[89Zr]Zr-PSMA-617 PET/CT in a Patient with Biochemical Recurrence of Prostate Cancer and Prior Indetermined Findings on [18F]PSMA-1007 Imaging.

We report a case of a 79-year-old male patient with a history of radical prostatectomy for prostate cancer. The patient presented with biochemical reoccurrence; however, previous conventional PSMA PET/CT using [18F]PSMA-1007 showed two indetermined findings with low uptake in the right iliac lymph nodes. Further MRI evaluation provided no additional information. A recently introduced PSMA tracer, [89Zr]Zr-PSMA-617 (half-life: 3.3 days), was administered in an attempt to confirm the diagnosis and aid in potential radiation planning. [89Zr]Zr-PSMA-617 PET/CT clearly revealed the previously indetermined right iliac lymph nodes as definitely metastatic and also identified additional lymph node metastases that were undetected in prior scans. This case highlights the potential superior sensitivity of [89Zr]Zr-PSMA-617 PET/CT in detecting recurrent disease, especially in unclear settings of [18F]PSMA-1007 PET/CT and demonstrates its potential for guiding targeted radiation therapy with curative intent.

Analysis of Molecular Imaging Biomarkers Derived from [18F]FDG PET/CT in mCRPC: Whole-Body Total Lesion Glycolysis (TLG) Predicts Overall Survival in Patients Undergoing [225Ac]Ac-PSMA-617-Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy.

Background/Objectives: The augmentation of [177Lu]Lu-PSMA-617 radioligand therapy by alpha emitting [225Ac]Ac-PSMA-617, known as the tandem therapy concept, is a promising escalating treatment option in advanced mCRPC. In this study, we evaluated the value of [18F]FDG PET/CT-derived molecular imaging biomarkers for predicting response and outcome to PSMA tandem RLT in n = 33 patients with insufficient response on [177Lu]Lu-PSMA-617 monotherapy. Methods: Six different molecular imaging parameters at baseline, i.e., before initiation of PSMA tandem RLT with respect to SUVmax, SUVpeak, SUV5, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were tested for association with response and overall survival (OS). Results: After the initiation of augmentation, 24.2% of patients with a previously insufficient response experienced partial remission, and 39.4% experienced stable disease. The median OS was 7 months (95% CI: 4-11 months). None of the tested parameters were able to predict the response (all p > 0.529). In contrast, the [18F]FDG PET/CT-derived whole-body molecular imaging parameter TLG was significantly (p = 0.029) associated with OS of patients undergoing [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT after insufficient response to [177Lu]Lu-PSMA-617 monotherapy. Conclusion: Implementing [18F]FDG PET/CT in the management of PSMA-RLT in clinical practice may contribute to outcome prediction and provide a route to more individualized management in mCRPC.

Ectopic Cushing Syndrome Localized by 68 Ga-DOTA-LM3 PET/CT.

ABSTRACT: A 53-year-old woman presented with signs of Cushing syndrome with challenges in diagnosis and localization. A novel somatostatin receptor (SSTR)-targeted PET/CT with 68 Ga-DOTA-LM3, an SSTR antagonist, revealed a suspicious focal finding in the pancreatic head, proven to be ectopic Cushing syndrome after surgical resection. This interesting image clearly shows the potential of PET imaging with SSTR antagonists as 68 Ga-DOTA-LM3 in the diagnosis of ectopic Cushing syndrome.

Analysis of Molecular Imaging and Laboratory Baseline Biomarkers in PSMA-RLT: Whole-Body Total Lesion PSMA (TLP) Predicts Overall Survival.

The aim of this retrospective study was to identify pre-therapeutic predictive laboratory and molecular imaging biomarkers for response and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Pre-therapeutic laboratory and [68Ga]Ga-PSMA-11 PET/CT data of n = 102 mCRPC patients receiving [177Lu]Lu-PSMA-617 RLT within a prospective registry (REALITY Study, NCT04833517) were analyzed including laboratory parameters such as alkaline phosphatase (ALP), prostate-specific antigen (PSA), gamma glutamyl transferase (GGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), neuron specific enolase (NSE), hemoglobin (Hb), and imaging parameters such as maximum standardized uptake value of the tumor lesions (SUVmax), the mean standardized uptake value of all tumor lesions (SUVmean), the whole-body molecular tumor volume (MTV), and the whole-body total lesion PSMA (TLP). Mann-Whitney U test, univariate and multivariable Cox-regression were performed to test for association of the parameters with response and OS. The SUVmean of all lesions was significantly different between responders and non-responders (SUVmean responders 8.95 ± 2.83 vs. non-responders 7.88 ± 4.46, p = 0.003), whereas all other tested biochemical and imaging parameters did not reveal significant differences. Hb and the molecular imaging parameters MTV and TLP showed a significant association with OS (p = 0.013, p = 0.005; p = 0.009) in univariant Cox regression; however, only TLP remained significant in multivariable analysis (Hazard ratio 1.033, p = 0.009). This study demonstrates a statistically significant association between the quantitative PET/CT imaging parameter SUVmean and PSA response, as well as between the baseline TLP and OS of mCRPC patients undergoing RLT.

Efficacy and safety of rechallenge [177Lu]Lu-PSMA-617 RLT after initial partial remission in patients with mCRPC: evaluation of a prospective registry (REALITY study).

AIM: Rechallenge of [177Lu]Lu-PSMA-617 radioligand therapy (RLT) was proposed for patients who initially responded to PSMA-RLT experiencing partial remission, but relapsed into progression after a certain period of remission. However, only limited data is available regarding this approach. In this study, we analyzed the efficacy and safety profile of one or more series of [177Lu]Lu-PSMA-617 RLT rechallenge in patients from a prospective registry (REALITY Study, NCT04833517) after they initially benefited from PSMA-RLT. METHODS: Forty-seven patients with metastatic castration-resistant prostate cancer (mCRPC) who had biochemical response to initial [177Lu]Lu-PSMA-617 RLT followed by disease progression received at least one (up to three) series of [177Lu]Lu-PSMA-617 RLT rechallenge. Biochemical response rates based on prostate-specific antigen (PSA) serum value, PSA-based progression-free survival (PFS) and overall survival (OS) were calculated. Adverse events of the treatment were assessed according to 'common terminology criteria for adverse events' (CTCAE). RESULTS: After one series of RLT rechallenge, a PSA decline of at least 50% was achieved in 27/47 patients (57.4%). The median PFS of all patients was 8.7 mo and the median OS was 22.7 mo, each calculated from the administration of the first rechallenge series. Patients who responded (PSA decline > 50%) to the rechallenge showed a median OS of 27.3 mo. Regarding PFS, a significant correlation (r = 0.4128, p = 0.0323) was found for these patients comparing initial and rechallenge RLT. Ten patients received a second and 3 patients received a third rechallenge series with 8/10 and 3/3 patients responding to repeated RLT rechallenge. No severe deterioration of adverse events rated by CTCAE criteria was observed. CONCLUSION: [177Lu]Lu-PSMA-617 RLT rechallenge is associated with significant PSA response and encouraging survival outcome as well as a very favourable safety profile and should therefore be considered as a straight-forward treatment option in mCRPC patients, who previously benefited from PSMA-RLT.

225 Ac-PSMA-617 Augmentation in High-Risk mCRPC Undergoing 177 Lu-PSMA-617 Radioligand Therapy : Pilot Experience From a Prospective Registry.

PURPOSE: This pilot study investigates the efficacy and safety profile as well as predictive biomarkers of 225 Ac-PSMA-617-augmented 177 Lu-PSMA-617 radioligand therapy (RLT) in a cohort of high-risk patients with metastatic castration-resistant prostate cancer (mCRPC), enrolled in a prospective registry (NCT04833517). PATIENTS AND METHODS: A group of n = 33 high-risk mCRPC patients received 177 Lu-PSMA-617 RLT, augmented by 1 or more cycles of 225 Ac-PSMA-617. Response was assessed by prostate-specific antigen (PSA) serum value after 2 cycles of treatment. Overall survival (OS) and PSA-based progression-free survival were evaluated using Kaplan-Meier analysis. To assess the side effect profile, Common Terminology Criteria for Adverse Events were applied. In total, 12 potential pretherapeutic biomarkers were tested for association with OS. RESULTS: The median decrease in serum PSA value was -49.1%, and 16/33 (48.5%) patients experienced a partial response after 2 cycles RLT. The median PSA-based progression-free survival and median OS was 7.2 and 14.8 months, respectively. Alkaline phosphatase ( P < 0.001), lactate dehydrogenase ( P = 0.035), Eastern European Oncology Group Performance Score ( P = 0.037), and the presence of visceral metastases ( P = 0.029) revealed significant association with OS in Kaplan-Meier analysis (log-rank test). Most of the recorded adverse events were rated as mild or moderate. Higher-grade adverse events were very limited with only 1 case (3.0%) of grade 3 anemia. Treatment-related mild xerostomia was recorded in 6/33 (18.2%) patients. CONCLUSIONS: 225 Ac-PSMA-617 augmentation in high-risk mCRPC undergoing 177 Lu-PSMA-617 RLT appears to be an effective treatment option with a favorable safety profile. The pretherapeutic values of alkaline phosphatase, lactate dehydrogenase, the Eastern European Oncology Group Performance Score, and the presence of visceral metastases may be appropriate biomarkers predicting survival outcome of this treatment regimen.

Histopathological Confirmed Polycythemia Vera with Transformation to Myelofibrosis Depicted on [18F]FDG PET/CT.

We present a case of a 59-year-old male diagnosed with polycythemia vera (PV) for many years, who presented with a relatively abrupt onset of heavy constitutional symptoms, including fatigue, night sweats, and a 10% weight loss over 6 weeks. Despite the known initial diagnosis of PV, the presence of profound B-symptoms prompted further investigation. A positron emission tomography/computed tomography (PET/CT) scan with 18F-Fluorodeoxyglucose ([18F]FDG) was performed to exclude malignant diseases. The [18F]FDG PET/CT revealed intense metabolic activity in the bone marrow of the proximal extremities and trunk skeleton, as well as a massively enlarged spleen with increased metabolic activity. Histopathologically, a transformation to myelofibrosis was revealed on a bone marrow biopsy. The case intends to serve as an exemplification for [18F]FDG PET/CT in PV with transformation to myelofibrosis (post-PV myelofibrosis).

Mind the Pitfall: Solitary Nodular Fasciitis Mimicking Extra-Nodal Manifestation of Hodgkin Lymphoma on [18F]FDG PET/CT.

We report a [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scan of a 17-year-old male presenting increased focal glucose metabolism of a histologically proven solitary nodular fasciitis mimicking an extranodal manifestation of Hodgkin lymphoma. This interesting image should draw attention to considering nodular fasciitis as a possible pitfall in the staging of malignant diseases.

[161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: preliminary dosimetry results and intra-individual head-to-head comparison to [177Lu]Lu-PSMA-617.

Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on 161Tb, which may provide advantages by emitting additional Auger and conversion electrons. In this pilot study, we present preliminary dosimetry data for [161Tb]Tb-PSMA-617 RLT in a direct comparison with [177Lu]Lu-PSMA-617. Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [177Lu]Lu-PSMA-617 and subsequently - after inadequate response - with [161Tb]Tb-PSMA-617. Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for 177Lu and OLINDA/EXM for 161Tb. The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated. Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001). Consequently, the mean TI was higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion: In this intra-individual head-to-head pilot study, [161Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [177Lu]Lu-PSMA-617. This preliminary data support 161Tb as a promising radionuclide for PSMA-RLT in mCRPC.

Change in total lesion PSMA (TLP) during [177Lu]Lu-PSMA-617 radioligand therapy predicts overall survival in patients with mCRPC: monocentric evaluation of a prospective registry.

PURPOSE: This study investigates imaging response of [177Lu]Lu-PSMA-617 radioligand therapy (RLT) based on the whole-body parameter total lesion PSMA (TLP), derived by PSMA-PET/CT and reflecting the total tumor burden, in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in a prospective registry (NCT04833517). METHODS: A total of n = 102 mCRPC patients received a [68Ga]Ga-PSMA-11 PET/CT at baseline and after two cycles of PSMA-RLT, in which TLP was measured by using a semi-automated tumor segmentation. TLP was defined as the summed products of volume and uptake (∑ Volume × SUVmean) of all tumor lesions. The Kaplan-Meier method was used to determine the most appropriate ∆TLP thresholds for classification into partial remission (PR), stable disease (SD), and progressive disease (PD) regarding overall survival (OS). Furthermore, we analyzed criteria that are also frequently used in established response frameworks, such as the occurrence of new metastases as independent criterion (I) or in combination with change in tumor burden (II), and the change in PSA serum value (III). RESULTS: For the ∆TLP thresholds -30%/+30% (and also for higher thresholds, -40%/+40% or -50%/+50%), significant differences between all three response categories became apparent (PR/PD: p = 0.001; PR/SD: p = 0.001; SD/PD: p = 0.018). Including the development of new metastases as independent criterion of PD, there was no significant difference in OS between SD and PD (p = 0.455), neither when applied in combination with TLP (p = 0.191). Similarly, significant differentiation between SD and PD was not achieved by PSA serum value (p = 0.973). CONCLUSION: In the largest monocentric study to date, TLP is shown to be a qualified prognostic biomarker, applying ∆TLP thresholds of -30%/+30%. It significantly differentiated between PR, SD, and PD, whereas other response criteria did not differentiate SD vs. PD. Using TLP, the development of new metastases is not a required information for predicting OS.

Change of glucometabolic activity per PSMA expression predicts survival in mCRPC patients non-responding to PSMA radioligand therapy: introducing a novel dual imaging biomarker.

Purpose: The value of [18F]fluorodeoxyglucose ([18F]FDG) PET/CT in monitoring prostate-specific membrane antigen (PSMA) targeted radioligand therapy (RLT) is still unclear. The aim of this study was to identify appropriate prognostic dynamic parameters derived from baseline and follow-up [18F]FDG and dual [18F]FDG/[68Ga]Ga-PSMA-11 PET/CT for monitoring early non-responding mCRPC patients undergoing PSMA-RLT. Methods: Twenty-three mCRPC patients of a prospective registry (NCT04833517), who were treated with [177Lu]Lu-PSMA-617 RLT and classified as early non-responders were included in this study. All patients received dual PET/CT imaging with [18F]FDG and [68Ga]Ga-PSMA-11 at baseline and after median two cycles of RLT. We tested potential biomarkers representing the "change of glucometabolic activity (cGA)" and "change of glucometabolic activity in relation to PSMA expression (cGAP)" composed of established parameters on [18F]FDG PET/CT as SUVmax, cumulative SUV of five lesions (SUV5), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and its corresponding parameters on [68Ga]Ga-PSMA-11 PET/CT, respectively, for association with overall survival (OS). Results: Kaplan-Meier analyses showed no significant association with OS for each tested cGA (cGASUVmaxp = 0.904, cGASUV5, p = 0.747 cGAMTVp = 0.682 and cGATLGp = 0.700), likewise the dual imaging biomarkers cGAPSUVmax (p = 0.136), cGAPSUV5 (p = 0.097), and cGAPTV (p = 0.113) failed significance. In contrast, cGAPTL, which is based on TLG and total lesion PSMA (TLP) showed a significant association with OS (p = 0.004). Low cGAPTL (cut-off 0.7) was associated with significant longer survival (17.6 vs. 12.9 months). Conclusion: The novel biomarker cGAPTL, which represents the temporal change of whole-body TLG normalized by TLP, predicts overall survival in the challenging cohort of patients non-responding to PSMA-RLT.

Dynamic DNA Methylation Changes in the COMT Gene Promoter Region in Response to Mental Stress and Its Modulation by Transcranial Direct Current Stimulation.

Changes in epigenetic modifications present a mechanism how environmental factors, such as the experience of stress, can alter gene regulation. While stress-related disorders have consistently been associated with differential DNA methylation, little is known about the time scale in which these alterations emerge. We investigated dynamic DNA methylation changes in whole blood of 42 healthy male individuals in response to a stressful cognitive task, its association with concentration changes in cortisol, and its modulation by transcranial direct current stimulation (tDCS). We observed a continuous increase in COMT promotor DNA methylation which correlated with higher saliva cortisol levels and was still detectable one week later. However, this lasting effect was suppressed by concurrent activity-enhancing anodal tDCS to the dorsolateral prefrontal cortex. Our findings support the significance of gene-specific DNA methylation in whole blood as potential biomarkers for stress-related effects. Moreover, they suggest alternative molecular mechanisms possibly involved in lasting behavioral effects of tDCS.