Cystic fibrosis: desensitization in delayed hypersensitivity reactions to elexacaftor/tezacaftor/ivacaftor.

Background: Cystic fibrosis transmembrane conductance regulator modulators are the only available treatment for cystic fibrosis. Although elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is well-tolerated, rash has been reported as very frequent. In severe rashes, ELX/TEZ/IVA withdrawal is necessary, leading to clinical deterioration. The objective of the study is to increment the experience of ELX/TEZ/IVA desensitization. Methods: Adult patients who developed a delayed hypersensitivity rash to ELX/TEZ/IVA between December 2021 and February 2023 and required withdrawal due to ineffective rescue medication were included. Skins test for ELX/TEZ/IVA and IVA were conducted to establish hypersensitivity mechanism. Balijepally ELX/TEZ/IVA desensitization protocol was selected. In cases where desensitization had to be discontinued due to rash, an extended desensitization was proposed. Clinical and health-related quality of life parameters were collected before ELX/TEZ/IVA and after desensitization. Results: 162 patients (81 women, 31.2 [23.8-42.5] years) started ELX/TEZ/IVA, developing rash 12 of them (7.4%, six women). Six patients (five women) required stopping ELX/TEZ/IVA and were selected for desensitization. Skin tests indicated delayed type-IV hypersensitivity in one patient. Two patients presented adequate tolerance to desensitization; while, four patients developed rash. Three of these patients, successfully concluded extended desensitization (one patient declined participation). No significant clinical deterioration or quality of life worsening was observed during desensitization; in fact, there was an improvement in practically all mesured parameters. All five patients who resumed ELX/TEZ/IVA are currently receiving therapy with good tolerance. Conclusion: Desensitization to ELX/TEZ/IVA could be a successful and safe strategy for reintroducing this essential treatment in cases of a delayed hypersensitivity rash.

Vulnerabilidad y determinantes sociales en diabetes / Vulnerability and social determinants in diabetes

Los determinantes sociales de la salud influyen significativamente en el desarrollo y en la progresión de enfermedades crónicas como la diabetes tipo2 (DM2). Este artículo examina los determinantes sociales clave, incluidos la educación, la estabilidad económica, el vecindario, así como la procedencia, la raza o la religión, que afectan a las personas con DM2. También se explora el papel del género como determinante social, enfatizando la necesidad de consideraciones específicas de género en la gestión y en la investigación de la DM2. Además, se analiza el impacto de la pobreza en los resultados de salud, destacando la relación bidireccional entre pobreza y enfermedad. Las medidas integrales que abordan estos determinantes son cruciales para mejorar la salud y el bienestar de las personas con DM2. Abordar las desigualdades sociales a través de intervenciones específicas puede contribuir a mejores resultados de tratamiento y a una atención médica equitativa (AU)

Social determinants of health significantly influence the development and progression of chronic diseases such as type2 diabetes (T2DM). This article examines key social determinants including education, economic stability, neighborhood, and factors such as ethnicity, race, or religion that impact individuals with T2DM. The role of gender as a social determinant is also explored, emphasizing the need for gender-specific considerations in T2DM management and research. Additionally, the impact of poverty on health outcomes is analyzed, highlighting the bidirectional relationship between poverty and disease. Comprehensive measures addressing these determinants are crucial to improving the health and well-being of individuals with T2DM. Addressing social inequalities through targeted interventions can contribute to better treatment outcomes and equitable healthcare (AU)

[Vulnerability and social determinants in diabetes]. / Vulnerabilidad y determinantes sociales en diabetes.

Social determinants of health significantly influence the development and progression of chronic diseases such as type2 diabetes (T2DM). This article examines key social determinants including education, economic stability, neighborhood, and factors such as ethnicity, race, or religion that impact individuals with T2DM. The role of gender as a social determinant is also explored, emphasizing the need for gender-specific considerations in T2DM management and research. Additionally, the impact of poverty on health outcomes is analyzed, highlighting the bidirectional relationship between poverty and disease. Comprehensive measures addressing these determinants are crucial to improving the health and well-being of individuals with T2DM. Addressing social inequalities through targeted interventions can contribute to better treatment outcomes and equitable healthcare.

Actualización en el uso de insulinas para el médico de familia / Update on the use of insulins for the primary care physician

El tratamiento con insulina en personas con diabetes mellitus tipo 2 (DM2) continúa siendo fundamental y su consumo ha aumentado en los últimos años. A pesar de ello, el grado de control para esta patología continúa siendo muy deficiente. El inicio del tratamiento con insulina se realiza con cifras muy por encima de las recomendaciones de las Guías de Práctica Clínica (GPC) y los pacientes están sometidos a cifras de glucemia muy elevadas durante largos periodos de tiempo. En este artículo se revisa el papel de la insulina siguiendo las diferentes GPC, los criterios para el inicio y la intensificación con dicha terapia, los diferentes tipos de insulina comercializados en nuestro país, la insulinización en situaciones especiales (tratamiento con corticoides, en el anciano frágil, personas en situación de cuidados paliativos, enfermedad renal crónica y personas que cumplen el Ramadán) y finalmente se aborda el problema de la inercia terapéutica en la insulinización (AU)

Insulin treatment in type 2 diabetes mellitus patients is still essential and its usage has increased during recent years. Despite this, the level of control continues to be very poor. Insulin treatment is initiated with control levels above the recommendations set by the Clinical Practice Guidelines (CPG) and patients are exposed to very high blood glucose levels during long periods of time. This paper reviews the role of insulin in the different CPG, the criteria for therapy initiation and intensification, the beginning of the intensification and the different types of insulin which are commercialized in our country. Moreover, we discuss insulinization in special situations such as corticosteroid treatment, fragile elderly patients, palliative care situations, chronic kidney disease or during Ramadan. Finally, the problem of therapeutic inertia in insulinization is also addressed (AU)

Quality indicators and excellence requirements for a multidisciplinary lung cancer tumor board by the Spanish Lung Cancer Group.

Multidisciplinary care is needed to decide the best therapeutic approach and to provide optimal care to patients with lung cancer (LC). Multidisciplinary teams (MDTs) are optimal strategies for the management of patients with LC and have been associated with better outcomes, such as an increase in quality of life and survival. The Spanish Lung Cancer Group has promoted this review about the current situation of the existing national LC-MDTs, which also offers a set of excellence requirements and quality indicators to achieve the best care in any patient with LC. Time and sufficient resources; leadership; administrative and institutional support; and recording of activity are key factors for the success of LC-MDTs. A set of excellence requirements in terms of staff, resources and organization of the LC-MDT have been proposed. At last, a list of quality indicators has been agreed to achieve and measure the performance of current LC-MDTs.

Exploratory analysis of clinical benefit of ipilimumab and nivolumab treatment in patients with metastatic melanoma from a single institution.

PURPOSE: We retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution. METHODS AND PATIENTS: Electronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan-Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models. RESULTS: Forty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2-NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR) < 5 (all p ≤ 0.05, log-rank test). These factors allowed the classification of patients into three prognostic risk groups (low/intermediate/high risk) for death. CONCLUSION: Overall survival of real-world patients from our cohort receiving ipilimumab plus nivolumab was lower than in previous studies. The ECOG score, LDH values, the presence of liver metastases and the NLR were independent prognostic factors for survival.

Análisis de pacientes con diabetes tipo 2 en un centro de salud urbano. Estudio DESENROQUE / Analysis of patients with type 2 diabetes in an urban Primary Healthcare centre. DESENROQUE Study

OBJETIVOS: Analizar el estado de salud de los pacientes con diabetes tipo 2 (DM2) en un centro de salud urbano y valorar el seguimiento realizado por parte de los profesionales sanitarios. Analizar las terapias farmacológicas en pacientes con DM2, así como valorar la individualización atendiendo a sus comorbilidades. MATERIAL Y MÉTODOS: Análisis descriptivo y transversal de pacientes con DM2. De un total de 920 pacientes se obtuvo una muestra aleatorizada y simple de 460 individuos, de los cuales se recogieron los parámetros relacionados con las comorbilidades asociadas y el tratamiento integral de la DM2. RESULTADOS: Nos encontramos ante una muestra de 460 pacientes (42,4% mujeres) con una edad media de 67,1 años (DE=13,07). El valor medio de su última HbA1c fue 6,75% (DE=1,24). El 83,7% cumplía con los objetivos individualizados propuestos de HbA1c atendiendo a su edad y comorbilidades. El 65,43% de los pacientes contaba con un seguimiento subóptimo por parte de los profesionales sanitarios. Con respecto a la adecuación del tratamiento, el 19,8% contaba con asociaciones farmacológicas no recomendadas o fármacos aplicados fuera de ficha técnica. El 74,3% contaba con un tratamiento integral de la DM2 mejorable. CONCLUSIONES: Aunque el 83,7% de los pacientes presentaba un buen control de la HbA1c, el tratamiento es glucocéntrico y mejorable en un alto porcentaje de los pacientes (74,3%). Dado que la terapia debe ajustarse a las necesidades de cada paciente, y siendo el IMC un factor determinante para la selección del tratamiento, llama la atención que en el 44,13% de los pacientes no esté registrado en su historia clínica

OBJECTIVES: To determine the health status of patients with type 2 diabetes (T2D) in an urban Primary Healthcare centre, and to assess the follow-up carried out by health professionals. To analyse the pharmacological treatment in patients with T2D, as well as to assess the individualisation according to their comorbidities. MATERIAL AND METHODS: Descriptive and cross-sectional analysis conducted on patients with DM2. Out of a total of 920 patients, a randomised and simple sample of 460 individuals was obtained, from which the parameters related to associated comorbidities and the integral treatment of T2D were collected. RESULTS: The study included 460 patients (42.4% women) with a mean age of 67.1 years (SD=13.07). The mean value of their last HbA1c was 6.75% (SD=1.24). The large majority (83.7%) fulfilled the proposed individualised HbA1c objectives according to their age and comorbidities. Approximately two-thirds (65.43%) of patients had a suboptimal follow-up by health professionals. As regards the suitability of the treatment, 19.8% had non-recommended pharmacological combinations or drugs applied outside the indications of the data sheet. A comprehensive T2D treatment that could be improved was observed in 74.3%. CONCLUSIONS: Although 83.7% of patients had good control of HbA1c, the treatment is centred on blood glucose and improvable in a high percentage of patients (74.3%). Given that the therapy must be adjusted to the needs of each patient, and since the BMI (body mass index) is a determining factor for the selection of treatment, it is striking that it is not recorded in the clinical histories of 44.13% of the patients

[Analysis of patients with type 2 diabetes in an urban Primary Healthcare centre. DESENROQUE Study]. / Análisis de pacientes con diabetes tipo 2 en un centro de salud urbano. Estudio DESENROQUE.

OBJECTIVES: To determine the health status of patients with type 2 diabetes (T2D) in an urban Primary Healthcare centre, and to assess the follow-up carried out by health professionals. To analyse the pharmacological treatment in patients with T2D, as well as to assess the individualisation according to their comorbidities. MATERIAL AND METHODS: Descriptive and cross-sectional analysis conducted on patients with DM2. Out of a total of 920 patients, a randomised and simple sample of 460 individuals was obtained, from which the parameters related to associated comorbidities and the integral treatment of T2D were collected. RESULTS: The study included 460 patients (42.4% women) with a mean age of 67.1 years (SD=13.07). The mean value of their last HbA1c was 6.75% (SD=1.24). The large majority (83.7%) fulfilled the proposed individualised HbA1c objectives according to their age and comorbidities. Approximately two-thirds (65.43%) of patients had a suboptimal follow-up by health professionals. As regards the suitability of the treatment, 19.8% had non-recommended pharmacological combinations or drugs applied outside the indications of the data sheet. A comprehensive T2D treatment that could be improved was observed in 74.3%. CONCLUSIONS: Although 83.7% of patients had good control of HbA1c, the treatment is centred on blood glucose and improvable in a high percentage of patients (74.3%). Given that the therapy must be adjusted to the needs of each patient, and since the BMI (body mass index) is a determining factor for the selection of treatment, it is striking that it is not recorded in the clinical histories of 44.13% of the patients.

Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.