The effect of walking and vitamin B supplementation on quality of life in community-dwelling adults with mild cognitive impairment : a randomized , controlled trial Objectives To examine the effect of walking and vitamin B supplementation on quality-of-life -LRB- QoL -RRB- in community-dwelling adults with mild cognitive impairment . Introduction Especially in older people , both mental and physical function decrease due to multiple age related changes , which in turn may affect quality of life -LRB- QoL -RRB- . The most obvious decrease in mental function is cognitive decline , which is a common aspect of aging . However , in some cases decline is more serious than expected for a certain age . This is specified as Mild Cognitive Impairment -LRB- MCI -RRB- . MCI is considered to be a potential transitional stage between normal cognitive function and Alzheimer 's disease , characterized by -LRB- 1 -RRB- subjective memory complaint -LRB- 2 -RRB- objective memory impairment -LRB- 3 -RRB- normal mental status -LRB- 4 -RRB- intact activities of daily living -LRB- ADL -RRB- -LRB- 5 -RRB- absence of dementia -LSB- 1 -RSB- . Independent of the latter four criteria , subjective memory complaints are related to lower QoL -LSB- 2 -RSB- . Moreover , MCI is associated with poor physical health and high risk of ADL dependence -LSB- 3 , 4 -RSB- . Since both cognitive and physical decline belong to the most important determinants of QoL in community dwelling elderly subjects -LSB- 5 -RSB- , subjects with MCI are likely to be susceptible to a decrease in QoL . The number of adults with MCI is increasing considerably due to the aging population . For multiple reasons , it is important to prevent a decrease in QoL . Apart from the personal benefits , a high rated QoL also reduces medical consumption and helps to maintain independency as long as possible -LSB- 6 -RSB- . This in turn may relieve significant others , caregivers and medical society in general . For this reason , attention should be paid to possible interventions contributing towards a higher level of overall QoL and it 's mental and physical components . In this respect , physical exercise and vitamin supplementation are interesting interventions worth investigating . Regular participation in moderate intensity aerobic training is reported to be beneficial in improving QoL and wellbeing , which is an important aspect of QoL -LSB- 7 , 8 -RSB- . Since walking is the most prevalent physical activity among older adults -LSB- 9 -RSB- , improving QoL by increasing the time spent on moderate intensity walking seems promising . Indeed , a community based walking program significantly improved both the physical and mental components of health-related QoL in older adults -LRB- n = 582 -RRB- -LSB- 10 -RSB- . Inconclusive evidence has been reported on the influence of vitamin B supplementation on QoL . Different aspects of QoL were not responsive to short term supplementation -LRB- range 4 -- 12 weeks -RRB- with different doses and combinations of B vitamins in men and women -LSB- 11 -- 13 -RSB- . Not much is known about QoL in community dwelling elderly with MCI . Moreover , no trials on the effect of exercise and vitamin B supplementation on QoL have been carried out yet in adults with MCI . The FACT-study -LRB- Folate physical Activity Cognition Trial -RRB- was developed to examine the effect of these interventions on cognition -LSB- 14 -RSB- . Aspects of QoL were measured as a secondary outcome . In the present paper , the effectiveness of 1 year moderate intensity walking -LRB- two sessions of 60 min per week -RRB- and daily vitamin supplementation -LRB- 5 mg folate , 50 mg vitamin B6 and 0.4 mg B12 -RRB- on both overall QoL and it 's health-related components is examined in community dwelling older adults with MCI . We hypothesize that 1 year moderate intensity walking benefits QoL . Concerning the effect of vitamin supplementation , this paper should be considered as explorative . Methods Study design The study was designed as a randomized , placebo controlled intervention trial , based on a two-by-two factorial design . The study-protocol has been described in detail elsewhere -LSB- 14 -RSB- and was approved by the VU University Medical Center medical ethics committee . Written informed consent was obtained from all participants . Participants In a medium-sized Dutch town community dwelling subjects aged 70 -- 80 years with MCI were identified using a population based two-step-screening -LSB- 15 -RSB- . The operational criteria for MCI according to the criteria of Petersen et al. -LSB- 1 -RSB- and additional inclusion criteria for the RCT are described in Table 1 . Subjects were not paid to participate in the study . Table 1Inclusion and exclusion criteria for participation in the trial Operationalization of Petersen criteria for MCI -LRB- 1 -- 5 -RRB- and additional inclusion criteria for the RCT -LRB- 6 -- 12 -RRB- 1 . Memory complaints -LRB- answer yes to question ` do you have memory complaints ' , or at least twice sometimes at cognition scale of Strawbridge -LSB- 16 -RSB- 2 . Objective memory impairment ; 10 WLT delayed recall ≤ 5 + percentage savings ≤ 100 -LSB- 17 -RSB- 3 . Normal general cognitive functioning ; TICS ≥ 19 + MMSE ≥ 24 -LSB- 18 , 19 -RSB- 4 . Intact daily functioning : no report of disability in activities of daily living on GARS-scale , except on the item ` taking care of feet and toe nails ' -LSB- 20 -RSB- 5 . Absence of dementia ; TICS ≥ 19 + MMSE ≥ 246 . Being able to perform moderate intensity physical activity , without making use of walking devices , e.g. , a rollator or a walking frame 7 . Not using vitamin supplements/vitamin injections/drinks with dose of vitamin B6 , B11 or B12 comparable to vitamin supplement given in intervention8 . Not suffering from epilepsy , multiple sclerosis , Parkinson 's disease , kidney disorder requiring haemodialysis , psychiatric impairment9 . Not suffering from depression as measured by the GDS -LRB- cut off ≤ 5 -RRB- -LSB- 21 -RSB- 10 . Not using medication for rheumatoid arthritis or psoriasis interfering with vitamin supplement11 . No alcohol abuse -LRB- men < 21 consumptions a week , women < 15 consumptions a week -RRB- 12 . Not currently living in a nursing home or on a waiting list for a nursing homeMCI = Mild Cognitive Impairment , RCT = Randomized Controlled Trial , 10 WLT = 10 Word Learning Test , TICS = Telephone Interview for Cognitive Status , MMSE = Mini Mental State Examination , GARS = Groningen Activity Restriction Scale , GDS = Geriatric Depression Scale Randomization After the baseline interview , subjects were randomly assigned to the interventions using the statistical computer program SPSS . Intervention groups were : -LRB- 1 -RRB- walking program or placebo activity program ; and -LRB- 2 -RRB- vitamin B supplementation or placebo supplementation . Randomization was stratified for physical activity level at baseline in minutes per day as measured by the LASA physical activity questionnaire -LSB- 22 -RSB- . For the flow of participants see Fig. 1 . Fig. 1Flow chart . TI = Telephone Interview , WP = Walking Program , PAP = Placebo Activity Program , FA/B12/B6 = Folic Acid , Vitamin B12 , Vitamin B6 supplementation , SO = significant other , T6 = follow-up after 6 months , T12 = follow-up after 12 months , * reason for exclusion : only baseline data available Exercise intervention Subjects assigned to the walking program -LRB- WP -RRB- participated twice a week 60 min in group-based moderate intensity walking during 1 year . Each session consisted of a warming up , moderate intensity walking exercises and a cooling down . The WP was based on ` Sportive Walking , ' an existing aerobic walking program -LSB- 23 -RSB- aimed at improving cardiovascular endurance . Therefore , duration and intensity of the walking exercises increased gradually during the program . Sessions took place outdoor in municipal parks . Subjects not assigned to the WP participated in a placebo activity program -LRB- PAP -RRB- with the same frequency , session duration and program duration . However , the PAP consisted of low intensity exercise , such as light range of motion movements and stretching . Sessions were divided into five themes : relaxation , activities of daily living , balance , flexibility , posture and a combination of all . For each theme three sessions were developed and the entire series of 18 sessions was repeated during the intervention period . The PAP was carried out in community centers . Both programs were supervised by qualified and trained instructors . Attendance to both programs was assessed by the percentage of attended sessions . Vitamin supplementation -LRB- FA/B12/B6 -RRB- Subjects in the vitamin supplementation group took one pill containing 5 mg vitamin B11 -LRB- Folic Acid -RRB- , 0.4 mg vitamin B12 -LRB- Cyanocobalamin -RRB- and 50 mg vitamin B6 -LRB- Pyridoxine-hydrochloride -RRB- daily during 1 year . This vitamin supplement is available on prescription in The Netherlands . Subjects randomized to the control group took an identically looking placebo pill . The pills were packed in blister packs for 1 week , which were labeled for each day of the week . Compliance with the vitamin supplementation was verified by pill counts in returned blister packs during the intervention . Outcome measures Baseline data on sociodemographic and background variables were collected using a postal screening questionnaire . The measurement of other baseline variables , as reported in Table 2 , has been described elsewhere -LSB- 14 -RSB- . In the present manuscript a distinction was made between ` overall quality of life , ' referring to a subjects overall enjoyment of life and ` health-related quality of life , ' referring to health-related factors affecting quality of life . The term QoL was used as an umbrella term for both overall and health-related QoL . The population-specific Dementia Quality of Life questionnaire -LRB- D-QoL -RRB- -LSB- 24 -RSB- was used to assess overall QoL and the generic Short Form 12 -LRB- SF12 -RRB- -LSB- 25 -RSB- to assess health-related QoL . The D-QoL is a 29 item measure especially developed for elderly with cognitive decline and dementia . The participant is asked about how much they enjoyed activities that were reported to be important for elderly such as ` watching animals . ' Moreover , the frequency of certain positive and negative feelings such as ` lovable ' or ` worried ' were asked for . Finally , they were asked to rate their overall quality of life . The participant was instructed to choose the best fitting answer from five item response scales . The answers were divided into five domains of QoL measuring sense of aesthetics , feelings of belonging , negative affect , positive affect/humor and self esteem . A mean score ranging from one to five was calculated for these subscales and for the total D-QoL . A higher score indicated better quality of life . Median internal consistency reliability of the D-QoL was 0.80 and median test -- retest reliability was 0.72 in a sample of 95 older adults with different stages of cognitive decline -LSB- 24 -RSB- . The SF12 consists of 12 items measuring eight concepts of both mental and physical health , i.e. , physical functioning , role-physical , bodily pain , general health , energy , social functioning , role emotional and mental health . These concepts are subdivided into two summary scores using a norm-based criterion : i.e. , mental and physical component summary scales -LRB- SF12-MCS and SF12-PCS -RRB- . The mean score is 50 with a standard deviation of 10 . For example , a score of 60 corresponds to a-QoL rating of one standard deviation above the average ratings in the general population . Test retest reliability for the SF-12 MCS was 0.76 in a sample of 187 adults in the United Kingdom and 0.77 in a sample of 232 adults in the United States . Reliability coefficients of the SF-12 PCS in these populations were 0.86 and 0.89 , respectively -LSB- 25 -RSB- . In the present study , measurement took place during a personal interview at baseline and after 6 and 12 months . Both the D-QoL and the SF-12 were administered by a trained interviewer who was unaware of the participants ' group allocation . Table 2Baseline characteristics of participants -LRB- n = 152 -RRB- Exercise interventionVitamin interventionWP -LRB- n = 77 -RRB- PAP -LRB- n = 75 -RRB- FA/B12/B6 -LRB- n = 78 -RRB- Placebo-pill -LRB- n = 74 -RRB- Age -LRB- Mean -LRB- SD -RRB- -RRB- 75 -LRB- 2.9 -RRB- 75 -LRB- 2.8 -RRB- 75 -LRB- 2.8 -RRB- 75 -LRB- 2.9 -RRB- Gender -LRB- % male -RRB- 48 * 645655MMSE -LRB- Median -LRB- 10th -- 90th ‰ -RRB- -RRB- 29 -LRB- 26 -- 30 -RRB- 29 -LRB- 27 -- 30 -RRB- 29 -LRB- 25 -- 30 -RRB- 29 -LRB- 27 -- 30 -RRB- Education -LRB- % low/middle/high -RRB- 61/22/1752 / 29/1957/26 / 1755/26/19Marital status -LRB- % living together -RRB- 75686973Physical activitya -LRB- min/day -RRB- -LRB- Median -LRB- 10th -- 90th ‰ -RRB- -RRB- 44 -LRB- 10 -- 155 -RRB- 39 -LRB- 11 -- 120 -RRB- 45 -LRB- 13 -- 155 -RRB- 38 -LRB- 9 -- 111 -RRB- Vitamin status -LRB- % deficient FA/B12/B6 -RRB- b46/8/048 / 8/049/9 / 045/7/0Homocysteine statusc -LRB- % hyperhomocysteinemia -RRB- 27232723Blood pressure -LRB- % hypertension -RRB- d27 * 142516BMI -LRB- kg/m2 -RRB- -LRB- Median -LRB- 10th -- 90th p ‰ -RRB- -RRB- 26.7 -LRB- 23.1 -- 31.5 -RRB- 26.6 -LRB- 23.5 -- 32.7 -RRB- 26.5 -LRB- 23.3 -- 32.8 -RRB- 26.7 -LRB- 23.5 -- 31.2 -RRB- Smoking -LRB- % smokers -RRB- 13151711Number of self-reported diseases -LRB- % 0,1,2 -RRB- e52/42/669 / 27/466/28 / 655/41/4WP = Walking Program , PAP = Placebo Activity Program , FA/B12/B6 = Folic Acid , Vitamin B12 , Vitamin B6 supplementation , MMSE = Mini Mental State Examination , Education : low = no education , primary education , lower vocational training ; intermediate = intermediate level secondary education , intermediate vocational training ; high = higher level secondary education , higher vocational training , university training . BMI = Body Mass Indexa ≥ 3.0 metabolic equivalents b Cut off points : FA red blood cell < 337 nmol/l or FA plasma < 6,3 nmol/l ; B12 ≤ 150 pmol/l ; B6 < 20 nmol/lc Homocysteine > 14 mmol/ld Hypertension = diastole ≥ 90 and systole ≥ 160e Cardiovascular disease , chronic obstructive pulmonary disease , diabetes , epilepsy , multiple sclerosis , Parkinson 's disease , psychiatric disease , renal failure requiring dialysis and/or rheumatoid arthritis * Significantly different from PAP -LRB- P < 0.05 -RRB- Statistical analyses Differences between groups on baseline characteristics were tested using independent t-tests -LRB- normally distributed variables -RRB- , Mann -- Whitney U tests -LRB- not normally distributed variables -RRB- and χ2 -LRB- categorical variables -RRB- . Within group differences were tested using dependent t-tests . Subsequently , data were analyzed according to a modified intention-to-treat principle , based on data from all randomized participants who provided data at baseline and at least one follow-up measurement . To evaluate the effects of the walking program and the vitamin supplementation on QoL , longitudinal regression analysis was used . The two follow-up measurements were defined as dependent variable and multi level analysis with two levels was used , -LRB- 1 -RRB- time of follow-up measurement -LRB- values corresponding with performance after six and 12 months intervention -RRB- ; -LRB- 2 -RRB- individual . According to the study protocol -LSB- 14 -RSB- , the effect of both interventions was examined independently from each other . Data were analyzed using a crude and an adjusted model . Independent variables were exercise intervention and vitamin intervention . By analyzing both interventions in the same model , results were adjusted for the possible influence of the other intervention . Moreover , all analyses were adjusted for baseline performance on the outcome measure by adding this as a covariate . In the adjusted model , education , baseline activity level , baseline vitamin status , attendance to the exercise program and compliance with the supplementation were added as covariates . Interaction between gender and the WP or FA/B6/B12-supplementation was checked in the adjusted model . In the case of significant interaction , results were reported for men and women separately . In the case of no interaction , gender was added to the adjusted model as an additional covariate . Also , in the ` adjusted model ' an interaction effect of the exercise program with attendance to the exercise program was checked . Finally , data were analyzed according to the per protocol principle , including all participants who attended at least 75 % of the sessions . This cut-off point is in concordance with previous exercise intervention studies in older adults -LSB- 26 , 27 -RSB- . Data were analyzed using SPSS for Windows -LRB- release 12.0.1 -RRB- . A significance level of 5 % was used for between group comparisons and of 10 % for interaction terms . For all analyses , regression coefficients and 95 % confidence intervals for the adjusted models were reported , with the regression coefficients directly indicating the difference in QoL ratings between the WP and the PAP or the FA/B12/B6-supplementation versus placebo supplementation . In the case of significant interaction , regression coefficients and the 95 % confidence intervals of the interaction terms were reported . Results Patient characteristics Hundred-seventy-nine participants were randomized to the interventions . Twenty-seven of them were excluded from the analyses , because they only provided baseline data . These subjects were more often married -LRB- 71 % vs. 52 % , P = 0.05 -RRB- and less often current smokers -LRB- 0 % vs. 14 % , P = 0.04 -RRB- than the remaining 152 participants who provided QoL data at baseline and at at least one follow-up measurement . The latter 152 participants were included in the analyses -LRB- see Fig. 1 -RRB- . Their mean age -LRB- SD -RRB- was 75 -LRB- 2.9 -RRB- years . Fifty-six percent was male . Additional baseline variables are described per factor in Table 2 . Compared to the PAP , the WP included fewer men -LRB- 48 % in WP vs. 64 % in PAP -RRB- and more subjects with hypertension -LRB- 27 % in WP vs. 14 % in PAP -RRB- . Ratings for both overall and health-related QoL at baseline and after 6 and 12 months intervention are presented in Table 3 . No baseline differences were observed on these measures , except for a higher rating of D-QoL self-esteem in subjects in the FA/B12/B6-group compared to subjects in the placebo-supplementation group . Table 3Means -LRB- standard deviations -RRB- of QoL ratings at baseline and after 6 and 12 months in older adults with MCIaWP PAPFA/B12/B6 Placebo T0 -LRB- n = 77 -RRB- T6 -LRB- n = 77 -RRB- T12 -LRB- n = 71 -RRB- T0 -LRB- n = 75 -RRB- T6 -LRB- n = 75 -RRB- T12 -LRB- n = 67 -RRB- T0 -LRB- n = 78 -RRB- T6 -LRB- n = 78 -RRB- T12 -LRB- n = 71 -RRB- T0 -LRB- n = 74 -RRB- T6 -LRB- n = 74 -RRB- T12 -LRB- n = 67 -RRB- D-QoL sumscore3 .5 -LRB- 0.26 -RRB- 3.5 -LRB- 0.29 -RRB- 3.5 -LRB- 0.27 -RRB- 3.5 -LRB- 0.32 -RRB- 3.5 -LRB- 0.34 -RRB- 3.5 -LRB- 0.34 -RRB- 3.5 -LRB- 0.32 -RRB- 3.5 -LRB- 0.32 -RRB- 3.5 -LRB- 0.33 -RRB- 3.4 -LRB- 0.24 -RRB- 3.5 -LRB- 0.31 -RRB- 3.5 -LRB- 0.27 -RRB- D-QoL aesthetics3 .5 -LRB- 0.63 -RRB- 3.5 -LRB- 0.64 -RRB- 3.6 -LRB- 0.60 -RRB- 3.5 -LRB- 0.70 -RRB- 3.5 -LRB- 0.71 -RRB- 3.5 -LRB- 0.65 -RRB- 3.5 -LRB- 0.64 -RRB- 3.5 -LRB- 0.68 -RRB- 3.6 -LRB- 0.61 -RRB- 3.4 -LRB- 0.68 -RRB- 3.5 -LRB- 0.67 -RRB- 3.6 -LRB- 0.64 -RRB- D-QoL belonging3 .7 -LRB- 0.50 -RRB- 3.7 -LRB- 0.49 -RRB- 3.7 -LRB- 0.44 -RRB- 3.8 -LRB- 0.45 -RRB- 3.7 -LRB- 0.47 -RRB- 3.7 -LRB- 0.46 -RRB- 3.8 -LRB- 0.50 -RRB- 3.6 -LRB- 0.50 -RRB- 3.6 -LRB- 0.48 -RRB- 3.7 -LRB- 0.44 -RRB- 3.8 -LRB- 0.45 -RRB- 3.8 -LRB- 0.40 -RRB- D-QoL negative affect2 .7 -LRB- 0.45 -RRB- 2.7 -LRB- 0.46 -RRB- 2.8 -LRB- 0.50 -RRB- 2.7 -LRB- 0.55 -RRB- 2.8 -LRB- 0.54 -RRB- 2.8 -LRB- 0.52 -RRB- 2.7 -LRB- 0.54 -RRB- 2.8 -LRB- 0.47 -RRB- 2.8 -LRB- 0.53 -RRB- 2.7 -LRB- 0.47 -RRB- 2.7 -LRB- 0.53 -RRB- 2.8 -LRB- 0.49 -RRB- D-QoL positive affect3 .8 -LRB- 0.39 -RRB- 3.7 -LRB- 0.46 -RRB- 3.8 -LRB- 0.40 -RRB- 3.8 -LRB- 0.40 -RRB- 3.7 -LRB- 0.44 -RRB- 3.8 -LRB- 0.43 -RRB- 3.8 -LRB- 0.41 -RRB- 3.7 -LRB- 0.47 -RRB- 3.8 -LRB- 0.44 -RRB- 3.8 -LRB- 0.39 -RRB- 3.8 -LRB- 0.43 -RRB- 3.8 -LRB- 0.39 -RRB- D-QoL self esteem3 .6 -LRB- 0.45 -RRB- 3.8 -LRB- 0.41 -RRB- 3.8 -LRB- 0.40 -RRB- 3.7 -LRB- 0.48 -RRB- 3.7 -LRB- 0.49 -RRB- 3.8 -LRB- 0.48 -RRB- 3.8 -LRB- 0.48 -RRB- * 3.8 -LRB- 0.48 -RRB- 3.9 -LRB- 0.48 -RRB- 3.6 -LRB- 0.43 -RRB- 3.7 -LRB- 0.43 -RRB- 3.7 -LRB- 0.38 -RRB- SF12-MCS54.6 -LRB- 6.85 -RRB- 55.6 -LRB- 6.40 -RRB- 55.3 -LRB- 4.39 -RRB- 54.7 -LRB- 8.07 -RRB- 55.0 -LRB- 7.34 -RRB- 55.3 -LRB- 6.24 -RRB- 55.5 -LRB- 7.49 -RRB- 55.9 -LRB- 6.91 -RRB- 55.8 -LRB- 4.90 -RRB- 53.8 -LRB- 7.36 -RRB- 54.6 -LRB- 6.86 -RRB- 54.8 -LRB- 5.76 -RRB- SF12-PCS48.2 -LRB- 7.15 -RRB- 48.1 -LRB- 7.57 -RRB- 50.5 -LRB- 6.13 -RRB- 48.7 -LRB- 7.86 -RRB- 48.8 -LRB- 8.47 -RRB- 49.8 -LRB- 7.04 -RRB- 47.9 -LRB- 8.20 -RRB- 47.4 -LRB- 8.79 -RRB- 49.8 -LRB- 6.68 -RRB- 49.1 -LRB- 6.67 -RRB- 49.6 -LRB- 7.00 -RRB- 50.6 -LRB- 6.49 -RRB- MCI = Mild Cognitive Impairment , WP = Walking Program , PAP = Placebo Activity Program , FA/B12/B6 = Folic Acid , Vitamin B12 , Vitamin B6 supplementation , D-QoL = Dementia Quality of Life , SF12-MCS = Short Form 12 Mental Component Summary , SF12-PCS = Short Form 12 Physical Component Summarya Higher rating indicates better QoL * P < 0.05 -LRB- difference between FA/B12/B6 and placebo -RRB- Attendance to the WP and the PAP Overall median attendance to the exercise programs -LRB- 10th − 90th percentile -RRB- was 63 -LRB- 0 -- 89 -RRB- percent and did not differ between the WP and the PAP . Especially in the first weeks , a considerable number of subjects discontinued participation , mostly because they did not want to participate in the exercise programs after all . Most frequent reasons for discontinuation of the program after the first weeks were health-related problems . No adverse events of the WP or PAP itself were reported . Adherent subjects attending at least 75 % of the sessions -LRB- n = 51 -RRB- were more often living together -LRB- 82 % vs. 65 % , P = 0.03 -RRB- and less physically active than non-adherers -LRB- n = 101 -RRB- , -LRB- median -LSB- 10th -- 90th percentile -RSB- was 36 -LSB- 13 -- 82 -RSB- vs. 44 -LSB- 10 -- 169 -RSB- min/day , P = 0.02 -RRB- . At baseline , adherers also had lower ratings of D-QoL-belonging -LRB- 3.6 -LSB- 0.41 -RSB- vs. 3.8 -LSB- 0.49 -RSB- , P = 0.02 -RRB- and higher SF12-MCS values -LRB- 56.5 -LSB- 5.6 -RSB- vs. 53.7 -LSB- 8.1 -RSB- , P = 0.02 -RRB- . Other baseline and QoL characteristics did not differ significantly . Compliance with the -LRB- FA/B12/B6 -RRB- supplementation Four participants did not return the blister packs . On the basis of pill counts in returned blister packs , median compliance -LRB- 10th -- 90th percentile -RRB- with the FA/B12/B6-supplementation was 100 -LRB- 97 -- 100 -RRB- percent and compliance with placebo-supplementation was 100 -LRB- 35 -- 100 -RRB- percent . Even though median compliance in both groups was 100 % , compliance in the placebo-group was significantly lower -LRB- P < 0.05 -RRB- . Eight subjects , one in the FA/B12/B6-group and seven in the placebo-group , did not take -LRB- vitamin -RRB- supplementation . Seven of them decided immediately after randomization not to participate in the interventions . The other wanted to participate in the exercise intervention only . Two participants discontinued taking vitamin pills during the trial after reporting sleep problems and increased forgetfulness ; one participant discontinued taking the placebo pills after reporting not feeling well . Modified intention to treat analyses Results of the walking program and FA/B6/B12 supplementation are presented in Table 4 . With respect to overall QoL , no positive significant main effect of the WP or FA/B6/B12 supplementation was found . A significantly detrimental effect of FA/B6/B12 supplementation was observed on D-QoL-belonging , -LRB- beta -LRB- 95 % CI -RRB- = − 0.18 -LRB- − 0.29 ; − 0.07 -RRB- , P < 0.01 -RRB- . A positive interaction between the WP and attendance to the WP was observed on D-QoL-belonging and D-QoL-positive affect . With each percent increase in attendance , D-QoL-belonging increased with 0.003 points -LRB- P = 0.04 -RRB- and D-QoL-positive affect with 0.002 points -LRB- P = 0.06 -RRB- in the WP compared to the PAP . With respect to health-related QoL , an interaction between the WP and gender was observed on the SF12-MCS -LRB- P = 0.06 -RRB- and therefore analysis for the SF12-MCS was stratified for gender . No main effects of the WP or FA/B12/B6-pills were observed . However , in men in the WP , SF12-MCS increased with 0.03 points with each percent increase in attendance -LRB- P = 0.08 -RRB- . Table 4Results of longitudinal multi level analyses on the effect of the WP and FA/B6/B12 supplementation on change in QoL -LRB- adjusted model -RRB- WP versus PAP Beta -LRB- 95 % CI -RRB- P-valueFA/B12/B6 versus placebo Beta -LRB- 95 % CI -RRB- P-valueD-QoL sumscore0 .04 -LRB- − 0.03 ; 0.10 -RRB- 0.25 − 0.06 -LRB- − 0.12 ; 0.004 -RRB- 0.07D-QoL aesthetics0 .06 -LRB- − 0.07 ; 0.20 -RRB- 0.37 − 0.07 -LRB- − 0.20 ; 0.07 -RRB- 0.33D-QoL belonging0 .00 -LRB- − 0.11 ; 0.11 -RRB- 0.96 − 0.18 -LRB- − 0.29 ; − 0.07 -RRB- 0.00D-QoL negative affect − 0.02 -LRB- − 0.12 ; 0.08 -RRB- 0.650.04 -LRB- − 0.05 ; 0.14 -RRB- 0.37D-QoL positive affect0 .04 -LRB- − 0.04 ; 0.13 -RRB- 0.34 − 0.04 -LRB- − 0.12 ; 0.04 -RRB- 0.33D-QoL self esteem0 .08 -LRB- − 0.02 ; 0.18 -RRB- 0.110.00 -LRB- − 0.10 ; 0.11 -RRB- 0.94SF12-PCS0.66 -LRB- − 1.23 ; 2.54 -RRB- 0.49 − 0.73 -LRB- − 2.65 ; 1.19 -RRB- 0.45SF12-MCS * Men − 0.82 -LRB- − 2.24 ; 0.60 -RRB- 0.250.25 -LRB- − 1.31 ; 1.81 -RRB- 0.76 Women1 .66 -LRB- − 1.50 ; 4.81 -RRB- 0.301.32 -LRB- − 1.93 ; 4.56 -RRB- 0.42 WP = Walking Program , PAP = Placebo Activity Program , FA/B12/B6 = Folic Acid , Vitamin B12 , Vitamin B6 supplementation , D-QoL = Dementia Quality of Life , SF12-MCS = Short Form 12 Mental Component Summary , SF12-PCS = Short Form 12 Physical Component Summary * Interaction WP and gender Per protocol analyses Subgroup analyses were performed in subjects attending 75 % or more of the WP or PAP sessions -LRB- n = 51 , 33 men and 18 women -RRB- . No between group differences were observed for FA/B12/B6-pills versus placebo-pills . A significant positive effect of the WP compared to the PAP was observed on D-QoL-positive affect , beta -LRB- 95 % CI -RRB- = 0.23 -LRB- 0.06 ; 0.39 -RRB- , P < 0.01 and a borderline significant positive effect on D-QoL-self esteem , beta -LRB- 95 % CI -RRB- = 0.17 -LRB- 0.001 ; 0.34 -RRB- , P = 0.05 . Discussion No positive main effect of walking or daily FA/B6/B12 supplementation was observed on QoL in community-dwelling adults with MCI . However , ratings of overall QoL -LRB- i.e. , feelings of belonging , positive affect -RRB- and the mental component of health-related QoL improved slightly with increasing attendance to the walking program . In a subgroup that attended at least 75 % of the sessions , a beneficial effect of the walking program was observed on positive affect and self esteem . To our knowledge , this is the first intervention study on QoL in community-dwelling adults with MCI . While memory complaints are reported to be negatively associated with QoL in healthy older adults with subjective memory complaints -LSB- 2 -RSB- , QoL ratings in our study population were already quite high at baseline . Baseline ratings on the DQOL sumscore and subscales fell ample above the midpoint of the scale , except for negative affect . Baseline scores on the SF-12MCS fell around a half standard deviation above the average in the general population and SF-12PCS fell about the average ratings . QoL-ratings have been reported to decrease as the severity of cognitive decline increases -LSB- 28 -RSB- . The possibility exists that MCI as operationalized in the present study may not have been serious enough to negatively influence overall and health-related QoL . In spite of the high baseline values , the QoL scales still allowed for further improvements , i.e. , there was no ceiling effect . However , it has been discussed before that QoL may represent a stable concept , which is difficult to change or that existing measures may not be responsive to subtle changes -LSB- 29 -RSB- . The relationship between physical activity and QoL has been studied extensively . However , it is difficult to draw a clear conclusion , since various definitions and operationalizations of QoL circulate . Moreover , comparisons between studies are being complicated by the wide variety of study populations and features of exercise intentions such as intensity , exercise mode , frequency and session and total duration -LSB- 30 -RSB- . However , Rejeski et al. -LSB- 31 -RSB- concluded in a review including 28 studies , of which 11 RCT 's , that physical activity positively influenced aspects of health-related QoL . In a recent meta-analysis of Netz et al. -LSB- 7 -RSB- including 36 studies , a small positive effect of exercise was observed on wellbeing in healthy older adults . In that meta-analysis four components of wellbeing were considered , including aspects that were also measured in the FACT-study , such as positive and negative affect , perception of physical fitness and physical symptoms . In the present study no main effects of the WP were observed in the modified intention to treat analyses . First , a possible explanation for the lack of effect may be that only participants with good QoL were able to attend enough sessions . In contrast to an earlier study , no baseline differences in number of chronic diseases , physical health-related QoL and endurance were observed between adherers -LRB- attending ≥ 75 % of the sessions -RRB- and non-adherers -LRB- attending < 75 % of the sessions -RRB- -LSB- 32 -RSB- . However , adherers rated their mental health-related QoL at baseline significantly better than non-adherers . The difference was three points , which approximately equaled a difference of 5 % . The possibility exists that subjects with lower mental health-related QoL were inclined to attend less sessions . Nevertheless , it is not likely that this biased our results , because non-adherers and drop-outs from the exercise programs were included in the modified intention to treat analyses . In future studies in subjects with cognitive decline , session attendance may be improved by informing subjects extensively about the study aims and the consequences of participation . Moreover , if possible with respect to logistic and financial issues , we advice to schedule time and staff for the close personal follow-up of temporary drop-outs . Second , it has been reported that the association between physical activity and QoL is lower among older adults who function at or above the norm -LSB- 31 -RSB- . By applying inclusion criteria for the present trial -LRB- e.g. , community dwelling , no ADL disabilities , being able to perform moderate intensity physical activity -RRB- , we presumably selected physically healthy and active subjects . This is supported by the high baseline activity levels . Two-thirds of the participants reported to be physically active at moderate intensity for 30 min or more per day . Subjects meeting this guideline are reported to have better health-related QoL than physically inactive adults -LSB- 8 -RSB- . Additionally , Netz et al. found that larger effects of exercise on wellbeing were observed in sedentary adults -LSB- 7 -RSB- . However , in the present study , no interaction between the walking program and baseline physical activity level was observed -LRB- results not presented -RRB- , indicating that inactive participants did not benefit more from the WP than active participants . Therefore , it is not likely that baseline physical activity level was a main cause of the lack of main effects . Finally , inconclusive evidence is available about the intensity and exercise mode of physical activity required to benefit QoL . Netz et al. -LSB- 7 -RSB- concluded that aerobic training of moderate intensity was most beneficial for wellbeing . In a cross-sectional study , it was also observed that moderate intensity physical activity was positively related to health-related QoL -LSB- 8 -RSB- . In contrast , in a review by Spirduso and Cronin -LSB- 33 -RSB- no evidence of a relationship between exercise intensity and the rate of improvement in QoL was found . If the former would be true , the possibility exists that the contrast between both programs in the present study would not have been large enough to induce differences in QoL . If the latter would be true , participants would have benefited from participation in both exercise programs regardless of intensity . Both programs may either have added to better self-efficacy , or may prevented a decline in self-efficacy . The walking program by training cardiovascular endurance ; the placebo activity program by training e.g. , balance and ADL . Self-efficacy refers to somebody 's belief that one has the capabilities to successfully manage situational demands and is mentioned to be a mediating mechanism for the effect of physical activity on QoL -LSB- 7 , 30 , 34 , 35 -RSB- . Thus , the presence of the low intensity placebo activity program in our study may have contributed towards the lack of between group differences . Nevertheless , several outcomes improved with increasing attendance to the walking program . In the per protocol analyses a beneficial effect was observed on positive affect . Self esteem also tended to improve . However , observed differences were small and approximated 5 % differences from baseline QoL ratings . As a rule of thumb , a minimal change of 5 % has been mentioned to signify clinical relevance . To obtain a change of 5 % by increasing attendance , the required increase in attendance would be 62 % for D-QoL-belonging and 94 % for D-QoL-positive affect and the SF12-MCS . Therefore , it can be questioned whether the observed effects are clinically relevant . No effect of the FA/B12/B6 supplementation was observed except for a negative effect on feelings of belonging . However , no theoretical rationale exists for this effect . Our findings are in line with previous RCT 's on the effect of vitamin B supplementation on aspects of QoL . Deijen et al. -LSB- 11 -RSB- observed no effect of supplementation with 20 mg vitamin B6 for 3 months on mood in healthy men -LRB- n = 76 -RRB- . Also no effect of supplementation with 750 μg folate , 15 μg vitamin B12 or 75 mg vitamin B6 daily for 35 days was observed on mood in women aged 65 or over -LRB- n = 75 -RRB- -LSB- 11 -RSB- . Finally , no effect on health-related QoL was observed of a weekly injection with 1 mg vitamin B12 for 4 weeks in adults with vitamin B12 deficiency -LRB- n = 140 -RRB- -LSB- 13 -RSB- . These findings may find its origin in the used operationalizations and measures of QoL that include very few items that directly relate to nutrition . Amarantos et al. -LSB- 36 -RSB- underline the need to develop QoL measures including items that relate nutrition to QoL . To conclude , the walking program and vitamin B supplementation were not effective in improving QoL in community-dwelling older adults with MCI within 1 year . However , increasing attendance to moderate intensity physical activity may benefit certain aspects of QoL .

O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O B I I O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

quality of life
aged
exercise
randomized controlled trial


Radiofrequency

ablation

of

osseous

metastases

for

the

palliation

of

pain

A

number

of

different

methods

have

been

proposed

for

pain

relief

in

cancer

patients

with

bone

metastases

each

with

different

indications

contraindications

and

complications

-LRB-

systemic

analgesics

bisphosphonates

antitumor

chemotherapy

radiotherapy

systemic

radio-isotopes

local

surgery

and

vertebroplasty

-RRB-

The

ideal

treatment

has

to

be

fast

safe

effective

and

tolerable

for

the

patient

CT-guided

radiofrequency

-LRB-

RF

-RRB-

ablation

may

fulfill

these

criteria

Our

experience

in

the

treatment

of

patients

-LRB-

lesions

-RRB-

with

painful

bone

metastases

using

RF

ablation

was

assessed

There

was

a

significant

decrease

in

the

mean

Brief

Pain

Inventory

-LRB-

BPI

-RRB-

score

for

worst

pain

for

average

pain

and

for

pain

interference

during

daily

life

-LRB-

and

units

respectively

-RRB-

and

weeks

after

treatment

There

was

a

marked

decrease

-LRB-

out

of

patients

and

weeks

after

treatment

-RRB-

in

the

use

of

analgesics

CT-guided

RF

ablation

appears

to

be

effective

for

treatment

of

painful

bone

metastases

Introduction

Painful

bone

metastases

are

a

common

cause

of

morbidity

in

patients

with

metastatic

cancer

especially

when

combined

with

possible

neural

compression

and

pathologic

fractures

Several

solid

cancers

are

associated

with

bone

involvement

most

often

prostate

and

breast

Thirty

to

seventy

percent

of

cancer

patients

develop

bone

metastases

-LSB-

-RSB-

They

indicate

widespread

disease

Treatment

of

local

disease

may

reduce

the

pain

of

these

patients

who

in

most

cases

have

a

life

expectancy

of

months

Such

treatment

must

be

fast

safe

effective

and

tolerable

A

number

of

treatment

methods

are

available

that

have

variable

success

and

complications

Radiation

therapy

is

the

preferred

treatment

in

this

setting

but

other

modalities

such

as

chemotherapy

hormonal

therapy

radiopharmaceutical

therapy

and

surgery

alone

or

in

combination

with

non-steroid

anti-inflammatory

drugs

-LRB-

NSAIDs

-RRB-

opioids

and

adjuvant

drugs

are

used

for

pain

palliation

-LSB-

-RSB-

Radiofrequency

-LRB-

RF

-RRB-

ablation

is

a

relatively

new

method

for

the

treatment

of

painful

bone

metastases

Previously

tumour

ablation

was

performed

with

percutaneous

ethanol

injection

under

CT

guidance

-LSB-

-RSB-

Administration

of

ethanol

was

described

in

terminally

ill

cancer

patients

with

bone

lesions

who

had

been

unsuccessfully

treated

by

radiation

therapy

and/or

chemotherapy

Radiofrequency

ablation

has

been

employed

for

the

treatment

of

hepatocellular

carcinoma

-LRB-

HCC

-RRB-

liver

metastases

renal

and

lung

tumours

as

well

as

for

the

treatment

of

osteoid

osteoma

for

which

it

has

become

the

treatment

of

choice

-LSB-

-RSB-

Competing

methods

include

chemical

ablation

-LRB-

with

ethanol

or

acetic

acid

-RRB-

and

thermal

therapies

such

as

with

laser

microwave

ultrasound

and

cryoablation

-LSB-

-RSB-

The

aim

of

this

study

was

to

demonstrate

the

effectiveness

of

RF

ablation

of

bone

metastases

using

CT

guidance

Materials

and

methods

Thirty

patients

were

retrospectively

identified

There

were

men

and

women

Their

ages

were

between

and

years

-LRB-

mean

standard

deviation

-LSB-

SD

-RSB-

years

-RRB-

The

patients

had

bone

metastases

which

were

treated

with

RF

ablation

under

CT

guidance

at

our

hospital

over

a

period

of

years

All

treated

lesions

were

osteolytic

with

a

combination

of

bone

destruction

and

a

soft

tissue

mass

In

there

was

a

solitary

lesion

and

in

patients

there

were

two

such

lesions

resulting

in

a

total

number

of

metastases

Bone

metastases

were

diagnosed

by

bone

scintigraphy

and

spiral

CT.

The

diagnosis

was

confirmed

with

a

core

biopsy

obtained

at

the

beginning

of

the

procedure

Their

topographical

distribution

and

the

originating

primary

malignancies

are

presented

in

Table

In

our

study

the

most

common

treated

metastases

originated

from

colon

cancer

which

was

probably

related

to

the

patient

population

treated

at

the

oncology

department

of

our

hospital

Table

metastasis

classification

with

regard

to

the

primary

malignant

lesion

and

the

site

of

the

skeleton

involvedSite

of

primary

neoplasm

originnSite

of

Lesion

diameter

was

between

and

cm

-LRB-

mean

SD

cm

-RRB-

For

sizes

over

cm

two

or

more

electrode

placements

were

needed

-LRB-

with

a

maximum

of

five

-RRB-

Previously

obtained

imaging

examinations

were

evaluated

for

lesion

characteristics

and

feasibility

of

electrode

positioning

and

ablation

Lesions

located

in

proximity

to

the

spinal

cord

and

major

nerves

-LRB-

less

than

cm

-RRB-

were

excluded

from

RF

treatment

Patient

selection

criteria

are

summarised

in

Table

The

study

was

in

accordance

with

the

ethical

principles

of

the

Helsinki

Declaration

and

informed

consent

was

obtained

in

each

case

Table

for

the

selection

of

patients

to

undergo

radiofrequency

ablationPatient

selection

criteriaBrief

Pain

Inventory

-LRB-

BPI

-RRB-

score

above

not

responding

to

chemotherapy

and/or

radiation

therapy

-LRB-

completion

of

therapy

at

least

weeks

before

the

radiofrequency

ablation

session

-RRB-

Chemotherapy-associated

complications

that

halted

this

treatmentLesions

adjacent

to

structures

sensitive

to

irradiationPatients

with

life

expectancy

greater

than

months

who

were

not

eligible

for

surgical

treatment

Patients

who

preferred

this

treatment

over

the

other

alternatives

Physical

examination

was

performed

by

the

oncologist

and

in

collaboration

with

the

radiologist

performing

the

ablation

Pain

was

assessed

with

the

Brief

Pain

Inventory

-LRB-

BPI

-RRB-

The

use

of

analgesics

was

recorded

the

day

before

the

procedure

Before

the

procedure

blood

cell

count

and

blood

clotting

analysis

were

performed

Minimal

requirements

were

platelet

-LRB-

PLT

-RRB-

count

ml

-LRB-

normal

range

ml

-RRB-

prothrombin

time

-LRB-

PT

-RRB-

international

normalised

ratio

-LRB-

INR

-RRB-

-LRB-

normal

range

-RRB-

and

partial

thromboplastin

time

-LRB-

PTT

-RRB-

s

-LRB-

normal

range

s

-RRB-

The

procedure

was

performed

under

conscious

sedation

-LRB-

administration

of

mg

of

bromazepam

PO

and

mg

of

pethidine

hydrochloric

acid

intramurally

min

prior

to

the

procedure

-RRB-

and

was

trained

in

regular

breathing

and

breath-holding

-LRB-

suspended

respiration

-RRB-

before

the

procedure

He/she

was

placed

in

the

appropriate

position

-LRB-

prone

supine

or

lateral

depending

on

the

site

of

the

lesion

-RRB-

and

a

scan

of

the

desired

area

with

a

slice

thickness

was

performed

using

a

Picker

-LRB-

Philips

Medical

Systems

Amsterdam

The

Netherlands

-RRB-

At

least

one

of

two

staff

radiologists

with

extensive

experience

in

biopsies

and

tumour

ablations

was

involved

in

all

ablations

The

lesion

's

exact

location

and

depth

in

relation

to

the

overlying

skin

was

determined

on

CT.

The

skin

was

then

prepared

with

povidone

iodine

-LRB-

-RRB-

solution

Local

anaesthesia

-LRB-

ml

of

lidocaine

hydrochloride

solution

-RRB-

was

administered

Radiofrequency

ablation

was

performed

with

a

RITA

Model

electrosurgical

generator

-LRB-

RITA

Medical

Systems

Mountain

View

CA

USA

-RRB-

and

a

seven-array

to

multitined

electrode

for

lesions

smaller

than

cm

-LRB-

out

of

-RRB-

or

a

nine-array

multitined

electrode

for

larger

lesions

-LRB-

out

of

-RRB-

The

electrode

tip

was

inserted

to

approximately

cm

from

the

centre

of

the

target

The

electrodes

were

then

deployed

slowly

taking

into

account

the

need

to

ablate

the

lesion

bone

interface

The

net

ablation

time

was

min

at

an

energy

level

of

W

with

the

target

goal

temperature

set

to

°C

During

the

procedure

the

infusion

port

of

the

electrode

was

flushed

with

a

lidocaine

hydrochloride

solution

in

order

to

reduce

patient

discomfort

and

to

decrease

tissue

overheating

and

vaporisation

The

number

of

electrode

placements

individual

-LRB-

per

electrode

-RRB-

and

total

ablation

times

the

total

energy

delivered

to

the

target

and

the

lesion

temperatures

achieved

were

recorded

After

each

session

a

dual-phase

spiral

CT

examination

with

intravenous

contrast

medium

was

performed

in

order

to

assess

response

as

confirmed

by

low

lesion

attenuation

values

and

lack

of

contrast

enhancement

Patients

were

hospitalised

and

observed

for

h.

Analgesics

were

administered

if

required

Before

patient

discharge

the

pain

was

re-evaluated

with

the

BPI

score

Post-ablation

assessment

was

completed

with

telephone

interview

after

one

four

and

eight

week

The

BPI

score

and

the

use

of

analgesics

were

recorded

again

Results

For

lesions

smaller

than

cm

-LRB-

out

of

-RRB-

one

placement

was

adequate

while

for

the

remaining

out

of

cases

of

lesions

that

were

larger

than

cm

two

or

more

placements

were

required

one

lesion

sized

cm

required

five

placements

accomplished

in

two

sessions

-LRB-

since

more

deployments

are

required

in

larger

lesions

-RRB-

The

total

procedure

time

ranged

between

and

min

-LRB-

mean

SD

min

Table

-RRB-

There

were

no

complications

and

post-treatment

CT

revealed

a

good

response

as

confirmed

by

low

lesion

attenuation

values

and

a

lack

of

contrast

medium

enhancement

consistent

with

necrosis

Post-procedural

CT

did

not

demonstrate

any

major

complications

-LRB-

such

as

haemorrhage

thrombosis

of

neighbouring

veins

or

skin

burns

-RRB-

Table

characteristics

andtreatmentNumber

of

lesionsSize

of

lesion

-LRB-

cm

-RRB-

Number

of

electrode

placementsTime

of

radiofrequency

energy

deposition

-LRB-

min

-RRB-

Eleven

patients

reported

no

pain

reduction

during

the

first

h

after

the

procedure

and

were

treated

with

analgesics

-LRB-

opioids

or

an

opioid/NSAID

combination

-RRB-

Nineteen

of

the

patients

reported

early

pain

reduction

In

of

the

patients

was

increased

pain

reported

Prior

to

the

procedure

the

mean

BPI

score

for

worst

pain

was

-LRB-

on

a

numerical

rating

scale

where

indicates

no

pain

and

indicates

worst

pain

imaginable

-RRB-

mean

pain

was

and

mean

pain

interference

with

daily

life

These

scores

were

reduced

to

and

h

after

the

procedure

dropped

to

and

after

week

to

and

after

weeks

and

to

and

after

weeks

respectively

These

results

revealed

a

marked

decrease

in

pain

with

subsequent

improvement

in

the

life

quality

for

all

participants

since

the

first

week

post-treatment

that

lasted

throughout

the

follow-up

-LRB-

Fig.

-RRB-

For

all

time

points

the

mean

BPI

score

for

worst

pain

for

average

pain

and

for

pain

interference

in

daily

life

improved

in

comparison

to

preprocedural

symptoms

-LRB-

p

paired

t

test

Figs.

-RRB-

Fig.

Brief

Pain

Inventory

-LRB-

BPI

-RRB-

scores

over

time

for

patients

treated

with

radiofrequency

ablation

a

Worst

pain

b

Average

pain

c

Interference

of

pain

in

everyday

lifeFig

tomography

scan

a

during

and

b

after

the

radiofrequency

session

with

the

patient

in

a

supine

position

The

electrode

is

deployed

inside

the

metastatic

lesion

of

the

left

acetabulum

-LRB-

metastasis

from

breast

cancer

-RRB-

There

is

no

enhancement

after

intravenous

contrast

media

administration

Before

the

radiofrequency

session

the

average

pain

score

was

During

the

first

h

after

radiofrequency

it

was

and

and

weeks

later

the

average

pain

scores

were

and

respectivelyFig

tomography

scan

images

at

the

level

of

the

sacrum

show

a

b

two

different

electrode

placements

within

a

soft

tissue

mass

involving

the

sacrum

and

right

iliac

bone

-LRB-

metastasis

from

thyroid

cancer

-RRB-

Before

the

radiofrequency

session

the

average

pain

score

was

During

the

first

h

after

radiofrequency

it

was

and

and

weeks

later

the

average

pain

scores

were

and

respectivelyFig

tomography

scan

image

during

the

electrode

placement

inside

a

a

metastatic

lesion

involving

a

rib

-LRB-

the

primary

neoplasm

originates

in

the

lung

-RRB-

Immediately

after

the

radiofrequency

session

the

contrast

enhancement

CT

scan

revealed

a

hypodense

area

-LRB-

necrosis

-RRB-

inside

the

lesion

Before

the

radiofrequency

session

the

average

pain

score

was

During

the

first

h

after

RF

it

was

and

and

weeks

later

the

average

pain

scores

were

and

respectively

Prior

to

RF

ablation

out

of

patients

received

opioids

or

an

opioid/NSAID

combination

The

remaining

patients

received

NSAIDs

One

week

after

treatment

out

of

patients

were

treated

with

a

combination

of

NSAID/low-dose

opioids

Six

out

of

thirty

used

NSAIDs

After

and

weeks

only

out

of

patients

received

any

medication

NSAIDs

One

patient

died

during

the

follow-up

for

reasons

not

related

to

RF

ablation

Discussion

In

patients

with

cancer

pain

originating

from

bone

metastases

can

be

difficult

to

treat

A

number

of

treatment

options

are

available

including

NSAIDs

opioids

and

adjuvant

drugs

medications

radiation

therapy

chemotherapy

hormonal

therapy

radiopharmaceutical

therapy

surgery

and

vertebroplasty

Medication

represents

the

first

line

of

treatment

NSAIDs

and

adjuvant

drugs

represent

basic

medication

potentially

followed

by

NSAID/low-dose

opioid

combinations

and

finally

increasing

the

opioid

dose

Radiation

therapy

is

another

treatment

option

that

may

also

be

employed

in

pathologic

or

impending

fractures

-LSB-

-RSB-

Approximately

of

patients

undergoing

radiation

therapy

will

experience

pain

relief

after

between

days

and

up

to

weeks

after

treatment

However

radiation

therapy

may

also

cause

complications

mostly

from

damage

of

adjacent

soft

tissues

-LSB-

-RSB-

Chemotherapy

and

radiopharmaceutical

therapy

are

the

only

systemic

methods

of

treatment

that

deal

with

even

small

foci

of

metastatic

cells

However

not

all

metastases

are

sensitive

to

chemotherapeutic

agents

Chemotherapy

is

often

not

well

tolerated

and

is

associated

with

complications

Radiopharmaceutical

therapy

can

be

more

useful

in

treating

patients

with

multifocal

bone

metastases

It

has

been

reported

that

radiopharmaceuticals

proved

efficient

in

pain

palliation

mostly

in

bone

metastases

from

breast

prostate

and

perhaps

small

cell

lung

cancer

As

in

the

case

of

chemotherapy

all

agents

have

advantages

and

possible

side

effects

Radiopharmaceutical

agents

vary

with

regard

to

the

analgesic

efficacy

duration

of

pain

palliation

ability

to

repeat

treatments

toxicity

and

expense

-LSB-

-RSB-

The

term

ablation

refers

to

the

local

destruction

of

the

tumour

by

the

means

of

application

of

either

chemical

agents

-LRB-

ethanol

acetic

acid

-RRB-

or

local

deposition

of

some

form

of

energy

-LRB-

radiofrequency

laser

microwave

ultrasound

and

cryoablation

-RRB-

Image-guided

RF

ablation

is

currently

used

for

the

treatment

of

various

tumours

with

good

results

According

to

preliminary

results

by

Dupuy

et

al.

-LSB-

-RSB-

RF

ablation

can

provide

palliative

treatment

for

patients

with

painful

osseous

metastases

Later

on

Callstrom

et

al.

-LSB-

-RSB-

reported

results

after

treating

patients

and

concluded

that

this

modality

provides

an

effective

and

safe

alternative

method

of

pain

palliation

in

patients

with

osteolytic

metastases

A

multicentre

study

involving

patients

with

painful

osseous

metastases

was

carried

out

by

Goetz

et

al.

-LSB-

-RSB-

and

showed

again

significant

reduction

of

pain

and

decrease

in

the

use

of

opioids

with

only

minor

complications

The

proposed

mechanisms

by

which

RF

ablation

decreases

pain

may

involve

pain

transmission

inhibition

by

destroying

sensory

nerve

fibres

in

the

periosteum

and

bone

cortex

reduction

of

lesion

volume

with

decreased

stimulation

of

sensory

nerve

fibres

destruction

of

tumour

cells

that

are

producing

nerve-stimulating

cytokines

-LRB-

tumour

necrosis

factor-alpha

-LSB-

TNF-α

-RSB-

interleukins

etc.

-RRB-

and

inhibition

of

osteoclast

activity

-LSB-

-RSB-

In

our

patients

we

observed

a

considerable

reduction

of

pain

and

improvement

of

the

quality

of

life

as

measured

by

the

BPI

score

A

decrease

in

the

use

of

analgesic

medications

was

notable

in

our

series

and

possibly

greater

than

others

reported

in

previous

studies

-LSB-

-RSB-

The

reduction

of

the

procedural

time

is

limited

by

both

the

time

needed

to

achieve

the

optimal

target

temperature

and

the

size

of

the

lesion

because

more

than

one

deployment

is

required

in

larger

bone

metastases

Although

a

few

patients

reported

mild

discomfort

during

the

ablation

of

the

sessions

was

forced

to

stop

owing

to

considerable

patient

distress

There

were

of

the

possible

adverse

effects

including

infection

haemorrhage

neurological

complications

skin

burns

or

the

so-called

post-ablation

syndrome

-LRB-

low-grade

fevers

°F

-LSB-

°C

-RSB-

-RRB-

myalgias

and

malaise

for

up

to

week

after

the

procedure

-RRB-

Pain

reduction

was

fast

and

occurred

within

the

first

h

for

some

and

during

the

first

week

in

the

majority

of

the

patients

This

appears

to

be

a

fairly

well-tolerated

procedure

and

the

combination

of

conscious

sedation

and

local

anaesthesia

is

adequate

for

its

needs

In

the

spine

RF

ablation

may

be

contraindicated

due

to

the

close

relationship

with

the

spinal

cord

and

nerve

root

Vertebroplasty

may

be

used

for

pain

relief

and

stabilisation

of

osteolytic

lesions

Pain

relief

occurs

within

hours

or

days

-LRB-

mean

h

-RRB-

of

the

procedure

sometimes

after

a

transient

worsening

of

pain

-LSB-

-RSB-

Mechanical

or

thermal

damage

to

the

adjacent

soft

tissue

from

needle

positioning

or

cement

leakage

are

the

potential

complications

In

our

study

there

were

no

lesions

threatening

the

stability

of

the

spine

There

are

two

conflicting

studies

in

the

literature

concerning

the

use

of

RF

ablation

in

spinal

metastases

One

of

them

has

demonstrated

that

the

presence

of

cancellous

or

cortical

bone

between

the

lesion

and

the

spinal

canal

can

provide

adequate

safety

for

the

procedure

-LSB-

-RSB-

Another

study

in

an

in

vivo

animal

model

with

the

use

of

magnetic

resonance

imaging

-LRB-

MRI

-RRB-

and

pathological

evaluation

has

demonstrated

that

the

placement

of

the

electrode

against

the

posterior

vertebral

body

wall

resulted

in

damage

of

the

spinal

cord

-LSB-

-RSB-

In

most

series

lesions

within

cm

of

the

spinal

cord

lesions

involving

the

posterior

wall

and

lesions

with

cortical

bone

destruction

with

involvement

of

soft

tissue

were

considered

to

represent

contraindications

to

treatment

-LSB-

-RSB-

All

spinal

metastases

treated

in

our

series

involved

the

anterior

part

of

the

vertebral

body

The

follow-up

period

for

this

study

was

weeks

a

period

that

we

believed

was

sufficient

to

demonstrate

that

RFA

provides

effective

palliation

There

is

however

a

need

for

randomised

prospective

studies

to

evaluate

the

method

and

to

compare

it

with

other

treatment

modalities

such

as

radiation

therapy

Continued

follow-up

is

warranted

to

determine

the

long-term

efficacy

of

this

interventional

approach

In

conclusion

imaged-guided

RF

ablation

of

painful

bone

metastases

is

promising

It

appears

to

be

effective

safe

and

well

tolerated

by

patients

B I O B I O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O B O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O B O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

radiofrequency ablation
osseous metastases
pain