Explore the vast range of titles available.

Prostate-specific membrane antigen (PSMA)-PET was introduced into clinical practice in 2012 and has since transformed the staging of prostate cancer. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were proposed to standardise PSMA-PET reporting. We aimed to compare the prognostic value of PSMA-PET by PROMISE (PPP) stage with established clinical nomograms in a large prostate cancer dataset with follow-up data for overall survival. In this multicentre retrospective study, we used data from patients of any age with histologically proven prostate cancer who underwent PSMA-PET at the University Hospitals in Essen, Münster, Freiburg, and Dresden, Germany, between Oct 30, 2014, and Dec 27, 2021. We linked a subset of patient hospital records with patient data, including mortality data, from the Cancer Registry North-Rhine Westphalia, Germany. Patients from Essen University Hospital were randomly assigned to the development or internal validation cohorts (2:1). Patients from Münster, Freiburg, and Dresden University Hospitals were included in an external validation cohort. Using the development cohort, we created quantitative and visual PPP nomograms based on Cox regression models, assessing potential PPP predictors for overall survival, with least absolute shrinkage and selection operator penalty for overall survival as the primary endpoint. Performance was measured using Harrell's C-index in the internal and external validation cohorts and compared with established clinical risk scores (International Staging Collaboration for Cancer of the Prostate [STARCAP], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN] risk scores) and a previous nomogram defined by Gafita et al (hereafter referred to as GAFITA) using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) estimates. We analysed 2414 male patients (1110 included in the development cohort, 502 in the internal cohort, and 802 in the external validation cohort), among whom 901 (37%) had died as of data cutoff (June 30, 2023; median follow-up of 52·9 months [IQR 33·9–79·0]). Predictors in the quantitative PPP nomogram were locoregional lymph node metastases (molecular imaging N2), distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases), tumour volume (in L), and tumour mean standardised uptake value. Predictors in the visual PPP nomogram were distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases) and total tumour lesion count. In the internal and external validation cohorts, C-indices were 0·80 (95% CI 0·77–0·84) and 0·77 (0·75–0·78) for the quantitative nomogram, respectively, and 0·78 (0·75–0·82) and 0·77 (0·75–0·78) for the visual nomogram, respectively. In the combined development and internal validation cohort, the quantitative PPP nomogram was superior to STARCAP risk score for patients at initial staging (n=139 with available staging data; AUC 0·73 vs 0·54; p=0·018), EAU risk score at biochemical recurrence (n=412; 0·69 vs 0·52; p<0·0001), and NCCN pan-stage risk score (n=1534; 0·81 vs 0·74; p<0·0001) for the prediction of overall survival, but was similar to GAFITA nomogram for metastatic hormone-sensitive prostate cancer (mHSPC; n=122; 0·76 vs 0·72; p=0·49) and metastatic castration-resistant prostate cancer (mCRPC; n=270; 0·67 vs 0·75; p=0·20). The visual PPP nomogram was superior to EAU at biochemical recurrence (n=414; 0·64 vs 0·52; p=0·0004) and NCCN across all stages (n=1544; 0·79 vs 0·73; p<0·0001), but similar to STARCAP for initial staging (n=140; 0·56 vs 0·53; p=0·74) and GAFITA for mHSPC (n=122; 0·74 vs 0·72; p=0·66) and mCRPC (n=270; 0·71 vs 0·75; p=0·23). Our PPP nomograms accurately stratify high-risk and low-risk groups for overall survival in early and late stages of prostate cancer and yield equal or superior prediction accuracy compared with established clinical risk tools. Validation and improvement of the nomograms with long-term follow-up is ongoing (NCT06320223). Cancer Registry North-Rhine Westphalia.

Cerebral atrophy is a key finding in patients with dementia and usually determined on MRI. We tested whether cerebral atrophy can be imaged with FDG PET by applying deformation-based morphometry (DBM). We retrospectively identified 26 patients with a biomarker-supported clinical diagnosis of Alzheimer’s disease (AD) who had received FDG PET on a fully-digital PET/CT system and structural MRI and compared them to 13 healthy elderly controls (HEC). We performed DBM with FDG PET data (FDG-DBM). As a reference standard for determining atrophy we used voxel-based morphometry of MRI data (MRI-VBM). For conventional analysis of hypometabolism, scaled FDG PET scans (reference: brain parenchyma) were compared between groups. Receiver operating characteristic (ROC) analyses were performed. ROI read-outs were tested for associations with cognitive test performance. FDG-DBM showed abnormalities in AD mainly in the bilateral hippocampi. Similarly, MRI-VBM showed hippocampal atrophy. By contrast, conventional FDG PET analysis revealed reduced bilateral temporo-parietal FDG uptake (all p  < 0.05, FWE-corrected). FDG-DBM measures of the hippocampus significantly separated AD from HEC with an AUC of 0.81; MRI-VBM achieved an AUC of 0.87; the difference between the two ROC curves was not significant ( p  = 0.40). Whereas FDG uptake of the hippocampus did not separate AD from HEC, FDG uptake of the Landau Meta-ROI achieved an AUC of 0.88. Verbal memory was significantly associated with FDG-DBM measures of the hippocampus ( p  = 0.009), but not of the Landau Meta-ROI ( p  > 0.1). The opposite held true for conventional FDG uptake ( p  > 0.1 and p  = 0.001, respectively). Hippocampal atrophy in AD can be detected by applying DBM to clinical, fully-digital FDG PET. It correlates with cognitive performance and might constitute a biomarker of neurodegeneration that is complementary to conventional FDG PET analysis of regional hypometabolism.

The present study aims at developing and evaluating an urea-based prostate specific membrane antigen (PSMA) inhibitor suitable for labeling with 111In for SPECT and intraoperative applications as well as 68Ga and 64Cu for PET imaging. The PSMA-based inhibitor-lysine-urea-glutamate-coupled to the spacer Phe-Phe-D-Lys(suberoyl) and functionalized with the enantiomerically pure prochelator (R)-1-(1-carboxy-3-carbotertbutoxypropyl)-4,7-carbotartbutoxymethyl)-1,4,7-triazacyclononane ((R)-NODAGA(tBu)3), to obtain (R)-NODAGA-Phe-Phe-D-Lys(suberoyl)-Lys-urea-Glu (CC34). CC34 was labeled with 111In, 68Ga and 64Cu. The radioconjugates were further evaluated in vitro and in vivo in LNCaP xenografts by biodistribution and PET studies. Biodistribution studies were also performed with 68Ga-HBED-CC-PSMA (HBED-CC: N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) and 111In-PSMA-617 for comparison. 68Ga-CC34, 64Cu-CC34, and 111In-CC34 were prepared in radiochemical purity > 95%. 68/natGa-CC34, 64/natCu-CC34, 111/natIn-CC34, 68/natGa-HBED-CC-PSMA, and 111/natIn-PSMA-617 exhibited high affinity for the LNCaP cells, with Kd values of 19.3 ± 2.5 nM, 27.5 ± 2.7 nM, 5.5 ± 0.9 nM, 2.9 ± 0.6 nM and 5.4 ± 0.8 nM, respectively. They revealed comparable internalization profiles with approximately 75% of the total cell associated activity internalized after 3 h of incubation. 68Ga-CC34 showed very high stability after its administration in mice. Tumor uptake of 68Ga-CC34 (14.5 ± 2.9% IA/g) in LNCaP xenografts at 1 h p.i. was comparable to 68Ga-HBED-CC-PSMA (15.8 ± 1.4% IA/g) (P = 0.67). The tumor-to-normal tissue ratios at 1 and 2 h p.i of 68Ga-CC34 were also comparable to 68Ga-HBED-CC-PSMA (P > 0.05). Tumor uptake of 111In-CC34 (28.5 ± 2.6% IA/g) at 1 h p.i. was lower than 111In-PSMA-617 (52.1 ± 6.5% IA/g) (P = 0.02). The acquisition of PET-images with 64Cu-CC34 at later time points showed wash-out from the kidneys, while tumor uptake still remained relatively high. This resulted in an increased tumor-to-kidney ratio over time. 68Ga-CC34 is comparable to 68Ga-HBED-CC-PSMA in terms of tumor uptake and tumor to normal tissue ratios. 64Cu-CC34 could enable high contrast imaging of PSMA positive tissues characterized by elevated expression of PSMA or when delayed imaging is required. 64Cu-CC34 is currently being prepared for clinical translation.

Irradiation of salivary glands remains the main dose-limiting side effect of therapeutic PSMA-inhibitors, especially when using alpha emitters. Thus, further advances in radiopharmaceutical design and therapy strategies are needed to reduce salivary gland uptake, thereby allowing the administration of higher doses and potentially resulting in improved response rates and better tumor control. As the uptake mechanism remains unknown, this work investigates the salivary gland uptake of [177Lu]Lu-PSMA-617 by autoradiography studies on pig salivary gland tissue and on PSMA-overexpressing LNCaP cell membrane pellets. Displacement studies were performed with non-labeled PSMA-617 and 2-PMPA, respectively. The uptake of [177Lu]Lu-PSMA-617 in glandular areas was determined to be partly PSMA-specific, with a high non-specific uptake fraction. The study emphasizes that [177Lu]Lu-PSMA-617 accumulation in pig salivary glands can be attributed to a combination of both specific and non-specific uptake mechanisms. The observation is of high impact for future design of novel radiopharmaceuticals addressing the dose-limiting salivary gland irradiation of current alpha endoradiotherapy in prostate cancer.

PurposeThe specific binding ratio (SBR) of 123I-FP-CIT (FP-CIT) in the putamen decreases with age by about 5% per decade and most likely is about 10% higher in females. However, the clinical utility of age and sex correction of the SBR is still a matter of debate. This study tested the impact of age and sex correction on the diagnostic performance of the putamen SBR in three independent patient samples.MethodsResearch sample: 207 healthy controls (HC) and 438 Parkinson’s disease (PD) patients. Clinical sample A: 183 patients with neurodegenerative parkinsonian syndrome (PS) and 183 patients with non-neurodegenerative PS from one site. Clinical sample B: 84 patients with neurodegenerative PS and 38 patients with non-neurodegenerative PS from another site. Correction for age and sex of the putamen SBR was based on linear regression in the HC or non-neurodegenerative PS, separately in each sample. The area under the ROC curve (AUC) was used as performance measure.ResultsThe putamen SBR was higher in females compared to males (PPMI: 14%, p < 0.0005; clinical sample A: 7%, p < 0.0005; clinical sample B: 6%, p = 0.361). Age-related decline of the putamen SBR ranged between 3.3 and 10.4% (p ≤ 0.019). In subjects ≥ 50 years, age and sex explained < 10% of SBR between-subjects variance. Correction of the putamen SBR for age and sex resulted in slightly decreased AUC in the PPMI sample (0.9955 versus 0.9969, p = 0.025) and in clinical sample A (0.9448 versus 0.9519, p = 0.057). There was a small, non-significant AUC increase in clinical sample B (0.9828 versus 0.9743, p = 0.232).ConclusionThese findings do not support age and sex correction of the putaminal FP-CIT SBR in the diagnostic workup of parkinsonian syndromes. This most likely is explained by the fact that the proportion of between-subjects variance caused by age and sex is considerably below the symptom threshold of about 50% reduction in neurodegenerative PS.

BackgroundThe recent phase III VISION-trial confirms the treatment efficacy of radioligand therapy with [177Lu]PSMA-617 (PSMA-RLT) in metastatic castration-resistant prostate cancer (mCRPC). In PSMA-RLT, the relatively low absorbed bone marrow dose allows for multiple therapy cycles with relatively low risk of haematological adverse events (hAE). However, as disease progression itself may be a cause of bone marrow impairment, the aim of this study was to assess potential relations between impairment of haematological status and response to PSMA-RLT.MethodsIn this retrospective analysis, haematological parameters (HP) of 64 patients with mCRPC were systematically acquired over two cycles (12–16 weeks) of PSMA-RLT from baseline to restaging. Changes in HP were analysed qualitatively (CTCAE 5.0) and quantitatively. The HP changes from baseline were compared to quantitative and qualitative biochemical and imaging response, using PCWG3 and PROMISE criteria.ResultsAll grade 3/4 hAE observed were associated with disseminated or diffuse bone involvement as well as biochemical non-response at restaging. Quantitatively, at baseline, HP inversely correlated with biochemical and volumetric (on PET) tumour burden as well as bone involvement pattern (p ≤ 0.043). Among patients with disseminated or diffuse bone involvement, percentage changes in HP (%HP) at restaging inversely correlated with serological and imaging tumour burden (p ≤ 0.017). Biochemical non-responders showed a significant decrease in %HP (p ≤ 0.001) while HP in biochemical responders remained stable (p ≥ 0.079).ConclusionDuring early cycles of PSMA-RLT, qualitative and quantitative bone marrow impairment appears to be closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events, showing a significant decline of haematological parameters. This implies that in patients with advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles.German Clinical Trial Register DRKS00013665. Registered 28 December 2017, retrospectively registered (www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013665)

Background Multiple system atrophy (MSA) is a rare, rapidly progressive alpha-synucleinopathy characterized by autonomic dysfunction, parkinsonism and marked cerebellar ataxia, with very limited treatment options. N-acetyl-DL-leucine (ADLL) (Tanganil™), a racemic derivative of leucine is usually well tolerated and has shown promise in improving cerebellar symptoms and reducing REM sleep behavior disorder (RBD), a common non-motor dream-sleep disorder feature of alpha-synucleinopathy. Given this dual potential, we treated three patients with advanced-stage MSA under compassionate use rules. Case presentations Three patients with advanced-stage MSA and severe cerebellar symptoms—two of whom also had moderate RBD—were treated with ADLL (Tanganil TM ), titrated to 5g/day over 10 days. While both patients with RBD reported self-assessed decrease of RBD symptoms within 2–3 weeks on the full dosage (approximately four weeks after treatment initiation), all three patients had major worsening of gait and balance during the same period, leading to sudden falls and overall health decline. These adverse events prompted early discontinuation of therapy. Gait improved within two weeks after discontinuation of therapy in two patients. In parallel, the RBD phenotype reoccurred. In the third, who had very advanced MSA and concurrent infections, gait only slowly improved over time and it remains unclear whether his worsening of truncal ataxia was attributable to ADLL (Tanganil TM ), or whether it was related to his concurrent infections with slow recovery. Conclusions While ADLL improved RBD, it was poorly tolerated in these three patients with advanced-stage MSA of predominantly cerebellar type. Further studies are needed to evaluate its safety and efficacy in different, preferably early, stages of MSA.

Erythropoietin-producing hepatocellular receptor A2 (EphA2), is a receptor tyrosine kinase involved in cell-cell interactions. It is known to be overexpressed in various tumors and is associated with poor prognosis. EphA2 has been proposed as a target for theranostic applications. Low molecular weight peptide-based scaffolds with low nanomolar affinities have been shown to be ideal in such applications. Bicyclic peptides have emerged as an alternative to traditional peptides for this purpose, offering affinities comparable to antibodies due to their constrained nature, along with high tissue penetration, and improved stability compared to linear counterparts. This study presents the development and comprehensive and preclinical evaluation of BCY18469, a novel EphA2-targeting bicyclic peptide-based radiotheranostic agent. The EphA2-targeting Bicycle peptide BCY18469 was identified through phage-display and chemically optimized. BCY18469 was radiolabeled with Ga, Lu and In. The physicochemical properties, binding affinity and internalization as well as specificity of the peptide were evaluated . PET/MR and SPECT/CT imaging studies were performed using [ Ga]Ga-BCY18469 and [ In]In-BCY18469, respectively, along with biodistribution of [ Lu]Lu-BCY18469 up to 24 h post injection in HT1080- and PC-3-tumor bearing BALB/c nu/nu EphA2-overexpressing xenograft mouse models. The EphA2-targeting bicyclic peptide BCY18469 showed high binding affinity toward human and mouse EphA2 (1.9 and 3.8 nM, respectively). BCY18469 specifically bound and internalized into EphA2-expressing HT1080 cells. Imaging studies showed high tumor enrichment at early time-points (SUV of 1.7 g/mL at 1 h p.i. and 1.2 g/mL at 2 h p.i. in PET/MRI, HT1080 xenograft) with tumor contrast as early as 5 min p.i. and kidney-mediated clearance. Biodistribution studies revealed high early tumor uptake (19.5 ± 3.5 %ID/g at 1 h p.i., HT1080 xenograft) with SPECT/CT imaging further confirming these findings (5.7 ± 1.5 %ID/g at 1 h p.i., PC-3 xenograft). BCY18469 demonstrated high affinity, specific targeting of EphA2, a favorable biodistribution profile, and clearance through renal pathways. These findings underscore the potentially important role of bicyclic peptides in advancing radiotheranostic approaches and encourage additional translational research.

Background Left-predominant neurodegeneration of the anterior temporal lobe (ATL) and the associated syndrome termed semantic variant primary progressive aphasia (svPPA) are well characterized. Less is known about right-predominant neurodegeneration of the ATL, which has been associated with the clinical syndrome named right temporal variant of frontotemporal dementia (rtvFTD). Here, we assessed glucose metabolism across the brain, cognitive performance, and mortality in patients with right-predominant neurodegeneration of the ATL. Methods Patients with predominant hypometabolism of the ATL on FDG PET (as a measure of neurodegeneration) were retrospectively identified and categorized into those with asymmetrical right, left, or symmetric bilateral involvement ( N  = 10, 17, and 8). We compared whole-brain, normalized regional glucose metabolism using SPM12, cognitive performance on the CERAD Neuropsychological Assessment Battery, and mortality risk (age- and sex-adjusted Cox proportional hazard model) between groups. Results Hypometabolism was most pronounced and extensive in patients with right-predominant neurodegeneration of the ATL. Beyond the right temporal lobe, right frontal and left temporal lobes were affected in these patients. Cognitive performance was similarly impaired in all three groups, with predominant naming and hippocampal-dependent memory deficits. Mortality risk was 6.1 times higher in patients with right- than left-predominant ATL neurodegeneration ( p  < 0.05). Median survival duration after PET was shortest in patients with right- and longest in patients with left-predominant ATL neurodegeneration (5.7 vs 8.3 years after examination). Discussion More extensive neurodegeneration and shorter survival duration in patients with right- than left-predominant neurodegeneration of the ATL might indicate that the former consult memory clinics at a later disease stage, when symptoms like naming and episodic memory deficits have already emerged. At the time of diagnosis, the shorter survival duration of patients with right- than left-predominant ATL neurodegeneration should be kept in mind when counseling patients and caregivers.

Patients with asymmetric hearing loss show an asymmetry of glucose metabolism of the primary auditory cortex (PAC). We investigated whether this asymmetry could serve as an objective predictor for speech recognition with CI. Nine patients underwent 18 FDG PET prior to CI surgery. Average normalized 18 FDG uptake of 25% of voxels with highest uptake was calculated for the PAC employing a probabilistic atlas and cerebellar cortex as reference. Differences in glucose metabolism of the PAC were assessed by an asymmetry index (AI-PAC). We tested the correlation between outcome of CI surgery (6 months post implantation), AI-PAC and clinical predictors. Pre-operative AI-PAC showed a positive correlation with speech recognition with CI (significant for sentences and numbers; trend for monosyllabic words). With a pre-operative AI-PAC ≥ 4.2%, patients reached good CI outcome in sentence recognition of 59–90% and number recognition of 90–100% and less favorable CI outcome in monosyllabic word recognition of 25–45%. Age at symptom onset was significantly associated with all measures of speech recognition, while deafness duration was only associated with sentence recognition. AI-PAC allows for a reliable and quantitative pre-operative prediction of early improvement in speech recognition after CI. 18 FDG PET may be a valuable addition to the objective pre-operative assessment of CI candidates. Further studies in larger cohorts and with longer follow-up times are needed.