First experiences with dynamic renal [68Ga]Ga-DOTA PET/CT: a comparison to renal scintigraphy and compartmental modelling to non-invasively estimate the glomerular filtration rate.

PURPOSE: The determination of the glomerular filtration rate (GFR) is decisive for a variety of clinical issues, for example, to monitor the renal function in radionuclide therapy patients. Renal scintigraphy using glomerularly filtered tracers allows combined acquisition of renograms and GFR estimation but requires repeated blood sampling for several hours. In contrast, dynamic PET imaging using the glomerularly filtered tracer [68Ga]Ga-DOTA bears the potential to non-invasively estimate the GFR by compartmental kinetic modelling. Here, we report the, to our knowledge, first comparison of human renal dynamic [68Ga]Ga-DOTA PET imaging in comparison to renal scintigraphy and compare PET-derived to serum creatinine-derived GFR measurements. METHODS: Dynamic [68Ga]Ga-DOTA PET data were acquired for 30 min immediately after tracer injection in 12 patients. PET and renal scintigraphy images were visually interpreted in a consensus read by three nuclear medicine physicians. The functional renal cortex was segmented to obtain time-activity curves. The arterial input function was estimated from the PET signal in the abdominal aorta. Single-compartmental tracer kinetic modelling was performed to calculate the GFR using complete 30-min (GFRPET-30) and reduced 15-min PET data sets (GFRPET-15) to evaluate whether a shorter acquisition time is sufficient for an accurate GFR estimation. A modified approach excluding minutes 2 to 10 was applied to reduce urinary spill-over effects. Serum creatinine-derived GFRCKD (CKD-EPI-formula) was used as reference standard. RESULTS: PET image interpretation revealed the same findings as conventional scintigraphy (2/12 patients with both- and 1/12 patients with right-sided urinary obstruction). Model fit functions were substantially improved for the modified approach to exclude spill-over. Depending on the modelling approach, GFRCKD and both GFRPET-30 and GFRPET-15 were well correlated with interclass correlation coefficients (ICCs) from 0.74 to 0.80 and Pearson's correlation coefficients (PCCs) from 0.74 to 0.81. For a subgroup of patients with undisturbed urinary efflux (n = 9), correlations were good to excellent (ICCs from 0.82 to 0.95 and PCCs from 0.83 to 0.95). Overall, GFRPET-30 and GFRPET-15 were excellently correlated (ICCs from 0.96 to 0.99 and PCCs from 0.96 to 0.99). CONCLUSION: Renal [68Ga]Ga-DOTA PET can be a suitable alternative to conventional scintigraphy. Visual assessment of PET images and conventional renograms revealed comparable results. GFR values derived by non-invasive single-compartmental-modelling of PET data show a good correlation to serum creatinine-derived GFR values. In patients with undisturbed urinary efflux, the correlation was excellent. Dynamic PET data acquisition for 15 min is sufficient for visual evaluation and GFR derivation.

Comparison of nodal staging between CT, MRI, and [18F]-FDG PET/MRI in patients with newly diagnosed breast cancer.

PURPOSE: To compare CT, MRI, and [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET/MRI) for nodal status, regarding quantity and location of metastatic locoregional lymph nodes in patients with newly diagnosed breast cancer. MATERIALS AND METHODS: One hundred eighty-two patients (mean age 52.7 ± 11.9 years) were included in this prospective double-center study. Patients underwent dedicated contrast-enhanced chest/abdomen/pelvis computed tomography (CT) and whole-body ([18F]-FDG PET/) magnet resonance imaging (MRI). Thoracal datasets were evaluated separately regarding quantity, lymph node station (axillary levels I-III, supraclavicular, internal mammary chain), and lesion character (benign vs. malign). Histopathology served as reference standard for patient-based analysis. Patient-based and lesion-based analyses were compared by a McNemar test. Sensitivity, specificity, positive and negative predictive values, and accuracy were assessed for all three imaging modalities. RESULTS: On a patient-based analysis, PET/MRI correctly detected significantly more nodal positive patients than MRI (p < 0.0001) and CT (p < 0.0001). No statistically significant difference was seen between CT and MRI. PET/MRI detected 193 lesions in 75 patients (41.2%), while MRI detected 123 lesions in 56 patients (30.8%) and CT detected 104 lesions in 50 patients, respectively. Differences were statistically significant on a lesion-based analysis (PET/MRI vs. MRI, p < 0.0001; PET/MRI vs. CT, p < 0.0001; MRI vs. CT, p = 0.015). Subgroup analysis for different lymph node stations showed that PET/MRI detected significantly more lymph node metastases than MRI and CT in each location (axillary levels I-III, supraclavicular, mammary internal chain). MRI was superior to CT only in axillary level I (p = 0.0291). CONCLUSION: [18F]-FDG PET/MRI outperforms CT or MRI in detecting nodal involvement on a patient-based analysis and on a lesion-based analysis. Furthermore, PET/MRI was superior to CT or MRI in detecting lymph node metastases in all lymph node stations. Of all the tested imaging modalities, PET/MRI showed the highest sensitivity, whereas CT showed the lowest sensitivity, but was most specific.

Evaluation of 18F-FDG PET/CT images acquired with a reduced scan time duration in lymphoma patients using the digital biograph vision.

BACKGROUND: The superior accuracy and sensitivity of 18F-FDG-PET/CT in comparison to morphological imaging alone leads to an upstaging in up to 30% of lymphoma patients. Novel digital PET/CT scanners might enable to reduce administered tracer activity or scan time duration while maintaining diagnostic performance; this might allow for a higher patient throughput or a reduced radiation exposure, respectively. In particular, the radiation exposure reduction is of interest due to the often young age and high remission rate of lymphoma patients. METHODS: Twenty patients with (suspected) lymphoma (6 for initial staging, 12 after systemic treatment, 2 in suspicion of recurrence) sequentially underwent 18F-FDG-PET/CT examinations on a digital PET/CT (Siemens Biograph Vision) with a total scan time duration of 15 min (reference acquisition protocol) and 5 min (reduced acquisition protocol) using continuous-bed-motion. Both data sets were reconstructed using either standalone time of flight (TOF) or in combination with point spread function (PSF), each with 2 and 4 iterations. Lesion detectability by blinded assessment (separately for supra- and infradiaphragmal nodal lesions and for extranodal lesions), lesion image quantification, and image noise were used as metrics to assess diagnostic performance. Additionally, Deauville Score was compared for all patients after systemic treatment. RESULTS: All defined regions were correctly classified in the images acquired with reduced emission time, and therefore, no changes in staging were observed. Lesion quantification was acceptable, that is, mean absolute percentage deviation of maximum and peak standardized uptake values were 6.8 and 6.4% (derived from 30 lesions). A threefold reduction of scan time duration led to an increase in image noise from 7.1 to 11.0% (images reconstructed with 4 iterations) and from 4.7 to 7.2% (images reconstructed with 2 iterations). No deviations in Deauville Score were observed. CONCLUSION: These results suggest that scan time duration or administered tracer activity can be reduced threefold without compromising diagnostic performance. Especially a reduction of administered activity might allow for a lower radiation exposure and better health economics. Larger trials are warranted to confirm our results.

Prospective comparison of the diagnostic accuracy of 18F-FDG PET/MRI, MRI, CT, and bone scintigraphy for the detection of bone metastases in the initial staging of primary breast cancer patients.

OBJECTIVES: To compare the diagnostic performance of [18F]FDG PET/MRI, MRI, CT, and bone scintigraphy for the detection of bone metastases in the initial staging of primary breast cancer patients. MATERIAL AND METHODS: A cohort of 154 therapy-naive patients with newly diagnosed, histopathologically proven breast cancer was enrolled in this study prospectively. All patients underwent a whole-body [18F]FDG PET/MRI, computed tomography (CT) scan, and a bone scintigraphy prior to therapy. All datasets were evaluated regarding the presence of bone metastases. McNemar χ2 test was performed to compare sensitivity and specificity between the modalities. RESULTS: Forty-one bone metastases were present in 7/154 patients (4.5%). Both [18F]FDG PET/MRI and MRI alone were able to detect all of the patients with histopathologically proven bone metastases (sensitivity 100%; specificity 100%) and did not miss any of the 41 malignant lesions (sensitivity 100%). CT detected 5/7 patients (sensitivity 71.4%; specificity 98.6%) and 23/41 lesions (sensitivity 56.1%). Bone scintigraphy detected only 2/7 patients (sensitivity 28.6%) and 15/41 lesions (sensitivity 36.6%). Furthermore, CT and scintigraphy led to false-positive findings of bone metastases in 2 patients and in 1 patient, respectively. The sensitivity of PET/MRI and MRI alone was significantly better compared with CT (p < 0.01, difference 43.9%) and bone scintigraphy (p < 0.01, difference 63.4%). CONCLUSION: [18F]FDG PET/MRI and MRI are significantly better than CT or bone scintigraphy for the detection of bone metastases in patients with newly diagnosed breast cancer. Both CT and bone scintigraphy show a substantially limited sensitivity in detection of bone metastases. KEY POINTS: • [18F]FDG PET/MRI and MRI alone are significantly superior to CT and bone scintigraphy for the detection of bone metastases in patients with newly diagnosed breast cancer. • Radiation-free whole-body MRI might serve as modality of choice in detection of bone metastases in breast cancer patients.

PSMA-positive nodal recurrence in prostate cancer : Salvage radiotherapy is superior to salvage lymph node dissection in retrospective analysis.

PURPOSE: This analysis compares salvage lymph node dissection (SLND) to salvage lymph node radiotherapy (SLNRT) of 68Ga-PSMA PET-positive nodal recurrences after radical prostatectomy (RPE). METHODS: A total of 67 SLNRT and 33 SLND consecutive patients with pelvic and/or para-aortic nodal recurrences after RPE were retrospectively analyzed. Biochemical recurrence-free survival rates (bRFS; PSA <0.2 ng/mL) were calculated according to Kaplan-Meier and survival curves were compared using the log rank test. For multivariable analysis, binary logistic regression analysis was performed (p < 0.05). RESULTS: Median follow-up was 17 months (range, 6-53 months) in SLND patients and 31 months (range, 3-56 months) in SLNRT patients (p = 0.027). SLNRT patients had significantly more tumours of pT3 and pT4 category (82% vs. 67%; p = 0.006), pathologically involved lymph nodes (45% vs. 27%; p = 0.001) and positive surgical margins (54% vs. 12%; p = 0.001) at time of RPE than SLND patients. PSA persistence after RPE was significantly more frequently observed in the SLNRT cohort (73% vs. 27%; p = 0.001). There was no significant difference in the distribution of PET-positive lymph nodes. Median PSA before SLND was higher than before SLNRT (3.07 ng/ml vs. 1.3 ng/ml; p = 0.393). The 2­year bRFS was significantly higher in the SLNRT vs. the SLND cohort (92% vs. 30%; p = 0.001) with lower rates of distant metastases (21% vs. 52%; p = 0.002) and secondary treatments (5% vs. 39%; p = 0.011) irrespective of ongoing androgen deprivation therapy at last contact. In multivariable analysis, SLNRT was significantly associated with prolonged bRFS (regression coefficient 1.436, hazard ratio 4.204, 95% CI 1.789-9.878; p = 0.001). CONCLUSION: Based on this retrospective study SLNRT might be the preferred treatment option for patients with nodal recurrence after previous RPE.

Treatment-related changes in neuroendocrine tumors as assessed by textural features derived from 68Ga-DOTATOC PET/MRI with simultaneous acquisition of apparent diffusion coefficient.

BACKGROUND: Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTRs), which is the molecular basis for 68Ga-DOTATOC positron-emission tomography (PET) and radiopeptide therapy (PRRT). However, SSTR expression fluctuates and can be subject to treatment-related changes. The aim of this retrospective study was to assess, which changes in PET and apparent diffusion coefficient (ADC) occur for different treatments and if pre-therapeutic 68Ga-DOTATOC-PET/MRI was able to predict treatment response to PRRT. METHODS: Patients with histopathologically confirmed NET, at least one liver metastasis > 1 cm and at least two 68Ga-DOTATOC-PET/MRI including ADC maps were eligible. 68Ga-DOTATOC-PET/MRI of up to 5 liver lesions per patients was subsequently analyzed. Extracted features comprise conventional PET parameters, such as maximum and mean standardized uptake value (SUVmax and SUVmean) and ADC values. Furthermore, textural features (TFs) from both modalities were extracted. In patients with multiple 68Ga-DOTATOC-PET/MRI a pair of 2 scans each was analyzed separately and the parameter changes between both scans calculated. The same image analysis was performed in patients with 68Ga-DOTATOC-PET/MRI before PRRT. Differences in PET and ADC maps parameters between PRRT-responders and non-responders were compared using Mann-Whitney test to test differences among groups for statistical significance. RESULTS: 29 pairs of 68Ga-DOTATOC-PET/MRI scans of 18 patients were eligible for the assessment of treatment-related changes. In 12 cases patients were treated with somatostatin analogues between scans, in 9 cases with PRRT and in 2 cases each patients received local treatment, chemotherapy and sunitinib. Treatment responders showed a statistically significant decrease in lesion volume and a borderline significant decrease in entropy on ADC maps when compared to non-responders. Patients treated with standalone SSA showed a borderline significant decrease in mean and maximum ADC, compared to patients treated with PRRT. No parameters were able to predict treatment response to PRRT on pre-therapeutic 68Ga-DOTATOC-PET/MRI. CONCLUSIONS: Patients responding to current treatment showed a statistically significant decrease in lesion volume on ADC maps and a borderline significant decrease in entropy. No statistically significant changes in PET parameters were observed. No PET or ADC maps parameters predicted treatment response to PRRT. However, the sample size of this preliminary study is small and further research needed.

Prostate-specific membrane antigen targeted PET imaging for prostate cancer recurrence.

PURPOSE OF REVIEW: Prostate-specific membrane antigen targeted PET imaging (PSMA PET) of biochemically recurrent prostate cancer (BCR) is implemented in routine management in many countries and recommended in European Association of Urology (EAU) and American Society of Clinical Oncology (ASCO) guidelines. Purpose of this review is to summarize recently published evidence of accuracy, management impact, and clinical benefit of PSMA PET in this setting and to state our opinion on the role of PSMA PET in future trials and clinical routine to improve patient outcomes. RECENT FINDINGS: The past two years saw an increase of evidence supporting superior detection rates and accuracy of PSMA PET versus standard imaging and other PET radiotracers in the localization of BCR. Systematic reviews, prospective trials and large-scale retrospective studies establish PSMA PET as a new benchmark imaging in this setting and demonstrate considerable impact on therapeutic and diagnostic management. Multiple studies have highlighted pitfalls of PSMA PET imaging warranting attention while interpreting these scans. SUMMARY: PSMA PET is the new imaging method of choice in BCR. Recent evidence shows unprecedented accuracy and high detection rates along with translation into management changes in a majority of patients. However, improvement of oncologic outcome has not been assessed yet. Implementation of PSMA PET into clinical trials and management of BCR will be crucial to demonstrate outcome improvement.

68Ga-PSMA-11 Positron Emission Tomography Detects Residual Prostate Cancer after Prostatectomy in a Multicenter Retrospective Study.

PURPOSE: Prostate specific antigen persistence after radical prostatectomy is associated with adverse outcomes in patients with prostate cancer. We sought to define regions at risk for residual disease as well as the accuracy of prostate specific membrane antigen ligand positron emission tomography in patients with prostate specific antigen persistence. MATERIALS AND METHODS: At 6 participating centers a total of 191 patients who underwent 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography or positron emission tomography/magnetic resonance imaging for persistently elevated postoperative prostate specific antigen (0.1 ng/ml or greater) were retrospectively included in study. The detection rate and the positive predictive value were determined. In 33 patients with additional prostate specific membrane antigen ligand positron emission tomography before prostatectomy we also determined the rate of positron emission tomography based persistence and recurrence. RESULTS: Prostate specific membrane antigen ligand positron emission tomography localized prostate cancer in 130 of 191 patients (68%) with prostate specific antigen persistence at a median prostate specific antigen of 1.1 ng/ml. The detection rate significantly increased with prostate specific antigen (p <0.001). Regarding prostate specific membrane antigen positron emission tomography/computerized tomography only 61 of 173 patients (35%) had disease confined to the pelvis while 57 of 173 (33%) had distant lesions. The most frequently affected nodal regions were the obturator in 42% and the presacral/mesorectal region in 40%. In 15 of the 33 patients (45%) with prostate specific membrane antigen ligand positron emission tomography before and after surgery at least 1 lesion was detected at baseline (positron emission tomography persistence), 8 (24%) had new lesions (positron emission tomography recurrence) and 10 (30%) had negative positron emission tomography findings. The positive predictive value of prostate specific membrane antigen ligand positron emission tomography was 91%. Systemic therapy initiation was significantly associated with distant lesions on prostate specific membrane antigen ligand positron emission tomography. CONCLUSIONS: Prostate specific membrane antigen ligand positron emission tomography localized prostate cancer in more than two-thirds of patients with high risk features and prostate specific antigen persistence after prostatectomy. Obturator and presacral/mesorectal nodes are at high risk for persistent metastasis.

EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.

Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer.

PURPOSE: Dosimetry is critical to achieve the optimal therapeutic effect of radioligand therapy (RLT) with limited side effects. Our aim was to perform image-based absorbed dose calculation for the new PSMA ligand (177)Lu-DKFZ-PSMA-617 in support of its use for the treatment of metastatic prostate cancer. METHODS: Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients (mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after administration of 3.6 GBq (range 3.4 to 3.9 GBq) (177)Lu-DKFZ-PSMA-617. Quantitative 3D SPECT OSEM reconstruction was performed with corrections for photon scatter, photon attenuation and detector blurring. A camera-specific calibration factor derived from phantom measurements was used for quantitation. Absorbed doses were calculated for various organs from the images using a combination of linear approximation, exponential fit, and target-specific S values, in accordance with the MIRD scheme. Absorbed doses to bone marrow were estimated from planar and SPECT images and with consideration of the blood sampling method according to the EANM guidelines. RESULTS: The average (± SD) absorbed doses per cycle were 2.2 ± 0.6 Gy for the kidneys (0.6 Gy/GBq), 5.1 ± 1.8 Gy for the salivary glands (1.4 Gy/GBq), 0.4 ± 0.2 Gy for the liver (0.1 Gy/GBq), 0.4 ± 0.1 Gy for the spleen (0.1 Gy/GBq), and 44 ± 19 mGy for the bone marrow (0.012 Gy/GBq). The organ absorbed doses did not differ significantly between cycles. The critical absorbed dose reported for the kidneys (23 Gy) was not reached in any patient. At 24 h there was increased uptake in the colon with 50 - 70 % overlap to the kidneys on planar images. Absorbed doses for tumour lesions ranged between 1.2 and 47.5 Gy (13.1 Gy/GBq) per cycle. CONCLUSION: The salivary glands and kidneys showed high, but not critical, absorbed doses after RLT with (177)Lu-DKFZ-PSMA-617. We suggest that (177)Lu-DKFZ-PSMA-617 is suitable for radiotherapy, offering tumour-to-kidney ratios comparable to those with RLT agents currently available for the treatment of neuroendocrine tumours. Our dosimetry results suggest that (177)Lu-DKFZ-PSMA-617 treatment with higher activities and more cycles is possible without the risk of damaging the kidneys.

Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4ß7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.

Nomogram including pretherapeutic parameters for prediction of survival after SIRT of hepatic metastases from colorectal cancer.

OBJECTIVES: Pre-therapeutic prediction of outcome is important for clinicians and patients in determining whether selective internal radiation therapy (SIRT) is indicated for hepatic metastases of colorectal cancer (CRC). METHODS: Pre-therapeutic characteristics of 100 patients with colorectal liver metastases (CRLM) treated by radioembolization were analyzed to develop a nomogram for predicting survival. Prognostic factors were selected by univariate Cox regression analysis and subsequent tested by multivariate analysis for predicting patient survival. The nomogram was validated with reference to an external patient cohort (n = 25) from the Bonn University Department of Nuclear Medicine. RESULTS: Of the 13 parameters tested, four were independently associated with reduced patient survival in multivariate analysis. These parameters included no liver surgery before SIRT (HR:1.81, p = 0.014), CEA serum level ≥ 150 ng/ml (HR:2.08, p = 0.001), transaminase toxicity level ≥2.5× upper limit of normal (HR:2.82, p = 0.001), and summed computed tomography (CT) size of the largest two liver lesions ≥10 cm (HR:2.31, p < 0.001). The area under the receiver-operating characteristic curve for our prediction model was 0.83 for the external patient cohort, indicating superior performance of our multivariate model compared to a model ignoring covariates. CONCLUSIONS: The nomogram developed in our study entailing four pre-therapeutic parameters gives good prediction of patient survival post SIRT. KEY POINTS: • Four individual parameters predicted reduced survival following SIRT in CRC. • These parameters were combined into a nomogram of pre-therapeutic risk stratification. • The model provided good prediction of survival in two independent patient cohorts.

Biodistribution and radiation dosimetry of 124I-mIBG in adult patients with neural crest tumours and extrapolation to paediatric models.

AIM: Positron emission tomography (PET) using 124I-mIBG has been established for imaging and pretherapeutic dosimetry. Here, we report the first systematic analysis of the biodistribution and radiation dosimetry of 124I-mIBG in patients with neural crest tumours and project the results to paediatric patient models. METHODS: Adult patients with neural crest tumours who underwent sequential 124I-mIBG PET were included in this retrospective single-center analysis. PET data were acquired 4, 24, 48, and/or 120 h after administration of a mean of 43 MBq 124I-mIBG. Whole-body counting and blood sampling were performed at 2, 4, 24, 48 and 120 h after administration. Absorbed organ dose and effective dose coefficients were estimated in OLINDA/EXM 2.2 according to the MIRD formalism. Extrapolation to paediatric models was performed based on mass-fraction scaling of the organ-specific residence times. Biodistribution data for adults were also projected to 123I-mIBG and 131I-mIBG. RESULTS: Twenty-one patients (11 females, 10 males) were evaluated. For adults, the organs exposed to the highest dose per unit administered activity were urinary bladder (1.54 ± 0.40 mGy/MBq), salivary glands (0.77 ± 0.28 mGy/MBq) and liver (0.65 ± 0.22 mGy/MBq). Mean effective dose coefficient for adults was 0.25 ± 0.04 mSv/MBq (male: 0.24 ± 0.03 mSv/MBq, female: 0.26 ± 0.06 mSv/MBq), and increased gradually to 0.29, 0.44, 0.69, 1.21, and 2.94 mSv/MBq for the 15-, 10-, 5-, 1-years-old, and newborn paediatric reference patients. Projected mean effective dose coefficients for 123I-mIBG and 131I-mIBG for adults were 0.014 ± 0.002 mSv/MBq and 0.18 ± 0.04 mSv/MBq, respectively. CONCLUSION: PET-based derived radiation dosimetry data for 124I-mIBG from this study agreed well with historical projected data from ICRP 53. The effective dose coefficients presented here may aid in guidance for establishing weight-based activity administration protocols.

High ¹²³I-MIBG uptake in neuroblastic tumours indicates unfavourable histopathology.

PURPOSE: Scintigraphy using (123)I-metaiodobenzylguanidine ((123)I-MIBG) is widely used for the detection of neuroblastic tumours. The aim of this study was to identify a possible correlation between the uptake intensity on (123)I-MIBG SPECT and histopathology of neuroblastic tumours. METHODS: (123)I-MIBG SPECT examinations were performed in 55 paediatric patients with neuroblastic tumour and compared to histopathology after surgical resection or biopsy at a mean of 2 weeks after SPECT. For each lesion International Neuroblastoma Pathology Classification System (INPC) stage, mitosis karyorrhexis index (MKI), location and a semiquantitative tumour-to-liver count-rate ratio (TLCRR) were determined. Also, the presence or absence of MYCN amplification, p1 deletion, urine catecholamine and neuron-specific enolase blood levels at the time of scanning were recorded. RESULTS: In the 55 patients, 61 lesions were evaluated with (123)I-MIBG SPECT and corresponding histopathological findings were reviewed (11 ganglioneuroma, 11 ganglioneuroblastoma and 39 neuroblastoma). TLCRR was significantly higher in the neuroblastoma group (mean TLCRR 2.7) than in the ganglioneuroblastoma group (mean TLCRR 1.0) and ganglioneuroma group (mean TLCRR 0.7) at the time of primary diagnosis (p < 0.001) and at follow-up (p = 0.039). Intense (123)I-MIBG uptake was found in tumour tissue with a high mitotic activity (MKI-high or MKI-intermediate) after treatment. Four ganglioneuromas (36 %), three ganglioneuroblastomas (27 %) and six neuroblastomas (15 %) were (123)I-MIBG-negative. CONCLUSION: In paediatric patients with peripheral neuroblastic tumours, strong (123)I-MIBG uptake indicates unfavourable histopathology. High uptake was seen in neuroblastomas and in tumours with a high mitotic activity.

18F-PSMA Cerenkov Luminescence and Flexible Autoradiography Imaging in a Prostate Cancer Mouse Model and First Results of a Radical Prostatectomy Feasibility Study in Men.

Intraoperative identification of positive resection margins (PRMs) in high-risk prostate cancer (PC) needs improvement. Cerenkov luminescence imaging (CLI) with 68Ga-PSMA-11 is promising, although limited by low residual activity and artificial signals. Here, we aimed to assess the value of CLI and flexible autoradiography (FAR) with 18F-PSMA-1007. Methods: Mice bearing subcutaneous PSMA-avid RM1-PGLS tumors were administered 18F-PSMA-1007, and PET/CT was performed. After the animals had been killed, organs were excised and measured signals in CLI and FAR CLI were correlated with tracer activity concentrations (ACs) obtained from PET/CT. For clinical assessment, 7 high-risk PC patients underwent radical prostatectomy immediately after preoperative 18F-PSMA PET/CT. Contrast-to-noise ratios (CNRs) were calculated for both imaging modalities in intact specimens and after incision above the index lesion. Results: In the heterotopic in vivo mouse model (n = 5), CLI did not detect any lesion. FAR CLI detected a distinct signal in all mice, with a lowest AC of 7.25 kBq/mL (CNR, 5.48). After incision above the index lesion of the prostate specimen, no increased signal was observed at the cancer area in CLI. In contrast, using FAR CLI, a signal was detectable in 6 of 7 patients. The AC in the missed index lesion was 1.85 kBq/mL, resulting in a detection limit of at least 2.06 kBq/mL. Histopathology demonstrated 2 PRMs, neither of which was predicted by CLI or FAR CLI. Conclusion: 18F-PSMA FAR CLI was superior to CLI in tracer-related signal detectability. PC was could be visualized in radical prostatectomy down to 2.06 kBq/mL. However, the detection of PRMs was limited. Direct anatomic correlation of FAR CLI is challenging because of the scintillator overlay.

Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy.

RATIONALE: 177Lu-PSMA ([177Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination regimes of programmed death-ligand 1 (PD-L1) inhibition and concomitant 177Lu-PSMA therapy have been proposed to increase the response rate. However, the interplay of immune landscape and 177Lu-PSMA therapy efficacy is poorly understood. METHODS: Between March 2018 and December 2021, a total of 168 patients were referred to 177Lu-PSMA therapy in our department and received a mean total dose of 21.9 GBq (three cycles in mean). All patients received baseline PSMA positron emission tomography to assess the PSMA uptake. The histopathological specimen of the primary prostate tumor was available with sufficient RNA passing quality control steps for genomic analysis in n=23 patients. In this subset of patients, tumor RNA transcriptomic analyses assessed 74 immune-related features in total, out of which n=24 signatures were not co-correlated and investigated further for outcome prognostication. RESULTS: In the subset of patients who received 177Lu-PSMA therapy, PD-L1 was not significantly associated with OS (HR per SD change (95% CI) 0.74 (0.42 to 1.30); SD: 0.18; p=0.29). In contrast, PD-L2 signature was positively associated with longer OS (HR per SD change 0.46 (95% CI 0.29 to 0.74); SD: 0.24; p=0.001; median OS 17.2 vs 5.7 months in higher vs lower PD-L2 patients). In addition, PD-L2 signature correlated with PSA-response (ϱ=-0.46; p=0.04). The PD-L2 signature association with OS was significantly moderated by L-Lactatdehydrogenase (LDH) levels (Cox model interaction p=0.01). CONCLUSION: Higher PD-L2 signature might be associated with a better response to 177Lu-PSMA therapy and warrants further studies investigating additional immunotherapy. In contrast, PD-L1 was not associated with outcome. The protective effect of PD-L2 signature might be present only in men with lower LDH levels.

Quantification performance of silicon photomultiplier-based PET for small 18F-, 68Ga- and 124I-avid lesions in the context of radionuclide therapy planning.

PURPOSE: The aim of this study was to investigate conditions for reliable quantification of sub-centimeter lesions with low18F,68Ga, and124I uptake using a silicon photomultiplier-based PET/CT system. METHODS: A small tumor phantom was investigated under challenging but clinically realistic conditions resembling prostate and thyroid cancer lymph node metastases (6 spheres with 3.7-9.7 mm in diameter, 9 different activity concentrations ranging from about 0.25-25 kBq/mL, and a signal-to-background ratio of 20). Radionuclides with different positron branching ratios and prompt gamma coincidence contributions were investigated. Maximum-, contour-, and oversize-based partial volume effect (PVE) correction approaches were applied. Detection and quantification performance were estimated, considering a ±30 % deviation between imaged-derived and true activity concentrations as acceptable. A standard and a prolonged acquisition time and two image reconstruction algorithms (time-of-flight with/without point spread function modelling) were analyzed. Clinical data were evaluated to assess agreement of PVE-correction approaches indicating lesion quantification validity. RESULTS: The smallest 3.7-mm sphere was not visible. If the lesions were clearly observed, quantification was, except for a few cases, acceptable using contour- or oversized-based PVE-corrections. Quantification accuracy did not substantially differ between 18F, 68Ga, and 124I. No systematic differences between the analyzed reconstruction algorithms or shorter and larger acquisition times were observed. In the clinical evaluation of 20 lesions, an excellent statistical agreement between oversize- and contour-based PVE-corrections was observed. CONCLUSIONS: At the lower end of size (<10 mm) and activity concentration ranges of lymph-node metastases, quantification with reasonable accuracy is possible for 18F, 68Ga, and 124I, possibly allowing pre-therapeutic lesion dosimetry and individualized radionuclide therapy planning.

Conventional Imaging, MRI and 18F-FDG PET/MRI for N and M Staging in Patients with Newly Diagnosed Breast Cancer.

Background: This study compares the diagnostic potential of conventional staging (computed tomography (CT), axillary sonography and bone scintigraphy), whole-body magnetic resonance imaging (MRI) and whole-body 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/)MRI for N and M staging in newly diagnosed breast cancer. Methods: A total of 208 patients with newly diagnosed breast cancer were prospectively included in this study and underwent contrast-enhanced thoracoabdominal CT, bone scintigraphy and axillary sonography as well as contrast-enhanced whole-body 18F-FDG PET/MRI. The datasets were analyzed with respect to lesion localization and characterization. Histopathology and follow-up imaging served as the reference standard. A McNemar test was used to compare the diagnostic performance of conventional staging, MRI and 18F-FDG PET/MRI and a Wilcoxon test was used to compare differences in true positive findings for nodal staging. Results: Conventional staging determined the N stage with a sensitivity of 80.9%, a specificity of 99.2%, a PPV (positive predictive value) of 98.6% and a NPV (negative predictive value) of 87.4%. The corresponding results for MRI were 79.6%, 100%, 100% and 87.0%, and were 86.5%, 94.1%, 91.7% and 90.3% for 18F-FDG PET/MRI. 18F-FDG PET/MRI was significantly more sensitive in determining malignant lymph nodes than conventional imaging and MRI (p < 0.0001 and p = 0.0005). Furthermore, 18F-FDG PET/MRI accurately estimated the clinical lymph node stage in significantly more cases than conventional imaging and MRI (each p < 0.05). Sensitivity, specificity, PPV and NPV for the M stage in conventional staging were 83.3%, 98.5%, 76.9% and 98.9%, respectively. The corresponding results for both MRI and 18F-FDG PET/MRI were 100.0%, 98.5%, 80.0% and 100.0%. No significant differences between the imaging modalities were seen for the staging of distant metastases. Conclusions:18F-FDG PET/MRI detects lymph node metastases in significantly more patients and estimates clinical lymph node stage more accurately than conventional imaging and MRI. No significant differences were found between imaging modalities with respect to the detection of distant metastases.