this study was performed in accordance with the rules and guidelines set forth by the human subjects committee at the university of kansas medical center . patients who received c - acetate pet / ctac scans were referred from both local and national sources . between july 2007 and september 2011 , 250 scans were evaluated for inclusion in the study . prior definitive treatments included radical prostatectomy , brachytherapy , and external beam radiation . for patients who had surgery , psa values were required to reach a nadir of less than 0.1 ng / ml for inclusion in this study . recurrence in this population was defined as a psa level greater than 0.2 ng / ml on the 2 most recent psa tests.18 for patients who received external beam radiation or brachytherapy , recurrence was determined by the american society for radiation oncology s ( astro s ) phoenix definition , which is the first time psa increases by 2 ng / ml above the nadir psa after completion of treatment.19 when combination therapies included surgery followed by radiation , recurrence was determined by the phoenix definition . for patients who received multiple separate treatments , patients who received only hormone therapy , chemotherapy , or nonstandard treatments , such as cryotherapy or supplements , were not included in the study . patients who did not have a psa level within 3 months of the c - acetate pet / ctac scan , patients who did not achieve a nadir in psa level after treatment , and patients with known metastatic disease before treatment , as established by the criteria of the american joint committee on cancer , were also excluded.20 of the 250 patients with available scans , 120 patients met inclusion criteria for this analysis . characteristics of the study population are summarized in table 1 . characteristics of study cohort the c - acetate was produced by a siemens rds 111 cyclotron housed at the university of kansas hospital in kansas city , ks . after producing c - co2 , a general electric tracerlab fx chemistry module was used to convert c - co2 to c - acetate by the grignard reaction . a mean of 40 mci of the radioisotope was available for intravenous injection at the time of the scan . although this dosage is higher than some c - acetate pet studies , it is congruent with the midrange of activity used in the dosimetry studies performed by seltzer et al.21 all patients had their c - acetate pet / ctac imaging performed at the university of kansas hospital using a general electric discovery st 16 pet / ctac scanner , which has an integrated 16-slice ct scanner . all images were interpreted by radiologists board certified by both the american board of nuclear medicine and the american board of radiology , with more than 5 years of experience in c - acetate pet / ctac interpretation . all positive findings were correlated with coregistered ct images and confirmed findings by biopsy ( n = 3 ) , disease progression on follow - up imaging ( n = 61 ) , lesion improvement after treatment on follow - up imaging ( n = 14 ) , or psa value improvement after treatment of lesion(s ) ( n = 4 ) . prostate - specific antigen kinetics results were calculated using all psa values starting from the time of recurrence up to the time of the c - acetate pet imaging . prostate - specific antigen doubling time was calculated in 2 ways : best - line fit and first and last observation methods . the formula used to calculate psadt in months is in which ln(2 ) is the natural logarithm of 2 , and b is the slope of all the log - scale psa measurements collected from the aforementioned time frame . in the best - line fit method popularized by memorial sloan - kettering cancer center , in the first and last observation method , b is given by in which ln(psafinal ) is the natural logarithm of the last recorded psa before the c - acetate pet scan , ln(psainitial ) is the natural logarithm of the psa at the time of recurrence , and tfinal  tinitial is the number of months between scan and recurrence . the calculation of psa velocity ( psav ) , in ng / ml per year , is defined by the slope of the least - squares regression line of the raw psa data . chi - squares , 2-sample t tests , and nonparametric tests were used to examine the differences of parameters of interest between those with positive and negative scans . whereas distinct psa or psa kinetics values highly correlate with patient outcomes after recurrence , continuous scales are clinically more useful if split into cutoff ranges . therefore , we grouped psa or psa kinetics values into deciles or quintiles to create equal - ordered categorical subgroups of patients to describe prostate cancer progression . subsequently , a psa or psa kinetics cutoff ( or cutoffs , when appropriate ) was established using  tests and logistic regression models . both the sensitivity and specificity associated with the identified psa or psa kinetics threshold were calculated . sensitivity is the percentage of patients who had a positive c - acetate pet / ctac scan with the immediate pretest psa or psa kinetics above the threshold , whereas specificity is the percentage of patients who had a negative c - acetate pet / ctac scan with the immediate pretest psa or psa kinetics below the threshold . to determine the discriminatory ability of psa or psa kinetics in association with the c - acetate pet / ctac scan , we calculated the receiver operating characteristic ( roc ) curves and the associated area under the curves ( auc ) , which is estimated by the c - statistic , of the models using a logistic regression technique . this study was performed in accordance with the rules and guidelines set forth by the human subjects committee at the university of kansas medical center . patients who received c - acetate pet / ctac scans were referred from both local and national sources . between july 2007 and september 2011 , 250 scans were evaluated for inclusion in the study . prior definitive treatments included radical prostatectomy , brachytherapy , and external beam radiation . for patients who had surgery , psa values were required to reach a nadir of less than 0.1 ng / ml for inclusion in this study . recurrence in this population was defined as a psa level greater than 0.2 ng / ml on the 2 most recent psa tests.18 for patients who received external beam radiation or brachytherapy , recurrence was determined by the american society for radiation oncology s ( astro s ) phoenix definition , which is the first time psa increases by 2 ng / ml above the nadir psa after completion of treatment.19 when combination therapies included surgery followed by radiation , recurrence was determined by the phoenix definition . for patients who received multiple separate treatments , patients who received only hormone therapy , chemotherapy , or nonstandard treatments , such as cryotherapy or supplements , were not included in the study . patients who did not have a psa level within 3 months of the c - acetate pet / ctac scan , patients who did not achieve a nadir in psa level after treatment , and patients with known metastatic disease before treatment , as established by the criteria of the american joint committee on cancer , were also excluded.20 of the 250 patients with available scans , 120 patients met inclusion criteria for this analysis . characteristics of the study population are summarized in table 1 . the c - acetate was produced by a siemens rds 111 cyclotron housed at the university of kansas hospital in kansas city , ks . after producing c - co2 , a general electric tracerlab fx chemistry module was used to convert c - co2 to c - acetate by the grignard reaction . a mean of 40 mci of the radioisotope was available for intravenous injection at the time of the scan . although this dosage is higher than some c - acetate pet studies , it is congruent with the midrange of activity used in the dosimetry studies performed by seltzer et al.21 all patients had their c - acetate pet / ctac imaging performed at the university of kansas hospital using a general electric discovery st 16 pet / ctac scanner , which has an integrated 16-slice ct scanner . all images were interpreted by radiologists board certified by both the american board of nuclear medicine and the american board of radiology , with more than 5 years of experience in c - acetate pet / ctac interpretation . all positive findings were correlated with coregistered ct images and confirmed findings by biopsy ( n = 3 ) , disease progression on follow - up imaging ( n = 61 ) , lesion improvement after treatment on follow - up imaging ( n = 14 ) , or psa value improvement after treatment of lesion(s ) ( n = 4 ) . prostate - specific antigen kinetics results were calculated using all psa values starting from the time of recurrence up to the time of the c - acetate pet imaging . prostate - specific antigen doubling time was calculated in 2 ways : best - line fit and first and last observation methods . the formula used to calculate psadt in months is in which ln(2 ) is the natural logarithm of 2 , and b is the slope of all the log - scale psa measurements collected from the aforementioned time frame . in the best - line fit method popularized by memorial sloan - kettering cancer center , in the first and last observation method , b is given by in which ln(psafinal ) is the natural logarithm of the last recorded psa before the c - acetate pet scan , ln(psainitial ) is the natural logarithm of the psa at the time of recurrence , and tfinal  tinitial is the number of months between scan and recurrence . the calculation of psa velocity ( psav ) , in ng / ml per year , is defined by the slope of the least - squares regression line of the raw psa data . chi - squares , 2-sample t tests , and nonparametric tests were used to examine the differences of parameters of interest between those with positive and negative scans . whereas distinct psa or psa kinetics values highly correlate with patient outcomes after recurrence , continuous scales are clinically more useful if split into cutoff ranges . therefore , we grouped psa or psa kinetics values into deciles or quintiles to create equal - ordered categorical subgroups of patients to describe prostate cancer progression . subsequently , a psa or psa kinetics cutoff ( or cutoffs , when appropriate ) was established using  tests and logistic regression models . both the sensitivity and specificity associated with the identified psa or psa kinetics threshold were calculated . sensitivity is the percentage of patients who had a positive c - acetate pet / ctac scan with the immediate pretest psa or psa kinetics above the threshold , whereas specificity is the percentage of patients who had a negative c - acetate pet / ctac scan with the immediate pretest psa or psa kinetics below the threshold . to determine the discriminatory ability of psa or psa kinetics in association with the c - acetate pet / ctac scan , we calculated the receiver operating characteristic ( roc ) curves and the associated area under the curves ( auc ) , which is estimated by the c - statistic , of the models using a logistic regression technique . in total , 68.3% ( 82 of 120 available psa values at the time of scan ) of the c - acetate pet / ctac scans were positive . there was a statistically significant difference of psa values between the positive and negative scans ( p < 0.001 for both median and mean differences ) . in our analysis , the roc curve is shown in figure 3 ( c - statistic , 0.76 ) . the putative sensitivity and specificity were 86.6% and 65.8% , respectively , when a psa value greater than 1.24 ng / ml was used as the threshold for determining the optimal time to perform c - acetate pet / ctac imaging . median and mean psa of positive and negative c acetate pet / ctac scans decile characteristics of psa at the time of c - acetate scan roc curve for psa prior to scan . of the 47 patients with calculable psa kinetics data , 74.5% ( 35 ) of 47 scans were positive . when 3 patients who had stable psa over time were included in the analysis , the median and mean psadt in log scale were 6.0 months ( range , 7683555 months ) and 75.0 months (  532.59 months ) . on the other hand , the median and mean psadt were 6.6 months ( range , 1.3270 months ) and 17.0 months (  40.68 months ) when the same 3 cases were excluded from the calculation . since these 3 patients met the study eligibility criteria and were included in all the analyses , only median value psadt was reported for the comparison between positive and negative scans . the median psadt was 7.08 and 5.58 for those with positive and negative scans , respectively ( p = 0.9323 ) . the psadt results were grouped by psadt  2 months , psadt > 2 months but  4 months , psadt > 4 months but < or > 6 months , and psadt > 6 months . in each respective group , there were positive scans in 66.7% of 6 patients , 80% of 10 patients , 57% of 7 patients , and 79% of 24 patients . there was no statistical significance in the proportion of positive scans across the psadt subgroups . the median and mean psav were 3.5 ng / ml per year ( range , 0.8506.4 ng / ml per year ) and 18.7 ng / ml per year ( 74.53 ng / ml per year ) , respectively . the median psav of positive scans was 4.4 ng / ml per year , and the median of negative scans was 0.61 ng / ml per year , respectively ( p = 0.0034 ) . in our analysis , using 5 equal groups ( quintiles ) of psav ( 0.564 ng / ml per year , 0.564 < psav  1.32 ng / ml per year , 1.32 < psav  3.96 ng / ml per year , 3.96 < psav  7.92 ng / ml per year , and psav > 7.92 ng / ml per year ) , the proportion of patients with a positive scan ranged from 33% to 60% in the first 2 quintiles and 89% to 90% in the last 3 quintiles . the roc curve corresponding to these cutoffs is shown in figure 4 ( c - statistic , 0.75 ) . the putative sensitivity and specificity were 74% and 75% when a psav value greater than 1.32 ng / ml per year was used as the cutoff for positive scans . hormone data for 119 patients were available , with immediate pretest psa values recorded for nearly all patients ( n = 118 ) . median and mean psa values were 3.52 ng / ml and 7.67  17.56 ng / ml , respectively ( range , 0.20127.32 ng / ml ) . from this same group , 49 ( 41.5% ) of the 188 patients had androgen deprivation therapy within 1 year of c - acetate pet / ctac imaging . for patients treated with antiandrogen therapy , the median and mean psa values from positive scans were 4.17 ng / ml and 12.38  23.18 ng / ml , respectively , whereas the median and the mean values for negative scans were 0.30 ng / ml and 2.3  6.13 ng / ml , respectively . both median and mean psa values between positive and negative scans were statistically significant ( p < 0.0001 and p = 0.0263 , respectively ) . in these patients , 25.0% , 66.7% , 81.8% , and 93.8% had positive scans in the subgroups defined as psa of  1 ng / ml , psa greater than 1 ng / ml but  2 ng / ml , psa greater than 2 ng / ml but  5 ng / ml , and psa > 5 ng / ml , respectively . in patients not treated with antiandrogen therapy in the previous year , positive scans were 26.7% , 50% , 77.3% , and 92.9% , respectively . there was no significant difference in correlations and trends between the androgen - deprived and androgen - intact patients . our analysis demonstrated that psa value at the time of scan was significantly associated with a positive c - acetate pet / ctac scan ( or , 12.2 ; 95% confidence interval , 3.98037.661 ) . the associations between c - acetate pet / ctac positivity and selected risk factors , including age at time of scan , type of definitive treatment , and androgen deprivation therapy , were not statistically significant . results from this logistic regression analysis are shown in table 4 ( c - statistic , 0.812 ) . psa doubling time and psa velocity were also examined for possible association with positive c - acetate pet / ctac scans . of these factors , data were separated into postprostatectomy and postradiotherapy groups , and each group was analyzed separately for psa threshold , velocity , doubling time , and presence of androgen deprivation therapy . no statistically significant results were found for either group . logistic regression model with positive c acetate pet outcomes and psa at scan ( n = 120 ) logistic regression models with outcomes being positive c acetate in total , 68.3% ( 82 of 120 available psa values at the time of scan ) of the c - acetate pet / ctac scans were positive . there was a statistically significant difference of psa values between the positive and negative scans ( p < 0.001 for both median and mean differences ) . in our analysis , the roc curve is shown in figure 3 ( c - statistic , 0.76 ) . the putative sensitivity and specificity were 86.6% and 65.8% , respectively , when a psa value greater than 1.24 ng / ml was used as the threshold for determining the optimal time to perform c - acetate pet / ctac imaging . median and mean psa of positive and negative c acetate pet / ctac scans decile characteristics of psa at the time of c - acetate scan roc curve for psa prior to scan . of the 47 patients with calculable psa kinetics data , 74.5% ( 35 ) of 47 scans were positive . when 3 patients who had stable psa over time were included in the analysis , the median and mean psadt in log scale were 6.0 months ( range , 7683555 months ) and 75.0 months (  532.59 months ) . on the other hand , the median and mean psadt were 6.6 months ( range , 1.3270 months ) and 17.0 months (  40.68 months ) when the same 3 cases were excluded from the calculation . since these 3 patients met the study eligibility criteria and were included in all the analyses , only median value psadt was reported for the comparison between positive and negative scans . the median psadt was 7.08 and 5.58 for those with positive and negative scans , respectively ( p = 0.9323 ) . the psadt results were grouped by psadt  2 months , psadt > 2 months but  4 months , psadt > 4 months but < or > 6 months , and psadt > 6 months . in each respective group , there were positive scans in 66.7% of 6 patients , 80% of 10 patients , 57% of 7 patients , and 79% of 24 patients . there was no statistical significance in the proportion of positive scans across the psadt subgroups . the median and mean psav were 3.5 ng / ml per year ( range , 0.8506.4 ng / ml per year ) and 18.7 ng / ml per year ( 74.53 ng / ml per year ) , respectively . the median psav of positive scans was 4.4 ng / ml per year , and the median of negative scans was 0.61 ng / ml per year , respectively ( p = 0.0034 ) . in our analysis , using 5 equal groups ( quintiles ) of psav ( 0.564 ng / ml per year , 0.564 < psav  1.32 ng / ml per year , 1.32 < psav  3.96 ng / ml per year , 3.96 < psav  7.92 ng / ml per year , and psav > 7.92 ng / ml per year ) , the proportion of patients with a positive scan ranged from 33% to 60% in the first 2 quintiles and 89% to 90% in the last 3 quintiles . the roc curve corresponding to these cutoffs is shown in figure 4 ( c - statistic , 0.75 ) . the putative sensitivity and specificity were 74% and 75% when a psav value greater than 1.32 ng / ml per year was used as the cutoff for positive scans . hormone data for 119 patients were available , with immediate pretest psa values recorded for nearly all patients ( n = 118 ) . median and mean psa values were 3.52 ng / ml and 7.67  17.56 ng / ml , respectively ( range , 0.20127.32 ng / ml ) . from this same group , 49 ( 41.5% ) of the 188 patients had androgen deprivation therapy within 1 year of c - acetate pet / ctac imaging . for patients treated with antiandrogen therapy , the median and mean psa values from positive scans were 4.17 ng / ml and 12.38  23.18 ng / ml , respectively , whereas the median and the mean values for negative scans were 0.30 ng / ml and 2.3  6.13 ng / ml , respectively . both median and mean psa values between positive and negative scans were statistically significant ( p < 0.0001 and p = 0.0263 , respectively ) . in these patients , 25.0% , 66.7% , 81.8% , and 93.8% had positive scans in the subgroups defined as psa of  1 ng / ml , psa greater than 1 ng / ml but  2 ng / ml , psa greater than 2 ng / ml but  5 ng / ml , and psa > 5 ng / ml , respectively . in patients not treated with antiandrogen therapy in the previous year , positive scans were 26.7% , 50% , 77.3% , and 92.9% , respectively . there was no significant difference in correlations and trends between the androgen - deprived and androgen - intact patients . our analysis demonstrated that psa value at the time of scan was significantly associated with a positive c - acetate pet / ctac scan ( or , 12.2 ; 95% confidence interval , 3.98037.661 ) . the associations between c - acetate pet / ctac positivity and selected risk factors , including age at time of scan , type of definitive treatment , and androgen deprivation therapy , were not statistically significant . results from this logistic regression analysis are shown in table 4 ( c - statistic , 0.812 ) . psa doubling time and psa velocity were also examined for possible association with positive c - acetate pet / ctac scans . of these factors , data were separated into postprostatectomy and postradiotherapy groups , and each group was analyzed separately for psa threshold , velocity , doubling time , and presence of androgen deprivation therapy . no statistically significant results were found for either group . logistic regression model with positive c acetate pet outcomes and psa at scan ( n = 120 ) logistic regression models with outcomes being positive c acetate the results of this analysis demonstrate that the positivity of a c - acetate pet / ctac scan is strongly correlated with absolute psa value at the time of image acquisition . our calculated optimal psa threshold value for obtaining a c - acetate pet / ctac scan is 1.24 ng / ml , with a putative sensitivity and specificity of 86.6% and 65.8% , respectively . these results are similar to the findings of european studies that used c - choline or f - choline . a large - scale investigation of c - choline by giovacchini et al22 calculated a psa threshold value of 1.4 ng / ml , with a sensitivity and specificity of 73% and 72% , respectively . castellucci et al23 found a higher optimal psa threshold value of 2.43 ng / ml when examining c - choline for imaging , with comparable sensitivity and specificity of 73% and 69% , respectively . similarly , graute et al24 established a psa threshold value of 1.74 ng / ml for f - choline that was associated with a sensitivity and specificity of 82% and 74% , respectively . our psav threshold of 1.32 ng / ml per year also supports many recent studies that have correlated psa kinetics and rate of scan positivity . for example , a meta - analysis of psa kinetics data compiled before july 2013 calculated a 65% detection rate for psadt of less than 6 months and a 71% detection rate for psav greater than 1 ng / ml per year.25 more recently , mamede et al26 demonstrated that even with recurrence at psa of less than 0.5 ng / ml , low psadt values were associated with high scan positivity rates . thus , many have come to view psa kinetics as the prime indicators for guiding the use of c - choline pet / ctac scans . despite the value of psadt and psav , defining a psa threshold determining the optimal time to perform a c - acetate pet / ctac scan after biochemical recurrence in prostate cancer should ideally maximize the likelihood of localizing recurrent tumor sites at a point in time early enough to allow for the successful use of salvage therapies . as mentioned previously , pfp is significantly improved for preradiotherapy psa levels less than 2.0 ng / ml . according to our analysis , this would imply that the optimal time to detect foci of recurrence after a failed radical prostatectomy is between psa greater than 1.24 ng / ml but  2.0 ng / ml . although psadt and psav could also offer this benefit , using a single , prescan psa level to determine when to scan has the compelling advantage that it does not require the gathering of sequential psa samples to calculate a psa doubling time or velocity , which risks over shooting the radiotherapy salvage threshold of psa of 2.0 ng / ml . moreover , in the reality of evaluating patients on referral , calculating psa velocity and doubling times from a series of psa values obtained from disparate laboratory methodologies is tenuous at best . our data suggest that by using only the most recent psa value to determine the timing of the scan , c - acetate pet / ctac imaging can detect early prostate cancer recurrence with reasonable sensitivity and specificity . a negative effect of antiandrogen therapy on acetate or choline pet sensitivity has widely been suspected.27 giovacchini et al22 did confirm a negative correlation on univariate logistic regression . however , the current study was unable to confirm this statistically , as the positivity of an c - acetate scan was still determined by psa value , regardless of the patient s hormone status . krause et al28 were also unable to establish a negative correlation between antiandrogen therapy and pet sensitivity . other patients characteristics , such as age , stage , and gleason score , failed to demonstrate predictive value for the c - acetate pet / ctac imaging in our analysis . to our knowledge , there are no previous large - scale c - acetate pet / ctac studies of recurrent prostate cancer in american men . however , whereas our study population was uniquely american , only one of our patients was african american . therefore , extrapolating our findings to an african american population , which is known to be at higher risk for prostate cancer occurrence and mortality , may not be justified . some patients had multiple types of therapies before the study and still met our inclusion criteria . it is plausible that patients who have failed one treatment may be more likely to develop recurrence and may have higher rates of pet positivity . this study also included a large group of nonsurgical patients , whereas some of the previous c - choline and f - choline studies included only patients who had postprostatectomy . nevertheless , our cohort most likely reflects typical clinical practice , where patients are referred for scanning with biochemical recurrence after differing treatment regimens . moreover , it is important to note that in this study and those like it , a positive scan does not definitively indicate a site of recurrence . although these studies seek to elucidate the best timing for c - acetate pet imaging , the putative positive areas of the scan could be false positives . in the world literature to date , there is a paucity of prospective trials of adequate size that have used tissue confirmation . our retrospective analysis of the first 250 c - acetate pet / ctac scans we performed for recurrent prostate cancer found that scans performed after the patient had achieved a psa value greater 1.24 ng / ml had the highest likelihood of producing positive findings . whereas our study also showed that a psav greater than 1.32 was also associated with a greater probability of positive findings , and multiple european studies have shown the value of a psadt of less than 6 months , we feel there may be unique advantages in a threshold model that is based on a single psa value . nevertheless , this study and those like it suffer from the lack of a large number of biopsy - confirmed results . a large prospective biopsy - proven trial of c - acetate , c - choline , and/or f - choline is needed to confirm these findings .
purposethe aim of this study was to identify which patient characteristics are associated with the highest likelihood of positive findings on 11c - acetate pet / computed tomography attenuation correction ( ctac ) ( pet / ctac ) scan when imaging for recurrent prostate cancer.methodsfrom 2007 to 2011 , 250 11c - acetate pet / ctac scans were performed at a single institution on patients with prostate cancer recurrence after surgery , brachytherapy , or external beam radiation . of these patients , 
 120 met our inclusion criteria . 
 logistic regression analysis was used to examine the relationship between predictability of positive findings and patients characteristics , such as prostate - specific antigen ( psa ) level at the time of scan , psa kinetics , gleason score , staging , and type of treatment before scan.resultsin total , 68.3% of the 120 11c - acetate pet / ctac scans were positive . 
 the percentage of positive scans and psa at the time of scanning and psa velocity ( psav ) had positive correlations . 
 the putative sensitivity and specificity were 86.6% and 65.8% , respectively , when a psa level greater than 1.24 ng / ml was used as the threshold for scanning . the putative sensitivity and specificity were 74% and 75% , respectively , when a psav level greater than 1.32 ng / ml / y was used as the threshold . 
 no significant associations were found between scan positivity and age , psa doubling time , gleason score , staging , or type of treatment before scanning.conclusionsthis retrospective study suggests that threshold models of psa greater than 1.24 ng / ml or psav greater than 1.32 ng / ml per year are independent predictors of positive findings in 11c - acetate pet / ctac imaging of recurrent prostate cancer .