Relevance of internal time and circadian robustness for cancer patients

International audienceAbstractBackgroundAdequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing.MethodsTwenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period.ResultsThree circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study.ConclusionsThe integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers

Teaching biological rhythms in endocrinology: cortisol and wrist temperature. Póster

This work has been developed as part of the Endocrinology and Metabolism student’s laboratory formation from Biology degree at the University of Murcia. Endocrinology and Metabolism is an elective oneterm course that is taught in the fourth year (4.5 ECTS) for "Biosanitary and Biotechnology" intensification. The course focuses on the study of global and intermediary human metabolism and hormonal regulation, both under normal and special situations. It is our objective to get undergraduate students of Endocrinology and Metabolism with the importance of hormonal diurnal fluctuations in endocrine systems through their involvement in an innovative research program. In addition, with the participation of PhD student in this program, we try to improve their skills in innovative teaching. In humans cortisol circadian rhythm peaks in the morning and shows the lowest levels during the midnight. This fluctuation of cortisol plasma level is reflected in saliva, allowing a simple, non invasive and unstressful sample collection. The influence of different factors, exercise, schedule and weekend shifts, on the rhythmic pattern of cortisol has been studied along various years.Campus Mare Nostrum, Universidad Politécnica de Cartagena, Universidad de Murcia, Región de Murci

A New Integrated Variable Based on Thermometry, Actimetry and Body Position (TAP) to Evaluate Circadian System Status in Humans

The disruption of the circadian system in humans has been associated with the development of chronic illnesses and the worsening of pre-existing pathologies. Therefore, the assessment of human circadian system function under free living conditions using non-invasive techniques needs further research. Traditionally, overt rhythms such as activity and body temperature have been analyzed separately; however, a comprehensive index could reduce individual recording artifacts. Thus, a new variable (TAP), based on the integrated analysis of three simultaneous recordings: skin wrist temperature (T), motor activity (A) and body position (P) has been developed. Furthermore, we also tested the reliability of a single numerical index, the Circadian Function Index (CFI), to determine the circadian robustness. An actimeter and a temperature sensor were placed on the arm and wrist of the non-dominant hand, respectively, of 49 healthy young volunteers for a period of one week. T, A and P values were normalized for each subject. A non-parametric analysis was applied to both TAP and the separate variables to calculate their interdaily stability, intradaily variability and relative amplitude, and these values were then used for the CFI calculation. Modeling analyses were performed in order to determine TAP and CFI reliability. Each variable (T, A, P or TAP) was independently correlated with rest-activity logs kept by the volunteers. The highest correlation (r = −0.993, p<0.0001), along with highest specificity (0.870), sensitivity (0.740) and accuracy (0.904), were obtained when rest-activity records were compared to TAP. Furthermore, the CFI proved to be very sensitive to changes in circadian robustness. Our results demonstrate that the integrated TAP variable and the CFI calculation are powerful methods to assess circadian system status, improving sensitivity, specificity and accuracy in differentiating activity from rest over the analysis of wrist temperature, body position or activity alone

Evaluación ambulatoria del estatus funcional del sistema circadiano humano= Ambulatory assessment of the functional status of the human circadian system

OBJETIVOS Esta tesis pretende desarrollar una herramienta de fácil aplicación, fiable, consistente y no invasiva que sea capaz de evaluar el estatus del sistema circadiano. Para conseguir este objetivo, se plantearon los siguientes objetivos específicos: 1. Crear un algoritmo para la evaluación ambulatoria y no invasiva del sistema circadiano mediante la integración de los ritmos de temperatura periférica, actividad motora y posición corporal en la variable compuesta TAP. 2. Validar la variable integrada TAP para la detección de sueño y vigilia en comparación con el gold standard para este propósito, la polisomnografía. Además, se pretende comprobar si TAP mejora la detección de sueño con respecto a las estimaciones obtenidas mediante la actigrafía convencional. 3. Transferir la utilidad de TAP, implementada en un dispositivo de registro ambulatorio en una patente internacional. 4. Evaluar la validez de la variable TAP para la detección de alteraciones circadianas en condiciones patológicas: 4.1. Revisar los conocimientos previos sobre cáncer y ritmos circadianos, prestando especial atención a los tratamientos que tienen en cuenta el sistema circadiano. 4.2. Estudiar las diferencias interindividuales del ritmo de actividad-reposo que podrían potencialmente afectar el resultado del tratamiento en pacientes de cáncer. 4.3. Evaluar cómo los tratamientos cronomodulados afectan la sincronización interna de diferentes ritmos circadianos en pacientes de cáncer. 4.4. Evaluar las perturbaciones circadianas de sujetos con deterioro cognitivo leve con el fin de establecer la utilidad de la variable TAP para evaluar objetivamente la progresión de la enfermedad. METODOLOGÍA En esta tesis, se evaluaron tres ritmos y procesaron con el fin de obtener la variable TAP que después se aplicó en varias condiciones de salud y enfermedad. Ritmo de temperatura Este ritmo se evaluó mediante un sensor de temperatura (Thermochron iButton DS1921H, Dallas, Maxim) cosido a una muñequera de modo que la superficie del sensor quedara en contacto con la arteria radial de la muñeca de la mano no dominante. Ritmo de actividad motora y posición corporal Estos ritmos se evaluaron gracias a un actímetro (Hobo Pendant G Acceleration Data Logger, Massachusetts, USA) colocado en el brazo no dominante mediante un brazalete deportivo. De la información proporcionada por el actímetro, se definieron 2 variables: actividad motora, expresada como grados de cambio de posición y posición corporal, definida como el ángulo entre el eje X y el plano horizontal. Procesamiento de los datos Cada variable se normalizó entre 0 y 1 después de haber eliminado los artefactos mediante inspección visual de los datos. Además, los datos de temperatura se invirtieron de modo que los valores máximos de todas las variables coincidieran en el mismo momento. Después, calculamos la media de las variables normalizadas para cada sujeto obteniendo la variable TAP cuyos valores varían entre 0 (para periodos de reposo) y 1 (para periodos activos). CONCLUSIÓN GENERAL La monitorización circadiana ambulatoria, no invasiva y fiable del estado funcional del sistema circadiano humano es un procedimiento muy útil para la prognosis de ciertas enfermedades como cáncer, deterioro cognitivo leve y perturbaciones del sueño. La monitorización conjunta y la integración de varias salidas del reloj biológico mejora la consistencia de los resultados y facilita la evaluación de la desincronización interna entre diferentes variables rítmicas. De este modo, la variable TAP, basada en la integración de los ritmos de Temperatura periférica, Actividad motora y Posición corporal, ha superado las premisas de alta fiabilidad, aceptación y versatilidad para el estudio ambulatorio y prolongado del estado del sistema circadiano humano en muy distintas situaciones de salud y enfermedad. Además, ha sido posible implementar este algoritmo en un dispositivo bajo patente internacional. OBJECTIVES This thesis aims to develop a reliable, consistent, non-invasive and easily applied tool based on multivariable recordings, able to depict circadian system status and circadian rhythmic synchrony in humans. In order to pursue this final goal, the following specific objectives were determined: 1. To create a multivariable tool able to reliably and non-invasively ambulatory assess the circadian system status by integrating wrist temperature, motor activity and body position rhythms into the composite TAP variable. 2. To validate this integrated variable for sleep and wake detection against the gold standard for this purpose, the polysomnography and test if TAP improves the detection from that obtained with actigraphy alone. 3. To test the validity of TAP variable in specific pathological conditions with known circadian impairments: 3.1. To review, the previous knowledge on cancer and circadian rhythms, as well as circadian-based treatments for this disease. 3.2. To study the inter-individual differences in rest-activity rhythm, that could potentially affect treatment outcome, in colorectal cancer patients. 3.3. To assess how chronomodulated treatment affects internal synchronization on cancer patients by multivariable recordings. 3.4. To evaluate circadian disturbances in mild cognitively impaired subjects, a previous condition to Alzheimer’s Disease, in order to establish its potential usefulness to objectively assess the disease progression. 4. To transfer the usefulness of TAP implemented in an ambulatory monitoring device for its clinical application and its potential commercialization by an international patent. METHODOLOGY In these PhD, three rhythms were recorded and processed as to obtain an integrated variable TAP in several conditions of health and disease. Temperature rhythm The wrist temperature rhythm was assessed using a temperature sensor (Thermochron iButton DS1921H, Dallas, Maxim) attached to a double-sided cotton sport wrist band, and the sensor surface was placed over the inside of the wrist on the radial artery of the non-dominant hand. Body position and rest-activity rhythm The body position and rest-activity rhythm was assessed using an actimeter (Hobo Pendant G Acceleration Data Logger, Massachusetts, USA) placed on the non-dominant arm by means of a sports band, with its X-axis parallel to the humerus bone. From the information provided by the actimeter, we defined 2 variables: motor activity (A) and body position (P). Motor activity was expressed as degrees of change in position. Body position was calculated as the angle between the X-axis of the actimeter and a horizontal plane. Thus, P oscillated between 0º for maximum horizontality and 90º for maximum verticality. Data processing Each variable was normalized between 0 and 1, after removing artifacts identified by visual inspection of the data. In addition, wrist temperature data were inverted in such a way that maximum values for all variables occurred at the same time. We then calculated the mean of the normalized variables for each subject, obtaining TAP values which range between 0 (for rest periods) and 1 (for active periods). GENERAL CONCLUSION The reliable ambulatory monitoring of circadian system in humans has proven very relevant for disease prognosis in such conditions as cancer, mild cognitive impairments and sleep disturbances. The joint recording and following integration of several clock outputs increase results’ consistency as isolated variable artifacts are minimized by the integration of several variables and enables the calculation of internal desynchronization among different rhythmic variables. TAP, integration of wrist Temperature, motor Activity and body Position rhythms, has supported the premises of high reliability, acceptance and versatility for the long-period ambulatory study of human circadian system status under several conditions of health and disease. Thus, these positive results have facilitated the implementation of TAP’s algorithm in a new device for ambulatory monitoring and registered in an international patent, already in exploitation

Uncovering different masking factors on wrist skin temperature rhythm in free-living subjects.

Most circadian rhythms are controlled by a major pacemaker located in the hypothalamic suprachiasmatic nucleus. Some of these rhythms, called marker rhythms, serve to characterize the timing of the internal temporal order. However, these variables are susceptible to masking effects as the result of activity, body position, light exposure, environmental temperature and sleep. Recently, wrist skin temperature (WT) has been proposed as a new index for evaluating circadian system status. In light of previous evidence suggesting the important relationship between WT and core body temperature regulation, the aim of this work was to purify the WT pattern in order to obtain its endogenous rhythm with the application of multiple demasking procedures. To this end, 103 subjects (18-24 years old) were recruited and their WT, activity, body position, light exposure, environmental temperature and sleep were recorded under free-living conditions for 1 week. WT demasking by categories or intercepts was applied to simulate a "constant routine" protocol (awakening, dim light, recumbent position, low activity and warm environmental temperature). Although the overall circadian pattern of WT was similar regardless of the masking effects, its amplitude was the rhythmic parameter most affected by environmental conditions. The acrophase and mesor were determined to be the most robust parameters for characterizing this rhythm. In addition, a circadian modulation of the masking effect was found for each masking variable. WT rhythm exhibits a strong endogenous component, despite the existence of multiple external influences. This was evidenced by simultaneously eliminating the influence of activity, body position, light exposure, environmental temperature and sleep. We therefore propose that it could be considered a valuable and minimally-invasive means of recording circadian physiology in ambulatory conditions

J Natl Compr Canc Netw

Sleep disruption is prevalent in patients and survivors of breast cancer. Most patients undergoing chemotherapy will experience transient sleep disruption, and nearly 60% will have chronic sleep problems. Numerous factors contribute to sleep disruption in women diagnosed with breast cancer. Sleep disruption is a consequence of several biological alterations, including circadian disruption and immune and metabolic deregulations. These systems also play significant roles in the control and progression of breast cancer. Sleep disruption is associated with many side effects and psychiatric and medical comorbidities. This article discusses the relationship between stress and posttraumatic stress disorder, depression and fatigue, and how sleep disturbance might be the cause or consequence of these disorders. Current evidence for management of sleep disturbance in breast cancer and high chronic use of hypnotic medication in this population is also discussed. Finally, the differences in management of sleep disturbance during acute cancer care and during the survivorship phase are discussed. More research is needed on accurate and timely assessment of sleep disturbance associated with breast cancer, and additional tailored approaches for the management of sleep problems in breast cancer should be developed

WT pattern after constant routine approach.

<p>Demasked WT waveforms obtained using the constant routine approach (see the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061142#s2" target="_blank">material and methods</a> section for details), employing either purification by categories (A) or by intercepts (B); in the latter case, three different environmental temperatures (15°, 20° and 25°C) are considered. The shaded area shows the mean sleep period. Data are expressed as Mean ± SEM. The values for Mesor, Amplitude and Acrophase as well as the %V of wrist temperature demasked by the simulated constant routine are expressed as Mean±95% Confidence Interval and are included at the bottom of the graph. * indicates p<0.001 according to the cosinor analysis.</p