A novel approach to guide GD2-targeted therapy in pediatric tumors by PET and [64Cu]Cu-NOTA-ch14.18/CHO.

Background: The tumor-associated disialoganglioside GD2 is a bona fide immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease. Therefore, a non-invasive approach for the assessment and visualization of GD2 expression in-vivo is of upmost interest and might enable a more appropriate treatment stratification. Methods: Recently, [64Cu]Cu-NOTA-ch14.18/CHO (64Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed. We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with 64Cu-GD2 PET/MRI. GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6). Results: In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased 64Cu-GD2 uptake and a high tracer uptake (SUVmax > 10) was measured in 4 of those 8 patients. Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1. In case of 64Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys. Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients. Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04). Conclusion: 64Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.

How [18F]FDG-PET/CT Affects the Management of Patients with Differentiated Thyroid Carcinoma in Clinical Routines.

PURPOSE: To investigate the impact of [18F]FDG-PET/CT on the management of differentiated thyroid carcinoma (DTC) in routine clinical settings. MATERIAL AND METHODS: In total, 98 patients (55 females, age 56 ± 18 years) with histologically confirmed thyroid cancer, including all types of DTC and poorly differentiated thyroid cancer (PDTC, n = 7), underwent [18F]FDG-PET/CT for staging or recurrence diagnostics performed using a state-of-the art clinical scanner (Biograph mCT, Siemens Healthineers) with a standardized examination protocol. The impact of PET/CT on clinical decision making was prospectively evaluated using standardized questionnaires completed by the referring physicians before and after PET/CT. Patient outcome was analyzed for OS drawn from patient records. RESULTS: Referring physicians were unable to establish a treatment plan for 81% of patients with thyroid cancer in the absence of PET/CT. The use of PET/CT had a notable influence on patient management, leading to the development of a well-defined treatment plan for 92% of patients. Moreover, after PET/CT a change in pre-PET/CT-intended treatments occurred in 32% of cases, and further invasive diagnostic could be waived in 7% of cases. [18F]FDG-PET/CT revealed a tumor detection rate of 68% (local tumor: 19%, lymph node metastases: 40%, distant metastases: 42%). HTg levels, when stimulated via TSH, were considerably higher in patients with metastases detected on PET/CT, compared to those without metastatic findings (p = 0.02). OS was significantly worse in patients with PDTC (p = 0.002) compared to follicular thyroid cancer (FTC) and PTC or even in patients with distant metastases at first diagnosis (p = 0.03). CONCLUSIONS: This prospective registry study confirms that [18F]FDG-PET/CT used in a routine clinical setting has a very important impact on the management of patients with thyroid cancer by initiating treatments and reducing the uses of additional imaging and invasive tests.

Additional Value of FDG-PET/MRI Complementary to Sentinel Lymphonodectomy for Minimal Invasive Lymph Node Staging in Patients with Endometrial Cancer: A Prospective Study.

BACKGROUND: Lymph node metastases (LNM) are rare in early-stage endometrial cancer, but a diagnostic systematic lymphadenectomy (LNE) is often performed to achieve reliable N-staging. Therefore, this prospective study aimed to evaluate the benefit of [18F]-Fluorodeoxyglucose (FDG) PET/MRI complementary to SPECT/CT guided sentinel lymphonodectomy (SLNE) for a less invasive N-staging Methods: 79 patients underwent a whole-body FDG-PET/MRI, SLN mapping with 99mTc-Nanocolloid SPECT/CT and indocyanine green (ICG) fluoroscopy followed by LNE which served as ground truth. RESULTS: FDG-PET/MRI was highly specific in N-staging (97.2%) but revealed limited sensitivity (66.7%) due to missed micrometastases. In contrast, bilateral SLN mapping failed more often in patients with macrometastases. The combination of SLN mapping and FDG-PET/MRI increased the sensitivity from 66.7% to 77.8%. Additional SLN labeling with dye (ICG) revealed a complete SLN mapping in 80% (8/10) of patients with failed or incomplete SLN detection in SPECT/CT, reducing the need for diagnostic systematic LNE up to 87%. FDG-PET/MRI detected para-aortic LNM in three out of four cases and a liver metastasis. CONCLUSIONS: The combination of FDG-PET/MRI and SLNE can reduce the need for diagnostic systematic LNE by up to 87%. PET/MRI complements the SLN technique particularly in the detection of para-aortic LNM and occasional distant metastases.

Radiosensitizing Favors Response to Peptide Receptor Radionuclide Therapy in Patients With Highly Proliferative Neuroendocrine Malignancies: Preliminary Evidence From a Clinical Pilot Study.

AIM/INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) represents a cornerstone of treatment regimens for patients with low proliferative neuroendocrine tumors (NETs). However, in patients experiencing somatostatin receptor-positive NET with higher proliferation rates, a value and potential therapeutic benefit of PRRT as part of multimodal treatment approaches and potentially with addition of radiosensitizing agents has not yet been established. PATIENTS AND METHODS: In this study, 20 patients with histologically confirmed gastroenteropancreatic (GEP) NET with proliferation rates (Ki67) between 15% and 55% were treated either with PRRT only (n = 10) or with a combination therapy (n = 10) comprising PRRT and capecitabine/temozolomide (CAP/TEM) for at least 2 consecutive cycles. RESULTS: Disease control rate in patients treated with PRRT alone was 60% (40% stable disease and 20% partial response). Strikingly, in patients treated with PRRT in combination with radiosensitization (CAP/TEM), the disease control rate was 90% (20% stable disease and 70% partial response). The median progression-free survival in the PRRT only group was 12 months, whereas the median progression-free survival in the PRRT + CAP/TEM group was 26 months and has not been yet reached for all patients in the group during the observation period. The median disease-specific survival for patients with PRRT alone was 51 months, whereas this end point was not yet reached in the PRRT + CAP/TEM group. Moreover, the PRRT + CAP/TEM group showed a significantly higher reduction of SSTR-PET-based metabolic tumor volume and chromogranin A levels compared with the PRRT only group. Importantly, adverse events of all grades did not differ between both groups. CONCLUSIONS: PRRT + CAP/TEM represents a highly promising and well-tolerated therapeutic regimen for patients experiencing somatostatin receptor-positive NET with higher (Ki67 ≥ 15%) proliferation rate. Prospective randomized clinical trials are warranted.

Optimization of Y-90 Radioembolization Imaging for Post-Treatment Dosimetry on a Long Axial Field-of-View PET/CT Scanner.

BACKGROUND: PET imaging after yttrium-90 (Y-90) radioembolization is challenging because of the low positron fraction of Y-90 (32 × 10-6). The resulting low number of events can be compensated by the high sensitivity of long axial field-of-view (LAFOV) PET/CT scanners. Nevertheless, the reduced event statistics require optimization of the imaging protocol to achieve high image quality (IQ) and quantification accuracy sufficient for post-treatment dosimetry. METHODS: Two phantoms (NEMA IEC and AbdoMan phantoms, mimicking human liver) filled with Y-90 and a 4:1 sphere (tumor)-to-background ratio were scanned for 24 h with the Biograph Vision Quadra (Siemens Healthineers). Eight patients were scanned after Y-90 radioembolization (1.3-4.7 GBq) using the optimized protocol (obtained by phantom studies). The IQ, contrast recovery coefficients (CRCs) and noise were evaluated for their limited and full acceptance angles, different rebinned scan durations, numbers of iterations and post-reconstruction filters. The s-value-based absorbed doses were calculated to assess their suitability for dosimetry. RESULTS: The phantom studies demonstrate that two iterations, five subsets and a 4 mm Gaussian filter provide a reasonable compromise between a high CRC and low noise. For a 20 min scan duration, an adequate CRC of 56% (vs. 24 h: 62%, 20 mm sphere) was obtained, and the noise was reduced by a factor of 1.4, from 40% to 29%, using the full acceptance angle. The patient scan results were consistent with those from the phantom studies, and the impacts on the absorbed doses were negligible for all of the studied parameter sets, as the maximum percentage difference was -3.89%. CONCLUSIONS: With 2i5s, a 4 mm filter and a scan duration of 20 min, IQ and quantification accuracy that are suitable for post-treatment dosimetry of Y-90 radioembolization can be achieved.

Selective Internal Radiotherapy (SIRT) and Chemosaturation Percutaneous Hepatic Perfusion (CS-PHP) for Metastasized Uveal Melanoma: A Retrospective Comparative Study.

Even with liver-targeted therapies, uveal melanoma with hepatic metastasis remains a challenge. The aim of this study was to compare the outcome of patients treated with either SIRT or CS-PHP. We included 62 patients with hepatic metastasized uveal melanoma (n = 34 with SIRT, receiving 41 cycles; n = 28 with CS-PHP, receiving 56 cycles) that received their treatments between 12/2013 and 02/2020 at a single center. We evaluated their response according to the RECIST 1.1, as well as progression-free survival (PFS) and overall survival (OS), after the initiation of the first cycle of the liver-directed treatment using Cox regression, adjusted via propensity score analysis for confounders, including the amount of hepatic involvement. The disease control rate was 18% for SIRT and 30% for CS-PHP. The median (range) of PFS was 127.5 (19-1912) days for SIRT and 408.5 (3-1809) days for CS-PHP; adjusted Cox regression showed no significant difference (p = 0.090). The median (range) of OS was 300.5 (19-1912) days for SIRT and 516 (5-1836) days for CS-PHP; adjusted Cox regression showed a significant difference (p = 0.006). In our patient cohort, patients treated with CS-PHP showed a significantly longer OS than patients treated with SIRT. CS-PHP might therefore be preferable for patients with liver-dominant metastatic uveal melanoma.

Image Quality and Quantitative PET Parameters of Low-Dose [18F]FDG PET in a Long Axial Field-of-View PET/CT Scanner.

PET/CT scanners with a long axial field-of-view (LAFOV) provide increased sensitivity, enabling the adjustment of imaging parameters by reducing the injected activity or shortening the acquisition time. This study aimed to evaluate the limitations of reduced [18F]FDG activity doses on image quality, lesion detectability, and the quantification of lesion uptake in the Biograph Vision Quadra, as well as to assess the benefits of the recently introduced ultra-high sensitivity mode in a clinical setting. A number of 26 patients who underwent [18F]FDG-PET/CT (3.0 MBq/kg, 5 min scan time) were included in this analysis. The PET raw data was rebinned for shorter frame durations to simulate 5 min scans with lower activities in the high sensitivity (HS) and ultra-high sensitivity (UHS) modes. Image quality, noise, and lesion detectability (n = 82) were assessed using a 5-point Likert scale. The coefficient of variation (CoV), signal-to-noise ratio (SNR), tumor-to-background ratio (TBR), and standardized uptake values (SUV) including SUVmean, SUVmax, and SUVpeak were evaluated. Subjective image ratings were generally superior in UHS compared to the HS mode. At 0.5 MBq/kg, lesion detectability decreased to 95% (HS) and to 98% (UHS). SNR was comparable at 1.0 MBq/kg in HS (5.7 ± 0.6) and 0.5 MBq/kg in UHS (5.5 ± 0.5). With lower doses, there were negligible reductions in SUVmean and SUVpeak, whereas SUVmax increased steadily. Reducing the [18F]FDG activity to 1.0 MBq/kg (HS/UHS) in a LAFOV PET/CT provides diagnostic image quality without statistically significant changes in the uptake parameters. The UHS mode improves image quality, noise, and lesion detectability compared to the HS mode.

177Lu-Prostate-Specific Membrane Antigen Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer and Prior 223Ra (RALU Study).

223Ra-dichloride (223Ra) and 177Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and effectiveness of sequential use of 223Ra and 177Lu-PSMA in patients with mCRPC are not well described. This study aimed to evaluate 177Lu-PSMA safety and efficacy in patients with mCRPC previously treated with 223Ra. Methods: The radium→lutetium (RALU) study was a multicenter, retrospective, medical chart review. Participants had received at least 1 223Ra dose and, in any subsequent therapy line, at least 1 177Lu-PSMA dose. Primary endpoints included the incidence of adverse events (AEs), serious AEs, grade 3-4 hematologic AEs, and abnormal laboratory values. Secondary endpoints included overall survival, time to next treatment/death, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. Results: Data were from 133 patients. Before 177Lu-PSMA therapy, 56% (75/133) of patients received at least 4 life-prolonging therapies; all patients received 223Ra (73% received 5-6 injections). Overall, 27% (36/133) of patients received at least 5 177Lu-PSMA infusions. Any-grade treatment-emergent AEs were reported in 79% (105/133) of patients and serious AEs in 30% (40/133). The most frequent grade 3-4 laboratory abnormalities were anemia (30%, 40/133) and thrombocytopenia (13%, 17/133). Median overall survival was 13.2 mo (95% CI, 10.5-15.6 mo) from the start of 177Lu-PSMA. Conclusion: In this real-world setting, 223Ra followed by 177Lu-PSMA therapy in heavily pretreated patients with mCRPC was clinically feasible, with no indication of impairment of 177Lu-PSMA safety or effectiveness.

Combined Metabolic and Functional Tumor Volumes on [18F]FDG-PET/MRI in Neuroblastoma Using Voxel-Wise Analysis.

PURPOSE: The purpose of our study was to evaluate the association between the [18F]FDG standard uptake value (SUV) and the apparent diffusion coefficient (ADC) in neuroblastoma (NB) by voxel-wise analysis. METHODS: From our prospective observational PET/MRI study, a subcohort of patients diagnosed with NB with both baseline imaging and post-chemotherapy imaging was further investigated. After registration and tumor segmentation, metabolic and functional tumor volumes were calculated from the ADC and SUV values using dedicated software allowing for voxel-wise analysis. Under the mean of thresholds, each voxel was assigned to one of three virtual tissue groups: highly vital (v) (low ADC and high SUV), possibly low vital (lv) (high ADC and low SUV), and equivocal (e) with high ADC and high SUV or low ADC and low SUV. Moreover, three clusters were generated from the total tumor volumes using the method of multiple Gaussian distributions. The Pearson's correlation coefficient between the ADC and the SUV was calculated for each group. RESULTS: Out of 43 PET/MRIs in 21 patients with NB, 16 MRIs in 8 patients met the inclusion criteria (PET/MRIs before and after chemotherapy). The proportion of tumor volumes were 26%, 36%, and 38% (v, lv, e) at baseline, 0.03%, 66%, and 34% after treatment in patients with response, and 42%, 25%, and 33% with progressive disease, respectively. In all clusters, the ADC and the SUV correlated negatively. In the cluster that corresponded to highly vital tissue, the ADC and the SUV showed a moderate negative correlation before treatment (R = -0.18; p < 0.0001) and the strongest negative correlation after treatment (R = -0.45; p < 0.0001). Interestingly, only patients with progression (n = 2) under therapy had a relevant part in this cluster post-treatment. CONCLUSION: Our results indicate that voxel-wise analysis of the ADC and the SUV is feasible and can quantify the different quality of tissue in neuroblastic tumors. Monitoring ADCs as well as SUV levels can quantify tumor dynamics during therapy.

Dual-Time-Point Posttherapy 177Lu-PSMA-617 SPECT/CT Describes the Uptake Kinetics of mCRPC Lesions and Prognosticates Patients' Outcome.

177Lu-PSMA-617 is an effective therapeutic option in metastasized castration-resistant prostate cancer (mCRPC). However, some patients progress under treatment. We hypothesized that the tracer kinetics within the metastases may influence the therapy effectiveness and tested this hypothesis by analyzing uptake parameters on 2 consecutive posttherapy SPECT/CT scans. Methods: mCRPC patients treated with 177Lu-PSMA-617 and with available posttherapy SPECT/CT imaging (24 and 48 h after the first treatment) were enrolled retrospectively. Volumes of interest were defined on lymph node metastasis (LNM) and bone metastasis (BM) on both SPECT/CT scans. The reduction of the percentage injected dose (%IDred) between the 2 SPECT/CT scans was computed. We compared %IDred of responders (prostate-specific antigen drop ≥ 50% after 2 cycles of 177Lu-PSMA-617) and nonresponders. We tested the association of %IDred with progression-free survival and overall survival (OS) using a univariate Kaplan-Meier (KM) analysis and a multivariate Cox regression model. Results: Fifty-five patients (median age, 73 y; range, 54-87 y) were included. %IDred in LNM and BM was greater in nonresponders than in responders (for LNM, 36% in nonresponders [interquartile range (IQR), 26%-47%] vs. 24% in responders [IQR, 12%-33%] [P = 0.003]; for BM, 35% in nonresponders [IQR, 27%-52%] vs. 18% in responders [IQR, 15%-29%] [P = 0.002]). For progression-free survival, in KM analysis, greater %IDred in LNM (P = 0.008) and BM (P = 0.001) was associated with shorter survival, whereas in multivariate analysis, only %IDred in LNM was retained (P = 0.03). In univariate KM analysis of OS, greater %IDred in BM was associated with shorter survival (P = 0.002). In multivariate OS analysis, BM %IDred (P = 0.009) was retained. Conclusion: The 177Lu-PSMA-617 clearance rate from mCRPC metastases appears to be a relevant prognosticator of response and survival, with faster clearing possibly signaling a shorter radiopharmaceutical residence time and absorbed dose. Dual-time-point analysis appears to be a feasible and readily available approach to estimate the likelihood of response and patients' survival.

How [18F]-FDG-PET/CT Affects Clinical Management of Patients with Germ Cell Tumors in the Real World.

OBJECTIVE: The aim of this study was to evaluate the impact of PET/CT on clinical management of patients with germ cell tumors (GCTs) conducted in a real-world setting, including avoidance of invasive procedures, additional diagnostic imaging, and changes in treatment. METHODS: Patients with GCTs were prospectively enrolled into a PET/CT registry study between May 2013 and April 2021. Intended patient management prior and after PET/CT was documented using standardized questionnaires. Changes in oncologic staging and clinical management after PET/CT were recorded, including planned treatment and planned additional diagnostics. RESULTS: Forty-three male patients with GCTs were included consecutively in this study. After PET/CT, oncologic staging changed in 22/43 patients (51%), with upstaging in seven cases (16%), downstaging in ten cases (23%), and cancer relapse in five cases (11%). The number of patients with intended curative treatment remained stable, while a considerable change in intended therapeutic intervention was noted after PET/CT, with an increase in planned chemotherapy from three to eleven patients and a decrease in planned surgical resection from eleven to two patients. In addition, PET/CT contributed to preventing patients from intended invasive procedures including biopsy and surgery in 8/43 (19%) cases and from additional diagnostic procedures in 25 (58%) cases. CONCLUSION: With the use of FDG-PET/CT as a tool to guide patient management in GCTs, we observed a notable impact on clinical staging and a consequent reduction in the need for additional invasive and diagnostic procedures. These findings are expected to be even more consequential in the future as treatment modalities improve and the life expectancy of GCT patients further increases. KEY POINTS: PET/CT considerably influences the clinical stage of GCT patients. PET/CT has remarkable influence on the choice of therapeutic interventions and reduces additional diagnostic procedures.

Non-invasive estimation of split renal function from routine 68Ga-SSR-PET/CT scans.

Objective: Patients with impaired kidney function are at elevated risk for nephrotoxicity and hematotoxicity from peptide receptor radionuclide therapy (PPRT) for advanced neuroendocrine tumors. Somatostatin receptor (SSR)-PET/CT imaging is the method of choice to identify sufficient SSR expression as a prerequisite for PRRT. Therefore, our study aimed to explore whether split renal function could be evaluated using imaging data from routine SSR-PET/CT prior to PRRT. Methods: In total, 25 consecutive patients who underwent SSR-PET/CT (Siemens Biograph mCT®) before PRRT between June 2019 and December 2020 were enrolled in this retrospective study. PET acquisition in the caudocranial direction started at 20 ± 0.5 min after an i.v. injection of 173 ± 20 MBq [68Ga]Ga-ha DOTATATE, and the kidneys were scanned at 32 ± 0.5 min p.i. The renal parenchyma was segmented semi-automatically using an SUV-based isocontour (SUV between 5 and 15). Multiple parameters including SUVmean of renal parenchyma and blood pool, as well as parenchyma volume, were extracted, and accumulation index (ACI: renal parenchyma volume/SUVmean) and total kidney accumulation (TKA: SUVmean x renal parenchyma volume) were calculated. All data were correlated with the reference standard tubular extraction rate (TER-MAG) from [99mTc]Tc-MAG3 scintigraphy and glomerular filtration rate (GFRCDK - EPI). Results: SUVmean of the parenchymal tracer retention showed a negative correlation with TERMAG (r: -0.519, p < 0.001) and GFRCDK - EPI (r: -0.555, p < 0.001) at 32 min p.i. The herein-introduced ACI revealed a significant correlation (p < 0.05) with the total tubular function (r: 0.482), glomerular renal function (r: 0.461), split renal function (r: 0.916), and absolute single-sided renal function (r: 0.549). The mean difference between the split renal function determined by renal scintigraphy and ACI was 1.8 ± 4.2 % points. Conclusion: This pilot study indicates that static [68Ga]Ga-ha DOTATATE PET-scans at 32 min p.i. may be used to estimate both split renal function and absolute renal function using the herein proposed "Accumulation Index" (ACI).

Diagnostic Performance of Dynamic Whole-Body Patlak [18F]FDG-PET/CT in Patients with Indeterminate Lung Lesions and Lymph Nodes.

BACKGROUND: Static [18F]FDG-PET/CT is the imaging method of choice for the evaluation of indeterminate lung lesions and NSCLC staging; however, histological confirmation of PET-positive lesions is needed in most cases due to its limited specificity. Therefore, we aimed to evaluate the diagnostic performance of additional dynamic whole-body PET. METHODS: A total of 34 consecutive patients with indeterminate pulmonary lesions were enrolled in this prospective trial. All patients underwent static (60 min p.i.) and dynamic (0-60 min p.i.) whole-body [18F]FDG-PET/CT (300 MBq) using the multi-bed-multi-timepoint technique (Siemens mCT FlowMotion). Histology and follow-up served as ground truth. Kinetic modeling factors were calculated using a two-compartment linear Patlak model (FDG influx rate constant = Ki, metabolic rate = MR-FDG, distribution volume = DV-FDG) and compared to SUV using ROC analysis. RESULTS: MR-FDGmean provided the best discriminatory power between benign and malignant lung lesions with an AUC of 0.887. The AUC of DV-FDGmean (0.818) and SUVmean (0.827) was non-significantly lower. For LNM, the AUCs for MR-FDGmean (0.987) and SUVmean (0.993) were comparable. Moreover, the DV-FDGmean in liver metastases was three times higher than in bone or lung metastases. CONCLUSIONS: Metabolic rate quantification was shown to be a reliable method to detect malignant lung tumors, LNM, and distant metastases at least as accurately as the established SUV or dual-time-point PET scans.

Long-term prognostic factors for PRRT in neuroendocrine tumors.

Aim/introduction: Peptide receptor radionuclide therapy (PRRT) is an effective and well-tolerated treatment option for patients with neuroendocrine tumors (NETs) that prolongs progression-free survival (PFS). However, the limited overall survival (OS) rates in the prospective phase III study (NETTER1) highlighted the need to identify patient-specific long-term prognostic markers to avoid unnecessary side effects and enable better treatment stratification. Therefore, we retrospectively analyzed prognostic risk factors in NET patients treated with PRRT. Methods: A total of 62 NET patients (G1: 33.9%, G2 62.9%, and G3 3.2%) with at least 2 cycles of PRRT with [177Lu]Lu-HA-DOTATATE (mean 4 cycles) were analyzed. Of which, 53 patients had primary tumors in the gastroenteropancreatic (GEP) system, 6 had bronchopulmonary NET, and 3 had NET of unknown origin. [68Ga]Ga-HA-DOTATATE PET/CT scans were performed before PRRT start and after the second treatment cycle. Different clinical laboratory parameters, as well as PET parameters, such as SUVmean, SUVmax, and PET-based molecular tumor volume (MTV), were collected, and their impact on the OS was investigated. Patient data with a mean follow-up of 62 months (range 20-105) were analyzed. Results: According to interim PET/CT, 16 patients (25.8%) presented with partial response (PR), 38 (61.2%) with stable disease (SD), and 7 (11.3%) with progressive disease (PD). The 5-year OS was 61.8% for all patients, while bronchopulmonary NETs showed poorer OS than GEP-NETs. Multivariable Cox regression analysis showed that chromogranin A level and MTV together were highly significant predictors of therapeutic outcome (HR 2.67; 95% CI 1.41-4.91; p = 0.002). Treatment response was also influenced by the LDH level (HR 0.98; 95% CI 0.9-1.0; p = 0.007) and patient age (HR 1.15; 95% CI 1.08-1.23; p < 0.001). ROC analysis revealed baseline MTV > 112.5 ml [Sens. 91%; Spec. 50%; AUC 0.67 (95% CI 0.51-0.84, p = 0.043)] and chromogranin A >1,250.75 µg/l [Sens. 87%; Spec. 56%; AUC 0.73 (95% CI 0.57-0.88, p = 0.009)] as the best cutoff values for identifying patients with worse 5-year survival. Conclusion: Our retrospective analysis defined MTV and chromogranin A in combination as significant prognostic factors for long-term OS. Furthermore, an interim PET/CT after two cycles has the potential in identifying non-responders who may benefit from a change in therapy at an early stage.

Evaluation of functional and metabolic tumor volume using voxel-wise analysis in childhood rhabdomyosarcoma.

BACKGROUND: Cross-sectional imaging-based morphological characteristics of pediatric rhabdomyosarcoma have failed to predict outcomes. OBJECTIVE: To evaluate the feasibility and possible value of generating tumor sub-volumes using voxel-wise analysis of metabolic and functional data from positron emission tomography/magnetic resonance imaging (PET/MR) or PET/computed tomography (CT) and MRI in rhabdomyosarcoma. MATERIALS AND METHODS: Thirty-four examinations in 17 patients who received PET/MRI or PET/CT plus MRI were analyzed. The volume of interest included total tumor volume before and after therapy. Apparent diffusion coefficients (ADC) and standard uptake values (SUV) were determined voxel-wise. Voxels were assigned to three different groups based on ADC and SUV: "viable tumor tissue," "intermediate tissue" or "possible necrosis." In a second approach, data were grouped into three clusters using the Gaussian mixture model. The ratio of these clusters to total tumor volume and changes due to chemotherapy were correlated with clinical and histopathological data. RESULTS: After chemotherapy, the proportion of voxels in the different groups changed significantly. A significant reduction of the proportion of voxels assigned to cluster 1 was found, from a mean of 36.4% to 2.5% (P < 0.001). There was a significant increase in the proportion of voxels in cluster 3 following chemotherapy from 24.8% to 81.6% (P = 0.02). The proportion of voxels in cluster 2 differed depending on the presence or absence of tumor recurrence, falling from 48% to 10% post-chemotherapy in the group with no tumor recurrence (P < 0.05) and from 29% to 23% (P > 0.05) in the group with tumor recurrence. CONCLUSION: Voxel-wise evaluation of multimodal data in rhabdomyosarcoma is feasible. Our initial results suggest that the different distribution of sub-volumes before and after therapy may have prognostic significance.

Safety and Survival Outcomes of 177Lu-Prostate-Specific Membrane Antigen Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer with Prior 223Ra treatment: The RALU Study.

The radium lutetium (RALU) study evaluated the feasibility of sequential α- and ß-emitter use in patients with bone-predominant metastatic castration-resistant prostate cancer. Methods: This preplanned interim retrospective analysis investigated safety and survival outcomes with 177Lu-PSMA in patients treated with prior 223Ra. Results: Forty-nine patients were evaluated. Patients received a median of 6 223Ra injections; 59% of patients received at least 4 177Lu-PSMA cycles. Most (69%) patients received at least 4 life-prolonging therapies before 177Lu-PSMA. Common Terminology Criteria for Adverse Events grade 3-4 treatment-emergent adverse events during 177Lu-PSMA therapy and a 30-d follow-up period included anemia (18%) and thrombocytopenia (2%). Median overall survival was 12.6 mo (95% CI, 8.8-16.1 mo) and 31.4 mo (95% CI, 25.7-37.6 mo) from starting 177Lu-PSMA or 223Ra, respectively. Conclusion: 177Lu-PSMA treatment was well tolerated in patients who had received prior 223Ra. 223Ra use before 177Lu-PSMA is feasible and can be considered for future assessment of the optimal treatment sequence.

Optimized Whole-Body PET MRI Sequence Workflow in Pediatric Hodgkin Lymphoma Patients.

18F-FDG PET/MRI might be the diagnostic method of choice for Hodgkin lymphoma patients, as it combines significant metabolic information from PET with excellent soft-tissue contrast from MRI and avoids radiation exposure from CT. However, a major issue is longer examination times than for PET/CT, especially for younger children needing anesthesia. Thus, a targeted selection of suitable whole-body MRI sequences is important to optimize the PET/MRI workflow. Methods: The initial PET/MRI scans of 84 EuroNet-PHL-C2 study patients from 13 international PET centers were evaluated. In each available MRI sequence, 5 PET-positive lymph nodes were assessed. If extranodal involvement occurred, 2 splenic lesions, 2 skeletal lesions, and 2 lung lesions were also assessed. A detection rate was calculated dividing the number of visible, anatomically assignable, and measurable lesions in the respective MRI sequence by the total number of lesions. Results: Relaxation time-weighted (T2w) transverse sequences with fat saturation (fs) yielded the best result, with detection rates of 95% for nodal lesions, 62% for splenic lesions, 94% for skeletal lesions, and 83% for lung lesions, followed by T2w transverse sequences without fs (86%, 49%, 16%, and 59%, respectively) and longitudinal relaxation time-weighted contrast-enhanced transverse sequences with fs (74%, 35%, 57%, and 55%, respectively). Conclusion: T2w transverse sequences with fs yielded the highest detection rates and are well suited for accurate whole-body PET/MRI in lymphoma patients. There is no evidence to recommend the use of contrast agents.

Multiparametric Dual-Time-Point [18F]FDG PET/MRI for Lymph Node Staging in Patients with Untreated FIGO I/II Cervical Carcinoma.

[18F]FDG PET/MRI was shown to have limited sensitivity for N-staging in FIGO I/II cervical carcinoma. Therefore, this prospective study aimed to investigate the additional value of multiparametric dual-time-point PET/MRI and to assess potential influencing factors for lymph node metastasis (LNM) detection. A total of 63 patients underwent whole-body dual-time-point [18F]FDG PET/MRI 60 + 90 min p.i., and 251 LN were evaluated visually, quantified multiparametrically, and correlated with histology. Grading of the primary tumor (G2/G3) had a significant impact on visual detection (sens: 8.3%/31%). The best single parameter for LNM detection was SUVavg, however, with a significant loss of discriminatory power in G2 vs. G3 tumors (AUC: 0.673/0.901). The independent predictors SUVavg, ∆SUVpeak, LN sphericity, ADC, and histologic grade were included in the logistic-regression-based malignancy score (MS) for multiparametric analysis. Application of MS enhanced AUCs, especially in G2 tumors (AUC: G2:0.769; G3:0.877) and improved the accuracy for single LNM from 34.5% to 55.5% compared with the best univariate parameter SUVavg. Compared with visual analysis, the use of the malignancy score increased the overall sensitivity from 31.0% to 79.3% (Youden optimum) with a moderate decrease in specificity from 98.3% to 75.6%. These findings indicate that multiparametric evaluation of dual-time-point PET/MRI has the potential to improve accuracy compared with visual interpretation and enables sufficient N-staging also in G2 cervical carcinoma.

Value of CT-Textural Features and Volume-Based PET Parameters in Comparison to Serologic Markers for Response Prediction in Patients with Diffuse Large B-Cell Lymphoma Undergoing CD19-CAR-T Cell Therapy.

The goal of this study was to investigate the value of CT-textural features and volume-based PET parameters in comparison to serologic markers for response prediction in patients with diffuse large B-cell lymphoma (DLBCL) undergoing cluster of differentiation (CD19)-chimeric antigen receptor (CAR)-T cell therapy. We retrospectively analyzed the whole-body (WB)-metabolic tumor volume (MTV), the WB-total lesion glycolysis (TLG) and first order textural features derived from 18F-FDG-PET/CT, as well as serologic parameters (C-reactive protein [CRP] and lactate dehydrogenase [LDH], leucocytes) prior and after CAR-T cell therapy in 21 patients with DLBCL (57.7 ± 14.7 year; 7 female). Interleukin 6 (IL-6) and IL-2 receptor peaks were monitored after treatment onset and compared with patient outcome judged by follow-up 18F-FDG-PET/CT. In 12/21 patients (57%), complete remission (CR) was observed, whereas 9/21 patients (43%) showed partial remission (PR). At baseline, WB-MTV and WB-TLG were lower in patients achieving CR (35 ± 38 mL and 319 ± 362) compared to patients achieving PR (88 ± 110 mL and 1487 ± 2254; p < 0.05). The "entropy" proved lower (1.81 ± 0.09) and "uniformity" higher (0.33 ± 0.02) in patients with CR compared to PR (2.08 ± 0.22 and 0.28 ± 0.47; p < 0.05). Patients achieving CR had lower levels of CRP, LDH and leucocytes at baseline compared to patients achieving PR (p < 0.05). In the entire cohort, WB-MTV and WB-TLG decreased after therapy onset (p < 0.01) becoming not measurable in the CR-group. Leucocytes and CRP significantly dropped after therapy (p < 0.01). The IL-6 and IL-2R peaks after therapy were lower in patients with CR compared to PR (p > 0.05). In conclusion, volume-based PET parameters derived from PET/CT and CT-textural features have the potential to predict therapy response in patients with DLBCL undergoing CAR-T cell therapy.