Analysis of immune-mediated reactions in patients with non-small cell lung cancer treated with nivolumab and its association with effectiveness.

OBJECTIVE: To study immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients treated with nivolumab, as well as to assess whether these reactions could be predictors of further effectiveness of therapy. METHODS: Retrospective, observational and longitudinal study. All NSCLC patients who received nivolumab between February 2015-May 2020 were included. In terms of safety, irAEs and their severity were registered and to evaluate the effectiveness, overall survival (OS) and progression free survival (PFS) were calculated. RESULTS: 75 patients were included. 32 patients (43%) were reported irAES. Mainly the irAEs affected the skin (36%). Followed by pneumonitis (20%), gastrointestinal reactions (12%), endocrine (12%) and hepatitis (12%). Regarding severity, 92% were moderate. The median PFS was 9.49 months on the group with irAEs versus 1.99 months on the group without irAEs group (p < 0.0001). The median OS was 17.44 months versus 7.67 months respectively (p = 0.0001). According to the incidence of irAEs developed ( = > 2 vs. 1 vs. 0), the median PFS was 20.53 versus 5.35 versus 1.99 months respectively (p < 0.0001). The median OS was 23.41 versus 15.80 versus 7.67 months, respectively (p = 0.0002). CONCLUSION: In a significant number of patients irAEs occur, generally of grade 1-2 severity, affecting mainly the skin, lungs and gastrointestinal system. We confirm that the development of irAEs in patients with NSCLC treated with nivolumab is a strong predictor of treatment effectiveness in both PFS and OS, with statistically significant results. On those patients who experience two or more immunorelated adverse events the greatest benefit has been observed.

[Lean Six Sigma in the implementation of automated dispensing systems: improving the safe use of medications in thoracic surgery.] / Lean Seis Sigma en la implantación de sistemas automatizados de dispensación: mejora del uso seguro del medicamento en cirugía torácica.

OBJECTIVE: Medications errors are a major problem that can cause a harm to inpatients. The main objective of the study was to compared medication errors in pharmacotherapeutic process before and after to carried out an intervention: to implant an automated dispensing cabine with to use Lean Six Sigma methodology. The secondary objective was to assess process performance, sigma level and defects per one million opportunities for medication error. METHODS: Quasi-experimental and randomized study carried out in a Thoracic Surgery Unit of a Spanish Hospital. A pharmaceutic recorded and assesed the medication errors detected during pre-intervention period (july-august 2017) and post-intervention period (march-april 2018). The steps analyzed were dispensing, storage and compounding/administration. The pharmacist observed a third of the medication dispensed, stored and compounded/administered during the study period. The observed medication was randomly selected using AleatorMetod.xls software. To perform the statistical analysis, Student's t test and Mann-Whitney U test were used to compare quantitative variables, and Chi-square test for qualitative variables. A significance level of p<0.05 was considered. RESULTS: The pharmaceutic recorded 4,538 drugs. After intervention, medication errors were decreased a 49% in total pharmacotherapeutic process (12.06% vs 6.15%; p<0.001). In addition, errors were decreased a 91.6% (4.27% vs 0.36%; p=0.004) in the step of medication storage; and a 75.8% (22.52% vs 5.46%; p<0.001) in the step of drugs compounding/administration. However, medication errors were increased in the step of medication dispensing (4.51% vs 15.29%; p<0.001). The process performance increased a 6% (87.9% vs 93.9%), sigma level increased from 2.67 to 3.04 and defects per one million opportunities for medication error decreased a 49%. CONCLUSIONS: To implant an automated dispensing cabinet with Lean Six Sigma methodology helps create a safer environment for the inpatient, reducing medication errors in the steps of storage and preparation/administration, as well as improving the total process performance and sigma level.

OBJETIVO: Los errores de medicación son un problema importante que pueden provocar un daño en los pacientes hospitalizados. El objetivo principal del estudio fue evaluar los errores de medicación en el circuito farmacoterapéutico antes y después de realizar una intervención: implantación de un Sistema Automatizado de Dispensación con la utilización de metodología Lean Seis Sigma. El objetivo secundario fue evaluar el rendimiento del proceso, el nivel sigma y los defectos por millón de oportunidades de error en la medicación. METODOS: Estudio cuasi-experimental y aleatorizado realizado en la Unidad de Cirugía Torácica de un Hospital Español. Un farmacéutico registró y evaluó los errores detectados durante las fases pre-intervención (julio-agosto 2017) y post-intervención (marzo-abril 2018). Las etapas analizadas fueron dispensación, almacenaje y preparación/administración. El farmacéutico observó un tercio de la medicación dispensada, almacenada y preparada/administrada durante el periodo de estudio. La medicación observada fue seleccionada de forma aleatoria utilizando el software AleatorMetod.xls. Para realizar el análisis estadístico se utilizó la prueba t de Student y el test U de Mann-Whitney para comparar variables cuantitativas y la prueba Chi-cuadrado para variables categóricas. Se consideró un nivel de significación de p<0,05. RESULTADOS: Se observaron 4.538 fármacos. Tras realizar la intervención, se redujeron un 49% los errores detectados durante el circuito farmacoterapéutico global (12,06% vs 6,15%; p<0,001). Además, se redujo un 91,6% (4,27% vs 0,36%; p=0,004) los errores en la etapa de almacenaje y un 75,8% (22,52% vs 5,46%; p<0,001) en la etapa de preparación/administración. Sin embargo, hubo un aumento en la etapa de dispensación (4,51% vs 15,29%; p<0,001). El rendimiento global se incrementó un 6% (87,9% vs 93,9%), el nivel de sigma aumentó de 2,67 a 3,04 y se redujeron un 49% de defectos por millón de oportunidades de error en la medicación. CONCLUSIONES: La implantación de Sistemas Automatizados de Dispensación con metodología Lean Seis Sigma ayuda a la creación de un entorno más seguro para el paciente, disminuyendo los errores de medicación en las etapas de almacenaje y preparación/administración, además de mejorar el rendimiento global del circuito.

Intervention by a clinical pharmacist carried out at discharge of elderly patients admitted to the internal medicine department: influence on readmissions and costs.

BACKGROUND: Patient education on pharmacological treatment could reduce readmissions. Our objective was to carry out a pharmacist intervention focused on providing information about high-risk medications to chronic patients and to analyse its influence on readmissions and costs. METHODS: A single-centre study with an intervention group and a retrospective control group was conducted. The intervention was carried out in all polymedicated patients ≥ 65 years who were admitted to internal medicine and signed the informed consent between June 2017 and February 2018. Patients discharged to nursing homes or long-term hospitals were excluded. The control group were all the patients who were admitted during the same months of 2014 who met the same inclusion criteria. The patients were classified according to the HOSPITAL score as having a low, intermediate, or high risk of potentially avoidable readmission. Outcome measures were 30-day readmission and cost data. To analyse the effect of the intervention on readmission, a logistic regression was performed. RESULTS: The study included 589 patients (286 intervention group; 303 control group). The readmission rate decreased from 20.13% to 16.43% in the intervention group [OR = 0.760 95% CI (0.495-1.166); p = 0.209)]. The incremental cost for the intervention to prevent one readmission was €3,091.19, and the net cost saving was €1,301.26. In the intermediate- and high-risk groups, readmissions were reduced 10.91% and 10.00%, and the net cost savings were €3,3143.15 and €3,248.71, respectively. CONCLUSIONS: The pharmacist intervention achieved savings in the number of readmissions, and the net cost savings were greater in patients with intermediate and high risks of potentially avoidable readmission according to the HOSPITAL score.

Impact of a Pharmaceutical Care Program at Discharge on Patients at High Risk of Readmission According to the Hospital Score.

Background: A significant percentage of hospital readmissions within 30 days of discharge are a result of avoidable drug-related problems. Stratifying patients according to readmission risk is key to pharmaceutical intervention (PI) design strategies to improve treatment outcomes. Objective: To assess whether a pharmaceutical care (PC) program at discharge in polymedicated patients at high potentially avoidable readmission (PAR) risk, according to the HOSPITAL score, improves 30-day readmission rate (30-dRR). Methods: This prospective controlled, quasi-experimental, 11-month study included 163 chronic polymedicated patients (>5 medications) at high PAR risk according to the HOSPITAL score. We calculated the 30-dRR and number of medication variations and Medication Regimen Complexity Index-E (MRCI-E) after PI. Results were compared with a retrospective cohort of chronic patients at high PAR risk. Results: The 30-dRR was 18.4% in the intervention group and 25.6% in the control group (odds ratio [OR] = 0.66; 95% CI = 0.38 to 1.14). Total medication reduction (-1.28; 95% CI = -1.88 to -0.68), number of high-risk medications in chronic patients (-0.58; 95% CI = -0.9 to -0.26), and MRCI-E (-6.42; 95% CI = -8.07 to -4.76) were statistically significant (P < .001). The number of medications at discharge was associated with an increased readmission risk (OR = 1.07; 95% CI = 1.01 to 1.14). Conclusions: The degree of polypharmacy and patients' treatment complexity after hospital discharge significantly reduced as a result of the PC program compared with the control group. This highlights the need for patient selection and prioritization strategies for implementing PIs focused on reducing polypharmacy and preventing drug-related problems that may cause PAR.

[Comparison of hospital consumption of immediate-release fentanyl: use or abuse?] / Comparación del consumo intrahospitalario de fentanilo de liberación inmediata en 2014 y 2017: ¿uso o abuso?

OBJECTIVE: Immediate-release fentanyl is indicated in the treatment of breakthrough pain in cancer patients who already receive opioids as background chronic analgesia. According to an alert issued by the Spanish Agency of Medicines, its consumption under non-authorized conditions has alarmingly increased in recent years, with a greater risk of abuse and dependence. The main objective of this study is to compare the off-label use of immediate-release fentanyl in our hospital during 2014 and 2017. METHODS: Retrospective cross-sectional descriptive study in which immediate-release fentanyl prescriptions were compared in adult patients admitted during 2014 and 2017 in a group 5 hospital. Variables were collected by the electronic medical record. The association study between qualitative variables was calculated using the χ2 test, and quantitative variables with the t-student test. RESULTS: In 2014, 0.43 immediate-release fentanyl prescriptions were made in our center for every 100 admissions, and in 2017 0.54/100 admissions. 22.1% (n=34) prescriptions were off-label in 2014, while in 2017 31.8% (n=76) (p=0.034). Both years, the most frequent off-label indications were healing of ulcers and wounds and non-cancer chronic pain. CONCLUSIONS: The use of immediate-release fentanyl in the hospital setting has considerably increased in comparison to 2014, as well as its off-label use.

OBJETIVO: El fentanilo de liberación inmediata está indicado en el tratamiento del dolor irruptivo en pacientes oncológicos que ya reciben opiáceos como analgesia de base crónica. Según una alerta emitida por la Agencia Española del Medicamento, su consumo en condiciones distintas a las autorizadas ha aumentado de manera alarmante en los últimos años, con mayor riesgo de que se produzca abuso y dependencia. El objetivo principal del estudio fue comparar el uso de fentanilo de liberación inmediata fuera de ficha técnica en pacientes hospitalizados en nuestro centro en 2014 y 2017. METODOS: Se realizó un estudio descriptivo transversal retrospectivo en el que se compararon las prescripciones de fentanilo de liberación inmediata en los pacientes adultos ingresados durante los años 2014 y 2017 en un hospital del grupo 5 (Hospital 12 de Octubre de Madrid). Las variables fueron recogidas mediante la historia clínica electrónica. El estudio de asociación entre las variables cualitativas se calculó mediante el test de la χ2, y las cuantitativas mediante la prueba de t-student. RESULTADOS: En 2014 se realizaron 0,43 prescripciones de fentanilo de liberación inmediata por cada 100 ingresos, y en 2017 0,54 por cada 100 ingresos. El 22,1% (n=34) de las prescripciones fueron fuera de ficha técnica en 2014, mientras que en 2017 resultaron el 31,8% (n=76) (p=0,034). Las indicaciones fuera de ficha técnica más frecuentes fueron la cura de úlceras y heridas, así como el tratamiento del dolor crónico no oncológico. CONCLUSIONES: El uso de fentanilo de liberación inmediata en el ámbito hospitalario sufre un aumento considerable en comparación con el año 2014, así como su uso fuera de las indicaciones autorizadas.

[Black precipitate in parenteral nutrition]. / Precipitado negro en nutrición parenteral.

INTRODUCTION: Introduction: a black precipitate was observed in the filter during the infusion of a parenteral nutrition without lipids. There are similar findings published in which copper and sulphur (from cysteine) were found in the composition of the precipitate. Objective: to determine if copper and cysteine are involved in the formation of the precipitate. Methods: samples of the parenteral nutrition solution were taken before and after its passage through the filter. Amino acids concentrations were analysed in both samples by ion exchange chromatography and post-column derivatization with ninhydrin in a Biochrom 30 device. Copper concentrations were measured by atomic absorption spectrometry in a PerkinElmer AAnalyst™ 200 device. Results: a decrease in cysteine concentration of 29.3% was found. The concentration of copper decreased by 75.9%. Conclusions: the decrease in the concentrations of cysteine and copper in the filtered solution suggest that both are involved in the formation of the black precipitate observed in the filter.

INTRODUCCIÓN: Introducción: durante la infusión de una nutrición parenteral sin lípidos se observó un precipitado negro en el filtro. Hay hallazgos similares publicados en los que se han detectado cobre y azufre (proveniente de la cisteína) en la composición del precipitado. Objetivo: comprobar que la cisteína y el cobre intervienen en la formación del precipitado. Métodos: se tomaron muestras de la solución de nutrición parenteral antes y después de su paso por el filtro. Se analizaron en ambas muestras las concentraciones de aminoácidos mediante cromatografía de intercambio iónico y derivatización post-columna con ninhidrina en un equipo Biochrom 30 y las de cobre mediante espectrometría de absorción atómica en un equipo PerkinElmer AAnalyst™ 200. Resultados: las concentraciones de cisteína y cobre en la solución disminuyeron en un 29,3% y 75,9%, respectivamente. Conclusiones: la disminución de las concentraciones de cisteína y cobre en la solución filtrada sugieren que ambos están involucrados en la formación del precipitado negro observado en el filtro.

Use of oral antineoplastic in special situations in a third level hospital: real life results.

OBJECTIVE: To analyse the effectiveness and safety of oral antineoplastic drugs  (ANEOs) that are authorized in special situations in a third-level hospital and to  compare the results obtained with the clinical evidence used for this  authorization. METHOD: Descriptive observational and retrospective study. We included all  adult patients who started treatment with ANEO in special situations during the  year 2016. We collected demographic, treatment-related and clinical variables  (overall survival (OS), progression-free survival (PFS)). Adverse reactions and  detected interactions were collected. An unadjusted comparison was made  between the results of the available evidence and those of the study patients. RESULTS: 34 patients were treated, 50% were men, the median age was 58  years (38-80) and they presented ECOG 1 in 64.7%. Most of the treated  patients were diagnosed with advanced colorectal cancer, treated with  trifluridine-tipiracil, followed by palbociclib in breast cancer, obtaining results  similar to those of the evidence. The median PFS was 2.8 months (95% CI 0.8- 4.8) and the 8-month SG (95% CI 3.4-12.5) for all patients. 26% of patients  required dose reduction because of treatment toxicity. We found 13 interactions,  which affected 15 patients, only two of category X. CONCLUSIONS: The effectiveness of ANEO in special situations in our center is  similar to that of available evidence. The impact on survival is low and adverse  effects are common.

Objetivo: Analizar la efectividad y seguridad de los antineoplásicos orales  (ANEO) autorizados en situaciones especiales en un hospital de tercer nivel y  comparar los resultados obtenidos con los de la evidencia disponible empleada  para autorizar el uso de estos fármacos.Método: Estudio descriptivo observacional y retrospectivo. Se incluyeron todos  los pacientes adultos que iniciaron tratamiento con ANEO en situaciones  especiales durante el año 2016. Se recogieron variables demográficas,  relacionadas con el tratamiento, y clínicas (supervivencia global (SG),  supervivencia libre de progresión (SLP)). Se recogieron reacciones adversas e  interacciones detectadas. Se realizó una comparación no ajustada entre los  resultados de la evidencia disponible y los de los pacientes del estudio.Resultados: Treinta y cuatro pacientes recibieron tratamiento, el 50% eran  hombres, la mediana de edad fue de 58 años (38-80), y presentaron ECOG 1 el  64,7%. La mayoría de los pacientes tratados presentaban diagnóstico de cáncer colorrectal avanzado, tratados con trifluridina-tipiracil, seguidos de  palbociclib en cáncer de mama, obteniendo resultados similares a los de la evidencia. La mediana de SLP fue de 2,8 meses (IC 95% 0,8-4,8) y la SG de 8  meses (IC 95% 3,4-12,5) para todos los pacientes. El 26% de los pacientes  requirieron una reducción de la dosis debido a la toxicidad del tratamiento. Se  encontraron 13 interacciones, que afectaron a 15 pacientes; solo dos de  categoría X.Conclusiones: La efectividad de los ANEO en situaciones especiales en nuestro  centro es similar al de la evidencia disponible. El impacto en la supervivencia es  bajo y los efectos adversos son comunes.

Subcutaneous versus intravenous administration of trastuzumab: preference of HER2+ breast cancer patients and financial impact of its use.

PURPOSE: To investigate the preference of HER2+ breast cancer patients and nursing professionals for subcutaneous (SC) versus intravenous (IV) trastuzumab and to evaluate the financial impact derived from the use of the SC formulation. METHODS: A cross-sectional questionnaire-based study was carried out to investigate preferences of all patients who started treatment with SC trastuzumab while they had received the IV formulation before. The preference of nursing staff in charge of preparation and administration was also analysed. The financial impact was evaluated considering the number of preparations of SC trastuzumab and the cost of IV and SC trastuzumab, the consumables used for preparation and administration and nursing staff time for preparation. RESULTS: 76 female patients were included, 84% completed the questionnaire. Of the patients, 94% declared to be satisfied with the SC route and 88% would prefer SC administration if they had to choose between IV and SC. Time saving was the main reason to justify satisfaction and preference (48 and 45% respectively). The most common adverse event related to SC trastuzumab was post-injection pain in the injection site, experienced by 77% of the patients. SC trastuzumab was preferred by 100% of the nursing staff. Total annual savings using SC formulation instead of the IV were 35.332€. CONCLUSIONS: SC trastuzumab is preferred by patients and the nursing staff versus the IV administration. The use of SC trastuzumab reduced the cost derived from trastuzumab administration.

[Use of leflunomide in a cytomegalovirus infection resistant: a report of a case]. / Uso de leflunomida en infección de citomegalovirus resistente: a propósito de un caso.

BACKGROUND AND OBJECTIVE: cytomegalovirus (CMV) infection is one of the most common complications in transplant patients, which can lead to multiple organ failure. The 80-90% of patients are cured with intravenous treatment standard (ganciclovir), or its oral prodrug (valganciclovir). In case there is no answer, we have alternatively another antiviral, foscarnet. A small number of patients do not respond to this, having a bad prognosis. The aim is to describe the case of a double lung transplant for cystic fibrosis, and recurrent CMV infection in which the use of leflunomide gets lower and even reach undetectable viral load. DESCRIPTION OF CASE: woman, 22 year old, double lung transplant for cystic fibrosis in March 2014. The CMV serology performed was positive in the donor and negative in the recipient. Controls viral load during prophylaxis with valganciclovir were negative in the receiver until the 6th month after transplantation, at which viral load was detected in controls (2 090 IU/ml). The patient was admitted to our hospital to receive intravenous treatment with ganciclovir, after one month with intravenous therapy viral load persisted positive (42 400 IU/ml). One study of resistance showed that was resistant to ganciclovir, so began treatment with intravenous foscarnet. This drug achieved negativizar viral load, so the treatment was discontinued, continuing with fortnightly controls viral load. After two months without treatment, viral load increased to 13 665 IU/ml, why was requested to Pharmacy Service the off-label use of leflunomide, with the intention that use oral therapy, instead of intravenous therapy. The patient was treated with valganciclovir until have the authorization of use of leflunomide, although unanswered, since in March 2015, at the start of leflunomide treatment the patient had a viral load of 17 344 IU/ml. The initial regimen was 100 mg of leflunomide daily for the first five days, followed by 20 mg every 12 hours. After fifteen days of treatment viral load had fallen to 531 IU/ml, becoming undetectable in one month. After four months of treatment the patient remains with undetectable viral load without having any adverse effect associated with it. CONCLUSION: our case is an example where the use of leflunomide in CMV infection resistant to other therapies is an effective and convenient alternative for patients because it keeps undetectable viral load with an oral therapy without having to enter the hospital for intravenous treatment.

Introducción: la infección por citomegalovirus (CMV) es una de las complicaciones más habituales en pacientes trasplantados, que puede desembocar en un fallo multiorgánico. El 80-90% de los pacientes se cura con el tratamiento estándar intravenoso (ganciclovir), o su profármaco oral (valganciclovir). En caso de no responder a ellos existe como alternativa otro antivírico, foscarnet. Un pequeño número de pacientes tampoco responden a este, teniendo un mal pronóstico. Objetivo: describir el caso de una paciente con trasplante bipulmonar por fibrosis quística y recidiva de infección por CMV en la cual el uso de leflunomida consigue disminuir e incluso llegar a niveles indetectables de la carga viral. Descripción del caso: mujer de 22 años, trasplantada bipulmonar por fibrosis quística en marzo del 2014. Las serologías de CMV realizadas fueron positivas en el donante y negativas en el receptor. Los controles de la carga viral durante la profilaxis con valganciclovir fueron negativos en el receptor hasta el sexto mes después del trasplante, momento en el que se detectó carga viral en los controles (2.090 UI/ml). La paciente ingresó en nuestro hospital para recibir tratamiento intravenoso con ganciclovir, persistiendo la carga viral positiva (42.400 UI/ml) al mes del inicio con esta terapia intravenosa. Un estudio de resistencias mostró que era resistente a ganciclovir, y por ello se inició tratamiento con foscarnet intravenoso. Con este fármaco se consiguió negativizar la carga viral, por lo que se suspendió el tratamiento, continuándose con controles quincenales de la carga viral. A los dos meses sin tratamiento se observó un aumento de la carga viral hasta 13.665 UI/ml, motivo por el cual se solicitó al Servicio de Farmacia el uso fuera de ficha técnica de leflunomida, con la intención de que la paciente recibiera terapia oral en lugar de intravenosa. La paciente fue tratada con valganciclovir hasta disponer de la autorización de uso de leflunomida, aunque sin respuesta, ya que en marzo del 2015, al inicio del tratamiento con leflunomida, la paciente presentaba una carga viral de 17.344 UI/ml. La pauta inicial fue de 100 mg de leflunomida al día durante los cinco primeros días, seguida de 20 mg cada 12 horas. A los quince días de tratamiento la carga viral había disminuido hasta 531 UI/ml, volviéndose indetectable antes del mes. Después de cuatro meses de tratamiento, la paciente mantiene la carga viral indetectable sin presentar ningún efecto adverso asociado al mismo. Conclusión: nuestro caso es un ejemplo en el que el uso de leflunomida en infección por CMV resistentes a otras terapias es una alternativa eficaz y conveniente para los pacientes, ya que mantiene indetectable la carga viral con una terapia oral, sin necesidad de ingresar en el hospital para tratamiento intravenoso.