Randomized Controlled Trials of Pediatric Massage : A Review The existing reviews of massage therapy -LRB- MT -RRB- research are either limited to infants , adults , or were conducted prior to the publication of the most recent studies using pediatric samples . Randomized controlled trials -LRB- RCTs -RRB- of pediatric MT are reviewed . A literature search yielded 24 RCTs of pediatric MT , defined as the manual manipulation of soft tissue intended to promote health and well-being in recipients between 2 and 19 years of age . Because RCTs of pediatric MT varied considerably in the amount and types of data reported , quantitative and narrative review methods were both used . Single-dose and multiple-dose effects were examined separately . Among single-dose effects , significant reductions of state anxiety were observed at the first session -LRB- g = 0.59 , P < 0.05 -RRB- and the last session -LRB- g = 1.10 , P < 0.01 -RRB- of a course of treatment . Effects for salivary cortisol -LRB- g = 0.28 -RRB- , negative mood -LRB- g = 0.52 -RRB- and behavior -LRB- g = 0.37 -RRB- were non-significant . Three of eleven multiple-dose effects were statistically significant . These were trait anxiety -LRB- g = 0.94 , P < 0.05 -RRB- , muscle tone -LRB- g = 0.90 , P < 0.01 -RRB- and arthritis pain -LRB- g = 1.33 , P < 0.01 -RRB- . Results of studies not permitting effect size calculation were judged to be generally consistent with quantitative results . MT benefits pediatric recipients , though not as universally as sometimes reported . Numerous weaknesses endemic to MT research -LRB- e.g. low statistical power , frequent failure to report basic descriptive statistics -RRB- are identified , and recommendations for future pediatric MT research are discussed . Introduction Background Massage therapy -LRB- MT -RRB- is one of the most widely used complementary and alternative medicine -LRB- CAM -RRB- therapies in the United States according to National Health Interview Survey data . It is estimated that consumers spend between 2 and 4 billion dollars on 75 million visits to massage therapists annually -LRB- 1 -RRB- . Studies indicate that parents are making increasing use of CAM therapies , including MT , for their children . One study found that 33 % of parents reported using CAM for their child within the past year , with MT being one of the most popular therapies -LRB- 2 -RRB- . Another study shows that families of children with special health care needs are almost twice as likely to have used CAM for their child -LRB- 3 -RRB- . CAM use is now prevalent , even in many traditional medical settings -LSB- e.g. 49 % of university-affiliated pain management centers in the US and Canada offer MT -LRB- 4 -RRB- -RSB- , yet pediatricians and other health care professionals are often not informed about the CAM therapies that are being used by their patients -LRB- 2 -RRB- . This may be especially true for pediatric CAM , where survey results indicate that 81 % of parents currently using CAM for their child wanted to discuss it with their pediatrician , but only 36 % did -LRB- 5 -RRB- . For CAM to truly be integrated into the health care system , it needs to be openly discussed and recognized for its value , particularly in the area of palliative care -LRB- 6 -RRB- . A scientific understanding of CAM therapies , such as pediatric MT , will permit a greater understanding of the value of this type of therapy . Numerous studies of MT for children and young adults have been conducted . These include randomized controlled trials -LRB- RCTs -RRB- , evaluation studies , descriptive case studies and reviews . However , the existing reviews of MT research are either limited to adult participants , limited to infants , were conducted prior to the publication of the most recent studies using pediatric samples , or neglected to quantify results . Ottenbacher and colleagues -LRB- 7 -RRB- quantitative review of tactile stimulation for infants and young children , published nearly 20 years ago , found statistically significant beneficial outcomes for five of the six categories examined -LRB- these were motor/reflex , cognitive/language , social/personal , physiological and overall development ; visual/auditory was non-significant -RRB- . Field -LRB- 8 -RRB- conducted a narrative review , including research on persons of all ages , and concluded that MT had a multitude of condition-specific effects in addition to consistently providing reductions of anxiety , depression and levels of stress hormones -LRB- most notably cortisol -RRB- that were observed across studies . The two most recent reviews are quantitative reviews that focus specifically on either infants or adults . A Cochrane review systematically examines MT for preterm and low birth-weight infants , and reaches the negative conclusion that ` there is insufficient evidence of effectiveness to warrant wider use of preterm infant massage ' -LRB- 9 -RRB- . The quantitative review of MT performed on adults confirmed -LRB- and quantified -RRB- some of Field 's conclusions while disputing others -LRB- 10 -RRB- . Substantial reductions resulting from multiple sessions of MT were noted for depression -LRB- g = 0.62 , P < 0.01 -RRB- and trait anxiety -LRB- g = 0.75 , P < 0.01 -RRB- , while MT 's effect on cortisol levels was not statistically significant -LRB- g = 0.14 -RRB- . While this review supported the value of MT by quantifying its ability to substantially reduce symptoms of psychological distress in adults , taken together this set of findings called into question some of the theories most often invoked to explain the benefits of MT , especially the theory that MT benefits recipients primarily by activating the parasympathetic nervous system -LRB- 10 -RRB- . Current Review While the latest quantitative reviews increase our understanding of MT and indicate new directions for research , they neglect MT performed on pediatric samples . The current review examines MT 's effects in pediatric samples -LRB- defined here as studies where the mean age of participants was between 2 and 19 years -RRB- , with a focus on RCTs . While some have argued against using RCTs to understand CAM modalities such as MT -LRB- 11 -RRB- , RCTs represent the state-of-the-art for establishing cause and effect relationships in treatment research because they are the most effective study design for ruling out alternate -LRB- i.e. non-treatment -RRB- explanations for observed effects , including spontaneous recovery , placebo effects and statistical regression -LRB- 12 -RRB- . Though there have been some new pediatric MT studies published since the reviews by Ottenbacher et al. -LRB- 7 -RRB- and Field -LRB- 8 -RRB- , the number of RCTs that examine pediatric MT is still quite small . In addition , a weakness of existing MT research is that , more often than not , studies in this area do not include the minimal statistical detail necessary to calculate effect sizes . For these reasons , a full meta-analytic treatment of MT research with pediatric samples is not possible . However , consistent with Rosenthal 's observation that a narrative literature review can only be improved by the addition of a simple , descriptive quantitative analysis -LRB- 13 -RRB- , we quantified results where possible , and include these results in combination with a narrative review of other RCTs . In some cases , the present findings are being compared with analogous findings in the adult literature . When these comparisons are made , we are referring to the adult meta-analysis conducted by Moyer et al. , unless otherwise stated -LRB- 10 -RRB- . Operational Definition A notable challenge in reviewing MT studies is that there are many forms of MT in practice . The American Massage Therapy Association -LRB- AMTA -RRB- defines massage as ` manual soft tissue manipulation , -LSB- including -RSB- holding , causing movement , and/or applying pressure to the body ' -LRB- 14 -RRB- . As written , this very broad definition includes numerous MT approaches commonly used in clinical practice that are relevant to the current review , but could also include rare forms of medical massage -LRB- e.g. optic nerve massage -LRB- 15 -RRB- , light compressive massage for congenital dacryocystocele -LRB- 16 -RRB- , cardiac massage -LRB- 17 -RRB- -RRB- , that are outside the intended scope of this review . For this reason , we focus on forms of MT that are consistent with traditional Swedish styles of massage . Swedish massage uses five main strokes to stimulate the circulation of blood through the body ; petrissage -LRB- kneading -RRB- , effleurage -LRB- stroking -RRB- , friction , tapotement -LRB- tapping -RRB- and vibration . For the purposes of this review , MT is typified by the manual manipulation of soft tissue , performed by a person other than the recipient , intended to promote health and well-being . This operational definition allows a range of MT styles to be included in this review . Studies vary on many details , including the amount of clothing worn by recipients , whether a massage chair or massage table was used , whether MT took place in a clinical setting or at home , and whether MT was performed by a person with full , partial , or no training as a massage therapist . Studies also vary in which anatomical regions are massaged . Despite all these variations , it is reasonable to expect that there will be some consistent outcomes that result from MT. Eventually , as a scientific understanding of MT grows , studies that examine the importance of these variations will be advisable , but currently the questions of greatest interest are at a more fundamental level . Types of Effects MT effects can be divided into single-dose and multiple-dose . Single-dose effects include MT 's influence on psychological or physiological states that are transient in nature and that might reasonably be expected to be influenced by a single session of MT. Multiple-dose effects are restricted to MT 's influence on variables that are considered to be more enduring , or that would likely be influenced only by a series of MT sessions performed over a period of time , as opposed to a single dose . Frequently , both single - and multiple-dose effects are examined in the same study . One example is a study of MT for autistic children that examined the single-dose effect of MT on salivary cortisol -LRB- immediately prior to , and immediately following , an individual session of MT -RRB- and the multiple-dose effect of MT on depression -LRB- at the beginning of , and at the conclusion of , a sequence of MT sessions over time -RRB- -LRB- 18 -RRB- . A second example is a study that evaluated children 's distress during burn treatment , which included the single-dose effect of MT for state anxiety and the multiple-dose effect of MT for depression -LRB- 19 -RRB- . Typically , studies include the terms ` short-term effect ' and ` long-term effect ' to indicate single - and multiple-dose effects , respectively . Our decision to use the single-dose and multiple-dose terminology is motivated by the desire to prevent any confusion that may arise related to how long an effect may last following the termination of treatment . None of the studies in the current review examine whether any MT effects last beyond the final day on which a participant receives treatment , making the use of the term ` long-term effect ' potentially misleading . The potential benefits of MT can be further classified according to whether they are primarily affective , physiological or behavioral in nature . Affective refers to effects most closely associated with the recipients ' feelings and emotions . Physiological effects are those concerned with recipients ' vital organismic processes . Behavioral effects are those related to the recipients ' observable responses to their environment . Study results reviewed here will first be separated by the single-dose versus multiple-dose distinction , then further categorized into affective , physiological and behavioral dimensions . Methods Literature Search A literature search was conducted by the first author -LRB- S.B. -RRB- using the keywords massage , child and pediatric to search the MEDLINE , LexisNexis , CINAHL and PsycInfo databases . We checked the NIH CRISP Database to search for other publicly funded studies currently in progress . MT researchers were also contacted to obtain studies that were unpublished , in press or otherwise not found by means of database searches . With the introduction of the first Massage Therapy Research Conference in Albuquerque , New Mexico -LRB- 43 -RRB- , leaders in the field of massage research were readily contacted . We used this opportunity to access current unpublished pediatric massage studies . Studies obtained by these methods were inspected to ensure that they examined a form of MT consistent with the present study 's operational definition of MT performed on a pediatric sample . Application of these criteria yielded 24 RCTs of MT with a pediatric sample . These studies , along with important details , are listed in Table 1 . Statistical Analysis For studies that provided sufficient data , between-groups comparisons on variables of interest were converted to Hedges ' g effect size by the second author -LRB- C.A.M. -RRB- . Hedges ' g , calculated as -LRB- Group mean 1 − Group mean 2 -RRB- / Pooled SD , estimates the number of standard deviations that the average member of a treatment group differs from the average member of a comparison group for a given outcome . Hedges ' g was selected over Cohen 's d , a similar standardized mean difference effect size . This choice was made for two reasons . First , in some cases the original study data could only be converted to g. Second , using g makes the results of the current review as consistent as possible with the existing meta-analysis of MT effects for adults . In cases where a study employed more than one measure to examine the same outcome variable , results of multiple measures completed by participants or by blinded observers -LRB- but not those completed by non-blind observers -RRB- were standardized and then averaged , yielding one effect size per variable for each study . Similarly , if a study examined the immediate effects of more than one application of treatment , the results of the multiple applications or assessments were standardized and , when similar in magnitude , averaged in order to calculate a single effect size for that study . In the single case where these assessments clearly differed in a systematic way -LRB- i.e. state anxiety , where the effects of a final session were always larger than the effects of the initial session ; paired sample t -LRB- 3 -RRB- = 4.46 , one-tailed P < 0.02 -RRB- , separate effects were calculated for each timepoint . Effect sizes were coded such that positive values , for any variable , indicate a more desirable outcome -LRB- e.g. a reduction in anxiety -RRB- for the participants who received MT. Individual study effect sizes were subjected to a correction for small sample bias , then weighted by their inverse variance and averaged to generate a mean effect size for each outcome variable -LRB- 20 -RRB- . All effect sizes were calculated according to a random effects model of error estimation . Statistical significance of the mean effect sizes was assessed by calculating the 95 % confidence interval for the population parameter . A significance level of 0.05 or better is inferred when zero is not contained within the confidence interval . Results Of the 24 RCTs , only 9 -- accounting for a total of 200 participants -- provided sufficient data for their results to be systematically quantified . Table 2 lists mean effect sizes for 16 outcome variables -LRB- g -RRB- , as well as the number of studies contributing to each effect size -LRB- k -RRB- , the total number of participants contributing to each effect size -LRB- N -RRB- and 95 % confidence intervals . Five of these sixteen effect sizes were statistically significant . For the single-dose effects category , these included state anxiety at the first session -LRB- g = 0.59 , P < 0.05 -RRB- and at the last session -LRB- g = 1.10 , P < 0.01 -RRB- of a course of treatment . Effects for salivary cortisol -LRB- g = 0.28 -RRB- , negative mood -LRB- g = 0.52 -RRB- and behavior -LRB- g = 0.37 -RRB- were non-significant . Only 3 of the 11 multiple-dose effect sizes were statistically significant . These were trait anxiety -LRB- g = 0.94 , P < 0.05 -RRB- , arthritis pain -LRB- g = 1.33 , P < 0.01 -RRB- and muscle tone -LRB- g = 0.90 , P < 0.01 -RRB- . Of the 24 RCTs , 15 -LRB- accounting for 458 research participants -RRB- do not report sufficient data to permit effect size calculation , a frequent problem in MT research that makes objective interpretation of results difficult . Nevertheless , by judiciously comparing the scant data presented in this subset of studies with the objective data previously summarized , it should be possible to see if there are any dramatic contrasts among the findings . These interpretations , within the context of the more objective findings , appear in the results categories that follow . Single-Dose Effects Affective Dimension State anxiety . Field et al. have conducted several pediatric MT studies where anxiety is an outcome measure . These studies date back to 1992 when MT was applied to a group of pediatric psychiatric patients -LRB- 21 -RRB- . Four studies with reportable effect sizes -LRB- No . 's 6 , 14 , 17 and 21 in Table 1 -RRB- , using a total of 81 participants , compared MT with either relaxation therapy or a reading comparison group with state anxiety -- a momentary emotional reaction consisting of apprehension , tension , worry and heightened autonomic nervous system activity -LRB- 22 -RRB- -- as a dependent variable . Three of the studies -LRB- No . 's 14 , 17 and 21 -RRB- used the State Trait Anxiety Inventory -LRB- two specify the child version -RRB- . One study -LRB- No. 6 -RRB- of MT for children with juvenile rheumatoid arthritis used a behavior observation of the child 's anxiety level performed by a blinded rater . MT consistently reduced state anxiety in these studies . This single-dose effect was unique in that it is significantly larger at the second timepoint , so we examined these separately . Results of a first session of MT yield a statistically significant effect , g = 0.59 -LRB- 95 % CI = 0.15 , 1.04 -RRB- . The effect at the last session is even greater , g = 1.10 -LRB- 95 % CI = 0.64 , 1.57 -RRB- . These results are depicted graphically in Fig. 1 . Possibly , the substantially larger effect occurring at the last session of treatment may be the result of participants ' increasing comfort with MT -LRB- or with the massage therapist -RRB- over the course of time , or the effect may be related to MT 's potential to reduce trait anxiety over a course of treatment -LRB- 8 -RRB- . These pediatric results are consistent with the same effect found for adults , where this effect has been estimated as g = 0.37 -LRB- 95 % CI = 0.14 , 0.59 -RRB- . Possibly , the larger effect for the pediatric samples examined here reflects a greater treatment aptitude for this population ; however , with such wide confidence intervals , this is only speculation . Studies where state anxiety was a dependent variable but effect sizes could not be calculated include samples of children who experienced Hurricane Andrew -LRB- 23 -RRB- , depressed adolescent mothers -LRB- 24 -RRB- , and children and adolescents with a range of illnesses including diabetes -LRB- 25 -RRB- , atopic dermatitis -LRB- 26 -RRB- , asthma -LRB- 27 -RRB- , bulimia -LRB- 28 -RRB- and leukemia -LRB- 29 -RRB- . The most commonly used measures across these studies were the State Trait Anxiety Inventory for Children -LRB- STAIC -RRB- and the State Trait Anxiety Inventory -LRB- STAI -RRB- for adolescents . A study of children who experienced Hurricane Andrew assessed both the single-dose effects of state anxiety and the multiple-dose effects of trait anxiety . These studies are consistent with the previously reported effect sizes , in that MT appears to decrease state anxiety . The MT in all of these studies was conducted either daily or twice weekly over a treatment period of 30 -- 45 days . MT sessions generally lasted between 20 and 30 min , the one exception being the leukemia study where MT sessions were 15 min in duration . Four of these studies trained parents to provide MT directly to their child and the remaining three either used trained massage therapists or massage students . Mood . Mood , which may be defined as ` transient episodes of feeling or affect ' -LRB- 30 -RRB- , has frequently been an outcome measure in pediatric MT studies . Study populations have included depressed adolescent mothers , and children and adolescents with cystic fibrosis , leukemia and bulimia . Two studies -LRB- No . 's 13 and 14 in Table 1 -RRB- , using a total of 50 participants , compared MT with either a reading or wait-list control to examine MT 's effect on mood . One of these studies -LRB- No. 14 -RRB- used the Profile of Mood States -LRB- POMS -RRB- -LRB- 31 -RRB- depressed mood subscale . The second study -LRB- No. 13 -RRB- used a faces scale and a modification of the Children 's Pain/Fear Thermometer Rating Scale . Taken together , these studies yield a non-significant effect , g = 0.52 -LRB- 95 % CI = − 0.05 , 1.10 -RRB- that is consistent with the results found for adult recipients -LRB- g = 0.34 , 95 % CI = − 0.08 , 0.76 -RRB- . These positive but non-significant results suggest at least four possibilities . One is that the tools that have been used to measure mood in these studies are not precisely capturing overall mood , but are being affected by correlates of mood such as depression , pain or fear . A second possibility is that MT 's modest effect on mood has not been examined with sufficient statistical power , resulting in wide confidence intervals . The third is that MT 's positive effect on mood is affected by a moderator variable that has not yet been examined -LRB- e.g. recipient 's comfort with MT ; the existence of a therapeutic bond between the recipient and provider , etc. -RRB- . Finally , the possibility that MT does not specifically have a positive effect on mood can not be definitively ruled out . Physiological Dimension Salivary cortisol . Two studies -LRB- No . 's 6 and 13 in Table 1 -RRB- , using a total of 50 participants , compared MT with either relaxation training or a wait-list control to examine MT 's single-dose effect on cortisol -- a stress hormone associated with activation of the sympathetic nervous system in response to certain kinds of stressors . In both studies , salivary cortisol -LSB- but not urinary cortisol , which less accurately captures short-term stress responses -LRB- 32 -RRB- most likely to respond to single-dose MT -RSB- was sampled pre - and post-MT session , with a delay of 20 -- 30 min after the session , because salivary cortisol samples reflect responses to stimulation occurring ∼ 20 min prior to collection . Both studies also took into account the diurnal cortisol cycle , characterized by an increase in secretory activity following awakening and a declining trend over the course of the day -LRB- 33 -RRB- . Combined , these studies yield a non-significant reduction , g = 0.28 -LRB- 95 % CI = − 0.27 , 0.84 -RRB- of salivary cortisol for the participants receiving MT in comparison to controls . This finding contrasts Field 's assertion that reductions in cortisol level are one of MT 's most reliable effects , but is consistent with meta-analytic findings based on adult samples , where cortisol effects were small and non-significant -LRB- g = 0.14 , 95 % CI = − 0.10 , 0.38 -RRB- -LRB- 10 -RRB- . Based on the available evidence , MT 's single-dose effect on cortisol levels appears to be small , and possibly zero . Behavioral Dimension Distress behaviors . One study -LRB- No. 20 in Table 1 -RRB- compared MT with standard care for children receiving burn treatment , and examined the children 's distress behaviors before and during this painful procedure . The Children 's Hospital of Eastern Ontario Pain Scale -LRB- 34 -RRB- was used to code distress behaviors before and during a dressing change -LRB- 35 -RRB- . Six behavior categories were assessed including cry , facial , verbal , torso , touch and legs . The MT group showed only an increase in torso movements during the dressing change , whereas the control group showed an increase in five out of the six distress behaviors . Combined observational ratings made by nurses , who were blind to the group to which the children were assigned , favored MT , g = 0.37 -LRB- 95 % CI = − 0.43 , 1.17 -RRB- . Though this effect favors MT , the wide confidence interval , which may be partially or wholly attributable to the small sample -LRB- n = 24 -RRB- , makes this result difficult to interpret . In several other studies with behavioral outcomes where effect sizes could not be calculated , researchers reported improvements in fidgetiness , activity , vocalization and cooperation . The most commonly used instrument in these studies is a Behavior Observation Scale that was first used to assess behavior after relaxation therapy classes -LRB- 36 -RRB- . Using this measure , behavior is observed three times during the 30 min prior to MT , during MT itself and during the 30 min after MT. Because the effect size data are inconclusive and researchers report positive behavioral improvements resulting from MT , further study on distress behaviors may be warranted . Multiple-Dose Effects Affective Dimension Depression . Depression , including motivational and cognitive deficits , vegetative signs , and disruptions in interpersonal relationships beyond those expected from ordinary unhappiness or poor mood -LRB- 37 -RRB- , has been examined in pediatric MT studies , albeit with small samples . Two studies -LRB- No . 's 13 and 17 in Table 1 -RRB- , using a total of 54 participants , examined whether MT would reduce depression in comparison to either a wait-list control or to progressive muscle relaxation . The first study -LRB- No. 13 -RRB- used the Children 's Depression Inventory-Short Form , and was the only study reviewed to use that measure . It is an abbreviated version of a widely used self-report measure of depression for children and adolescents . The second study -LRB- No. 17 -RRB- used the Center for Epidemiological Studies-Depression scale , which was also used in several studies that did not permit effect size calculation . Though the mean effect favored MT , g = 0.48 , this effect is not statistically significant -LRB- 95 % CI = − 0.06 , 1.02 -RRB- . This result is inconclusive , but promising given that the confidence interval approaches significance , and also because the estimated effect is not greatly different from statistically significant reductions of depression found in adult samples -LRB- g = 0.62 , 95 % CI = 0.37 , 0.88 -RRB- . It is also generally consistent with the conclusions reached by the authors of studies that did not permit effect size calculation . Still , the possibility that MT does not reduce depression for pediatric recipients to the extent it does in adults can not be ruled out . At this point , further study on MT for pediatric depression is needed . Trait anxiety . One study -LRB- No. 13 in Table 1 -RRB- , using a sample of children and adolescents with attention-deficit hyperactivity disorder , examines MT 's effect on trait anxiety , a dispositional , internalized proneness to be anxious -LRB- 38 -RRB- , with enough detail to permit effect size calculation . This study , which also appears in the adult MT meta-analysis , uses the Revised Children 's Manifest Anxiety Scale to compare MT with a wait-list condition and yields a large , statistically significant effect -LRB- g = 0.94 , 95 % CI = 0.20 , 1.68 -RRB- that is consistent MT 's anxiolytic effects demonstrated in numerous studies with adult recipients . This result is consistent with author claims in the ` Hurricane Andrew ' study , where improvements in children 's trait anxiety at the end of the MT treatment are reported . Reduction of trait anxiety , resulting from a course of MT sessions , is certainly worthy of further study in pediatric populations . Pain . Four pediatric studies have been conducted that include pain as an outcome measure . Three of these studies used the Happy Faces Scale while only one study , a study of children with juvenile rheumatoid arthritis -LRB- and the only study with sufficient data for calculating effect sizes -RRB- , used the Varni/Thompson Pediatric Pain Questionnaire . This study -LRB- No. 6 in Table 1 -RRB- assessed pain in three ways -- child self report , parent report and physician report . The children and a pediatric rheumatologist , who was blind to group assignment , generated reports of pain reduction that were consistent ; parents ' ratings were omitted from effect size calculation due to their non-blind status and proneness to bias . In comparison to a relaxation therapy group , MT yielded a large , statistically significant pain reduction -LRB- g = 1.33 , 95 % CI = 0.37 , 2.29 -RRB- . This very large effect , in contrast with other studies that have shown mixed results for pain reduction resulting from MT , suggests that MT may be particularly well-suited to pain reduction for children with this condition . Three RCT 's that do not permit effect size calculation looked at MT 's impact on pain , and concluded that children experienced reductions of pain resulting from MT. Samples in these studies included children who experienced Hurricane Andrew -LRB- 23 -RRB- , adolescents with attention-deficit hyperactivity disorder -LRB- 39 -RRB- and children with atopic dermatitis -LRB- 26 -RRB- . These reports , combined with the findings in the juvenile rheumatoid arthritis study , indicate that MT for pain reduction in pediatric recipients is worthy of further examination . Physiological Dimension Muscle tone . Two recent studies that assess muscle tone -LRB- No . 's 23 and 24 in Table 1 -RRB- yield g = 0.90 -LRB- 95 % CI = 0.23 , 1.57 -RRB- . The first examines MT for children with cerebral palsy who received 30 min of MT 2 times per week for 12 weeks . This study also assesses spasticity , motor functioning , facial expressions and limb activity . The second study , of children with Down syndrome provided 30 min of MT 2 times per week for 8 weeks . Children 's development , and fine and gross motor functioning , was evaluated . Both studies used the Arms , Legs and Trunk Muscle Tone Scale -LRB- ALT Muscle Tone Scale -RRB- , which was designed during the pilot phase of the Down syndrome study . There is modest support that MT improves muscle tone , though it must be pointed out that the two studies diverge greatly in their individual results . Study number 23 in Table 1 had virtually no effect , while study number 24 had a huge effect . It must be noted that because these results come from a newly developed measure , the validity of the measure is not yet well-established . This may account for the divergent results across studies . Range of motion . One study -LRB- No. 23 in Table 1 -RRB- , with a sample of children suffering from cerebral palsy , yields non-significant improvements in range of motion , g = 0.31 -LRB- 95 % CI = − 0.57 , 1.19 -RRB- . The study notes that right and left hip extension , but not abduction , improved . Study authors note that increased muscle tone may have led to an increase in range of motion , but this result , based on a single study with 20 participants , is inconclusive . Immune measures . Two studies -LRB- No . 's 17 and 22 in Table 1 -RRB- examined markers of immune system functioning in HIV + adolescents or children . Though study authors are quick to point out that there were some within-group effects for those who received MT , a between-groups analysis that compares MT recipients with controls yields no effect -LRB- g = 0.06 , 95 % CI = − 0.52 , 0.63 -RRB- . In light of this result , specific MT effects on CD4 count were then examined separately , to account for the fact that the numerous immune system markers reported in those studies , and combined in the process of effect size calculation , might be obscuring this most important measure of disease progression in HIV + persons . When an effect size for CD4 count only is generated from these two studies , the effect is only marginally larger and still non-significant -LRB- g = 0.24 , 95 % CI = − 0.33 , 0.82 -RRB- . Though these studies , and another study of MT for children with leukemia -LRB- 29 -RRB- , make much of within-groups MT effects on immune system markers , the available between-groups data show that MT 's effect on immune system function is probably small and possibly zero . Pulmonary function . One study -LRB- No. 14 in Table 1 -RRB- examined whether MT might generate an improvement in peak air flow for a sample of 20 children with cystic fibrosis . In comparison to a reading control group , the children receiving MT had higher peak air flow , g = 0.47 -LRB- 95 % CI = − 0.41 , 1.35 -RRB- , indicating MT may be of specific value to children with this condition . Another study -LRB- 27 -RRB- that does not permit effect size calculation reports multiple measures of breathing improvement for asthmatic children ages 6 -- 8 years , though older children -LRB- ages 9 -- 14 years -RRB- showed fewer improvements . Overall , evidence for MT effects on pulmonary function is promising , and further study is warranted . Skin condition . Two RCT 's examine MT 's effect on skin condition . Children with atopic dermatitis were studied to determine the effect of MT on redness , scaling , lichenification , excoriation and pruritus -LRB- 26 -RRB- . Though effect sizes can not be calculated , study authors indicate some improvement following MT. Pediatric patients with hypertrophic scarring -LRB- HTS -RRB- were also studied and vascularity , pliability and height of the HTS revealed no appreciable effects . There is some evidence that pruritis decreased in certain patients with mature burn scars following MT. There is insufficient evidence to validate MT effects on skin condition in pediatric recipients . Glucose level . -LRB- No. 7 in Table 1 -RRB- One study of children with diabetes examined the effect of MT on blood glucose levels -LRB- 25 -RRB- . The authors conclude that MT lowers mean blood glucose levels and that compliance for insulin and food regulation improved , though data necessary for effect size calculation are not reported . Behavioral Dimension Developmentally appropriate functioning . Two studies -LRB- No . 's 23 and 24 in Table 1 -RRB- used the Developmental Programming for Infants and Young Children -LRB- DPIYC -RRB- scale to assess developmentally appropriate functioning in recipients following MT. The average effect was small and non-significant -LRB- g = 0.24 , 95 % CI = − 0.38 , 0.86 -RRB- , though it must be pointed out that the studies had divergent results . Study number 24 yields a modest improvement in developmentally appropriate functioning in a sample of children with Down syndrome . Study number 23 , with a sample of cerebral palsy sufferers , yields no effect . Possibly , these divergent results are the result of the different populations sampled within the studies . Taken together these results are inconclusive , but the encouraging results of the study with children who have Down syndrome indicate that further studies should be done with children having this or a related condition . Spasticity . One study -LRB- No. 23 in Table 1 -RRB- , with a sample of children suffering from cerebral palsy , examined whether MT had an effect on spasticity by using the Spasticity scale/modified Ashworth scale . The small , non-significant effect -LRB- g = 0.26 , 95 % CI = − 0.62 , 1.14 -RRB- does not support an MT effect on spasticity . Because this study was very small -LRB- n = 20 -RRB- , further testing in this area may be beneficial . Hostility . One study -LRB- No. 21 in Table 1 -RRB- , with a small sample of aggressive adolescents , examined whether MT might reduce hostility compared with relaxation therapy . This study yields g = − 0.85 -LRB- 95 % CI = − 1.85 , 0.15 -RRB- , a non-significant effect , but one that almost reaches significance in the wrong direction . The most tenable conclusion from this finding , a result based on a very small sample , is that MT has no effect on hostility beyond that provided by relaxation therapy to which it was compared . Though participants were randomly assigned , the MT group was approximately three points higher on the SCL-90R Hostility subscale prior to treatment . While scores decreased in the MT group during the treatment period , they also did in the relaxation therapy group , such that the MT group is still three points higher than the relaxation therapy group at the end of the treatment period . The authors ' assertion that ` by the end of the study -LSB- massaged adolescents -RSB- reported feeling less hostile ' obfuscates the fact that there was no between-groups effect . Related measures used in this study , such as the Overt Aggression Scale , were completed not by study participants , but by their legal guardians who were not blinded to group assignment , making their ratings prone to bias . Nevertheless , when all such measures included in the study are used to calculate an effect size , regardless of blinding , the result still converges on no effect . Classroom behavior . One study -LRB- No. 13 in Table 1 -RRB- examined the classroom behavior of students with attention-deficit hyperactivity disorder using the Conners Teacher Rating Scale . Six factors of this scale were used including hyperactivity , conduct , emotional-indulgent , anxious-passive , asocial and daydream/attention problems . In comparison with a wait-list control , MT yielded g = 0.66 -LRB- 95 % CI = − 0.07 , 1.39 -RRB- , an effect that , while non-significant , is encouraging . Further studies of MT for this population are needed to confirm whether it might be of value in improving behavior , an outcome that seems possible given MT 's relatively well-established potential to reduce anxiety . Studies that do not permit effect size calculation also suggest some improvements in classroom behavior following a course of MT. Improved classroom behavior and social relatedness are reported in studies of preschool children -LRB- 40 -RRB- and children with autism -LRB- 41 -RRB- . Cognitive performance . -LRB- No. 11 in Table 1 -RRB- A study of MT for children in preschool concludes that MT impacts cognitive performance -LRB- 42 -RRB- . This study used three subtests of the Wechsler Preschool and Primary Scale of Intelligence -- Revised , but does not report sufficient data to quantify the effect . Sleep and relaxation . -LRB- No . 's 1 , 2 and 18 in Table 1 -RRB- Though none permit effect size calculation , three studies have examined the effect of MT on sleep and relaxation . In one study , parents of children with autism recorded their children 's sleep behavior in sleep diaries that included 5-point Likert scales -LRB- 41 -RRB- . It is reported that the MT group showed decreases in fussing/restlessness , crying , self-stimulation behavior and getting out of bed . Nighttime sleep recordings were conducted for a previously mentioned study of MT for child and adolescent psychiatric patients -LRB- 21 -RRB- . A video camera was set up on a tripod in the participant 's room . The video tapes were subsequently coded for quiet sleep , active sleep , awake and lying quietly , and awake and active . Percentage of time asleep increased significantly from the first to last day of MT and the percentage of nighttime wakefulness decreased over the same time frame . Finally , children who experienced Hurricane Andrew were rated by an observer on a visual analogue scale -LRB- VAS -RRB- , based on the child 's apparent relaxation level -LRB- 23 -RRB- . The VAS relaxation score increased significantly from the first to the last day of MT for the MT group . Possibly , MT promotes sleep and relaxation , but current studies do not permit this effect to be quantified . Discussion Available data reveals that MT provides benefit to pediatric recipients , though not as universally as has sometimes been reported . Benefits from both single-dose and multiple-dose sessions are evident . Most of the statistically significant effect sizes were observed for affective outcomes ; findings for the behavioral and physiological dimensions were less consistent . These results parallel known MT effects in adult recipients , where multiple-dose reductions of depression and trait anxiety are the largest effects . In reviewing MT for pediatric recipients , we encountered several weaknesses endemic to the MT research literature that should be addressed in subsequent studies . These included -LRB- i -RRB- low statistical power , -LRB- ii -RRB- frequent failure to report basic descriptive statistics , -LRB- iii -RRB- descriptions of results that do not logically follow study designs , and -LRB- iv -RRB- lack of replication . We discuss these in turn . Low statistical power . Most pediatric MT studies were conducted with fewer than 30 participants . When studies are this small , only the largest effects have any likelihood of being uncovered . As researchers engaged in our own clinical MT studies , we are sensitive to the expense and difficulty involved in recruiting participants , but our empathy , unfortunately , does nothing to change the mathematics of the situation . The statistical power of MT studies must be increased -LRB- primarily by conducting studies with larger samples -RRB- if we wish to discover anything beyond the largest effects . Failure to report basic descriptive statistics . Many pediatric MT studies have appeared in journals with lax standards for the reporting of data ; there is no other explanation for why studies would fail to report the most basic descriptive statistics . When a report does not include the standard deviations that describe the spread of the data , that report has almost no value as scientific evidence . This must not be allowed to continue in MT research , because it represents an enormous waste of resources . Simply put , researchers who take the time , effort and expense to perform a study should not allow the results of that study to be published without the statistics that permit an understanding of the outcome . If a journal does not require them , then the onus is on the researcher to ensure that the statistics are reported . Results that do not logically follow study designs . The importance of between-groups designs in MT has been noted -LRB- 12 -RRB- . Why , then , do so many MT studies that employ a between-groups design emphasize within-group comparisons ? The likely answer is that planned between-groups comparisons were non-significant -LRB- possibly due to low statistical power -RRB- , so study authors may given in to the temptation to report the statistically significant , but misleading , within-group effect . This problem is rampant in MT research , and represents a real threat to the way this research will be perceived in the future . Many of the consumers of MT research are committed practitioners who have not had training in statistics and research design -LRB- though it must be noted that research literacy among MT practitioners is increasing -RRB- . As such , they may be inclined to believe that coming across the sacrosanct ` P < 0.05 ' is proof of an MT effect , without realizing that this ` effect ' may be nothing more than the effect of time , a placebo effect and/or regression to the mean . Knowledgeable consumers of MT research must learn to distinguish within-group effects from between-groups effects , and MT researchers must clearly present between-groups findings when their studies employ a between-groups design . Lack of replication . All but two of the pediatric MT studies we reviewed were conducted by the Touch Research Institute at the University of Miami . Their contribution to MT research has been considerable ; however , scientific understanding is hampered when one laboratory is responsible for almost all of the results in an area of inquiry . Replication of results is a foundation of scientific progress , so it is necessary that other researchers contribute to this field . Given recent interest in CAM modalities , the small number of studies from other laboratories is surprising . We hope that this is about to change , and the success of the recent Highlighting Massage Therapy in CAM Research Conference -LRB- 43 -RRB- suggests that it will . Three pediatric MT RCT 's from other research groups , currently in progress , support our optimism . Two of these examine MT for children and adolescents with cancer . While the results of a study that will examine pain , mood , stress and relaxation outcomes from MT and heat therapy for terminal children -LRB- 44 -RRB- can not yet be reported , preliminary results of another study examining anxiety , fatigue , pain and nausea outcomes from MT in a sample of children with cancer -LRB- 45 -RRB- are promising ; in particular , reductions of anxiety are expected to be consistent with what has been reported in this review . The third study , conducted by the first author of this review -LRB- S.B. -RRB- and researchers at the UCLA Pediatric Exercise Laboratory -LRB- 46 -RRB- , evaluates pre-exercise MT for children with and without heart disease . Preliminary results show significant improvement in VO2 -LRB- oxygen consumption -RRB- for children who have an MT session prior to performing an exercise regimen on a stationary bicycle . If these results are validated in final analyses , they will be generally consistent with the finding that MT can improve pulmonary function . There are two other studies worth mentioning that have received IRB approval from Children 's Memorial Hospital in Chicago and will be enrolling participants shortly . These studies are an evaluation of MT for reduction of pain , nausea and anxiety in pediatric cancer patients -LRB- 47 -RRB- and an evaluation of MT on immune function and heart rate variability in HIV-infected pediatric patients -LRB- 48 -RRB- . The outcome measures for the first study are self-report ratings of pain , nausea and anxiety , whereas the second study evaluates T-Helper cells -LRB- CD4 + -RRB- , T-Suppressor cells -LRB- CD8 + -RRB- , Total B cells -LRB- CD3 , CD19 -RRB- , Natural Killer cells -LRB- CD56 + -RRB- , viral load and heart rate variability . Conclusion Current research indicates that MT is not a panacea for conditions studied in the pediatric population . In contrast to what has sometimes been claimed , there is little to no evidence to date to support effects such as improved immune system functioning , reduction of spasticity , or amelioration of hostility . In addition , there is currently scant evidence that MT provides benefits by first reducing cortisol , as MT 's effect on this stress hormone is seen to be small when analyzed correctly -LRB- i.e. in between-groups as opposed to within-group comparisons -RRB- . There is , however , a set of MT effects that have been shown to have real value to the pediatric population . MT shows a considerable impact on the state and trait anxiety levels of children . Because these effects are strong , and also because they are consistent with the findings in adults , future research on the anxiolytic effects of MT on pediatric recipients does not need to simply replicate previous studies . The greatest progress can now be made by focusing on the mediators and moderators of MT effects on anxiety , and on testing explanatory theories of these outcomes . MT effects on arthritis pain and muscle tone also appear to be strong , but these results do need to be replicated , as they are based on single studies . Other pediatric outcomes that are promising , but in need of further study , include MT 's effects on depression , negative mood , certain types of behavior -LRB- likely due to reductions of anxiety -RRB- and air flow in those suffering from pulmonary disorders such as cystic fibrosis . As increased statistical power in the form of additional studies is brought to bear on these potential benefits , it is likely that some will be quantitatively validated . Finally , it has been noted that prior MT research has not accounted for the communication that inevitably takes place between massage therapists and their recipients , nor has it examined the likelihood that therapists and recipients develop a therapeutic relationship during the course of MT -LRB- 10 -RRB- . This is also true in pediatric MT studies . MT has important parallels -LRB- in both process and outcomes -RRB- to psychotherapy -LRB- 10 -RRB- , a treatment that relies on communication and therapeutic relationship to provide effects . It seems likely that MT effects , especially those belonging to the affective category , are mediated or moderated by these previously unexamined factors . These should not be neglected in subsequent pediatric MT research . As adult consumers continue to explore and utilize all of their health care options , children will increasingly be recipients of MT. With this in mind , it is essential that we continue to study the benefits of MT for children , and the explanatory models that underlie them , so children 's health and wellness can be maximized . The value of MT has been examined for many specific conditions that afflict children . It is our hope that this review has consolidated those findings , indicated areas that require further study , and led to an increased scientific understanding of pediatric MT.

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 B O O O O O O O O O O O O O O O O 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 B I O O O O O O O O O B 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 B I 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 B O O O O O O O O O O O O O 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O O O O O O O O O O O O O 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 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 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 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The

diagnostic

value

of

in

patients

with

differentiated

thyroid

cancer

Background

The

purpose

of

this

prospective

study

was

to

evaluate

the

clinical

diagnostic

value

of

-LRB-

-RRB-

positron

emission

tomography

-LRB-

PET

-RRB-

in

patients

with

advanced

differentiated

thyroid

carcinoma

-LRB-

DTC

-RRB-

and

to

compare

the

imaging

results

with

the

whole-body

scan

-LRB-

WBS

-RRB-

Introduction

Papillary

and

follicular

thyroid

cancer

are

the

most

frequent

histological

types

of

thyroid

cancer

-LRB-

-RRB-

-LSB-

-RSB-

Total

thyroidectomy

with

or

without

lymph

node

dissection

is

the

initial

therapy

followed

by

radioactive

iodine

therapy

In

the

routine

follow-up

of

low-risk

patients

diagnostic

whole-body

scanning

-LRB-

WBS

-RRB-

is

not

recommended

in

the

recently

published

guidelines

-LSB-

-RSB-

-LRB-

-RRB-

but

is

still

considered

to

be

valuable

in

the

follow-up

of

the

high-risk

patients

Measurement

of

the

serum

level

of

thyroglobulin

-LRB-

Tg

-RRB-

under

recombinant

human

thyroid-stimulating

hormone

-LRB-

rhTSH

-RRB-

stimulation

or

suppression

and

ultrasonography

have

gained

a

more

central

role

in

monitoring

for

recurrent

thyroid

cancer

-LSB-

-RSB-

-LRB-

-RRB-

In

patients

with

increasing

or

elevated

Tg

a

blind

treatment

with

high-dose

can

be

applied

followed

by

a

post-treatment

scan

which

also

serves

as

a

diagnostic

tool

-LSB-

-RSB-

However

with

this

strategy

unnecessary

high

radiation

exposure

and

high

TSH

level

must

be

taken

into

account

especially

in

patients

who

subsequently

have

no

uptake

on

their

post-treatment

scan

Improvement

of

diagnostic

imaging

for

the

detection

of

recurrent

or

metastatic

disease

and

a

better

-LRB-

anatomical

-RRB-

localisation

e.g.

using

advanced

imaging

technique

such

as

emission

tomography

-LRB-

PET

-RRB-

CT

would

allow

more

selective

application

of

therapy

and

might

avoid

unnecessary

high-dose

treatments

Several

iodine

isotopes

such

as

play

an

important

role

in

nuclear

medicine

both

for

diagnostic

purposes

and

for

therapy

is

a

positron

emitting

isotope

and

therefore

suitable

PET

imaging

Its

half-life

is

days

with

a

very

complex

decay

scheme

leading

to

extra

non

or

partially

annihilation

radiation

coincidence

detection

-LSB-

-RSB-

Approximately

of

the

desintegrations

results

in

positron

emissions

While

the

radioisotopes

and

especially

are

used

on

a

wide

scale

in

diagnosis

and

treatment

of

all

thyroid

disorders

has

received

little

attention

This

isotope

would

allow

thyroid

cancer

imaging

using

the

high-resolution

PET

technique

-LSB-

-RSB-

has

so

far

mainly

been

used

for

dosimetry

or

thyroid

volume

measurements

-LSB-

-RSB-

However

the

recent

development

of

combined

PET/CT

scanners

may

increase

clinical

application

in

thyroid

cancer

patients

as

detailed

anatomical

information

is

combined

with

the

location

of

iodine

positive

tissue

-LSB-

-RSB-

has

recently

been

applied

for

staging

of

differentiated

thyroid

cancer

as

reported

in

a

few

case

reports

and

small

series

with

promising

results

-LSB-

-RSB-

However

the

diagnostic

value

of

imaging

as

compared

to

-LRB-

low

and

high-dose

-RRB-

scintigraphy

has

to

be

further

investigated

PET

may

be

able

to

detect

recurrent

or

residual

disease

in

differentiated

thyroid

carcinoma

-LRB-

DTC

-RRB-

with

a

higher

sensitivity

than

the

conventional

-LRB-

diagnostic

-RRB-

scans

because

of

the

higher

spatial

resolution

In

this

way

imaging

could

possibly

be

a

useful

diagnostic

tool

during

the

follow-up

of

DTC

patients

Therefore

we

have

performed

a

pilot

study

in

the

early

treatment

phase

of

thyroid

cancer

to

get

an

impression

of

the

diagnostic

potential

of

for

detection

and

staging

of

advanced

DTC

We

compared

the

imaging

results

with

the

diagnostic

and

post-treatment

Materials

and

methods

Twenty

patients

with

histologically

proven

advanced

DTC

including

extrathyroidal

tumour

growth

-LRB-

-RRB-

extra-nodal

tumour

growth

or

distant

metastasis

-LRB-

-RRB-

were

examined

in

this

study

These

patients

had

undergone

-LRB-

near

-RRB-

total

thyroidectomy

Four

to

weeks

after

surgery

diagnostic

after

MBq

of

was

obtained

followed

by

an

ablative

dose

of

MBq

Post-treatment

WBS

was

obtained

after

days

At

the

time

of

ablation

serum

Tg

and

Tg

antibodies

-LRB-

TgAb

-RRB-

levels

were

also

determined

All

studied

patients

underwent

diagnostic

scan

and

post-treatment

months

after

ablation

therapy

-LRB-

Fig.

-RRB-

The

Tgoff

levels

-LRB-

under

TSH

stimulation

after

thyroid

hormone

withdrawal

or

after

rhTSH

injection

-RRB-

were

also

measured

just

before

the

administration

of

the

diagnostic

low-dose

The

Medical

Ethics

Committee

of

University

Medical

Center

Groningen

approved

the

study

protocol

and

all

patients

gave

written

informed

consent

Fig.

diagram

showed

a

schematic

course

of

the

investigations

performed

months

after

ablation

Tg

was

measured

by

immunoradiometric

assay

-LRB-

Brahms

Henningsdorf

Germany

-RRB-

with

a

functional

sensitivity

-LRB-

i.e.

the

Tg

concentration

with

a

vital

capacity

of

-RRB-

of

ng/ml

as

determined

by

the

laboratory

Thyroglobulin

antibodies

-LRB-

TgAb

-RRB-

were

detected

by

both

immunoradiometric

assay

-LRB-

Brahms

Henningsdorf

Germany

-RRB-

with

a

cutoff

of

U/ml

and

by

immunoluminometric

assay

-LRB-

Abbott

Hoofddorp

Netherlands

-RRB-

on

the

Architect

i

platform

-LRB-

Abbott

-RRB-

with

a

cutoff

of

U/ml

Both

cutoff

concentrations

were

determined

by

Brahms

and

Abbott

respectively

In

patients

the

Tg

level

was

determined

after

thyroid

hormone

withdrawal

and

in

one

patient

after

rhTSH

due

to

poor

physical

condition

-LRB-

Table

-RRB-

Table

characteristics

and

imaging

resultsPtAge

sexTNMTgoff

-LRB-

ng/ml

-RRB-

TSH

-LRB-

mU/l

-RRB-

pelvis

CV

pelvis

CV

pelvis

MR

cv

p

MRI

pelvis

thyroid

bed

lung

Neck

thyroid

bed

lung

Neck

CT

lung

no

abnormal

lesions

MRI

neck

a

a

Skull

CV

pelvis

CV

CV

Skull

p

MR

cv

pb

Neck

MRI

neck

Neck

Neck

MRI

neck

Neck/SC

pelvis

MRI

pelvis

pb

bed

Neck/thyroid

bed

US

neck/FNAC

Pelvis

Pelvis

MRI

pelvis

Neck

MRI

neck

US

neck

and

FNAC

inconclusive

FDG

PET

prosthesis

MRI

pelvis/femur

reactive

tissue

around

the

femur

prosthesis

FDG

PET

lesions

in

costae

and

skull

MRI

skull

p

FDG

PET

X-pelvis

n

bone

scan

US

neck

and

FNAC

n

FDG

PET

US

neck

and

FNAC

n

FDG

PET

MRI

neck

US

neck

and

FNAC

n

FDG

PET

US

neck/FNAC

n

FDG

PET

and

CT

lung

MRI

neck

p

US

neck

lymph

node

not

accessible

for

FNA

FDG

PET

p

Papillar

f

follicular

Pt

I-WBS

post-treatment

Dx

I-WBS

diagnostic

CV

cervical

vertebrae

SC

sternal

clavicular

not

visible

just

visible

visible

clearly

visible

n

negative

p

positive

FNAC

fine

needle

aspiration

cytology

FDG-PET

fluorodeoxyglucose

positron

emission

tomography

arhTSH

stimulated

bIn

these

two

patients

no

additional

radiologic

imaging

of

the

neck

-LRB-

no.

-RRB-

and

pelvis

-LRB-

no.

-RRB-

was

performed

to

confirm

the

findings

on

the

PET

and

due

to

poor

physical

condition

and

due

to

the

lack

curative

therapeutic

options

Tracer

iodide

solution

was

obtained

from

Ritverc

Isotope

Products

St.

Petersburg

Russia

and

was

imported

by

I.D.B.

Holland

BV

-LRB-

Baarle-Nassau

The

Netherlands

-RRB-

Radiochemical

purity

using

instant

thin

layer

chromatography

and

radionuclide

purity

using

germanium

-LRB-

HP-Ge

-RRB-

detector

were

tested

before

release

according

to

standard

radiopharmaceutical

procedures

Before

use

the

solution

was

filtered

using

a

Millipore

bacterial

filter

-LRB-

μm

-RRB-

and

diluted

with

sterile

saline

A

sterility

test

was

performed

on

each

batch

but

data

were

only

available

after

administration

due

to

the

length

of

the

test

procedure

-LRB-

days

-RRB-

PET

scanning

Diagnostic

imaging

was

performed

h

after

intravenous

administration

of

MBq

of

-LSB-

-RSB-

A

Siemens

PET

camera

-LRB-

Exact

HR

Knoxville

TN

USA

-RRB-

was

used

for

imaging

The

patient

was

positioned

in

the

scanner

and

a

standard

clinical

whole-body

PET

study

was

performed

in

ETTE

mode

over

seven

to

eight

positions

-LRB-

from

the

upper

thigh

up

until

the

top

of

the

skull

-RRB-

of

emission

and

transmission

standard

energy

window

setting

of

keV

Images

were

reconstructed

with

attenuation-weighted

OSEM

two

iterations

and

eight

subsets

The

total

time

needed

for

the

scan

was

approximately

min

In

the

initial

four

patients

the

images

were

repeated

h

after

administration

-LRB-

thus

h

after

therapeutic

dose

of

-RRB-

using

the

same

acquisition

settings

as

after

h.

Narrowing

of

the

energy

window

-LRB-

or

keV

mode

-RRB-

for

imaging

during

high-dose

therapy

to

reduce

the

effects

of

γ-rays

-LRB-

keV

-RRB-

of

and

-LRB-

keV

-RRB-

and

to

improve

image

quality

as

described

in

the

phantom

study

-LRB-

and

clinical

application

in

one

thyroid

cancer

patient

-RRB-

by

Lubberink

et

al.

-LSB-

-RSB-

was

not

possible

in

our

institution

due

to

technical

reasons

e.g.

camera

characteristics

The

images

were

very

noisy

and

blurred

and

were

excluded

from

the

study

This

poor

image

quality

could

partially

be

explained

by

the

poor

statistics

due

to

the

very

low

radioactivity

left

in

the

body

after

h

and

partially

by

technical

reasons

as

described

above

Data

analysis

The

and

scans

were

visually

interpreted

by

two

independent

experienced

nuclear

medicine

physicians

-LRB-

HTP

PLJ

-RRB-

The

findings

on

the

scans

were

compared

with

the

findings

on

the

diagnostic

and

post-therapeutic

Correlation

with

radiologic

imaging

-LRB-

US

CT

MRI

-RRB-

and/or

cytological

-LRB-

fine

needle

aspiration

cytology

FNAC

-RRB-

investigation

was

done

to

confirm

the

findings

or

in

case

of

discordant

findings

on

the

scan

and

If

no

abnormal

uptake

was

seen

on

the

PET

scan

and

additional

radiologic

imaging

-LRB-

MRI

US

-RRB-

with

or

without

FNAC

and

fluorodeoxyglucose

-LRB-

FDG

-RRB-

PET

were

also

performed

to

detect

local

or

metastatic

disease

and/or

used

as

a

follow-up

diagnostic

tool

Results

From

December

until

April

consecutive

patients

with

advanced

DTC

were

included

in

this

prospective

study

The

group

consisted

of

ten

women

and

ten

men

median

age

of

years

-LRB-

range

years

-RRB-

Individual

patient

characteristics

and

the

findings

on

the

PET

scan

and

are

summarised

in

Table

Physiological

uptake

of

was

observed

in

the

salivary

glands

esophagus

gastrointestinal

tract

and

bladder

as

it

is

also

normally

seen

on

the

scans

vs

diagnostic

Eleven

patients

-LRB-

no.

-RRB-

showed

uptake

on

the

scan

In

only

three

of

them

-LRB-

no.

-RRB-

was

the

uptake

also

observed

on

the

diagnostic

scan

but

the

uptake

was

clearer

and

the

abnormalities

were

more

extensive

on

the

scan

-LRB-

Fig.

-RRB-

In

nine

patients

-LRB-

no.

-RRB-

no

uptake

was

observed

on

both

the

scans

Results

of

additional

radiologic

imaging

-LRB-

MRI

and/or

US-FNAC

-RRB-

are

also

listed

in

Table

Fig.

patient

-LRB-

no.

-RRB-

showed

a

clearly

visible

lesion

in

the

cervical

vertebrae

on

the

-LRB-

a

arrow

-RRB-

comparable

with

the

lesion

visible

on

the

post-treatment

-LRB-

c

arrow

-RRB-

This

lesion

was

vaguely

visible

on

the

diagnostic

-LRB-

b

arrow

-RRB-

Physiologic

uptake

in

the

esophagus

gastrointestinal

tract

and

bladder

is

observed

on

the

It

has

also

been

noticed

that

the

Tgoff

level

-LRB-

after

endogenous

TSH

stimulation

-RRB-

was

not

detectable

-LRB-

ng/ml

TSH

mU/L

-RRB-

without

the

presence

of

Tg

antibodies

in

five

-LRB-

Table

no.

-RRB-

of

the

patients

However

two

of

these

five

patients

showed

lesions

on

the

-LRB-

and

post-treatment

scan

-RRB-

confirmed

by

MRI

Diagnostic

was

negative

in

all

five

vs

post-treatment

Nine

-LRB-

no.

-RRB-

out

of

the

patients

with

uptake

on

the

scan

had

lesions

which

were

also

visible

on

the

post-treatment

scan

-LRB-

Fig.

-RRB-

In

two

patients

-LRB-

no.

-RRB-

no

uptake

was

observed

on

the

post-treatment

scan

and

no

anatomical

localisation

could

be

confirmed

FDG

PET

showed

however

lesions

in

the

costae

and

pelvis

in

patient

no.

-LRB-

Fig.

-RRB-

Fig.

patient

-LRB-

no.

-RRB-

showed

a

clearly

visible

lesion

in

the

left

lower

neck

region

or

on

the

-LRB-

a

arrow

-RRB-

comparable

with

the

lesion

visible

on

the

post-treatment

-LRB-

c

arrow

-RRB-

No

uptake

was

observed

on

the

diagnostic

-LRB-

b

-RRB-

Fig.

uptake

in

the

right

costae

-LRB-

arrow

-RRB-

and

left

hip

is

seen

on

the

FDG-PET

-LRB-

c

-RRB-

in

patient

no.

whereas

the

post-treatment

-LRB-

a

-RRB-

was

negative

The

-LRB-

b

-RRB-

showed

only

uptake

around

the

femur

prosthesis

on

the

right

side

which

is

also

observed

on

the

FDG-PET

which

could

be

explained

by

reactive

tissue

on

the

MRI

The

complementary

uptake

of

radioiodine

and

FDG

is

also

known

as

the

flip-flop

phenomenon

which

was

first

described

by

Joensuu

and

Ahonen

-LSB-

-RSB-

Two

patients

-LRB-

no.

-RRB-

showed

uptake

on

the

post-treatment

scan

which

was

not

visible

on

the

scan

In

one

MRI

confirmed

the

uptake

in

the

skull

and

in

the

other

no

anatomical

localisation

could

be

found

for

the

uptake

in

the

pelvis

region

In

seven

patients

-LRB-

no.

-RRB-

no

uptake

was

observed

on

both

the

scans

In

four

of

seven

patients

-LRB-

no.

-RRB-

no

lesions

could

be

found

with

MRI

and/or

US-FNAC

in

one

of

these

four

-LRB-

no.

-RRB-

FDG-PET

showed

uptake

in

the

lungs

which

was

confirmed

by

CT.

One

patient

-LRB-

no.

-RRB-

showed

slightly

enlarged

lymph

node

in

the

superior

mediastinum

on

the

MRI

which

was

not

accessible

for

US-guided

FNAC

In

two

patients

-LRB-

no.

-RRB-

MRI/US

of

the

neck

will

be

obtained

-LRB-

due

to

patient

delay

-RRB-

Results

of

additional

radiologic

imaging

are

listed

in

Table

Discussion

This

pilot

study

showed

that

detected

more

abnormalities

in

comparison

to

the

diagnostic

but

showed

comparable

findings

with

the

post-treatment

Eleven

patients

had

positive

scanning

and

only

three

had

visible

abnormalities

with

the

low-dose

scan

Moreover

also

showed

abnormalities

in

two

of

the

five

patients

with

undetectable

Tg

while

the

low-dose

diagnostic

scan

was

negative

in

all

five

These

findings

suggest

that

better

predicts

the

outcome

of

high-dose

treatment

and

would

be

better

suited

as

a

diagnostic

tool

to

base

clinical

decisions

on

such

as

additional

surgery

or

application

of

high

dose

Therefore

should

be

performed

before

considering

high-dose

treatment

A

negative

could

mean

omitting

treatment

and

further

additional

imaging

should

be

performed

to

detect

-LRB-

non-iodine

avid

-RRB-

metastatic

disease

Two

patients

-LRB-

no.

-RRB-

showed

uptake

in

the

skull

and

pelvis

region

respectively

on

the

post-treatment

which

was

not

visible

on

the

Possible

explanations

for

these

findings

might

be

the

low

dose

of

in

which

-LRB-

small

-RRB-

lesions

in

the

skull

might

be

missed

and

false-positive

uptake

of

in

the

bowel

which

could

be

mistaken

for

abnormality

Our

results

are

in

agreement

with

the

study

by

Freudenberg

et

al.

-LSB-

-RSB-

In

their

study

patients

with

advanced

DTC

underwent

high-dose

CT

combined

FDG-PET

and

US

post-thyroidectomy

during

routine

clinical

staging

The

overall

lesion

detectability

for

high-dose

was

comparable

with

the

vs

respectively

Moreover

combined

modality

which

showed

an

overall

lesion

detectability

of

resulted

in

a

change

of

staging

in

two

patients

and

a

change

in

management

in

one

It

has

been

questioned

why

would

be

a

suitable

diagnostic

tool

when

blind

treatment

is

given

anyway

in

the

clinical

practice

Blind

treatment

with

high-dose

in

patients

known

with

negative

low-dose

diagnostic

scanning

but

with

elevated

Tg

has

been

used

as

a

diagnostic

therapeutic

and

prognostic

tool

Patients

without

iodine

accumulation

on

the

post-treatment

WBS

which

could

be

an

indication

for

tumour

dedifferentiation

had

a

worse

prognosis

compared

to

those

with

a

positive

post-treatment

WBS

-LSB-

-RSB-

Repeating

high

doses

of

may

bear

the

risks

in

terms

of

long-term

risk

of

secondary

malignancies

In

addition

repeated

long-lasting

TSH

stimulation

might

have

adverse

effects

on

tumour

growth

This

aspect

of

long-lasting

TSH

stimulation

may

be

prevented

when

performing

the

after

rhTSH

stimulation

before

the

decision

of

giving

additional

high-dose

However

comparative

studies

are

needed

to

evaluate

the

yield

of

the

under

endogenous

TSH

stimulation

and

after

rhTSH

stimulation

Additional

advantages

of

would

include

the

better

resolution

of

this

tomographic

method

and

the

ease

of

combining

this

with

CT

data

to

increase

the

diagnostic

value

as

shown

by

Freudenberg

et

al.

-LSB-

-RSB-

Moreover

would

allow

more

precise

dosimetric

calculations

-LSB-

-RSB-

although

that

was

not

a

focus

of

this

study

Another

aspect

which

favours

performing

of

before

blind

high-dose

is

the

radiation

dose

The

effective

dose

of

is

in

the

same

order

of

magnitude

as

-LSB-

-RSB-

The

effective

dose

of

is

mSv/MBq

with

a

thyroid

uptake

of

and

increases

mSv/MBq

with

a

thyroid

uptake

of

-LSB-

-RSB-

The

total

radiation

exposure

has

been

calculated

at

mSv

for

a

dose

of

MBq

The

administered

dose

is

comparable

to

the

dose

administered

for

routine

nuclear

medicine

scans

However

the

total

radiation

exposure

of

is

just

a

fraction

compared

to

the

total

radiation

exposure

of

the

therapeutic

dose

of

-LRB-

mSv

for

MBq

-LSB-

-RSB-

which

was

also

mentioned

in

the

study

by

Freudenberg

et

al.

-LSB-

-RSB-

The

issue

whether

stunning

is

a

real

phenomenon

and

its

clinical

relevance/consequence

is

debatable

Stunning

effect

after

-LRB-

higher

-RRB-

diagnostic

dose

of

has

been

described

and

discussed

in

the

literature

The

applied

diagnostic

dose

could

impair

the

ability

of

the

residual

thyroid

carcinoma

tissue

to

accumulate

the

subsequently

applied

high-dose

dose

The

degree

of

stunning

probably

depends

on

the

absorbed

radiation

dose

and

the

time

between

the

diagnostic

and

therapeutic

dose

Stunning

was

not

seen

with

diagnostic

doses

of

MBq

-LRB-

mCi

-RRB-

or

lower

-LSB-

-RSB-

whereas

stunning

was

frequently

observed

after

a

diagnostic

dose

of

MBq

-LRB-

mCi

-RRB-

-LSB-

-RSB-

There

is

also

evidence

that

a

short

time

interval

between

the

administration

of

the

diagnostic

and

therapeutic

dose

may

diminish

the

effect

of

stunning

-LSB-

-RSB-

Most

authors

who

have

described

stunning

administered

the

therapeutic

dose

several

days

after

the

completion

of

the

diagnostic

scan

-LSB-

-RSB-

Stunning

is

not

seen

when

the

therapeutic

dose

is

administered

within

several

hours

Furthermore

the

time

interval

between

the

administration

of

a

high

dose

of

and

the

performance

of

a

post-therapy

WBS

may

influence

the

observation

of

stunning

-LSB-

-RSB-

A

longer

time

interval

allows

more

time

for

soft

tissue

clearance

of

which

results

in

a

higher

sensitivity

of

the

post-therapy

WBS

No

stunning

was

seen

at

the

post-therapy

performed

days

after

doses

of

MBq

-LRB-

mCi

-RRB-

after

MBq

-LRB-

mCi

-RRB-

-RRB-

and

MBq

-LRB-

mCi

-RRB-

diagnostic

scan

-LSB-

-RSB-

In

our

study

we

used

a

rather

a

low

dose

of

-LRB-

MBq

-RRB-

and

a

short

interval

-LRB-

day

-RRB-

between

the

administration

of

the

diagnostic

dose

of

and

the

administration

of

the

therapeutic

dose

and

a

long

interval

-LRB-

days

-RRB-

between

the

therapeutic

dose

and

the

post-therapy

If

stunning

does

exist

after

it

is

therefore

unlikely

to

have

reduced

the

efficacy

of

treatment

in

our

study

is

however

poorly

available

with

high

costs

but

the

advantages

of

could

outweigh

these

disadvantages

and

can

lead

to

more

clinical

application

in

the

follow-up

of

DTC

patients

when

will

become

more

available

Conclusions

In

this

study

proved

to

be

a

superior

diagnostic

tool

as

compared

to

low-dose

diagnostic

scans

and

adequately

predicted

findings

on

subsequent

high-dose

post-treatment

scans

In

combination

with

the

high

resolution

and

the

possibilities

to

combine

with

CT

this

could

lead

to

improved

clinical

decision

making

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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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

positron emission tomography
differentiated thyroid cancer
diagnostic value