Dosage of anti-PD-1 monoclonal antibodies: a cardinal open question

Discovery and clinical development of monoclonal antibodies with the ability to interfere in the regulation of the immune response have significantly changed the landscape of oncology in recent years. Among the active agents licensed by the regulatory agencies, nivolumab and pembrolizumab are paradigmatic as the most relevant ones according to the magnitude of available data derived from the extensive preclinical and clinical experience. Although in both cases the respective data sheets indicate well-defined dosage regimens, a review of the literature permits to verify the existence of many issues still unresolved about dosing the two agents, so it must be considered an open question of potentially important consequences, in which to work to improve the effectiveness and efficiency of use (AU)

Dosage of anti-PD-1 monoclonal antibodies: a cardinal open question.

Discovery and clinical development of monoclonal antibodies with the ability to interfere in the regulation of the immune response have significantly changed the landscape of oncology in recent years. Among the active agents licensed by the regulatory agencies, nivolumab and pembrolizumab are paradigmatic as the most relevant ones according to the magnitude of available data derived from the extensive preclinical and clinical experience. Although in both cases the respective data sheets indicate well-defined dosage regimens, a review of the literature permits to verify the existence of many issues still unresolved about dosing the two agents, so it must be considered an open question of potentially important consequences, in which to work to improve the effectiveness and efficiency of use.

Determining personalized treatment by gene expression profiling in metastatic breast carcinoma patients: a pilot study.

PURPOSE: The present study evaluates the massive study of gene expression in metastatic breast carcinoma (MBC) patients using microarray gene expression profiling (MAGE) complemented with conventional sequencing, immunohistochemistry (IHC) and fluorescent "in situ" hybridization (FISH), seeking to optimize the treatment in a subset of heavily pretreated patients and with limited life expectancy. PATIENTS, MATERIAL AND METHODS: MBC patients in hormone therapy progression with survival expectancy of at least 3 months (m) have been included. The MAGE contains gene probes representing genes known to potentially interact with available drugs as cited in the literature. RESULTS: Thirty-nine procedures were performed from October 2010 to April 2016. Within the 30 evaluable procedures, considering all hormonal manipulations as a single line, the patients had received a median of 4 treatment lines prior to MAGE (range 1-7). Progression was observed in 6 cases, stable disease (SD) in 7 cases and partial response (PR) in 16 cases, which implies a clinical benefit rate (SD + PR) of 76%. Actuarial median progression-free survival (PFS) was 6 m (95% CI 2.5-9.5) in patients with clinical benefit. The median overall survival (OS) for the entire series was 11 m (95% CI 2.2-19.8). CONCLUSION: Data presented here indicate that the use of MAGE provides relevant information to establish personalized treatment in frail patients with limited life expectancy in which therapeutic futility is a particularly difficult burden to assume.

[Influence of genetic polymorphisms in UGT1A1, UGT1A7 and UGT1A9 on the pharmacokynetics of irinotecan, SN-38 and SN-38G]. / Influencia de los polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre la farmacocinética de irinotecán, SN-38 y SN-38G.

OBJECTIVE: To evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. METHODS: Plasma concentrations of irinotecan, SN-38 and SN- 38G from 72 patients were pooled to develop a population pharmacokinetic model using NONMEM VII. M3 method was used to account for plasma concentrations below the limit quantification. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. The model was internally validated using normalized visual predictive check (NVPC) and normalized predictive distribution errors (NPDE). RESULTS: The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. The presence of UGT1A1*28, UGT1A7*3, UGT1A9*22 genotypes decreases SN-38 clearance between 20 and 36%. Internal validation confirms the population pharmacokinetic model describe the time course of irinotecan, SN-38 and SN-38G plasma concentration and their associated variability in cancer patients. CONCLUSION: The inclusion of pharmacokinetic-pharmacogenomic information can add value to the individualized dose adjustment of irinotecan, because it will let quantitatively handle dose reductions in patients with iatrogenic toxicity due to UGT1A1 genetic polymorphisms.

Objetivo: Evaluar la influencia de los polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre la farmacocinética poblacional de irinotecán y sus metabolitos, SN-38 y SN-38G. Metodología: Las concentraciones plasmáticas de irinotecán, SN-38 y SN-38G determinadas en 72 pacientes se utilizaron para desarrollar un modelo farmacocinético poblacional en el programa NONMEM VII. Se empleó el método M3 para incluir en el análisis las concentraciones por debajo del límite de cuantificación de la técnica analítica. Se evaluó el efecto de la edad, sexo, superficie corporal, bilirrubina total, medicación concomitante, tipo de tumor y polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre los parámetros farmacocineticos del modelo. La validación interna del modelo farmacocinético se realizó mediante normalized visual predictive check (NVPC) y normalized predictive distribution error (NPDE). Resultados: El valor medio (variabilidad interpaciente, %) del aclaramiento de irinotecán, SN-38 y SN-38G ha sido 42,9 (56,4%), 1340 (76,8%) y 188 L/h (70,1%), respectivamente. La presencia de alelos con baja actividad enzimática (UGT1A1*28, UGT1A7*3 y UGT1A9*22) redujo el aclaramiento de SN-38 entre un 20 y un 36%. La validación interna ha confirmado que el modelo farmacocinético poblacional resulta adecuado para describir la evolución temporal de las concentraciones plasmáticas de irinotecán, SN-38 y SN-38G y su variabilidad en pacientes oncológicos. Conclusión: La inclusión de información farmacocinética-farmacogenética puede añadir valor a la personalización de la dosificación de irinotecán por cuanto que permitirá manejar cuantitativamente las reducciones de dosis en pacientes con toxicidad iatrogénica debido a los polimorfismos genéticos en UGT1A1.

Influencia de los polimorfismos genéticos enUGT1A1, UGT1A7 y UGT1A9 sobre la farmacocinética de irinotecán, SN-38 y SN-38G / Influence of genetic polymorphisms in UGT1A1, UGT1A7 and UGT1A9 on the pharmacokynetics of irinotecan, SN-38 and SN-38G

Objetivo: Evaluar la influencia de los polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre la farmacocinética poblacional de irinotecán y sus metabolitos, SN-38 y SN-38G. Metodología: Las concentraciones plasmáticas de irinotecán, SN-38 y SN-38G determinadas en 72 pacientes se utilizaron para desarrollar un modelo farmacocinético poblacional en el programa NONMEM VII. Se empleó el método M3 para incluir en el análisis las concentraciones por debajo del límite de cuantificación de la técnica analítica. Se evaluó el efecto de la edad, sexo, superficie corporal, bilirrubina total, medicación concomitante, tipo de tumor y polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre los parámetros farmacocineticos del modelo. La validación interna del modelo farmacocinético se realizó mediante normalized visual predictive check(NVPC) y normalized predictive distribution error (NPDE). Resultados: El valor medio (variabilidad interpaciente, %) del aclaramiento de irinotecán, SN-38 y SN-38G ha sido 42,9 (56,4%), 1340 (76,8%) y 188 L/h (70,1%), respectivamente. La presencia de alelos con baja actividad enzimática (UGT1A1*28, UGT1A7*3 y UGT1A9*22) redujo el aclaramiento de SN-38 entre un 20 y un 36%. La validación interna ha confirmado que el modelo farmacocinético poblacional resulta adecuado para describir la evolución temporal de las concentraciones plasmáticas de irinotecán, SN-38 y SN-38G y su variabilidad en pacientes oncológicos. Conclusión: La inclusión de información farmacocinética-farmacogenética puede añadir valor a la personalización de la dosificación de irinotecán por cuanto que permitirá manejar cuantitativamente las reducciones de dosis en pacientes con toxicidad iatrogénica debido a los polimorfismos genéticos en UGT1A1 (AU)

Objective: To evaluate the Influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. Methods: Plasma concentrations of irinotecan, SN-38 and SN-38G from 72 patients were pooled to develop a population pharmacokinetic model using NONMEM VII. M3 method was used to account for plasma concentrations below the limit quantification. The effect of age, sex, body surface area, total bilirubin, comedication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. The model was internally validated using normalized visual predictive check (NVPC) and normalized predictive distribution errors (NPDE). Results: The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. The presence of UGT1A1*28, UGT1A7*3, UGT1A9*22 genotypes decreases SN-38 clearance between 20 and 36%. Internal validation confirms the population pharmacokinetic model describe the time course of irinotecan, SN-38 and SN-38G plasma concentration and their associated variability in cancer patients. Conclusion: The inclusion of pharmacokinetic-pharmacogenomic information can add value to the individualized dose adjustment of irinotecan, because it will let quantitatively handle dose reductions in patients with iatrogenic toxicity due to UGTIAVs genetic polymorphisms (AU)

Epidermal growth factor receptor (EGFR) mutations in a series of non-small-cell lung cancer (NSCLC) patients and response rate to EGFR-specific tyrosine kinase inhibitors (TKIs).

INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes.

Epidermal growth factor receptor (EGFR) mutations in a series of non-small-cell lung cancer (NSCLC) patients and response rate to EGFR-specific tyrosine kinase inhibitors (TKIs)

INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes (AU)

A novel EGFR nonsense mutation in a non-small-cell lung cancer (NSCLC) patient who did not derive any clinical benefit with combination chemotherapy and erlotinib.

Most of the somatic epidermal growth factor receptor (EGFR) mutations described to date in non-smallcell lung cancer (NSCLC) patients are located in the kinase domain and are considered activating mutations. Some of these mutations are associated with response to specific EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib. Here we report a case of a previously undescribed EGFR nonsense mutation in a lung adenocarcinoma patient who did not derive any clinical benefit with combination chemotherapy and erlotinib. To the best of our knowledge this is the second report in the literature describing an EGFR nonsense mutation in lung cancer patients.

A novel EGFR nonsense mutation in a non-small-cell lung cancer (NSCLC) patient who did not derive any clinical benefit with combination chemotherapy and erlotinib

Most of the somatic epidermal growth factor receptor (EGFR) mutations described to date in non-smallcell lung cancer (NSCLC) patients are located in the kinase domain and are considered activating mutations. Some of these mutations are associated with response to specific EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib. Here we report a case of a previously undescribed EGFR nonsense mutation in a lung adenocarcinoma patient who did not derive any clinical benefit with combination chemotherapy and erlotinib. To the best of our knowledge this is the second report in the literature describing an EGFR nonsense mutation in lung cancer patients (AU)

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[Can or should blood pressure be measured at pharmacy offices?]. / ¿Se puede o debe medir la presión arterial en las oficinas de farmacia?

OBJECTIVE: To evaluate concordance between blood-pressure (BP) measurements at the pharmacy office (PhO) and the nurse office (NO) in the health care centre (HCC). DESIGN: Descriptive study. SETTING: Community. METHODS: 36 PhO have voluntarily participated in the province of Albacete, where they have done 3 BP measures, without previous instructions and with their usual measurements devices, for 3-5 subjects, who were referred to their HCC so that they were taken another 3 BP measures in the NO with their Hg sphymomanometer and in their usual measure conditions (blind measures in relation to those taken at the PhO). These subjects were given a stamped envelope to send the BP measurements (taken at the NO), to the Official Pharmacy College. RESULTS: The 6 BP measurements have been completed to 96 subjects with an average of 57.3 years old (women 63%). The differences between PhO and NO were > 5 mmHg in 58 subjects (60.4%) in the case of SBP and in 45 subjects (46.9%) in the case of DBP, and it was more than 15 mmHg in the 17 subjects (17.7%) with SBP and in 9 subjects (9.4%) with DBP. The difference average was 9.5 mmHg (SD, 8.4 mmHg) and 6.4 mmHg (SD, 5.3 mmHg) respectively. The use rate of digit 0 was 22% at the PhO and 46.5% at the NO. In most of PhO, measurement electronic devices have been used for the BP, but not validated for clinical use. CONCLUSIONS: The PhO can be a good place for the hypertension screening, but the chemist must be trained in the BP correct measurement and use validated electronic devices. Standardization measurement conditions and the use of validated electronic devices must be extended to the NO.

¿Se puede o debe medir la presión arterial en las oficinas de farmacia? / Can blood pressure be measured or not in pharmacy offices?

Objetivo. Evaluar la concordancia entre las medidas de la presión arterial (PA) de la oficina de farmacia (OF) y la consulta de enfermería (CE) del centro de salud (CS).Diseño. Estudio descriptivo. Emplazamiento. Marco comunitario. Métodos. De forma voluntaria han participado 36 OF de la provincia de Albacete en las que han realizado 3 medidas de PA, sin instrucciones previas y con sus aparatos de medida habituales, a 3-5 sujetos que posteriormente acudían a sus CS para que en la CE les llevaran a cabo otras 3 mediciones de PA con sus esfigmomanómetros de mercurio y en sus condiciones habituales de medida (medición ciega respecto de las realizadas en la OF). A los sujetos se les entregaba un sobre franqueado para remitir las medidas de PA de la CE al colegio de farmacéuticos. Resultados. Se han completado las 6 medidas de PA a 96 sujetos con una edad media de 57,3 años (63 por ciento mujeres). Las diferencias entre la OF y la CE fueron > 5 mmHg en 58 sujetos (60,4 por ciento) en el caso de la PAS y en 45 sujetos (46,9 por ciento) en el caso de la PAD, y llegaron a ser de más de 15 mmHg en 17 sujetos (17,7 por ciento) en la PAS y en 9 sujetos (9,4 por ciento) en la PAD. La media de las diferencias fue de 9,5 mmHg (DE, 8,4 mmHg) y de 6,4 mmHg (DE, 5,3 mmHg), respectivamente. La proporción de utilización del dígito 0 fue del 22 por ciento en la OF y del 46,5 por ciento en la CE. En la mayoría de las OF se han utilizado dispositivos electrónicos de medida de la PA, pero no validados para uso clínico. Conclusiones. La OF puede ser un buen lugar para el cribado de la HTA, pero el farmacéutico/a debe estar entrenado en la medida correcta de la PA y utilizar aparatos electrónicos validados. La estandarización en las condiciones de medida y el uso de aparatos electrónicos validados se debe hacer extensible a la CE (AU)

Automedidas domiciliarias de presión arterial y su relación con el diagnóstico de la hipertensión arterial y con la afección orgánica: estudio comparativo con monitorización ambulatoria / Home self-measurements of blood pressure and relationship with diagnosis of hypertension and target organ damage: comparative study with ambulatory monitoring

FUNDAMENTO: El diagnóstico de la hipertensión arterial (HTA) requiere una metodología de la medición exacta y precisa. Las técnicas clásicas sobrestiman con frecuencia su prevalencia y no se relacionan bien con la repercusión orgánica. El objetivo de este trabajo es conocer la asociación entre la automedición domiciliaria de la presión arterial y la afección orgánica de la HTA. PACIENTES Y MÉTODO: Estudio descriptivo en el cual se comparaba la asociación de diferentes técnicas de medida de la presión arterial (PA) con el diagnóstico de HTA y su repercusión orgánica. Mediante muestreo de selección de casos consecutivos, se seleccionaron 64 pacientes con HTA no tratados mayores de 18 años. A todos se les realizaron tres mediciones de PA con esfigmomanómetro de mercurio en la consulta y se les adiestró para hacer 20 automedidas por la mañana en la consulta y 20 automedidas por la tarde en su domicilio con un aparato automático Omron 705CP. El mismo día se realizó una monitorización ambulatoria de la PA (MAPA) de 24 h con un dispositivo Takeda TM-2420; además, se realizó visualización del fondo de ojo, determinación de microalbuminuria y ecocardiografía. RESULTADOS: Los valores medios de las presiones clínicas fueron significativamente superiores a los de las automedidas domiciliarias y a los de la MAPA, que tenían una buena correlación y concordancia entre sí. La correlación de las automedidas domiciliarias con el índice de masa ventricular izquierda (IMVI) fue significativamente superior a la de las presiones arteriales clínicas y similar a la de la MAPA, siendo esta correlación independiente de la edad, el sexo y el índice de masa corporal de los sujetos. La mejor correlación de las automedidas domiciliarias de PA con la MAPA y con el IMVI se obtuvo con los valores medios de la segunda a la sexta automedida. CONCLUSIONES: Un programa mínimo de automedidas domiciliarias de PA con aparatos automáticos obtiene un valor pronóstico y de relación con la afección orgánica de la HTA similar al de la MAPA (AU)

[Home self-measurements of blood pressure and relationship with diagnosis of hypertension and target organ damage: comparative study with ambulatory monitoring]. / Automedidas domiciliarias de presión arterial y su relación con el diagnóstico de la hipertensión arterial y con la afección orgánica: estudio comparativo con monitorización ambulatoria.

BACKGROUND: The diagnosis of arterial of hypertension (AH) requires an accurate and precise measurement methodology. The habitual techniques overstimate the prevalence of AH and have a poor correlation with organ damage. The objective of the study is to know the associations between self-measurements of blood pressure (BP) at home and target organ damage of AH. PATIENTS AND METHOD: Descriptive study which compare the association of different techniques of BP measurement with the diagnosis of AH and its organ damage. Sampling selection of consecutive cases; we select 64 cases of hypertensives not treated hypertensive patients, older than 18 years. We achieved 3 BP measurements with mercury sphygmomanometer in the office and 20 self-measurements in the morning in the office and 20 self-measurements in the afternon at home with a automatic validated device, Omron 705CP; the same day BP was measured with ambulatory blood pressure measurement (ABPM) of 24 h with a Takeda TM-2420 device; we achieved eye fundus study, microalbuminuria analysis and echocardiogram. RESULTS: Mean values of office BP was higher than self-measurements at home and ABPM; these techniques had good correlations and concordance between them. The correlation of selfmeasurements at home with LVMI was higher than office BP and similar to ABPM; this correlation is independent of age, sex and body mass index. The best correlation of self-measurements at home with APBM and LVMI was with the mean values of 2nd-6th self-measurements. CONCLUSIONS: A minimum program of self-measurements of BP at home with automatic devices has a prognostic value and relationship with organ damage of AH similar to ABPM.

[Idiopathic retroperitoneal fibrosis. An atypical case of multisystem presentation]. / Fibrosis retroperitoneal idiopática. Un caso atípico de presentación multisistémica.

Idiopathic retroperitoneal fibrosis (IRF) is a disease difficult to diagnose. It is considered by different authors of autoimmune origin given its similarity to other connective tissue diseases. We present the case of a female patient diagnosed by a postmortem study, of IRF with multiorgan involvement (lymph nodes, serose tissue, liver, spleen, adrenal glands, thyroid and kidneys) and atypical presentation, not finding other similar cases in the national literature.