Long-term effectiveness and safety of tolvaptan in autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: Evidence on the long-term use of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) is limited. The aim was to evaluate the tolvaptan effectiveness and safety in real clinical setting. MATERIAL AND METHODS: A single-center observational study (2016-2022) involving ADPKD patients treated with tolvaptan was conducted. Annual change in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) before and after treatment initiation were evaluated. Change in total kidney volume (TKV), blood pressure (BP) and urinary albuminuria at 12, 24 and 36 months after initiation were also determined. Adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were analyzed. RESULTS: A total of 22 patients were included. No significant differences pre- vs post tolvaptan treatment in annual rate of change in eGFR (-3.52ml/min/1.73m2 [-4.98%] vs -3.98ml/min/1.73m2 [-8.48%], p=0.121) and sCr (+0.06mg/dL [4.22%] vs +0.15mg/dL [7.77%], p=0.429) were observed. Tolvaptan improved urinary osmolality at 12 (p=0.019) and 24 months (p=0.008), but not at 36 months (p=0.11). There were no changes in TKV, BP control and urinary albuminuria at 12, 24 or 36 months. A worse response was shown in patients with rapid kidney function decline (p=0.042). A 36.4% of the patients developed grade III/IV AEs. A 22.7% discontinued treatment due to unacceptable toxicity. CONCLUSIONS: This study shows a modest benefit of tolvaptan in ADPKD patients, as well as safety concerns.

Effect of Concomitant Use of Proton Pump Inhibitors on Immunotherapy Clinical Response in Advanced Cancer Patients: Real-Life Setting.

The alteration of the gut microbiota mediated by proton pump inhibitor (PPI) drugs could be involved in the clinical response associated with immunotherapy [immunocheckpoint inhibitors (ICIs)] in cancer patients. Due to the current controversy in the scientific evidence, it has been proposed to evaluate the correlation between the concomitant use of PPIs and the effectiveness of immunotherapy in a real clinical practice setting. Single-center retrospective cohort study that included patients treated with anti-PD-1 or anti-CTLA4, including nivolumab, pembrolizumab, atezolizumab, or the combination ipilimumab-nivolumab in metastatic neoplastic disease. The clinical effectiveness of ICI, measured in progression-free survival (PFS) and overall survival (OS), was compared between the PPI-use versus PPI-no-use group. PPI-use group was associated with lower PFS [hazard ratio (HR):1.89 (1.38-2.59), P<0.001] and OS [HR: 2.02 (1.45-2.82), P<0.001] versus PPI-no-use group. However, this difference was not observed for pembrolizumab PFS [HR: 1.38 (0.93-2.39), P=0.160] and OS [HR: 1.41 (0.81-2.44), P=0.187]. The study showed significantly lower PFS and OS in the chronic PPI-use group (P<0.001), recent PPI-use group (P<0.001) and concomitant PPI-use group (P=0.001, 0.007) versus PPI-no-use group. However, late PPI use >30 days after the onset of ICI has no significant effect on the efficacy of treatment [HR: 0.92 (0.49-1.70), P=0.791; HR: 1.10 (0.59-2.05), P=0.756]. The concomitant use of PPIs in immunotherapy is associated with worse clinical outcomes compared with the group without PPI use. In addition, the study shows how the late use of PPIs does not have a significant effect on clinical benefit.

Risk factors determining adherence to tyrosine kinase inhibitors in chronic myeloid leukaemia.

OBJECTIVE: Tyrosine kinase inhibitors (TKIs) have successfully changed the natural course of chronic myeloid leukaemia (CML). Although they are highly effective drugs, their clinical benefit is conditioned by adherence. This study aims to analyse the adherence of CML patients treated with TKIs and to identify the main factors influencing their adherence to TKIs treatment. MATERIAL AND METHODS: An 8-month prospective, observational, multicentre study which included patients diagnosed with CML on treatment with TKIs attending the outpatient departments (OPD) of the Pharmacy Services of the participating hospitals. Adherence was assessed using two methods: the Simplified Medication Adherence Questionnaire (SMAQ) and the register of treatment dispensations from the OPDs. To analyse the predictors of adherence, a questionnaire was developed to report demographic and socio-economic information on the patients. RESULTS: A total of 130 patients enrolled in this study. Adherence rate was 56.9% (n = 74) among individuals, not conditioned by the type of drug used: imatinib (54.8%), nilotinib (63.6%) or dasatinib (54.3%) (p = 0.67). The patient educational level (p = 0.047) and employment status (p = 0.028) were predictors of non-adherence to treatment. CONCLUSIONS: Adherence is one of the most relevant parameters affecting the effectiveness of highly effective chronic treatments. Approximately half of our patients showed inadequate adherence to treatment with TKIs, with employment status and the individual's level of education emerging as the determining factors.

Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study.

INTRODUCTION: Identifying polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene is gaining importance to be able to predict fluoropyrimidine-associated toxicity. The aim of this project was to describe the frequency of the DPYD variants DPYD*2A (rs3918290); c.1679T>G (rs55886062); c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in the Spanish oncological patients. MATERIAL AND METHODS: Cross-sectional and multicentric study (PhotoDPYD study) conducted in hospitals located in Spain designed to register the frequency of the most relevant DPYD genetic variants in oncological patients. All oncological patients with DPYD genotype were recruited in the participant hospitals. The measures determined where the presence or not of the 4 DPYD previously described variants. RESULTS: Blood samples from 8054 patients with cancer from 40 different hospitals were used to determine the prevalence of the 4 variants located in the DPYD gene. The frequency of carriers of one defective DPYD variant was 4.9%. The most frequently identified variant was c.1129-5923C>G (rs75017182) (HapB3), in 2.9%, followed by c.2846A>T (rs67376798) in 1.4%, c.1905 + 1G>A (rs3918290, DPYD*2A) in 0.7% and c.1679T>G (rs55886062) in 0.2% of the patients. Only 7 patients (0.08%) were carrying the c.1129-5923C>G (rs75017182) (HapB3) variant, 3 (0.04%) the c.1905 + 1G>A (rs3918290, DPYD*2A) and one (0.01%) the DPYD c.2846A>T (rs67376798, p.D949V) variant in homozygosis. Moreover, 0.07% were compound heterozygous patients, 3 carrying the DPYD variants DPYD*2A + c.2846A>T, 2 the DPYD c.1129-5923C>G + c.2846A>T and one the DPYD*2A + c.1129-5923C>G variants. CONCLUSIONS: Our results demonstrate the relatively high frequency of DPYD genetic variants in the Spanish patient with cancer population, which highlights the relevance of their determination before initiating a fluoropirimidine-containing regimen.

Definition of a therapeutic range for predicting long-term infliximab response in patients with inflammatory bowel disease / Definición de un rango terapéutico para predecir la respuesta al infliximab a largo plazo en pacientes con enfermedad inflamatoria intestinal

Introduction: Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD.MethodsThis single-centre retrospective study (2017–2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined.ResultsMultivariate analysis determined that IFX concentrations>7μg/mL at week 8, and at 6 months, are associated with inflammatory remission (p=0.046, 0.045). IFX>7μg/mL at 12 months predicted remission at 18 months of treatment (p=0.006). IFX values>3μg/mL at 12 months are associated with stable SGA at 18 months (p=0.001). Such values at 18 months are associated with stable SGA at 24 months (p=0.044).Conclusions and relevanceThe predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance. (AU)

Introducción: La monitorización de infliximab (IFX) juega un papel importante en la optimización del tratamiento en pacientes con enfermedad inflamatoria intestinal (EII). El objetivo del estudio fue determinar el potencial predictivo de la monitorización de IFX para la respuesta clínica sostenida, y evaluar su utilidad en la eficacia del tratamiento y del control de los síntomas.MétodosEstudio retrospectivo unicéntrico (2017-2019) que incluyó pacientes con EII tratados con IFX. Se analizaron los niveles séricos y la inmunogenicidad asociada al fármaco en la semana 8 postinducción, y a los 6, 12 y 24 meses. Se registraron los parámetros clínicos y los marcadores inflamatorios correspondientes a la evaluación global subjetiva (SGA), proteína C reactiva (PCR) y calprotectina fecal (CF). Se determinaron los factores asociados a la interrupción precoz y a la intensificación de la dosis de IFX.ResultadosEl análisis multivariante determinó que las concentraciones de IFX>7μg/ml en la semana 8, y a los 6 meses, se asocian a la remisión inflamatoria (p=0,046-0,045). El IFX>7μg/ml a los 12 meses predijo la remisión a los 18 meses de tratamiento (p=0,006). Los valores de IFX>3μg/ml a los 12 meses se asocian a una SGA estable a los 18 meses (p=0,001). Dichos valores a los 18 meses se asocian a SGA estable a los 24 meses (p=0,044).Conclusiones y relevanciaSe confirma el potencial predictivo de la monitorización de los niveles plasmáticos de IFX como estrategia para evaluar la respuesta clínica sostenida a largo plazo. Nuestros resultados destacan la importancia de su introducción en la práctica clínica habitual para permitir la identificación temprana de los no respondedores, la optimización del tratamiento, la prevención de recaídas y mejorar el mantenimiento de la terapia a largo plazo. (AU)

A slowdown of hepatitis C diagnosis in high-prevalence groups and with decentralized diagnostic strategies during the COVID-19 pandemic.

INTRODUCTION: the COVID-19 pandemic has had a major impact on hepatitis C virus (HCV) diagnosis by hindering the path to elimination. Albeit, in an uneven manner, depending on the risk group and diagnostic strategy. METHODS: the requests of antibodies/RNA by venipuncture at hospitals and Primary Care centers (centralized) and via venipuncture or dried blood spot tests at prison and drug treatment centers referred for central processing (integrated decentralized) were recorded for one year, before and after the onset of the COVID-19 health crisis. RESULTS: a total of 20,600 tests (51 % male, 47.9 ± 1 5.8 years) were recorded. Among them, 96.5 % of the cases came from centralized and 3.5 % from decentralized settings, with an active infection rate of 0.2 % and 2.3 % (p < 0.001), respectively. There was a 31.3 % decrease in the number of requests during the pandemic compared to the pre-pandemic period, which was more pronounced in the decentralized than centralized diagnosis setting (60 vs 30 %, p < 0.001). In addition, there was a 31.5 % decline in screening and 18.2 % decrease in the diagnosis of new cases of active infection, with a statistically significant decrease in decentralized compared to centralized diagnosis. CONCLUSIONS: during the COVID-19 pandemic, a decline in HCV diagnostic effort was observed, especially in decentralized strategies, with a higher prevalence of infection. Our results suggest a diagnostic delay that will prevent Spain from reaching the elimination target in 2023. Therefore, the reactivation of strategies, particularly targeting the priority groups, is urgently required.

Imatinib plasma levels in patients with chronic myeloid leukaemia under routine clinical practice conditions.

INTRODUCTION: The addition of imatinib to the therapeutic arsenal for chronic myeloid leukaemia (CML) has changed the natural course of the disease, in such a way that it is now considered a chronic pathology. However, to achieve therapeutic success, it is necessary to reach adequate plasma concentrations to ensure efficacy and safety.In this study, we aimed to evaluate the plasma concentration of imatinib, analysing its influence on effectiveness and safety in patients with CML. METHODS: We performed a descriptive, multicentre study in which imatinib plasma levels from patients diagnosed with CML between 2019-2020 were analysed. An optimal therapeutic range of 750-1500 ng/mL was established for the stratification of patients, according to their minimum plasma concentrations measured at steady state (Cssmin). RESULTS: A total of 28 patients were included, of whom only 39.3% (n = 11) showed Cssmin within the therapeutic range. 100% of patients with Cssmin >750 ng/mL achieved an optimal molecular response, while only 50% of patients with Cssmin <750 ng/mL achieved an optimal molecular response (p = 0.0004). The toxicity rate was 36.4% for patients with Cssmin >1500 ng/mL and 5.9% for those with Cssmin <1500 ng/mL (p = 0.039). CONCLUSIONS: This study aimed to describe the correlation between the toxicity and effectiveness of imatinib according to its Cssmin in routine clinical practice conditions. Based on our findings, it would be certainly justified to monitor patient plasma concentrations of imatinib on a daily routine basis in our hospitals.

Definition of a therapeutic range for predicting long-term infliximab response in patients with inflammatory bowel disease.

INTRODUCTION: Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD. METHODS: This single-centre retrospective study (2017-2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined. RESULTS: Multivariate analysis determined that IFX concentrations>7µg/mL at week 8, and at 6 months, are associated with inflammatory remission (p=0.046, 0.045). IFX>7µg/mL at 12 months predicted remission at 18 months of treatment (p=0.006). IFX values>3µg/mL at 12 months are associated with stable SGA at 18 months (p=0.001). Such values at 18 months are associated with stable SGA at 24 months (p=0.044). CONCLUSIONS AND RELEVANCE: The predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance.

Efficacy and Safety of Erenumab, Galcanezumab, and Fremanezumab in the Treatment of Drug-Resistant Chronic Migraine: Experience in Real Clinical Practice.

BACKGROUND: Due to the recent introduction of new biologic drugs for chronic migraine, a global evaluation in real clinical practice is necessary. OBJECTIVE: The objective was to evaluate the effectiveness and safety in real clinical practice of drugs targeting the calcitonin gene-related peptide receptor (CGRPr) in patients with chronic migraine. METHODS: Single-center, restrospective study (2019-2022), including patients with chronic migraine treated with erenumab, galcanezumab, or fremanezumab. Effectiveness variables were recorded, namely, number of migraine headache days per month (MHD), Migraine Disability Assessment Scale (MIDAS) score, and Headache Impact Test-6 (HIT-6) score, assessing changes at week 12, 24 from baseline. Toxicity was recorded following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. RESULTS: In all, 104 patients were included (46.2% erenumab, 41.3% galcanezumab, 12.5% fremanezumab). A reduction in MHD, MIDAS, and HIT-6 was achieved at weeks 12 and 24 with erenumab (p75% at week 24 than those intensified; P = 0.041). There was no difference in efficacy (P = 0.154) or improvement in quality of life (P = 0.783, P = 0.150), but there was greater toxicity (P < 0.001) among nonresponders with erenumab 70 mg versus erenumab 140 mg. CONCLUSIONS: The results confirm the effectiveness and safety of anticalcitonin gene-related peptide (CGRP) drugs in real clinical practice. However, the study shows little benefit from erenumab intensification, with similar effectiveness and worse tolerability than the standard dose.

Mayor ralentización en el diagnóstico de la hepatitis C en estrategias descentralizas y en grupos de alta prevalencia durante la pandemia por COVID-19 / A slowdown of hepatitis C diagnosis in high-prevalence groups and with decentralized diagnostic strategies during the COVID-19 pandemic

Introducción: la pandemia por COVID-19 ha tenido una importante repercusión en el diagnóstico del virus de la hepatitis C (VHC) obstaculizando el camino hacia su eliminación,aunque es probable que de forma desigual según la estrategia diagnóstica y el grupo de riesgo.Métodos: se registraron las solicitudes de anticuerpos/ARNpor venopunción en hospital y Atención Primaria (centralizado) y mediante venopunción o test de gota de sangre seca enprisión y centros de drogodependencias remitidos para procesamiento central (descentralizado integrado) durante un añoantes y después del inicio de la alerta sanitaria por COVID-19.Resultados: se registró un total de 20.600 determinaciones(51 % varones, 47,9 ± 15,8 años) realizadas el 96,5 % deforma centralizada y el 3,5 % de forma descentralizada,con una tasa de infección activa del 0,2 % y el 2,3 %(p < 0,001), respectivamente. Durante el periodo de pandemia, comparado con el de prepandemia, hubo un descensoen el número de determinaciones del 31,3 %, que fue mayor en diagnóstico descentralizado comparado con centralizado (60 vs. 30 %, p < 0,001). Además, se contabilizó undescenso en el cribado del 31,5 % y en el diagnóstico denuevos casos de infección activa, del 18,2 %, con mayordescenso en el diagnóstico descentralizado comparado concentralizado.Conclusiones: durante la pandemia por COVID-19 se ha objetivado un descenso en el esfuerzo diagnóstico del VHC,especialmente en estrategias descentralizadas y con mayorprevalencia de infección. Estos resultados sugieren un retraso diagnóstico que dificultará alcanzar la meta de eliminación en nuestro país en 2023, por lo que urge reactivarestrategias principalmente en grupos prioritarios. (AU)

Efficacy and safety of high doses of irinotecan in patients with metastatic colorectal cancer treated with the FOLFIRI regimen based on the UGT1A1 genotype: A systematic review.

OBJECTIVE: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 of irinotecan recommended in the drug's summary of product characteristics in  metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or *1/*28  who are treated with the FOLFIRI regimen. METHOD: A systematic review of the literature was carried out in Medline and  Embase searching for articles published up to December 2021. The methods  used were based on the recommendations of the Preferred Reporting Items for  Systematic Reviews and Meta-Analyses (PRISMA) statement. The criteria  for the inclusion of studies were previously defined based on the two secondary goals addressed in this review: 1) To analyze the magnitude of the differences  in clinical responses and 2) To study the magnitude of the differences in  adverse effects of irinotecan at high doses, as compared to the doses  described in the summary of product characteristics corresponding to the  FOLFIRI regimen in patients with metastatic colorectal cancer with genotypes  UGT1A1*1/* 1 or *1/*28. RESULTS: The search yielded a total of 985 references, of which 13 were selected for analysis. Seven evaluated both efficacy and safety and six  only safety. With regard to the studies that evaluated both efficacy and safety,  six out of seven (85.7%) were in favor of increasing irinotecan dose according  to the objective response rate and progression-free survival. Two of them even  recommended dose increases based on overall survival. Irinotecan safety  studies suggest that doses higher than 180 mg/m2 are tolerated by  most UGT1A1*1/*1 and *1/*28 patients. CONCLUSIONS: The present systematic review shows the advisability of considering adjusting the dose of irinotecan when used as part of the FOLFIRI regimen based on the polymorphisms of the UGT1A1 gene as this may increase the likelihood of an adequate clinical response.

OBJETIVO: El objetivo de la presente revisión sistemática es analizar los datos  publicados sobre la eficacia y seguridad de las dosis superiores a los 180  mg/m2 de irinotecán recomendadas en la ficha técnica en pacientes con cáncer  colorrectal metastásico tratados con el esquema FOLFIRI y con  genotipo UGT1A1*1/*1 y *1/*28.Método: Se realizó una revisión sistemática mediante una búsqueda bibliográfica en Medline y Embase de los artículos publicados hasta diciembre de 2021. Los métodos utilizados se basaron en los  recomendados según Preferred Reporting Items for Systematic Reviews and  Meta-Analyses (PRISMA). Los criterios para la inclusión de los estudios se  definieron previamente en base a los dos objetivos secundarios que aborda  esta revisión: 1) Analizar la magnitud de la diferencia de la respuesta clínica y 2) estudiar la magnitud de la diferencia de los efectos  dversos a irinotecán a dosis altas, en comparación con las dosis descritas en la ficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28. RESULTADOS: La estrategia de búsqueda reportó un total de 98 referencias, de  las que 13 fueron seleccionadas para el análisis, 7 (53,8%)  evaluando tanto  eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con  los estudios que evaluaron eficacia y seguridad, 6 (85,7%) se mostraron  favorables al aumento de dosis en términos de tasa de respuesta objetiva y  supervivencia libre de progresión e, incluso, en 2 de ellos en supervivencia  global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán  superiores a 180 mg/m2 son toleradas por la mayor parte de los  pacientes UGT1A1*1/*1 y *1/*28. CONCLUSIONES: La presente revisión sistemática muestra la conveniencia de  valorar el ajuste de dosis de irinotecán dentro del esquema FOLFIRI en función  de los polimorfismos del gen UGT1A1, con un potencial aumento de  las probabilidades de una adecuada respuesta clínica.

Eficacia y seguridad de dosis altas de irinotecán en pacientes con cáncer colorrectal metastásico tratados con el esquema FOLFIRI en función delgenotipo de UGT1A1: Revisión sistemática / Efficacy and safety of high doses of irinotecan in patients with metastatic colorectal cancer treated with the FOLFIRI regimen based on the UGT1A1 genotype: A systematic review

Objetivo: El objetivo de la presente revisión sistemática es analizar losdatos publicados sobre la eficacia y seguridad de las dosis superioresa los 180 mg/m2 de irinotecán recomendadas en la ficha técnica enpacientes con cáncer colorrectal metastásico tratados con el esquemaFOLFIRI y con genotipo UGT1A1*1/*1 y *1/*28.Método: Se realizó una revisión sistemática mediante una búsquedabibliográfica en Medline y Embase de los artículos publicados hastadiciembre de 2021. Los métodos utilizados se basaron en los recomendados según Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA). Los criterios para la inclusión de los estudios se definieron previamente en base a los dos objetivos secundarios que abordaesta revisión: 1) Analizar la magnitud de la diferencia de la respuestaclínica y 2) estudiar la magnitud de la diferencia de los efectos adversosa irinotecán a dosis altas, en comparación con las dosis descritas en laficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28.Resultados: La estrategia de búsqueda reportó un total de 98 referencias, de las que 13 fueron seleccionadas para el análisis, 7 (53,8%) evaluando tanto eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con los estudios que evaluaron eficacia y seguridad,6 (85,7%) se mostraron favorables al aumento de dosis en términos detasa de respuesta objetiva y supervivencia libre de progresión e, incluso,en 2 de ellos en supervivencia global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán superiores a 180 mg/m2 sontoleradas por la mayor parte de los pacientes UGT1A1*1/*1 y *1/*28. (AU)

Objective: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 ofirinotecan recommended in the drug’s summary of product characteristicsin metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or*1/*28 who are treated with the FOLFIRI regimen.Method: A systematic review of the literature was carried out in Medlineand Embase searching for articles published up to December 2021. Themethods used were based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.The criteria for the inclusion of studies were previously defined based on thetwo secondary goals addressed in this review: 1) To analyze the magnitudeof the differences in clinical responses and 2) To study the magnitude of thedifferences in adverse effects of irinotecan at high doses, as compared tothe doses described in the summary of product characteristics corresponding to the FOLFIRI regimen in patients with metastatic colorectal cancerwith genotypes UGT1A1*1/* 1 or *1/*28.Results: The search yielded a total of 985 references, of which 13 wereselected for analysis. Seven evaluated both efficacy and safety and six only safety. With regard to the studies that evaluated both efficacy andsafety, six out of seven (85.7%) were in favor of increasing irinotecan doseaccording to the objective response rate and progression-free survival.Two of them even recommended dose increases based on overall survival.Irinotecan safety studies suggest that doses higher than 180 mg/m2 aretolerated by most UGT1A1*1/*1 and *1/*28 patients. (AU)

Adherence to subcutaneous biologic treatment for inflammatory bowel disease / Adherencia al tratamiento con biológicos por vía subcutánea en enfermedad inflamatoria intestinal

Background: Nonadherence to medication is common in patients with inflammatory bowel disease (IBD) and can result in disease complications, therapy escalation, and the need for corticosteroids. The aim of this study was to assess the adherence to self-administered subcutaneous biologic medications prescribed for IBD and to identify the risk factors for nonadherence.Methods: A retrospective cohort study on IBD patients initiated on subcutaneous biologic therapy between January 2016 and July 2019 was performed. Medical records were retrospectively reviewed for collection of demographic and IBD data. Medication possession ratios (mMPRs) during the first 12 months of treatment and at the end of the follow-up period (global, 42 months) were calculated. Nonadherence was defined as an mMPR of <90%. Multiple regression analysis was performed to assess the risk factors for nonadherence to therapy.Results: A total of 154 patients (84 male and 70 female; mean age at biologic treatment initiation, 36±14 years; Crohn's disease, n=118; ulcerative colitis, n=31; indeterminate colitis, n=5) were included; 121 received adalimumab (ADA) and 33 received ustekinumab (UST); 63% were naive to anti-TNF therapy, while 16.9% previously received more than two biologic treatments. Mean time from IBD diagnosis to subcutaneous biological agent use was 16±10 months. Mean duration of subcutaneous agent use was 17.6 (SD, 11.0) and 17.08 (SD, 6.8) months for ADA and UST, respectively. Global nonadherence (mMPR≤90%) rate was 6.6% for all patients receiving subcutaneous treatment, 6.3% for ADA, and 6.5% for UST. Nonadherence during the first 12 months of treatment (n=98) was 6.1% for all patients, 2.7% for ADA, and 16% for UST. In the multivariate analysis, UST use was independently associated with higher nonadherence only within the first 12 months (OR, 6.7; 95% CI, 1.1–39.5).(AU)

Antecedentes y objetivos: La falta de adherencia al tratamiento médico es muy frecuente en los pacientes con enfermad inflamatoria intestinal (EII), puede determinar el desarrollo de complicaciones, el uso de corticoides y la necesidad de escalar tratamientos en estos pacientes. Los objetivos de este estudio son analizar la adherencia al tratamiento biológico de administración subcutánea en pacientes con EII e identificar factores de riesgo para la no-adherencia al tratamiento.Métodos: Estudio unicéntrico retrospectivo de cohorte en pacientes con EII que recibieron tratamiento biológico subcutáneo (adalimumab y ustekinumab) entre enero de 2016 y julio de 2019. Se realizó revisión retrospectiva de la historia clínica para recoger datos demográficos y de la EII. Se calculó el ratio modificado de posesión de la medicación (mMPR) para los primeros 12 meses de tratamiento y para el final del seguimiento (global-42 meses). Se definió como no-adherencia (adherencia inadecuada) si el mMPR era <90%. Se realizó un análisis de regresión logística para evaluar los factores de riesgo asociados con la no-adhesión.Resultados: Se incluyeron 154 pacientes (84/70; edad media de inicio de tratamiento biológico 36±14 años; enfermedad de Crohn n=118, Colitis Ulcerosa n=31, Colitis Indeterminada n=5). De ellos, 121 (78,6%) recibieron adalimumab (ADA) y 33 (21,4%) ustekinumab (UST); 97/154 (63%) de los pacientes no recibieron tratamiento biológico previo y 26/154 (16,9%) recibieron >2 agentes biológicos antes del tratamiento subcutáneo. El tiempo medio entre el diagnóstico de EII y el uso del biológico subcutáneo fue de 16±10 meses. El tiempo medio de uso de tratamiento subcutáneo se prolongó durante 17,6±11,0 y 17,08±6,8 meses para ADA y UST, respectivamente. La tasa global de no-adherencia al tratamiento fue 6,5% (10/154 pacientes) y específicamente del 6,1% (8/121 pacientes) y del 6,6% (2/33 pacientes) para el uso de ADA y UST, respectivamente.(AU)

Hepatitis C virus infection screening reduces mortality and is cost-effective independently of the intervention test.

INTRODUCTION: Chronic infection due to hepatitis C virus (HCV) is frequently asymptomatic even in advanced stages of liver disease. Implementation of a screening program based on different HCV tests may enable an earlier diagnosis of HCV liver disease and subsequent application of highly effective treatment. PATIENTS AND METHODS: A Markov model which compares three different screening strategies for hepatitis C versus no screening in low-risk prevalence (general population) and high-risk prevalence population (people who inject drugs or prison population) was designed, taking into account age at the start of screening and participation. The three strategies were: 1) serological detection of antibodies against the HCV, 2) dried blood spot test (DBS) to detect antibodies against HCV and 3) detection of RNA from HCV. Quality-adjusted life-years (QALY) were taken as a measurement of effectiveness. The incremental cost-effectiveness ratio (ICER) was calculated and a deterministic and probabilistic sensitivity analysis was performed. RESULTS: All three screening strategies were found to be cost-effective with an ICER of €13,633, €12,015 and €12,328/QALY for AntiHCV, DBS-AntiHCV and DBS-RNA HCV, respectively. There was a decrease in mortality due to liver disease in comparison to no screening for AntiHCV (40.7% and 52%), DBS-AntiHCV (45% and 80%) and DBS-RNA HCV (45.2% and 80%) for low-prevalence and high-prevalence populations, respectively. CONCLUSION: All test interventions for HCV screening are cost-effective for the early detection of HCV infection, also achieving a reduction in mortality. Thus, implementation of screening programs for HCV should not be halted by decisions on monetary policy.

Biomarkers for characterization and therapeutic orientation in castration-resistant prostate cancer. / Biomarcadores para la caracterización y orientación terapéutica en Cáncer de Próstata Resistente a la Castración (CPRC).

Whole exome sequencing studies haverevealed the molecular landscape of metastatic CastrateResistant Prostate Cancer (mCRPC) providingnew information about prognostic and predictive factorsof response to therapies. These studies highlightedpotentially actionable targets leading to the beginingof the biomarker-driven era in prostate cancer.Alterations in androgen receptor (AR), DNA repair genes,PI3K-AKT-MTOR pathway or in genes involved incell cycle are frequently observed in mCRPC patientsand may be relevant in the resistance induced mechanismto approve therapy in this setting. Poly(ADP-ribose)polymerase (PARP) inhibitor in BRCA mutatedpatients, pembrolizumab (inmune checkpoint inhibitors)in mCRPC patients with mismatch repair genedefects and microsatellite instability and ipatasertib(AKT inhibitor) in patients with loss of function inPTEN are examples on how molecular information canbe useful to improve treatment selection. Nonethelessthe heterogeneity of advanced PC, the lack of consensusregarding the optimal biological source of analysisand the optimal time and technique for the analisysare still challenges that need to be defined in the nextfuture. The aim is to review the current literature concerningprognostic and predictive marker of responseto therapies in the mCRPC setting.

Estudios de secuenciación completa delexoma han revelado el perfil molecular del pacientecon Cáncer de Próstata Resistente a la Castración metastásico(CPRCm) proporcionando nueva informaciónsobre factores pronósticos y predictivos de respuestaa las distintas alternativas terapéuticas. Muchos deestos estudios han resaltado numerosas dianas molecularesaccionables desde un punto de vista farmacológico,conduciéndonos al comienzo de la medicina deprecisión en el Cáncer de Próstata (CP). Alteracionesen el Receptor de Andrógenos (RA), en genes reparadoresde DNA, en la vía de PI3K-AKT-MTOR o en genesimplicados en el ciclo celular son frecuentementeobservadas en CPRCm y pueden ser relevantes en la selección terapéutica y en la comprensión de los mecanismosde resistencia.Los inhibidores de la poli (ADP-ribosa) polimerasaen pacientes con mutaciones en BRCA, pembrolizumab(inhibidor de los puntos de control inmunológico)en pacientes CPRCm con alteraciones en genesimplicados en el "mismatch repair" o inestabilidad demicrosatélites e ipatasertib (inhibidor de AKT) en pacientescon pérdida de función de PTEN son ejemplosde cómo la información molecular puede ser útil paraoptimizar la selección terapéutica en este escenario.No obstante, la heterogeneidad del CP avanzado, lafalta de consenso sobre la fuente biológica óptima parael análisis, el momento y la técnica de análisis continúansiendo desafíos a definir en un fututo próximo.El objetivo es revisar la literatura actual sobre marcadorespronósticos y predictivos de respuesta a tratamientoen el entorno del CPRCm.

Biomarcadores para la caracterización y orientación terapéutica en cáncer de próstata resistente a la castración (cprc) / Biomarkers for characterization and therapeutic orientation in castration-resistant prostate cáncer

- Estudios de secuenciación completa delexoma han revelado el perfil molecular del pacientecon Cáncer de Próstata Resistente a la Castración metastásico (CPRCm) proporcionando nueva informaciónsobre factores pronósticos y predictivos de respuestaa las distintas alternativas terapéuticas. Muchos deestos estudios han resaltado numerosas dianas moleculares accionables desde un punto de vista farmacológico, conduciéndonos al comienzo de la medicina deprecisión en el Cáncer de Próstata (CP). Alteracionesen el Receptor de Andrógenos (RA), en genes reparadores de DNA, en la vía de PI3K-AKT-MTOR o en genes implicados en el ciclo celular son frecuentementeobservadas en CPRCm y pueden ser relevantes en la selección terapéutica y en la comprensión de los mecanismos de resistencia.Los inhibidores de la poli (ADP-ribosa) polimerasaen pacientes con mutaciones en BRCA, pembrolizumab (inhibidor de los puntos de control inmunológico) en pacientes CPRCm con alteraciones en genesimplicados en el “mismatch repair” o inestabilidad demicrosatélites e ipatasertib (inhibidor de AKT) en pacientes con pérdida de función de PTEN son ejemplosde cómo la información molecular puede ser útil paraoptimizar la selección terapéutica en este escenario.No obstante, la heterogeneidad del CP avanzado, lafalta de consenso sobre la fuente biológica óptima parael análisis, el momento y la técnica de análisis continúan siendo desafíos a definir en un fututo próximo.El objetivo es revisar la literatura actual sobre marcadores pronósticos y predictivos de respuesta a tratamiento en el entorno del CPRCm. (AU)

Whole exome sequencing studies haverevealed the molecular landscape of metastatic Castrate Resistant Prostate Cancer (mCRPC) providingnew information about prognostic and predictive factors of response to therapies. These studies highlighted potentially actionable targets leading to the begining of the biomarker-driven era in prostate cancer.Alterations in androgen receptor (AR), DNA repair genes, PI3K-AKT-MTOR pathway or in genes involved incell cycle are frequently observed in mCRPC patientsand may be relevant in the resistance induced mechanism to approve therapy in this setting. Poly(ADP-ribose) polymerase (PARP) inhibitor in BRCA mutatedpatients, pembrolizumab (inmune checkpoint inhibitors) in mCRPC patients with mismatch repair genedefects and microsatellite instability and ipatasertib (AKT inhibitor) in patients with loss of function inPTEN are examples on how molecular information canbe useful to improve treatment selection. Nonethelessthe heterogeneity of advanced PC, the lack of consensus regarding the optimal biological source of analysisand the optimal time and technique for the analisysare still challenges that need to be defined in the nextfuture. The aim is to review the current literature concerning prognostic and predictive marker of responseto therapies in the mCRPC setting. (AU)

Adecuación a las recomendaciones diagnósticas en pacientes con neumonía por Pneumocystis jirovecii tratados con pentamidina intravenosa / Adequacy to diagnostic recommendations in patients with Pneumocystis jirovecii pneumonia treated with intravenous pentamidine

Objetivos. Determinar la tasa de confirmación microbiológica en el diagnóstico de la neumonía por Pneumocystis jirovecii en pacientes tratados con pentamidina intravenosa y la potencial correlación con la efectividad y seguridad del tratamiento. Material y métodos. Estudio retrospectivo unicéntrico (2010-2020), que incluyó aquellos pacientes que recibieron tratamiento con pentamidina intravenosa durante al menos 48 horas. Se registró el procedimiento de recogida de la muestra y el análisis microbiológico realizado. Se determinó la eficacia según la tasa de mortalidad a los 14 días e ingreso en Unidad de Vigilancia Intensiva (UVI), y el control de la enfermedad, mediante la duración de estancia hospitalaria y tiempo desde la finalización del tratamiento hasta el alta. El perfil de seguridad se evaluó según la Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Resultados. Un total de 17 pacientes con neumonía por P. jirovecii fueron tratados con pentamidina (76,5% hombres (n=13); edad media [desviación estándar]: 58,6 [15,5]). En el 47,1% (n=8) de los casos se estableció una confirmación microbiológica del patógeno. El empleo dirigido con pentamidina redujo de forma significativa el tiempo desde la finalización del tratamiento hasta el alta hospitalaria (p=0,019). El perfil de seguridad fue aceptable, apareciendo toxicidad grado I en un paciente. Conclusiones. El estudio muestra como más del 50% de los pacientes reciben tratamiento a partir de un diagnóstico presuntivo y sin ajustarse a las recomendaciones establecidas, repercutiendo en la duración de ingreso y recuperación del paciente. Serán necesarios futuros estudios con un mayor tamaño muestral para consolidar los resultados obtenidos (AU)

Objectives. To determine the rate of microbiological confirmation in the diagnosis of Pneumocystis jirovecii pneumonia in patients treated with intravenous pentamidine and the potential correlation with treatment effectiveness and safety. Material and methods. Single-centre retrospective study (2010-2020), which included those patients who received intravenous pentamidine treatment for at least 48 hours. The sample collection procedure and the microbiological analysis performed were recorded. Efficacy was determined by 14-day mortality rate and admission to the Intensive Care Unit (ICU), and disease control was determined by length of hospital stay and time from completion of treatment to discharge. The safety profile was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.Results. A total of 17 patients with P. jirovecii pneumonia were treated with pentamidine (76.5% male (n=13); mean age [standard deviation]: 58.6 [15.5]). Microbiological confirmation of the pathogen was established in 47.1% (n=8) of cases. Targeted use of pentamidine significantly reduced the time from treatment completion to hospital discharge (p=0.019). The safety profile was acceptable, with grade I toxicity occurring in one patient. Conclusions. The study shows that more than 50% of patients receive treatment based on a presumptive diagnosis and without adhering to the established recommendations, with repercussions on the duration of admission and recovery of the patient. Future studies with a larger sample size will be necessary to consolidate the results obtained. (AU)

Evaluación de la relación exposición-respuestade cetuximab en pacientes con cáncer colorrectal metastásico y cáncer de cabeza y cuello / Assessment of exposure-response relationship for cetuximab in patients with metastatic colorectal cancer and head and neck cancer

Objetivo: Evaluar, en condiciones de vida real, la relación entre lasconcentraciones valle en estado estacionario de cetuximab y el control dela enfermedad, así como buscar la relación entre estas concentraciones y lasupervivencia. Además, estudiar si existe una concentración límite que sepueda asociar con la probabilidad de beneficio clínico.Método: Estudio observacional prospectivo llevado a cabo en pacientescon cáncer colorrectal metastásico o cáncer de cabeza y cuello entratamiento con cetuximab. Se realizó un análisis de regresión de ecuacionesde estimación generalizadas para evaluar la asociación entre laconcentración valle en estado estacionario de cetuximab y la respuesta altratamiento (progresión o beneficio clínico). Mediante modelos de riesgosproporcionales de Cox, se evaluó la asociación entre la mediana de concentracionesvalle en estado estacionario de cetuximab en cada pacienteo la última medida con la supervivencia global y la supervivencia librede progresión, en cada una de las patologías. Asimismo, se buscó unpunto de corte óptimo a través del área bajo la curva de característicasoperativas del receptor. Resultados: Se analizaron 30 muestras de 16 pacientes. La concentraciónvalle en estado estacionario mediana fue 26,86 mg/l y se encontróuna gran variabilidad inter e intraindividual (desviación estándar de 32,4 y16,9 mg/l, respectivamente). Se observó una asociación positiva entre laconcentración valle en estado estacionario y el beneficio clínico (odds ratio1,24; intervalo de confianza del 95%: 0,95-1,63; p = 0,113), aunque noalcanzó significación estadística debido a la baja potencia.

Objective: There is limited scientific evidence on the cetuximab exposure-response relationship and no concentration threshold has been associatedwith optimal disease control. The aims were to assess, in a real-lifesetting, the relationship between steady state cetuximab concentrations(Ctrough, SS) and disease control.Method: A prospective observational study in patients with metastaticcolorectal cancer or head and neck cancer treated with cetuximab. Steadystate trough concentrations were compared with the results of radiologicalassessment of response (progression or clinical benefit). Generalizedestimating equations analysis was performed. To test the association betweensteady state concentrations and overall survival and progression-freesurvival, Cox proportional hazard models were developed. An optimalcut-off point was searched using the area under the receiver operatingcharacteristic curve.Results: A total of 30 steady state cetuximab concentrations from16 patients were analysed. Median Ctrough, SS was 26.86 mg/L andthere was marked inter- and intraindividual variability (standard deviation 32.4 mg/L and 16.9 mg/L, respectively). A positive associationwas found between cetuximab Ctrough, SS and clinical benefit (odds ratio1.24, 95% confidence interval: 0.95-1.63, p = 0.113), although withoutreaching statistical significance. The area under the receiver operatingcharacteristic curve (n = 30) had moderate discrimination power (0.71;95% confidence interval 0.49‑0.93), and the empirical optimal cutoffpoint was 19.12 mg/L. However, no association was observed betweencetuximab Ctrough, SS and survival in metastatic colorectal cancer or neckcancer patients.

Adherence to subcutaneous biologic treatment for inflammatory bowel disease.

BACKGROUND: Nonadherence to medication is common in patients with inflammatory bowel disease (IBD) and can result in disease complications, therapy escalation, and the need for corticosteroids. The aim of this study was to assess the adherence to self-administered subcutaneous biologic medications prescribed for IBD and to identify the risk factors for nonadherence. METHODS: A retrospective cohort study on IBD patients initiated on subcutaneous biologic therapy between January 2016 and July 2019 was performed. Medical records were retrospectively reviewed for collection of demographic and IBD data. Medication possession ratios (mMPRs) during the first 12 months of treatment and at the end of the follow-up period (global, 42 months) were calculated. Nonadherence was defined as an mMPR of <90%. Multiple regression analysis was performed to assess the risk factors for nonadherence to therapy. RESULTS: A total of 154 patients (84 male and 70 female; mean age at biologic treatment initiation, 36±14 years; Crohn's disease, n=118; ulcerative colitis, n=31; indeterminate colitis, n=5) were included; 121 received adalimumab (ADA) and 33 received ustekinumab (UST); 63% were naive to anti-TNF therapy, while 16.9% previously received more than two biologic treatments. Mean time from IBD diagnosis to subcutaneous biological agent use was 16±10 months. Mean duration of subcutaneous agent use was 17.6 (SD, 11.0) and 17.08 (SD, 6.8) months for ADA and UST, respectively. Global nonadherence (mMPR≤90%) rate was 6.6% for all patients receiving subcutaneous treatment, 6.3% for ADA, and 6.5% for UST. Nonadherence during the first 12 months of treatment (n=98) was 6.1% for all patients, 2.7% for ADA, and 16% for UST. In the multivariate analysis, UST use was independently associated with higher nonadherence only within the first 12 months (OR, 6.7; 95% CI, 1.1-39.5). CONCLUSIONS: High global adherence to self-administered subcutaneous biologic treatment was shown in our study, with higher rates of adherence to ADA than to UST within the first 12 months.

Patient-reported outcomes and digital literacy of patients treated in an oncology day hospital unit.

INTRODUCTION: Patient-reported outcomes (PROs) use, via a computer registry, allows patients to report their symptoms enabling the detection of early signs of progression of the disease. For such a record, the patient needs to show certain skills in new technologies use. The present study aimed to analyse the perception and degree of digital literacy of patients undergoing oncological treatment in an Oncology Day Hospital (ODH). METHODS: A cross-sectional descriptive study was performed, where the degree of literacy of patients attending antineoplastic treatment at the ODH was examined by means of an anonymous survey. RESULTS: A total of 122 patients have been included in the study. The proportion of subjects who use the electronic mail (TM) and the Internet on a daily basis was 45.1% and 70.5%, respectively, and up to 77.9% from the subjects considered that the use of digital 2.0 strategies could help improve communication between healthcare professional and patient.The TM was determined by the age, educational level and employment status of the individual. Furthermore, the age of the patients conditioned their perception of the usefulness of the web 2.0 tools (T2.0). CONCLUSION: This study allowed us to establish a target patient profile to conduct the efficient monitoring of cancer progression by PROs. The results have shown that approximately 60% of the patients in our population could be potential candidates to receive PROs-based health care. This approach enables earlier detection of symptoms and signs of progression and consequently, improves health outcomes for cancer patients.