Correction to: Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA.

The author names and family names of the originally published article was inversed. Correct presentation is presented here.

Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA.

PURPOSE: The purpose of this study was to perform a prospective integrated analysis of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS). METHODS: A total of 20 patients with histologically confirmed EwS underwent multiple 18F-FDG-PET/CT, performed at the time of each patient's initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 18F-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels. RESULTS: Twenty patients underwent a total of 87 18F-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen κ = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8-104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive 18F-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%. CONCLUSION: The combination of 18F-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.

99mTc-MIP-1404 SPECT/CT for Patients With Metastatic Prostate Cancer: Interobserver and Intraobserver Variability in Treatment-Related Longitudinal Tracer Uptake Assessments of Prostate-Specific Membrane Antigen-Positive Lesions.

BACKGROUND: Tc-MIP-1404 is a SPECT-suitable prostate-specific membrane antigen (PSMA) ligand for detection of prostate cancer. In patients with metastatic prostate cancer, there are no data as yet on interobserver and intraobserver variability when assessing PSMA-positive lesions for longitudinal changes of tracer uptake. METHODS: Tc-MIP-1404 SPECT/CT scans of 22 patients with metastatic prostate cancer were analyzed, and each subject was imaged at 2 separate points in time, before and after treatment. Mean interval between scans was 10 months. Three independent observers visually assessed a total of 96 PSMA-positive metastases (bone, 69; lymph node, 22; viscera, 3) or local recurrences (n = 2) for longitudinal changes in tracer uptake on planar scintigraphy and SPECT/CT. All lesions were categorized as regressive, stable, or progressive based on visual findings and on peak SUV (SUVpeak) of quantitative SPECT/CT (progressive, >30% SUVpeak increase; regressive, <30% SUVpeak decrease; or stable, all others). RESULTS: Quantitative analysis of PSMA-positive lesions yielded significantly higher interobserver agreement (90.6%; 95% confidence interval [CI], 0.83%-0.96%) than visual assessments by either SPECT/CT (76.0%; 95% CI, 0.66%-0.84%) or planar scintigraphy (56.3%; 95% CI, 0.46%-0.66%). Intermethod comparison of aggregated results yielded significantly higher agreement between quantitative and visual SPECT/CT (85.1%; 95% CI, 0.80%-0.89%), as opposed to quantitative SPECT/CT and planar scintigraphy (53.1%; 95% CI, 0.47%-0.59%) or visual SPECT/CT and planar scintigraphy (54.9%; 95% CI, 0.49%-0.61%). In visual and quantitative analysis of 96 PSMA-positive lesions, the number of discrepancies ranged from 9 (9.4%) for quantitative SPECT/CT to 42 (43.8%) for planar scintigraphy. Overall reader confidence was higher for SPECT/CT than for planar scintigraphy (P < 0.001). Intraobserver agreement was near-perfect for all methods, whether SPECT/CT (visual, all κ = 0.94-0.97; quantitative κ = 0.94-0.98) or planar scintigraphy (all κ = 0.90-0.94). CONCLUSIONS: Quantitative evaluation of longitudinal change in tracer uptake by PSMA-positive lesions measured via SPECT/CT is superior to visual interpretation of images by planar scintigraphy or SPECT/CT. Compared with visual evaluation, quantitative SPECT/CT is highly reproducible, showing near-perfect agreement among observers and higher reader confidence.

PSMA SPECT/CT with 99mTc-MIP-1404 in biochemical recurrence of prostate cancer: predictive factors and efficacy for the detection of PSMA-positive lesions at low and very-low PSA levels.

BACKGROUND: The in vivo expression of the prostate-specific membrane antigen (PSMA) can be investigated using the SPECT-suitable tracer 99mTc-MIP-1404. We investigated the performance of 99mTc-MIP-1404 PSMA SPECT/CT in the detection of PSMA-positive tumor lesions in patients suffering from biochemical recurrence of prostate cancer presenting with serum levels of the prostate-specific antigen (PSA) below 1 ng/mL. METHODS: We retrospectively analyzed 99mTc-MIP-1404-SPECT/CT scans of 50 patients (25 with low PSA levels between > 0.5 and 1 ng/mL and 25 with very low PSA levels between 0.2 and 0.5 ng/mL) that had undergone whole-body planar scintigraphy and SPECT/CT of the thorax, abdomen and pelvis 3-4 h p.i. of 691 ± 72 MBq 99mTc-MIP-1404. All datasets were evaluated for the presence and location of PSMA-positive tumor lesions, in which maximal standardized uptake values (SUVmax) were also measured. Based on the results of the quantitative evaluation as well as on biochemical and histological parameters, predictive factors for a positive 99mTc-MIP-1404 scan result were determined. The influence of 99mTc-MIP-1404 PSMA SPECT/CT on further therapy planning was assessed, based on the decision-making of the interdisciplinary tumor board. RESULTS: Pathological 99mTc-MIP-1404 uptake was detected in a total of 25 patients (50%). In the very low PSA subgroup, detection rates of PSMA-positive lesions suggestive of tumor recurrence were 44%, in the low-PSA subgroup 56%. Gleason scores ≥ 8 and the presence of antiandrogen deprivation therapy were further significant predictors of pathological 99mTc-MIP-1404 uptake. This was paralleled by significantly higher lesional SUVmax patients with PSA levels > 0.5 ng/mL and Gleason scores ≥ 8 compared to those without these two features. Changes in therapeutic strategy following MIP-1404 imaging were recommended by the interdisciplinary tumor board in 25/50 of patients. CONCLUSION: 99mTc-MIP-1404 PSMA-SPECT/CT demonstrated a high performance in detecting PSMA-positive lesions suggestive of tumor recurrence in patients with biochemical recurrence of prostate cancer and low and very low serum PSA levels. Results from MIP-1404 PSMA SPECT/CT have therapeutic impact in one-half of the patients examined by this technology.

68Ga-PSMA-11 PET/CT derived quantitative volumetric tumor parameters for classification and evaluation of therapeutic response of bone metastases in prostate cancer patients.

BACKGROUND: To evaluate the role of 68Gallium prostate-specific membrane antigen-positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) derived quantitative volumetric tumor parameters in comparison with fully diagnostic conventional CT and serum-PSA levels for classification and evaluation of therapeutic response of bone metastases in patients with metastasized prostate cancer (PC). METHODS: A total of 177 men with biochemical recurrence of prostate cancer suffering from bone metastases underwent PET/CT with [68Ga] Ga-PSMA-HBED-CC (68Ga-PSMA-11). To calculate 68Ga-PSMA-11 PET quantitative volumetric tumor parameters including whole-body total-lesion PSMA (TL-PSMA), whole-body PSMA-tumor volume (PSMA-TV), as well as the established maximum standard uptake values (SUVmax) and mean standard uptake values (SUVmean), all 443 68Ga-PSMA-11-positive bone lesions in the field of view were assessed quantitatively. Quantitative volumetric tumor parameters were correlated with CT-derived volume and bone density measurements of metastatic bone lesions, serum prostate-specific antigen (PSA) levels, and Gleason Scores. In the 20 patients suffering from bone metastases who underwent 68Ga-PSMA-11 PET/CT before and after therapy, CT-derived volume and bone density measurements of metastatic lesions were compared to biochemical response determined by serum-PSA levels. RESULTS: In 177 patients, a total of 443 68Ga-PSMA-11 PET-positive bone lesions were detected. Of these, 50 lesions (11%) were only detectable on PET but not on conventional CT. PET-positive/CT-negative bone metastases demonstrated a significantly lower PSMA uptake compared to PET-positive/CT-positive bone lesions (p < 0.05). SUVmax, SUVmean, PSMA-TV, and TL-PSMA of bone metastases were significantly higher (p < 0.05) in patients with Gleason Scores > 7 compared to those with Gleason Scores ≤ 7. In the linear regression analysis, an association was determined between SUVmean, Gleason Scores, lesion classification, and serum-PSA levels but not for CT-derived bone density measurements. No significant correlation could be found between changes of bone density and CT-derived volume measurements of metastatic bone lesions and changes of serum-PSA levels (p > 0.05) before and after therapy, while a highly significant correlation was observed for changes of PSMA-TV, TL-PSMA, and serum-PSA levels (p < 0.001). CONCLUSION: Our results suggest that 68Ga-PSMA-11 PET/CT might be a valuable tool for the detection and follow-up of bone metastases in patients with metastasized prostate cancer. 68Ga-PSMA-11 PET-derived quantitative volumetric parameters demonstrated a highly significant correlation with changes of serum-PSA levels during the course of therapy. No such correlation could be determined for bone density measurements of metastatic bone lesions. Compared to the fully diagnostic CT scan, a significantly higher proportion of bone metastases was detected on 68Ga-PSMA-11 PET.

Assessment of Treatment Response by 99mTc-MIP-1404 SPECT/CT: A Pilot Study in Patients With Metastatic Prostate Cancer.

BACKGROUND: We investigated the role of Tc-MIP-1404 (Progenics Pharmaceuticals, Inc, New York, NY) SPECT/CT of PSMA expression in the assessment of treatment response in patients with metastatic prostate cancer. METHODS: We retrospectively analyzed Tc-MIP-1404 SPECT/CT scans from 28 patients with metastatic prostate cancer examined before initiation and after completion of therapy. Eight of these patients had been treated with androgen deprivation therapy, 10 with docetaxel, and another 10 with external beam radiotherapy. On the CT images from SPECT/CT, treatment response was assessed according to RECIST 1.1 criteria; independently from that analysis, maximal standardized uptake values (SUVmax) were quantified in representative tumor lesions and treatment response assumed at differences in SUVmax greater than 30%. Radiographic response assessment was correlated to biochemical response (BR) based on prostate-specific antigen serum levels. RESULTS: The concordance rate between SPECT and BR was 75% (95% confidence interval [CI], 0.55-0.89) (Cohen κ = 0.57; 95% CI, 0.29-0.85; P ≤ 0.01), higher than for that between SPECT and CT with 57% (95% CI, 0.37-0.76) (κ = 0.40; 95% CI, 0.14-0.65; P ≤ 0.01), as well as that between CT and BR with 50% (95% CI, 0.31-0.69) (κ = 0.31; 95% CI, 0.06-0.57, P ≤ 0.05). Discordant findings between SPECT and CT were most likely due to limitations of CT in assessing metastases in lymph nodes, as well as bone involvement, which was sometimes not detectable on CT scans. CONCLUSIONS: The high agreement between treatment response, as assessed by Tc-MIP-1404 SPECT/CT and BR, suggests a possible role of that imaging tool for monitoring treatment in metastatic prostate cancer. Larger, ideally prospective trials are needed to help to reveal the full potential of SPECT imaging of PSMA expression in that regard.

68Ga-PSMA-11 PET/CT-derived metabolic parameters for determination of whole-body tumor burden and treatment response in prostate cancer.

PURPOSE: We aimed at evaluating the role of 68Ga-PSMA-11 PET/CT-derived metabolic parameters for assessment of whole-body tumor burden and its capability to determine therapeutic response in patients with prostate cancer. METHODS: A total of 142 patients with biochemical recurrence of prostate cancer underwent PET/CT with [68Ga]Ga-PSMA-HBED-CC (68Ga-PSMA-11). Quantitative assessment of all 641 68Ga-PSMA-11-positive lesions in the field of view was performed to calculate PSMA-derived parameters, including whole-body PSMA tumor volume (PSMA-TV) and whole-body total lesion PSMA (TL-PSMA), as well as the established SUVmax and SUVmean values. All PET-derived parameters were tested for correlation with serum PSA levels and for association with Gleason scores. In 23 patients who underwent 68Ga-PSMA-11 PET/CT before and after therapy with either external beam radiation, androgen deprivation, or docetaxel chemotherapy, SUVmax and TL-PSMA were compared to radiographic response assessment of CT images based on RECIST 1.1 criteria and to biochemical response determined by changes of serum PSA levels. RESULTS: PSMA-TV and TL-PSMA demonstrated a significant correlation with serum PSA levels (P < 0.0001) and TL-PSMA was significantly different for different Gleason scores. The agreement rate between TL-PSMA derived from PET and biochemical response was 87% (95% confidence interval, 0.66-0.97; Cohen's κ = 0.78; P < 0.01) and, thus, higher than for SUVmax, which was 74% (95% CI, 0.52-0.90; κ = 0.55; P < 0.01). Furthermore, agreement with PSA was higher for TL-PSMA and SUVmax than for CT-based response evaluation. Discordant findings between PET and CT were most likely due to limitations of CT and RECIST in rating small lymph nodes as metastases, as well as bone involvement, which was sometimes not detectable in CT. CONCLUSION: 68Ga-PSMA-11 PET/CT-derived metabolic tumor parameters showed promising results for evaluation of treatment response. Especially, TL-PSMA demonstrated higher agreement rates with biochemical response compared to SUVmax. Larger, ideally prospective trials are needed to help to reveal the full potential of metabolic parameters derived from PET imaging with 68Ga-PSMA-11.

SPECT/CT With the PSMA Ligand 99mTc-MIP-1404 for Whole-Body Primary Staging of Patients With Prostate Cancer.

BACKGROUND: Tc-MIP-1404 (Progenics Pharmaceuticals, Inc, New York, NY) is a novel ligand binding to prostate-specific membrane antigen suitable for SPECT. There are, as yet, no data concerning its use in whole-body primary staging and its interobserver variability in patients with prostate cancer (PC) prior to therapy. METHODS: A search of our clinical database from April 2013 to May 2017 yielded 93 patients with histologically confirmed cancer in whom Tc-MIP-1404 SPECT/CT had been performed for primary whole-body staging before therapy. Whole-body planar and SPECT/CT images of the lower abdomen and thorax had been obtained 3 to 4 hours postinjection of 706 ± 72 MBq Tc-MIP-1404. Images were visually analyzed for extent and location of abnormal uptake by 2 experienced nuclear physicians. Interobserver agreement for detection of primary tumor and metastatic lesions was assessed. In addition, SUVs of prostate-specific membrane antigen-positive regions of the prostate were determined in all patients, and from these, a variable reflecting total tumor load in the prostate gland was calculated (TUprostate). Follow-up reports of subsequent therapeutic interventions were available in 52 (56%) of all patients with a median follow-up of 18 months. RESULTS: In 90 (97%) of 93 patients, prostate uptake above background was detected as correlate of the histologically diagnosed PC. Forty-eight lymph node and 29 bone metastases were detected in 16 and 9 patients, respectively. In addition, 3 patients had disseminated bone metastases. No distant organ metastases were found. Interobserver agreement was high for the overall scan result (97%), as well as for the detection of the primary tumor (97%), of lymph node metastases (97%), and of bone metastases (99%). Recurrence of PC occurred in 5 patients in whom follow-up was available (10%). TUprostate was significantly higher in patients with Gleason scores of 8 or greater compared with patients with Gleason scores of 7 or less and at prostate-specific antigen (PSA) serum levels of 10 ng/mL or greater compared with PSA serum levels of 10 ng/mL or less. TUprostate of greater than 26 in the primary tumor predicted the occurrence of lymph node or bone metastases with a sensitivity of 82% and specificity of 76%. CONCLUSIONS: MIP-1404 SPECT/CT has a high accuracy and low interobserver variability in the diagnosis of PC and allows detection of lymph node and bone metastases in a significant proportion of as yet untreated PC patients. TUprostate is correlated with Gleason score and PSA serum concentration and allows prediction of the occurrence of lymph node and bone metastases with moderate accuracy at primary staging.