Preliminary Clinical Study Of The Targeted Molecular Probe ^99mTc-PSMA SPECT/CT For Prostate Cancer Imaging

BackgroundProstate cancer（PCa）is one of the most common malignancies in men and ranks third with a mortality rate,according to 2015 European Union statistics.In China,especially in developed cities,the incidence of PCa ranks sixth among male malignancies with a mortality rate that has increased more than 10-fold in the past two decades.Imaging plays an important role in the clinical diagnosis of PCa,but the traditional imaging methods based on morphological structure,such as transrectal ultrasound（TRUS）,CT,MRI,etc.are insufficient in the diagnosis of PCa.At present,relevant studies have shown that about 40%of PCa lesions cannot be found in traditional imaging based on morphological structure.Therefore,in order to improve the early diagnosis of PCa and the detection of recurrence and metastasis,the exploration of accurate morphological and functional characterization is crucial to the clinical management of PCa.Over 90%of PCa overexpresses prostate specific membrane antigen（PSMA）,especially in the middle-late PCa or metastatic Castration Resistant prostate Cancer（m CRPC）expression was significantly increased in the trend.As a new tumor marker,PSMA has become an attractive target for PCa imaging and treatment in recent years.Radionuclide labeled PSMA small molecule probe can detect PCa lesions efficiently and specifically,which is helpful for clinical staging.This study,consisted of two parts,intends to evaluate the clinical diagnosis value of technetium-99m-labelled small molecule against PSMA(^99mTc-HYNICGlu-Urea-A,^99mTc-PSMA)in PCa.PartⅠObjectiveBone is the most common distant site of PCa.Currently,China guidelines recommend the use of[^99mTc]medronate(^99mTc-medronate,^99mTc-MDP)as an imaging agent for whole-body bone scintigraphy（SPECT/CT）to diagnose PCa bone metastasis.Although ^99mTc-MDP SPECT/CT imaging is highly sensitive to the diagnosis of PCa bone metastases,its specificity is susceptible to interference by factors such as fractures,and it is difficult to distinguish from certain benign bone lesions.The detection rate of bone lesions was low at low PSA level with ^99mTc-MDP SPECT/CT imaging.⁶⁸Ga-PSMA PET/CT imaging is one of the most widely studied radionuclide labeled PSMA small-molecule probe imaging in recent years.Many studies at home and abroad have proved that ⁶⁸Ga-PSMA PET/CT imaging is superior to ^99mTc-MDP SPECT/CT imaging in the diagnosis of PCa bone metastasis.However,currently there are few studies on ^99mTc-PSMA SPECT/CT imaging in China.Therefore,the purpose of this study was to study the imaging effect of ^99mTc-PSMA SPECT/CT in finding PCa bone metastases by comparing the difference between^99mTc-PSMA SPECT/CT and ^99mTc-MDP SPECT/CT imaging in the diagnosis of PCa bone metastases.Meterials and Methods29 patients who were diagnosed with PCa by pathology were Prospectively analyzed from October 2019 to February 2020,and they all underwent ^99mTc-PSMA SPECT/CT and ^99mTc-MDP SPECT/CT imaging.1.According to the examination results,the patients were divided into the group with bone metastasis and the group without bone metastasis.For all 29 patients,the number of positive and negative cases with bone metastases diagnosed by the two methods were counted,and the sensitivity and specificity were calculated.2.The bone“Positive lesions”were divided into specific anatomical regions and scored as“typical tumor”and“equivocal tumor”.The proportion of"typical tumor"and"equivocal tumor"was calculated.3.Based on per bone“Positive lesion”,Wilcoxon rank-sum test was used to compare the difference in the number of bone metastases focus detected by two methods under different Gleason scores and PSA.Results1.Among the 29 patients,there were 11 patients clinically diagnosed as bone metastases,18 without bone metastases.For all 29 patients,^99mTc-PSMA SPECT/CT imaging detected 11 and ^99mTc-MDP SPECT/CT imaging detected 15bone metastases,with the sensitivity of 100%（11/11）and 90.9%（10/11）,the specificity of 100%（18/18）and 72.2%（13/18）.2.Based on per bone“Positive lesion”,8 patients with positive ^99mTc-PSMA SPECT/CT imaging and ^99mTc-MDP SPECT/CT imaging were analyzed.There was no significant difference in the concentration of ^99mTc-PSMA and ^99mTc-MDP in bone lesions.The proportion of“typical tumor”and“equivocal tumor”detected by the two methods were 6.4:1（PSMA）and 1.3:1（MDP）,respectively.3.Based on per bone“Positive lesion”,In a total of 15 patients,at least one of the two methods detected a“positive lesion”in the bone.There was no significant difference in detecting the number of bone“Positive lesions”focus between the two methods（P<0.05）.PartⅡ ObjectiveEmerging data from published studies are demonstrating the superiority of ⁶⁸Ga-PSMA PET/CT imaging in PCa.Updated in March 2019 European Association of Urology（EAU）Oncology guidelines recommend that PSMA imaging should be chosen for the biochemical recurrence（BR）patients with PSA≥0.2ng/m L.However,the yield of ⁶⁸Ge/⁶⁸Ga generator with ⁶⁸Ga is low and the number of units of PET/CT in most countries and regions is far less than the number of units of SPECT/CT.This limits the wide application of ⁶⁸Ga-PSMA PET/CT imaging.Therefore,in this study,^99mTc,which is more easily obtained than ⁶⁸Ga,was used as the radionuclide marker.The aim of this study was to investigate relationship between factors affecting detection rate and ^99mTc-PSMA SPECT/CT imaging detection rates of PCa.This modality will help clinicians more precisely select patients who may benefit from^99mTc-PSMA SPECT/CT imaging.Meterials and MethodsThe ^99mTc-PSMA SPECT/CT imaging results and clinical data of a total of 29patients with pathologically confirmed PCa were included from October 2019 to February 2020.1.For all 29 patients,29 patients were divided into positive and negative groups according to the results of ^99mTc-PSMA SPECT/CT imaging,and the sensitivity and specificity were calculated.To investigate the relationship between ^99mTc-PSMA SPECT/CT imaging results and Gleason score,age,and PSA.2.9 BR patients were divided into positive and negative groups based on the^99mTc-PSMA SPECT/CT imaging results.To investigate the relationship between^99mTc-PSMA SPECT/CT imaging results and PSA and PSA dynamic parameters（PSAdt,PSAvel）.The cut-off values of the predictors of positive results of^99mTc-PSMA SPECT/CT imaging were calculated through receiver operating characteristic（ROC）curve analysis.3.The ratio of ^99mTc-PSMA（target/non-target,T/NT）between tumor and muscle uptake was calculated by region of interest（ROI）in 9 BR patients.Results1.For all 29 patients,^99mTc-PSMA SPECT/CT imaging sensitivity 81.8%（18/22）,specificity 100%（7/7）.For 10 untreated patients,the sensitivity of ^99mTc-PSMA SPECT/CT imaging was 100%（10/10）.For 9 BR patients,the sensitivity of^99mTc-PSMA SPECT/CT was 66.7%（6/9）.2.29 PCa patients were divided into PSMA-positive group and PSMA-negative group based on the ^99mTc-PSMA SPECT/CT imaging results.The PSA level of the PSMA-positive group was significantly higher than that of the PSMA-negative group（P<0.0001）.Age（P=0.509>0.05）and Gleason score（P=0.846>0.05）showed no significant statistical difference between the PSMA positive group and the negative group.3.9 BR patients were divided into PSMA positive group and PSMA negative group based on the ^99mTc-PSMA SPECT/CT imaging results.There was a significant statistical difference in the median value of PSA between the PSMA-positive group and the PSMA-negative group（Mann-Whitney U test,P=0.024<0.05）.In ROC analysis,the PSA value of 0.825ng/ml is the cut-off value to distinguish the positive and negative results of ^99mTc-PSMA SPECT/CT imaging.However,PSAdt and PSAvel had no significant statistical difference between the PSMA-positive group and the PSMA-negative group.Conclusions1.^99mTc-PSMA SPECT/CT imaging is superior to ^99mTc-MDP SPECT/CT imaging in sensitivity and specificity of bone metastases in PCa.There was no significant difference in the concentration of ^99mTc-PSMA and ^99mTc-MDP in bone lesions.Although there was no significant difference in the number of bone“Positive lesions”detected by the two methods under different Gleason scores and PSA,the percentage of“equivocal”bone metastases detected by ^99mTc-PSMA SPECT/CT imaging was lower than that by ^99mTc-MDP SPECT/CT imaging,and the chance of misdiagnosis of bone“Positive lesions”was reduced,helping to reduce additional tests and reducing the financial burden on patients.In summary,in terms of detecting PCa bone metastasis,patients with PCa who have received ^99mTc-PSMA SPECT/CT do not need to receive ^99mTc-MDP SPECT/CT.2.The targeted molecular probe ^99mTc-PSMA SPECT/CT showed high sensitivity and specificity in both untreated and BR patients.The detection rate of PCa by^99mTc-PSMA SPECT/CT imaging is affected by PSA level.When PSA value was>0.825ng/ml in BR patients,^99mTc-PSMA SPECT/CT imaging efficiency was higher,and patients were more able to benefit from the examination,which could provide an important basis for clinical decision-making.4.As a novel PCa molecular imaging model,the targeted molecular probe99mtc-psma SPECT/CT has high sensitivity and specificity in detecting PCa primary and metastatic sites.It is economical and convenient for clinical use and is easy to be popularized,especially in the medical units that cannot be equipped with PET/CT.It brings a new opportunity for the precise targeted diagnosis,visual diagnosis and one-stop diagnosis of PCa.