Influence of Multimodal Treatment on Rest/Activity and Autonomic Regulation in Breast Cancer Patients with Cancer-Related Fatigue: Results of a Tri-Centre Trial with a Comprehensive Cohort Design.

INTRODUCTION: Breast cancer patients with cancer-related fatigue (BC-CRF) often have lower physical activity. To investigate how this could be improved, we evaluated a multimodal treatment (MT) and a combination of MT with aerobic training (CT) and compared these with aerobic training (AT) regarding rest/activity rhythm and state autonomic regulation (State aR). METHODS: In this pragmatic comprehensive cohort design study, the explorative analysis focused on actigraphy and State aR including the rest/activity regulation subscale (State aR-R/A) which were assessed at baseline (T0), after 10 weeks of intervention (T1), and State aR additionally 6 months later (T2). STATISTICS: General linear modelling including propensity scores. RESULTS: 65 BC-CRF were randomized, and 61 were allocated by preference to the treatment arms. 105 patients started the intervention. At T1, State aR-R/A improved the most in MT (+3.49, CI [2.42; 4.55]) compared to AT (+1.59, CI [0.13; 3.06]) and CT (+1.68, CI [0.83; 2.52]), showing superiority of MT to AT (p = 0.048). At T2 MT was sustainably superior to AT regarding State aR-R/A (+3.61, CI [2.38; 4.83] p < 0.01) and State aR also showed superiority of MT to AT (p = 0.006). AT T1 24-h activity was higher in MT compared to AT (p = 0.029). CONCLUSIONS: MT was superior to AT regarding State aR total score after 6 months, State aR-R/A after 10 weeks, and after 6 months. Actigraphically measured total activity also improved after 10 weeks.

Relaxation of dynamically prepared out-of-equilibrium initial states within and beyond linear response theory.

We consider a realistic nonequilibrium protocol, where a quantum system in thermal equilibrium is suddenly subjected to an external force. Due to this force, the system is driven out of equilibrium and the expectation values of certain observables acquire a dependence on time. Eventually, upon switching off the external force, the system unitarily evolves under its own Hamiltonian and, as a consequence, the expectation values of observables equilibrate towards specific constant long-time values. Summarizing our main results, we show that, in systems which violate the eigenstate thermalization hypothesis (ETH), this long-time value exhibits an intriguing dependence on the strength of the external force. Specifically, for weak external forces, i.e., within the linear response regime, we show that expectation values thermalize to their original equilibrium values, despite the ETH being violated. In contrast, for stronger perturbations beyond linear response, the quantum system relaxes to some nonthermal value which depends on the previous nonequilibrium protocol. While we present theoretical arguments which underpin these results, we also numerically demonstrate our findings by studying the real-time dynamics of two low-dimensional quantum spin models.

When Utilitarian Claims Backfire: Advertising Content and the Uptake of Insects as Food.

A key challenge for climate change mitigation on the consumer side is to break habits that excessively lead to carbon emission. One of the culturally most robust human routines is the heavy reliance of the Western societies on conventional meat sources such as beef, pork, and poultry, which were recently accused of causing particularly high climate costs. In this light, the UN (FAO) has suggested the increasing use of insects as an alternative source of animal protein intended for human diets. Yet, insects have not reached the mainstream of Western cuisine. Currently, a frequent promotion strategy of insects is to highlight the Utilitarian benefits associated with their consumption (e.g., with respect to the environment or one's health). The present research addresses the efficacy of such claims in a consumer research study involving 180 participants recruited from the general population in Germany. Arguing based on social-cognitive research in the area of moral and environmental psychology, we hypothesized and found that a focus on beneficial, but temporally distant motives (e.g., health)-counterintuitively-decreases consumption in comparison to immediate, hedonic advertisements (e.g., tasty). Furthermore, our study provides process evidence suggesting pretrial expectations induced by a particular claim mediate the relationship between claims and consumption. Thus, the present research not only refutes a state-of-the-art approach in the promotion of insects as food, but also provides an alternative approach and process evidence by integrating psychological factors.

Audio reproduction for personal ambient home assistance: concepts and evaluations for normal-hearing and hearing-impaired persons.

Within the Lower Saxony Research Network Design of Environments for Ageing (GAL), a personal activity and household assistant (PAHA), an ambient reminder system, has been developed. One of its central output modality to interact with the user is sound. The study presented here evaluated three different system technologies for sound reproduction using up to five loudspeakers, including the "phantom source" concept. Moreover, a technology for hearing loss compensation for the mostly older users of the PAHA was implemented and evaluated. Evaluation experiments with 21 normal hearing and hearing impaired test subjects were carried out. The results show that after direct comparison of the sound presentation concepts, the presentation by the single TV speaker was most preferred, whereas the phantom source concept got the highest acceptance ratings as far as the general concept is concerned. The localization accuracy of the phantom source concept was good as long as the exact listening position was known to the algorithm and speech stimuli were used. Most subjects preferred the original signals over the pre-processed, dynamic-compressed signals, although processed speech was often described as being clearer.

Information and communication technologies for promoting and sustaining quality of life, health and self-sufficiency in ageing societies--outcomes of the Lower Saxony Research Network Design of Environments for Ageing (GAL).

Many societies across the world are confronted with demographic changes, usually related to increased life expectancy and, often, relatively low birth rates. Information and communication technologies (ICT) may contribute to adequately support senior citizens in aging societies with respect to quality of life and quality and efficiency of health care processes. For investigating and for providing answers on whether new information and communication technologies can contribute to keeping, or even improving quality of life, health and self-sufficiency in ageing societies through new ways of living and new forms of care, the Lower Saxony Research Network Design of Environments for Ageing (GAL) had been established as a five years research project, running from 2008 to 2013. Ambient-assisted living (AAL) technologies in personal and home environments were especially important. In this article we report on the GAL project, and present some of its major outcomes after five years of research. We report on major challenges and lessons learned in running and organizing such a large, inter- and multidisciplinary project and discuss GAL in the context of related research projects. With respect to research outcomes, we have, for example, learned new knowledge about multimodal and speech-based human-machine-interaction mechanisms for persons with functional restrictions, and identified new methods and developed new algorithms for identifying activities of daily life and detecting acute events, particularly falls. A total of 79 apartments of senior citizens had been equipped with specific "GAL technology", providing new insights into the use of sensor data for smart homes. Major challenges we had to face were to deal constructively with GAL's highly inter- and multidisciplinary aspects, with respect to research into GAL's application scenarios, shifting from theory and lab experimentation to field tests, and the complexity of organizing and, in our view, successfully managing such a large project. Overall it can be stated that, from our point of view, the GAL research network has been run successfully and has achieved its major research objectives. Since we now know much more on how and where to use AAL technologies for new environments of living and new forms of care, a future focus for research can now be outlined for systematically planned studies, scientifically exploring the benefits of AAL technologies for senior citizens, in particular with respect to quality of life and the quality and efficiency of health care.

Modulation of pineal activity during the 23rd sunspot cycle: melatonin rise during the ascending phase of the cycle is accompanied by an increase of the sympathetic tone.

In two groups of female CD-rats nocturnal urine (19-23 h, 23-3 h, 3-7 h) was collected at monthly intervals over 658 days (I: 1997-1999) and 494 days (II: 1999-2000) coinciding with the ascending limb (1996-2000) of the 23rd sunspot cycle (1996-2008). The excretion of 6-sulfatoxymelatonin (aMT6s: I, II) was determined as well as the ratio of noradrenaline/adrenaline (NA/A: I) reflecting the activity of the sympathetic nervous system. AMT6s was higher in II than I (19-7 h: +24%; P < 0.001; 23-3 h: +30% and 3-7 h: +17%, P < 0.001), and progressively increased (19-23 h) showing linear regressions (1: R = +0.737, P = 0.003; II: R = +0.633, 0.008) which correlated (I) with the Planetary Index (Ap: R = +0.598, P = 0.020), an established estimate of geomagnetic disturbances due to solar activity. NA/A rose at all intervals (I: 46-143%) correlating with Ap (R = +0.554-0.768; P = 0.0399-0.0013). These results indicate that melatonin secretion rises as solar activity increases during the ascending limb of a sunspot cycle accompanied by growing geomagnetic disturbances (Ap) which elevate the sympathetic tone and thus affect the pineal gland, initially stimulating the activity of arylalkylamine N-acetyltransferase and subsequently fostering the expression of N-acetylserotonin O-methyltransferase (rate-limiting enzyme for melatonin biosynthesis) if Ap increases further. The potential (patho) physiological significance of these findings is discussed and the need for a systematic continuation of such studies is emphasized.

Multimodal therapy concept and aerobic training in breast cancer patients with chronic cancer-related fatigue.

UNLABELLED: HYPOTHESE: Cancer-related fatigue (CRF) and sleep disorders are some of the most wearing and common symptoms in disease-free breast cancer patients (BC). Aerobic training (AT) is the treatment with the best available evidence, even though it seems to be insufficient with regards to improvements in cognitive fatigue. We introduced a new multimodal therapy concept (MM) consisting of psycho-, sleep-education and new approaches based on anthroposophic medicine such as eurythmy and painting therapy. STUDY DESIGN: This pilot study will test the implementation of MM and yield first results of the MM and AE in our centres. METHODS: 31 out of 34 patients suffering from BC and CRF were fully assessed in a ten-week intervention study. 21 patients chose MM and 10 decided on AT. CRF was measured with the help of the Cancer Fatigue Scale (CFS-D), and the global quality of sleep was measured with the Pittsburgh Sleep Quality Index (PSQI). We also captured autonomic regulation (aR) and patients' satisfaction with questionnaires. Statistical analysis was done with SAS 9.1.3 for windows. RESULTS: The new MM therapy can be implemented with high satisfaction among patients. Significant improvements were found in the MM group with regards to CFS-D, global quality of sleep, sleep efficiency (PSQI), aR and rest/activity regulation compared to baseline (all p<0.05). In the AT group aR orthostatic-circulatory and rest/activity regulation improved significantly (p<0.05), too. However, no improvement in cognitive fatigue was seen in either group. CONCLUSION: The multimodal therapy concept was feasible and improved cancer fatigue, sleep quality, autonomic and rest-/activity regulation in breast cancer patients. It may therefore constitute a valuable treatment option in addition to aerobic training for BC patients with CRF. A further study with larger sample size needs to be carried out to assess the efficacy of combined multimodal-aerobic therapy.

Longitudinal melatonin production in female laboratory rats during 1997-2006: possible modulatory effects of changing solar activity.

Earlier we reported that the urinary excretion of 6-sulfatoxymelatonin (aMT6s) displayed seasonal rhythms in laboratory rats and hypothesized that the horizontal intensity H of the geomagnetic field may act as seasonal zeitgeber. To test this, long-term experiments were performed with female Sprague-Dawley rats. In experiment I (n=12: 1997-1999) nocturnal aMT6s displayed a winter-summer increase by 30% and a rhythm with a phase-length of 24 months peaking in July 1998. In experiment II (n=12; 1999-2000) the winter-summer increase amounted to 40%. The estimated rhythm had a phase-length of 18 months with a peak in September 2000. Compared to experiment I both the rhythm-adjusted mean (MESOR, + 28%) and amplitude (+68%) were elevated. In experiment III (n=30; 2003-2004) the winter-summer increment was just 20%. A circannual rhythm with a peak in April/May was found. The MESOR was 13% higher than in experiment I but the amplitude was depleted ( -14%). In experiment IV (n=15; 2005-2006) a slight winter-summer increase (+15%) was found and a low-amplitude rhythm of 24 months phase-length peaking in June 2006. The MESOR was similar to experiment I but the amplitude was depressed (-36%). These results demonstrate that female rats within two years of age show elevated aMT6s during summer/spring which supports our initial hypothesis. The apparent inter-experimental amplitude variation indicates the involvement of additional variables. Based on our initial hypothesis, we postulate an involvement of the solar cycle affecting H leading to year to year variations and present supportive analyses.

Search for seasonal rhythmicity of pineal melatonin production in rats under constant laboratory conditions: spectral chronobiological analysis, and relation to solar and geomagnetic variables.

Earlier we reported that in a number of experiments pineal melatonin production in rats under constant laboratory conditions displayed seasonal rhythms but subsequently were not always able to confirm this. Since there was no indication under which conditions such rhythms may be present, we performed four consecutive identical experiments with untreated female Sprague-Dawley rats within the same animal room during 1997-2006. Nocturnal urine samples (19-23, 23-3, 3-7 h) were collected at monthly intervals over 494-658 d with 12 animals each in experiments I and II (1997-1999, 1999-2000), 30 animals in experiment III (2002-2004), and 15 in experiment IV (2005-2006). 6-Sulfatoxymelatonin (aMT6s) was measured by ELISA. The excreted aMT6s at each time interval as well as total nocturnal aMT6s-excretion (19-7 h) was submitted to standard statistical analyses as well as to a spectral chronobiological analysis to determine the period lengths of the components involved which was followed by processing with the single cosinor method. Seasonal rhythm components (circannual period length: 360 ± 60 d) were detected in experiment III (2002-2004) for the overall nocturnal excretion as well as for two sub-intervals (23-3 and 3-7 h) and in one night interval of experiment II (23-3 h). Multiple components with mostly short period lengths of around 100 d and some long ones of 500-650 d were found in the other experiments. Systematic MESOR and amplitude variations were observed during the experiments, being highest in experiment II (19-7 h, also 23-3 h and 3-7 h) and lowest in experiments I and IV. These results illustrate that seasonal melatonin rhythms are not a general phenomenon in female laboratory rats indicating an involvement of unknown environmental cues. As an extension of our earlier hypothesis regarding a seasonal Zeitgeber function of the horizontal intensity H of the geomagnetic field showing circannual variations, we assume further modulation by the 11-yrs' sunspot cycle which leads to geomagnetic disturbances and could facilitate seasonal aMT6s rhythmicity during specific years.

Boltzmann-type approach to transport in weakly interacting one-dimensional fermionic systems.

We investigate transport properties of one-dimensional fermionic tight binding models featuring nearest and next-nearest neighbor hopping, where the fermions are additionally subject to a weak short range mutual interaction. To this end we employ a pertinent approach which allows for a mapping of the underlying Schrödinger dynamics onto an adequate linear quantum Boltzmann equation. This approach is based on a suitable projection operator method. From this Boltzmann equation we are able to numerically obtain diffusion coefficients in the case of nonvanishing next-nearest neighbor hopping, i.e., the nonintegrable case, whereas the diffusion coefficient diverges without next-nearest neighbor hopping. For the latter case we analytically investigate the decay behavior of the current with the result that arbitrarily small parts of the current relax arbitrarily slowly which suggests anomalous diffusive transport behavior within the scope of our approach.

The Lower Saxony research network design of environments for ageing: towards interdisciplinary research on information and communication technologies in ageing societies.

Worldwide, ageing societies are bringing challenges for independent living and healthcare. Health-enabling technologies for pervasive healthcare and sensor-enhanced health information systems offer new opportunities for care. In order to identify, implement and assess such new information and communication technologies (ICT) the 'Lower Saxony Research Network Design of Environments for Ageing' (GAL) has been launched in 2008 as interdisciplinary research project. In this publication, we inform about the goals and structure of GAL, including first outcomes, as well as to discuss the potentials and possible barriers of such highly interdisciplinary research projects in the field of health-enabling technologies for pervasive healthcare. Although GAL's high interdisciplinarity at the beginning slowed down the speed of research progress, we can now work on problems, which can hardly be solved by one or few disciplines alone. Interdisciplinary research projects on ICT in ageing societies are needed and recommended.

Acoustic user interfaces for ambient-assisted living technologies.

This contribution discusses technologies for acoustic user interaction in ambient-assisted living (AAL) scenarios. Acoustic user interfaces allow for a natural and convenient way to interact with technical systems e.g. via sound or speech presentation or via speech input by means of automatic speech recognition (ASR) as well as by detection and classification of acoustic events. Older persons targeted by AAL technologies especially need more easy-to-use methods to interact with inherently complex supporting technology. As an example we designed and evaluated an application for acoustic user interaction with a multi-media reminder and calendar system. For this purpose, mainly older participants were involved in user studies to continuously evaluate and support the development strictly following a user-centred design process. The results suggest a wide acceptance of acoustic user interfaces by older users either for controlling inherently complex AAL systems by using robust ASR technologies or as a natural and ambient way of presenting information to the user. However, further research is needed to increase the robustness of ASR systems when using hands-free equipment, i.e. to provide a real ambient way of interaction, and to introduce personalised speech and sound presentation schemes accounting for the individual hearing capabilities and sound preferences.

Projection-operator approach to master equations for coarse-grained occupation numbers in nonideal quantum gases.

We aim at deriving an equation of motion for specific sums of momentum mode occupation numbers from models for electrons in periodic lattices experiencing elastic scattering, electron-phonon scattering, or electron-electron scattering. These sums correspond to "grains" in momentum space. This equation of motion is supposed to involve only a moderate number of dynamical variables and/or exhibit a sufficiently simple structure such that neither its construction nor its analyzation or solution requires substantial numerical effort. To this end we compute, by means of a projection operator technique, a linear(ized) collision term which determines the dynamics of the above grain sums. This collision term results as nonsingular finite-dimensional rate matrix and may thus be inverted regardless of any symmetry of the underlying model. This facilitates calculations of, e.g., transport coefficients, as we demonstrate for a three-dimensional Anderson model featuring weak disorder.

Effect of chronic exposure to a GSM-like signal (mobile phone) on survival of female Sprague-Dawley rats: modulatory effects by month of birth and possibly stage of the solar cycle.

During 1997-2008 two long-term (I and II) and two life-long (III and IV) experiments were performed analyzing the effect of chronic exposure to a low-intensity GSM-like signal (900 MHz pulsed with 217 Hz, 100 µW/cm² average power flux density, 38-80 mW/kg mean specific absorption rate for whole body) on health and survival of unrestrained female Sprague-Dawley rats kept under identical conditions. Radiofrequency (RF)-exposure was started at 52-70 days of age and continued for 24 (I), 17 (II) and up to 36 and 37 months, respectively (III/IV). In the first two experiments (1997-2000) 12 exposed and 12 sham-exposed animals each were observed until they were maximally 770 or 580 days old. In experiment I no adverse health effects of chronic RF-exposure were detectable, neither by macroscopic nor detailed microscopic pathological examinations. Also in experiment II no apparent macroscopic pathological changes due to treatment were apparent. Median survival time could not be estimated since in none of the groups more than 50% of the animals had died. In the course of two complete survival experiments (2002-2005; 2005-2008) 30 RF- and 30 sham-exposed animals each were followed up until their natural end or when they became moribund and had to be euthanized. A synoptical data analysis was performed. Survival data of all four groups could be fitted well by the Weibull distribution. According to this analysis median survival was significantly shortened under RF-exposure in both experiments by 9.06% (95% CI 2.7 to 15.0%) (p=0.0064); i.e by 72 days in experiment III and 77 days in experiment IV as compared to the corresponding sham-treated animals (III: 799 days; IV: 852 days). Both groups of animals of experiment III showed reduced median survival times by 6.25% (95% CI -0.3 to 12.4%) (p=0.0604) compared to the corresponding groups of experiment IV (53 days: sham-exposed animals, 48 days: RF-exposed animals) which may be due to the fact that animals of experiment III were born in October and animals of experiment IV in May indicating that the month of birth affects life span. From the results of the last two experiments it has to be concluded that chronic exposure to a low-intensity GSM-like signal may exert negative health effects and shorten survival if treatment is applied sufficiently long and the observational period covers the full life span of the animals concerned. The current data show that survival of rats kept under controlled laboratory conditions varies within certain limits depending on the month of birth. In view of our previous observations regarding an inhibitory or no effect of RF-exposure on DMBA-induced mammary cancer during the 1997-2000 period, an additional modulatory influence on a year-to-year basis should be considered which might be related to changing solar activity during the the 11-years' sunspot cycle. These potentially complex influences of the natural environment modulating the effects of anthropogenic RF-signals on health and survival require a systematic continuation of such experiments throughout solar cycle 24 which started in 2009.

Dynamical typicality of quantum expectation values.

We show that the vast majority of all pure states featuring a common expectation value of some generic observable at a given time will yield very similar expectation values of the same observable at any later time. This is meant to apply to Schrödinger type dynamics in high dimensional Hilbert spaces. As a consequence individual dynamics of expectation values are then typically well described by the ensemble average. Our approach is based on the Hilbert space average method. We support the analytical investigations with numerics obtained by exact diagonalization of the full time-dependent Schrödinger equation for some pertinent, abstract Hamiltonian model. Furthermore, we discuss the implications for the applicability of projection operator methods with respect to initial states, as well as for irreversibility in general.

Occurrence of exponential relaxation in closed quantum systems.

We investigate the occurrence of exponential relaxation in a certain class of closed, finite systems on the basis of a time-convolutionless projection operator expansion for a specific class of initial states with vanishing inhomogeneity. It turns out that exponential behavior is to be expected only if the leading order predicts the standard separation of time scales and if, furthermore, all higher orders remain negligible for the full relaxation time. The latter, however, is shown to depend not only on the perturbation (interaction) strength, but also crucially on the structure of the perturbation matrix. It is shown that perturbations yielding exponential relaxation have to fulfill certain criteria, one of which relates to the so-called "Van Hove structure." All our results are verified by the numerical integration of the full time-dependent Schrödinger equation.

The anti-tumor activity of pineal melatonin and cancer enhancing life styles in industrialized societies.

This review discusses the potential role of the anti-tumor activity of pineal melatonin for the aetiology and prevention of cancers related to life-styles in industrialized societies, e.g. frequent long-distance flights as well as chronic night shift work leading to circadian disturbances of neuroendocrine parameters including melatonin. Experimental studies show that melatonin controls not only the growth of well-differentiated cancers, but also possesses anti-carcinogenic properties. Therefore, it is plausible that disturbances of circadian melatonin rhythmicity could be functionally involved in elevated cancer risks among aircrew members and nurses frequently working on night shifts. Due to the suppression of melatonin by light it can be assumed that too much artificial light at night could, at least in part, be responsible for generally increasing rates of e.g. breast cancer in industrialized countries. It is discussed under which conditions a transient substitutional therapy with melatonin could be justified or which forms of living could help to physiologically foster melatonin secretion to optimise control over cancerous growth and development.

Tracking the elusive antiestrogenic effect of melatonin: a new methodological approach.

OBJECTIVES: Detection of the antiestrogenic effect of melatonin on various breast cancer cell lines and its dependence of the differential expression of estrogen receptors (ERalpha and ERbeta) and melatonin receptors (mt1 and RZRalpha). SETTING AND DESIGN: Dose-response curves of estradiol were determined in 6 different breast cancer cell lines using a colorimetric proliferation assay in the absence or presence of various melatonin concentrations. METHODS: In order to detect the minor growth inhibitory effect of melatonin, a simple yet novel approach was employed: instead of incubating cells at single estradiol-concentrations at increasing melatonin levels, breast cancer cells were grown in microwell-plates for 4 days at increasing concentrations of estradiol (10(-12)M - 10(-10)M) in the absence or presence of melatonin (10(-9)M - 10(-8)M). Cell number was determined using Alamar blue and colorimetry. RT-PCR was performed for the expression of ERalpha, ERbeta, RZRalpha and mt1. RESULTS: Melatonin at concentrations of 10(-9)M and 5 x 10(-9)M shifted the dose-response curves of estradiol to higher concentrations. Responsiveness to melatonin depended on expression of ERalpha but not on ERbeta. mRNA of ERbeta was not detectable in the breast cancer cell lines used. Only small amounts of mt1 transcripts were detectable in MCF-7 cells of one source. In MCF-7 cells transfected with the mt1 gene and in an ovarian cancer cell line mt1 was expressed at significant levels. RZRalpha was expressed in all tested cell lines at different amounts. CONCLUSION: The growth of all ERalpha-positive breast cancer cell lines can be inhibited by melatonin. The effect in most cell lines is weak yet clearly reproducible. RZRalpha clearly contributes to the growth inhibitory effect of melatonin.

Melatonin in clinical oncology.

The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology. Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status).