ABSTRACT
Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade. We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-ß. Increases in IFNγ concentrations in the tissue culture supernatants were detected upon in-culture activation with the anti-CD137 and anti-PD-1 mAb combinations or concanavalin A as a positive control. No other cytokine from a wide array was informative of stimulation with these mAbs. Interestingly, increases in Ki67 and other activation markers were substantiated in lymphocytes from cell suspensions gathered at the end of 72 h cultures. In mice bearing bilateral tumors in which one was excised prior to in vivo anti-CD137 + anti-PD-1 treatment to perform the fragment culture evaluation, no association was found between IFNγ production from the fragments and the in vivo therapeutic outcome in the non-resected contralateral tumors. The experimental system permitted freezing and thawing of the fragments with similar functional outcomes. Using a series of patient-derived tumor fragments from excised solid malignancies, we showed IFNγ production in a fraction of the studied cases, that was conserved in frozen/thawed fragments. The small tumor fragment culture technique seems suitable to preclinically explore immunotherapy combinations.
Subject(s)
Immunotherapy , Tumor Necrosis Factor Receptor Superfamily, Member 9 , Animals , Tumor Necrosis Factor Receptor Superfamily, Member 9/agonists , Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism , Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology , Mice , Humans , Immunotherapy/methods , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/immunology , Female , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/drug therapy , Neoplasms/pathology , Interferon-gamma/metabolism , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Tumor Cells, Cultured , Mice, Inbred C57BL , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic useABSTRACT
OBJECTIVES: Studying the psychosocial sphere of patients who undergo any treatment allows to have more information about its repercussion and can help the choice of an appropriate and personalized treatment. Due to the absence of specific instruments at present, the objective is to design and validate a health questionnaire regarding the treatment received with ESWL. METHODS: It was carried out in 6 phases using a sampleof 50 patients treated with ESWL in 2015 in ourcenter, whom we interviewed by telephone. In phase1 the items were proposed based on bibliographic review,in phase 2 those that scored below 7 were eliminatedaccording to the evaluation from 0 to 10 on theitems made by specialists. In phase 3, values of 1 to 5were assigned to each item and those with correctedcorrelation more than 0.2 and not significant (p>0.05)discriminant power with U-Mann Whitney were eliminated.In phase 4 the reliability of the questionnaire waschecked with two indexes (Cronbach's alpha and twoGuttman's halves). In phase 5, the factor analysis withVarimax rotation was performed to calculate the constructvalidity and in stage 6, the scores were analyzedto establish reference values. RESULTS: 50 patients (32 men, 18 women). Medianage 59 years (27-79). In phase 1, 35 items were proposed,9 of which were eliminated in phase 2. The initialquestionnaire with 26 items was distributed, with 18being eliminated in phase 3. The final questionnaire wasformed with 8 items. In phase 4 the results of Cronbach'salpha and Guttman's two halves index were 0.44 and0.323 respectively. In phase 5 after factor analysis, wefound 4 factors with 2 items each (background, impactof the acute picture, post-treatment, quality of life) able toexplain 71.19% of the variance. The median scores ofthe scale, extreme values and quartiles studied in phase6 were respectively: P50: 17 (minimum-maximum 9-25),P25: 14 and P75: 20. CONCLUSIONS: The study carried out has provided anew instrument for assessing satisfaction after treatmentwith ESWL with adequate reliability and validity values.Future studies will be necessary to contrast its true clinicalusefulness.
OBJETIVO: Estudiar la esfera psicosocial de los pacientes que se someten a algún tratamiento permite tener más información sobre la repercusión del mismo y puede ayudar a la elección de un tratamiento adecuado y personalizado. Debido a la ausencia deinstrumentos específicos actualmente, el objetivo es diseñary validar un cuestionario de salud en pacientes tratados con LEOC.MATERIAL Y MÉTODOS: Se realizó en 6 fases utilizando una muestra de 50 pacientes tratados con LEOC en 2015 en nuestro centro, a los que entrevistamos por vía telefónica. En la fase 1 se propusieron ítems a partir de revisión bibliográfica. En la fase 2 se eliminaron losque puntuaban por debajo de 7 según la valoración de 0-10 sobre los ítems efectuada por especialistas en la materia. En la fase 3 se asignaron valores de 1 a 5 a cada ítem y se eliminaron aquellos cuya correlación corregida fuera mayor de 0,2 y cuya potencia discriminante con U-Mann Whitney no fuera significativa (p>0,05). En la fase 4 se comprobó la fiabilidad del cuestionario con dos índices (alfa de Cronbach y dos mitades de Guttman). En la fase 5 se realizó el análisis factorial con rotación Varimax para el cálculo de la validez de constructo. Finalmente, en la fase 6 se tipificaron de las puntuaciones para establecer valores de referencia. RESULTADOS: 50 pacientes (32 hombres, 18 mujeres). Mediana edad 59 años (27-79). Fase 1: 35 ítems propuestos. Fase 2: 9 ítems eliminados. Distribución de cuestionario con 26 ítems. Fase 3: 18 ítems eliminados.Cuestionario final constituido por 8 ítems. Fase 4: valores de fiabilidad del cuestionario (alfa de Cronbach 0,44 e índice por técnica de dos mitades de Guttman 0,323). Fase 5: análisis factorial hallando 4 factores con 2 ítems cada uno (antecedentes, repercusión delcuadro agudo, post-tratamiento, calidad de vida) capaces de explicar el 71,19% de la varianza. Fase 6: mediana puntuación 50:17(mínimo-máximo 9-25), P25:14 y P75:20. CONCLUSIONES: El trabajo realizado ha proporcionado un nuevo instrumento de evaluación de salud tras tratamiento con LEOC con valores de fiabilidad y validez adecuados. Serán necesarios futuros estudios para contrastar su verdadera utilidad clínica.
Subject(s)
Lithotripsy , Urolithiasis , Female , Humans , Male , Personal Satisfaction , Quality of Life , Reproducibility of Results , Surveys and Questionnaires , Urolithiasis/therapyABSTRACT
Objetivo: Estudiar la esfera psicosocial de los pacientes que se someten a algún tratamiento permite tener más información sobre la repercusión del mismo y puede ayudar a la elección de un tratamiento adecuado y personalizado. Debido a la ausencia de instrumentos específicos actualmente, el objetivo es diseñar y validar un cuestionario de salud en pacientes tratados con LEOC. Material y métodos: Se realizó en 6 fases utilizando una muestra de 50 pacientes tratados con LEOC en 2015 en nuestro centro, a los que entrevistamos por vía telefónica. En la fase 1 se propusieron ítems a partir de revisión bibliográfica. En la fase 2 se eliminaron los que puntuaban por debajo de 7 según la valoración de 0-10 sobre los ítems efectuada por especialistas en la materia. En la fase 3 se asignaron valores de 1 a 5 a cada ítem y se eliminaron aquellos cuya correlación corregida fuera mayor de 0,2 y cuya potencia discriminante con U-Mann Whitney no fuera significativa (p>0,05). En la fase 4 se comprobó la fiabilidad del cuestionario con dos índices (alfa de Cronbach y dos mitades de Guttman). En la fase 5 se realizó el análisis factorial con rotación Varimax para el cálculo de la validez de constructo. Finalmente, en la fase 6 se tipificaron de las puntuaciones para establecer valores de referencia. Resultados: 50 pacientes (32 hombres, 18 mujeres). Mediana edad 59 años (27-79). Fase 1: 35 ítems propuestos. Fase 2: 9 ítems eliminados. Distribución de cuestionario con 26 ítems. Fase 3: 18 ítems eliminados. Cuestionario final constituido por 8 ítems. Fase 4: valores de fiabilidad del cuestionario (alfa de Cronbach 0,44 e índice por técnica de dos mitades de Guttman 0,323). Fase 5: análisis factorial hallando 4 factores con 2 ítems cada uno (antecedentes, repercusión del cuadro agudo, post-tratamiento, calidad de vida) capaces de explicar el 71,19% de la varianza. Fase 6: mediana puntuación 50:17(mínimo-máximo 9-25), P25:14 y P75:20. Conclusiones: El trabajo realizado ha proporcionado un nuevo instrumento de evaluación de salud tras tratamiento con LEOC con valores de fiabilidad y validez adecuados. Serán necesarios futuros estudios para contrastar su verdadera utilidad clínica
Objectives: Studying the psychosocial sphere of patients who undergo any treatment allows to have more information about its repercussion and can help the choice of an appropriate and personalized treatment. Due to the absence of specific instruments at present, the objective is to design and validate a health questionnaire regarding the treatment received with ESWL. Methods: It was carried out in 6 phases using a sample of 50 patients treated with ESWL in 2015 in our center, whom we interviewed by telephone. In phase 1 the items were proposed based on bibliographic review, in phase 2 those that scored below 7 were eliminated according to the evaluation from 0 to 10 on the items made by specialists. In phase 3, values of 1 to 5 were assigned to each item and those with corrected correlation more than 0.2 and not significant (p>0.05) discriminant power with U-Mann Whitney were eliminated. In phase 4 the reliability of the questionnaire was checked with two indexes (Cronbachs alpha and two Guttman's halves). In phase 5, the factor analysis with Varimax rotation was performed to calculate the construct validity and in stage 6, the scores were analyzed to establish reference values. Results: 50 patients (32 men, 18 women). Median age 59 years (27-79). In phase 1, 35 items were proposed, 9 of which were eliminated in phase 2. The initial questionnaire with 26 items was distributed, with 18 being eliminated in phase 3. The final questionnaire was formed with 8 items. In phase 4 the results of Cronbachs alpha and Guttmans two halves index were 0.44 and 0.323 respectively. In phase 5 after factor analysis, we found 4 factors with 2 items each (background, impact of the acute picture, post-treatment, quality of life) able to explain 71.19% of the variance. The median scores of the scale, extreme values and quartiles studied in phase 6 were respectively: P50: 17 (minimum-maximum 9-25), P25: 14 and P75: 20. Conclusions: The study carried out has provided a new instrument for assessing satisfaction after treatment with ESWL with adequate reliability and validity values. Future studies will be necessary to contrast its true clinical usefulness
