Nigrostriatal blood-brain barrier opening in Parkinson's disease.

BACKGROUND: The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD. METHODS: Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after. RESULTS: The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions. CONCLUSION: BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

Efficacy of [177Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). RESULTS: The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7-not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8-28.1) in pancreatic, and 17.6 months (14.4-33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity. CONCLUSION: This study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

[18F]DCFPyL PET/CT versus [18F]fluoromethylcholine PET/CT in Biochemical Recurrence of Prostate Cancer (PYTHON): a prospective, open label, cross-over, comparative study.

PURPOSE: Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). METHODS: This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. RESULTS: A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. CONCLUSIONS: The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.

Contribution of positron emission tomography/magnetic resonance imaging in musculoskeletal malignancies.

Positron emission tomography/computed tomography (PET/CT) is a promising hybrid imaging technique for evaluating musculoskeletal malignancies. Both technologies, independently are useful for evaluating this type of tumors. PET/MR has great potential combining metabolic and functional imaging PET with soft tissue contrast and multiparametric sequences of MR. In this paper we review the existing literature and discuss the different protocols, new available radiotracers to conclude with the scarce evidence available the most useful/probable indications of the PET MR for the for musculoskeletal malignancies.

Functional impact of subthalamotomy by magnetic resonance-guided focused ultrasound in Parkinson's disease: a hybrid PET/MR study of resting-state brain metabolism.

PURPOSE: Subthalamotomy using magnetic resonance-guided focused ultrasound (MRgFUS) has become a potential treatment option for the cardinal features of Parkinson's disease (PD). The purpose of this study was to evaluate the effects of MRgFUS-subthalamotomy on brain metabolism using different scale levels. METHODS: We studied resting-state glucose metabolism in eight PD patients before and after unilateral MRgFUS-subthalamotomy using hybrid [18F]FDG-PET/MR imaging. We used statistical nonparametric mapping (SnPM) to study regional metabolic changes following this treatment and also quantified whole-brain treatment-related changes in the expression of a spatial covariance-based Parkinson's disease-related metabolic brain pattern (PDRP). Modulation of regional and network activity was correlated with clinical improvement as measured by changes in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor scores. RESULTS: After subthalamotomy, there was a significant reduction in FDG uptake in the subthalamic region, globus pallidus internus, motor and premotor cortical regions, and cingulate gyrus in the treated hemisphere, and the contralateral cerebellum (p < 0.001). Diffuse metabolic increase was found in the posterior parietal and occipital areas. Treatment also resulted in a significant decline in PDRP expression (p < 0.05), which correlated with clinical improvement in UPDRS motor scores (rho = 0.760; p = 0.002). CONCLUSIONS: MRgFUS-subthalamotomy induced metabolic alterations in distributed nodes of the motor, associative, and limbic circuits. Clinical improvement was associated with reduction in the PDRP expression. This treatment-induced modulation of the metabolic network is likely to mediate the clinical benefit achieved following MRgFUS-subthalamotomy.

Pharmacokinetics, metabolism, and excretion of (14)C-labeled belinostat in patients with recurrent or progressive malignancies.

BACKGROUND: Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (50-70%), with renal excretion accounting for ~30-50%. A Phase 1 human mass balance study was conducted to identify species-dependent variations in belinostat metabolism and elimination. METHODS: Patients received a single 30-min intravenous (i.v.) infusion of (14)C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography-tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m(2) on Days 1-5 every 21 days) was permitted. RESULTS: Belinostat was extensively metabolized and mostly cleared from plasma within 8 h (N = 6), indicating that metabolism is the primary route of elimination. Systemic exposure for the 5 major metabolites was >20% of parent, with belinostat glucuronide the predominant metabolite. Mean recovery of radioactive belinostat was 94.5% ± 4.0%, with the majority excreted within 48 and 96 h in urine and feces, respectively. Renal elimination was the principal excretion route (mean 84.8% ± 9.8% of total dose); fecal excretion accounted for 9.7% ± 6.5%. Belinostat was well tolerated, with mostly mild to moderate adverse events and no treatment-related severe/serious events. CONCLUSION: Mass balance was achieved (~95% mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites.

Prospective study on stereotactic body radiotherapy for small pancreatic neuroendocrine tumors: tolerance and effectiveness analysis.

INTRODUCTION: Surgery is the standard treatment for pancreatic neuroendocrine tumors (pNETs), obtaining favorable results but associating high morbidity and mortality rates. This study assesses stereotactic body radiation therapy (SBRT) as a radical approach for small (< 2 cm) nonfunctioning pNETs. MATERIALS AND METHODS: From January 2017 to June 2023, 20 patients with small pNETs underwent SBRT in an IRB-approved study. Endpoints included local control, tolerance, progression-free survival, and overall survival (OS). Diagnostic assessments comprised endoscopy, CT scans, OctreScan or PET-Dotatoc, abdominal MRI, and histological confirmatory samples. RESULTS: In a 30-month follow-up of 20 patients (median age 55.5 years), SBRT was well-tolerated with no grade > 2 toxicity. 40% showed morphological response, 55% remained stable. Metabolically, 50% achieved significant improvement. With a median OS of 41.5 months, all patients were alive without local or distant progression or need for surgical resection. CONCLUSION: SBRT is a feasible and well-tolerated approach for small neuroendocrine pancreatic tumors, demonstrating effective local control. Further investigations are vital for validation and extension of these findings.

Brain hypometabolism in non-demented microtubule-associated protein tau H1 carriers with Parkinson's disease.

BACKGROUND AND PURPOSE: The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype. METHODS: We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late-onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a [18F]-Fluorodeoxyglucose PET-MR scan. RESULTS: MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the [18F]-Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus. CONCLUSION: PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.

BBB opening with focused ultrasound in nonhuman primates and Parkinson's disease patients: Targeted AAV vector delivery and PET imaging.

Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson's disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson's disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders.

Primary Chemoradiotherapy Treatment (PCRT) for HER2+ and Triple Negative Breast Cancer Patients: A Feasible Combination.

Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio−chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation was delivered concomitantly during the first 3 weeks of chemotherapy, and it was based on a 15 fractions scheme, 40.5 Gy/2.7 Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy (CT) was based on Pertuzumab−Trastuzumab−Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. A total of 58 patients were enrolled; 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved >90% loss of invasive carcinoma cells in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype, respectively, achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies were applied simultaneously: fractionation of RT (radiotherapy) in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging.

Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16-20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.

Additional value of hybrid PET/MR imaging versus MR or PET performed separately to assess cardiovascular disease.

INTRODUCTION AND OBJECTIVES: Hybrid positron emission tomography (PET) and magnetic resonance (MR) imaging is an emerging technology in the diagnosis of cardiovascular disease; however, there have been no reports of its use in the national clinical setting. Our objective was to evaluate the additional value of integrated PET/MR systems compared with MR and PET performed separately in this setting. METHODS: We prospectively included 49 patients, 30 to assess myocardial viability (coronary group) and 19 to assess inflammatory, infectious, and tumoral diseases (noncoronary heart disease group). All patients underwent cardiac 18F-fluorodeoxyglucose PET/MR. PET/MR studies included attenuation correction sequences, followed by simultaneous cardiac PET and cardiac MR acquisition, with protocols adapted to the clinical indication (cine, tissue characterization and/or late enhancement imaging). RESULTS: Most (87.8%) PET/MR studies were initially interpretable. Use of PET/MR improved diagnosis vs PET or MR performed separately in 42.1% of coronary cases and 88.9% of noncoronary cases. PET/MR enabled reclassification of 87.5% of coronary cases initially classified as showing inconclusive results on MR or PET and 70% of noncoronary cases. CONCLUSIONS: In our series, multimodality PET/MR technology provided additional diagnostic value in some patients with cardiovascular disease compared with MR and PET performed separately, especially in cases of noncoronary heart disease and in those with inconclusive results on MR or PET. In our experience, the main benefits of PET/MR include the possibility of simultaneous acquisition, the in vivo integration of anatomical/functional/metabolic aspects, and the interaction of different experts in imaging modalities.

223Ra-dichloride response in a patient with Paget disease and bone metastases secondary to castration-resistant prostate cancer.

PURPOSE: Paget disease is commonly asymptomatic and discovered when an imaging test is performed for another clinical indication or when elevated serum alkaline phosphatase is found. Bone pain usually appears late in the disease process and is only present in a minority of patients. For diagnosis, X-ray and bone scan are the most recommended imaging methods; radionuclide imaging of the skeleton has become the standard, since it is the most sensitive test for detecting increased bone activity. For treatment, either bisphosphonates or calcitonin are recommended. METHODS: We present a 74-year-old patient diagnosed with prostate cancer in 2001 who developed bone metastases concomitant with a Paget bone disease. RESULTS: This patient received treatment with Ra-223, having stable disease in bone scan and no relevant toxicities. CONCLUSIONS: There is no clinical experience with Ra-223 and Paget disease, since it is characterized classically as a high bone turnover disease and therefore there is no rationale to administer a drug that has a high bone affinity. Nevertheless, Ra-223 is not contraindicated.

Fast Patch-Based Pseudo-CT Synthesis from T1-Weighted MR Images for PET/MR Attenuation Correction in Brain Studies.

UNLABELLED: Attenuation correction in hybrid PET/MR scanners is still a challenging task. This paper describes a methodology for synthesizing a pseudo-CT volume from a single T1-weighted volume, thus allowing us to create accurate attenuation correction maps. METHODS: We propose a fast pseudo-CT volume generation from a patient-specific MR T1-weighted image using a groupwise patch-based approach and an MRI-CT atlas dictionary. For every voxel in the input MR image, we compute the similarity of the patch containing that voxel to the patches of all MR images in the database that lie in a certain anatomic neighborhood. The pseudo-CT volume is obtained as a local weighted linear combination of the CT values of the corresponding patches. The algorithm was implemented in a graphical processing unit (GPU). RESULTS: We evaluated our method both qualitatively and quantitatively for PET/MR correction. The approach performed successfully in all cases considered. We compared the SUVs of the PET image obtained after attenuation correction using the patient-specific CT volume and using the corresponding computed pseudo-CT volume. The patient-specific correlation between SUV obtained with both methods was high (R(2) = 0.9980, P < 0.0001), and the Bland-Altman test showed that the average of the differences was low (0.0006 ± 0.0594). A region-of-interest analysis was also performed. The correlation between SUVmean and SUVmax for every region was high (R(2) = 0.9989, P < 0.0001, and R(2) = 0.9904, P < 0.0001, respectively). CONCLUSION: The results indicate that our method can accurately approximate the patient-specific CT volume and serves as a potential solution for accurate attenuation correction in hybrid PET/MR systems. The quality of the corrected PET scan using our pseudo-CT volume is comparable to having acquired a patient-specific CT scan, thus improving the results obtained with the ultrashort-echo-time-based attenuation correction maps currently used in the scanner. The GPU implementation substantially decreases computational time, making the approach suitable for real applications.