetic risk

Associations between taste perception profiles and empirically derived dietary patterns: an exploratory analysis among older adults with metabolic syndrome

Taste perception is a primary driver of food choices; however, little is known about how perception of all five tastes (sweet, salt, sour, bitter, umami) collectively inform dietary patterns. Our aim was to examine the associations between a multivariable measure of taste perception—taste perception profiles—and empirically derived dietary patterns. The cohort included 367 community-dwelling adults (55–75 years; 55% female; BMI = 32.2 ± 3.6 kg/m2) with metabolic syndrome from PREDIMED-Plus, Valencia. Six taste perception profiles were previously derived via data-driven clustering (Low All, High Bitter, High Umami, Low Bitter and Umami, High All But Bitter, High All But Umami); three dietary patterns were derived via principal component analysis (% variance explained = 20.2). Cross-sectional associations between profiles and tertials of dietary pattern adherence were examined by multinomial logistic regression. Overall, there were several significant differences in dietary pattern adherence between profiles: the vegetables, fruits, and whole grains pattern was significantly more common for the High All But Umami profile (OR range for high vs. low adherence relative to other profiles (1.45–1.99; 95% CI minimum lower, maximum upper bounds: 1.05, 2.74), the non-extra virgin olive oils, sweets, and refined grains pattern tended to be less common for Low All or High Bitter profiles (OR range: 0.54–0.82), while the alcohol, salty foods, and animal fats pattern tended to be less common for Low Bitter and Umami and more common for High All But Bitter profiles (OR range: 0.55–0.75 and 1.11–1.81, respectively). In conclusion, among older adults with metabolic syndrome, taste perception profiles were differentially associated with dietary patterns, suggesting the benefit of integrating taste perception into personalized nutrition guidance