High efficacy of particle beam therapies against tumors under hypoxia and prediction of the early stage treatment effect using 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography.

OBJECTIVE: Compared with radiation therapy using photon beams, particle therapies, especially those using carbons, show a high relative biological effectiveness and low oxygen enhancement ratio. Using cells cultured under normoxic conditions, our group reported a greater suppressive effect on cell growth by carbon beams than X-rays, and the subsequent therapeutic effect can be predicted by the cell uptake amount of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) the day after treatment. On the other hand, a hypoxic environment forms locally around solid tumors, influencing the therapeutic effect of radiotherapy. In this study, the influence of tumor hypoxia on particle therapies and the ability to predict the therapeutic effect using 18F-FLT were evaluated. METHODS: Using a murine colon carcinoma cell line (colon 26) cultured under hypoxic conditions (1.0% O2 and 5.0% CO2), the suppressive effect on cell growth by X-ray, proton, and carbon irradiation was evaluated. In addition, the correlation between decreased 18F-FLT uptake after irradiation and subsequent suppression of cell proliferation was investigated. RESULTS: Tumor cell growth was suppressed most efficiently by carbon-beam irradiation. 18F-FLT uptake temporarily increased the day after irradiation, especially in the low-dose irradiation groups, but then decreased from 50 h after irradiation, which is well correlated with the subsequent suppression on tumor cell growth. CONCLUSIONS: Carbon beam treatment shows a strong therapeutic effect against cells under hypoxia. Unlike normoxic tumors, it is desirable to perform 18F-FLT positron emission tomography 2-3 days after irradiation for early prediction of the treatment effect.

[18F]FES PET Resolves the Diagnostic Dilemma of COVID-19-Vaccine-Associated Hypermetabolic Lymphadenopathy in ER-Positive Breast Cancer.

Coronavirus disease (COVID-19) vaccination is known to cause a diagnostic dilemma due to false-positive findings on [18F]FDG PET in vaccine-associated hypermetabolic lymphadenopathy. We present two case reports of women with estrogen-receptor (ER)-positive cancer of the breast who were vaccinated for COVID-19 in the deltoid muscle. [18F]FDG positron emission tomography (PET) demonstrated primary breast cancer and multiple axillary lymph nodes with increased [18F]FDG uptake, diagnosed as vaccine-associated [18F]FDG-avid lymph nodes. Subsequent [18F]FES PET revealed single axillary lymph node metastasis in the vaccine-associated [18F]FDG-avid lymph nodes. To the best of our knowledge, this is the first study showing the usefulness of [18F]FES PET in diagnosing axillary lymph node metastasis in COVID-19-vaccinated patients harboring ER-positive breast cancer. Thus, [18F]FES PET has potential applications in the detection of true-positive metastatic lymph nodes in patients with ER-positive breast cancer regardless of the ipsilateral or contralateral side, who have received COVID-19 vaccination.

Droplets Adhesion to Surgical Masks during Standard Oral Surgery.

The most common routes of transmission of coronavirus disease 2019 are droplet and contact infections. During dental treatment, several instruments and procedures used generate droplets of saliva and blood, such as during the extraction of an impacted third molar (M3). Surgical masks are often used during tooth extraction. However, the surface structures of surgical masks against droplets are not fully understood. Therefore, we analyzed the droplets that adhered to the surgical masks during impacted M3 extraction using electron microscopy. The surgical mask was divided into three layers and observed using electron microscopy. The outer and inner layers had a similar mesh-like structure, whereas the middle layer had a denser three-dimensional structure. Droplets ranging from 20-100 µm in size, generated during the extraction, adhered to the fibers of the outer layer of the mask. Fewer droplets adhered to the middle layer than to the outer layer. Droplets did not reach the inner layer. In conclusion, we suggest that a surgical mask can prevent droplet infection when performing impacted M3 extraction. This study is expected to contribute to the study of infection control strategies during dental treatments in the future.

Quantitative Assessment of Bone Marrow Activity Using 18 F-FLT PET in Aplastic Anemia and Myelodysplastic Syndromes.

PURPOSE: Peripheral cytopenias are typical of blood test abnormalities associated with a variety of conditions, including aplastic anemia (AA) and myelodysplastic syndromes (MDSs). We prospectively investigated the feasibility of quantitative analysis of whole-body bone marrow activity using PET with 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) in AA and MDS. PATIENTS AND METHODS: Sixty-eight patients with cytopenia underwent 18 F-FLT PET/MRI scan, with simultaneous bone marrow aspiration and biopsy for hematopoiesis evaluation. SUVs were measured in the vertebrae (Th3, 6, and 9 and L3), bilateral iliac crests, and extremities. SUV and bone marrow pathology were compared between AA and MDS and analyzed in relation to severity of AA and prognosis of MDS. RESULTS: Of the 68 patients with cytopenia, 12 were diagnosed with AA, 27 with MDS, 12 with bone marrow neoplasia, 2 with myelofibrosis, and 15 with other conditions. Iliac 18 F-FLT SUVs were significantly correlated with bone marrow cell numbers and cell density ( r = 0.47, P < 0.001 and ρ = 0.65, P < 0.001, respectively). There was a significant positive correlation between iliac and vertebral SUVs in AA and MDS ( r = 0.65, P < 0.05 and r = 0.70, P < 0.001, respectively), and the slope of the regression line was significantly steeper in AA than in MDS ( P < 0.05). In AA patients, vertebral 18 F-FLT SUVs significantly decreased with disease progression, and in MDS patients, higher whole-body 18 F-FLT uptake was associated with shorter overall survival (hazards ratio, 3.18; 95% confidence interval, 1.07-9.47; P = 0.037). CONCLUSIONS: Quantitative whole-body bone marrow imaging using 18 F-FLT PET helps distinguish AA from MDS and assess the severity of AA and prognosis of MDS.

Radiobrominated probe targeting activated p38α in inflammatory diseases.

OBJECTIVE: p38α, a member of the mitogen-activated protein kinase superfamily, is activated by external stimuli, followed by nuclear translocation for the regulation of inflammatory responses at the transcriptional and translational levels in inflammatory diseases. Thus, activated p38α would be an appropriate target molecule for in vivo noninvasive imaging and targeted radionuclide therapy. For this purpose, we designed a radiobrominated compound, 6-(4-[77Br]bromo-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([77Br]4-BR), based on a potent p38α selective inhibitor, R1487, for use with single-photon emission computed tomography. We synthesized [77Br]4-BR and evaluated its effectiveness as an activated p38α imaging probe compared with our previous radioiodinated probe (6-(2-fluoro-4-[125I]iodophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([125I]4-IR)) in a mouse inflammatory model. METHODS: We designed [77Br]4-BR by replacing the radioiodine of [125I]4-IR or the fluorine of R1487 with radiobromine at the 4-position of the phenoxy ring. We synthesized 4-BR via a four-step process. The inhibitory potency of 4-BR was measured using an ADP-Glo™ kinase assay system. Radiosynthesis of [77Br]4-BR was performed via an organotin-radiobromine exchange reaction using the corresponding tributyltin precursor. Radioactivity biodistribution was evaluated in normal ddY mice and turpentine oil-induced inflammation model mice for 120 min after intravenous administration of [77Br]4-BR. The temporal changes in radioactivity in blood fractions were compared between [77Br]4-BR and [125I]4-IR. RESULTS: 4-BR was synthesized at a total yield of 9.1% and showed a p38α inhibitory potency similar to that of 4-IR. [77Br]4-BR was successfully obtained from a tributyltin precursor with high radiochemical yield (89.9%), purity (95.9%), and molar activity (2.0 TBq/µmol). [77Br]4-BR showed accumulation of high radioactivity in the inflamed tissue (3.4% ± 0.9% ID/g, peaking at 15 min), rapid delivery throughout the body, and rapid blood clearance with approximately half of the blood radioactivity existing as an intact form at 60 min. Although the maximum radioactivity accumulation in inflamed tissue after [77Br]4-BR administration was approximately half that of [125I]4-IR because of its faster blood clearance and lower free fraction in the input function, the inflamed tissue-to-blood ratio was comparable between [77Br]4-BR and [125I]4-IR. CONCLUSIONS: [77Br]4-BR would be a promising imaging agent for detecting activated p38α in inflammatory diseases.

PET Imaging of Estrogen Receptors for Gynecological Tumors.

ABSTRACT: In the past few decades, PET with 18F-FDG has been used for the diagnosis of gynecological malignancies and is considered to be superior to conventional imaging methods in diagnostic accuracy for detecting metastatic lesions and local recurrence and in evaluating the treatment response. On the other hand, several gynecological tumors, such as endometrial cancer and leiomyoma, and breast cancer are estrogen-dependent, in which estrogen is essential for their development and progression. 18F-FES is an 18F-labeled compound of estradiol, the most bioactive type of estrogen, and 18F-FES PET has been well-established for diagnosis, staging, and posttherapeutic follow-up in patients with estrogen receptor-positive breast cancer. Compared with in vitro assessment of tumor biopsy material, PET imaging has the advantages of being able to measure in vivo tumor behavior, characterize the entire tumor burden, and capture the heterogeneity of the tumor phenotype. In this article, we review the phenotyping of estrogen-related gynecological tumors other than breast cancer using 18F-FES PET and demonstrate the additional value of 18F-FES PET to 18F-FDG PET in their diagnosis and prognostication. Moreover, promising PET tracers other than 18F-FES and 18F-FDG for the evaluation of estrogen-related gynecological tumors are introduced.

Cerebral Oxidative Stress in Early Alzheimer's Disease Evaluated by 64Cu-ATSM PET/MRI: A Preliminary Study.

Oxidative stress imaging using diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) was applied to the evaluation of patients with early Alzheimer's disease (eAD). Ten eAD patients (72 ± 9 years) and 10 age-matched healthy controls (HCs) (73 ± 9 years) participated in this study. They underwent dynamic PET/MRI using 11C-PiB and 64Cu-ATSM with multiple MRI sequences. To evaluate cerebral oxidative stress, three parameters of 64Cu-ATSM PET were compared: standardized uptake value (SUV), tracer influx rate (Kin), and a rate constant k3. The input functions were estimated by the image-derived input function method. The relative differences were analyzed by statistical parametric mapping (SPM) using SUV and Kin images. All eAD patients had positive and HC subjects had negative PiB accumulation, and MMSE scores were significantly different between them. The 64Cu-ATSM accumulation tended to be higher in eAD than in HCs for both SUV and Kin. When comparing absolute values, eAD patients had a greater Kin in the posterior cingulate cortex and a greater k3 in the hippocampus compared with lobar cortical values of HCs. In SPM analysis, eAD had an increased left operculum and decreased bilateral hippocampus and anterior cingulate cortex compared to HCs. 64Cu-ATSM PET/MRI and tracer kinetic analysis elucidated cerebral oxidative stress in the eAD patients, particularly in the cingulate cortex and hippocampus.

Development of Low Molecular Weight Ligands for Integrin αvß3.

We designed and synthesized non-peptide organic molecular ligands for integrin αvß3. Candidate ligands featured amidino analog and carboxy groups as binding sites on either side of a spacer, which consisted of benzophenone or an analog, such as diphenyl sulfide, diphenyl sulfoxide, diphenyl sulfone, or diphenyl ether. Competitive binding assays to integrin αvß3 with respect to [125I]echistatin were used to determine inhibitory activity of the synthetic ligands. Ligands bearing 2-aminobenzimidazoyl and glycyl groups separated by a benzophenone spacer demonstrated more potent binding than did a linear Arg-Gly-Asp (RGD) tripeptide that represents the native integrin αvß3 binding motif. Ligands possessing 2-aminobenzimidazoyl and carboxy groups and diphenyl sulfoxide or diphenyl ether spacers inhibited binding of [125I]echistatin with IC50 values similar to that of the linear RGD tripeptide.

Development of Radiohalogenated Osimertinib Derivatives as Imaging Probes for Companion Diagnostics of Osimertinib.

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for treating non-small-cell lung cancer (NSCLC) with EGFR mutations. Genetic testing is required to detect the mutation for selecting patients who can use osimertinib. Here, we report an attempt to develop nuclear imaging probes that detect the EGFR mutations. We designed and synthesized I-osimertinib and Br-osimertinib with a radioactive or nonradioactive halogen atom at an indole ring in osimertinib and evaluated them. In vitro assays suggested that both I-osimertinib and Br-osimertinib exhibit a specifically high activity toward NSCLC with EGFR L858R/T790M mutations. In biodistribution experiments, the accumulation of both [125I]I-osimertinib and [77Br]Br-osimertinib in tumors with mutations was significantly higher than that in blood and muscle. However, these osimertinib derivatives showed a significantly higher accumulation in lungs than in tumors. Therefore, for detecting the mutations in lung cancer, further structural modifications of the probes are required.

Metastatic invasive lobular breast cancer presenting as linitis plastica of the colon: Tumour characterization using [18 F]FES PET/MRI.

Metastatic invasive lobular breast cancer (ILC) to the colon is rare and usually ER-positive. We present an ER-negative case of metastatic ILC presenting as linitis plastica of the colon where [18 F]FES PET/MRI allowed the evaluation of the ER phenotypic transformation in the colonic metastasis from the ER-positive breast ILC in vivo.

Assessing the ADC of Bone-marrow on Whole-body MR Images in Relation to the Fat-suppression Method and Fat Content.

PURPOSE: To compare apparent diffusion coefficients (ADCs) of bone marrow on diffusion-weighted imaging (DWI) between two fat-suppression techniques, and to evaluate the association between bone-marrow ADCs and the proton density fat fraction (PDFF). METHODS: Seventy-seven patients underwent whole-body DWI with short-inversion time inversion-recovery (STIR) (DWISTIR) and/or STIR + selective water-excitation (spectral-spatial RF [SSRF]) (DWISTIR+SSRF). ADCs of lumbar vertebrae (L3 and L4) were compared between DWISTIR and DWISTIR+SSRF, and correlated with the PDFF. RESULTS: Lumbar ADCs obtained by DWISTIR and DWISTIR+SSRF were significantly correlated (L3: r = 0.90, P < 0.0001, L4: r = 0.90, P < 0.0001). Lumbar ADCs (× 10-6 mm2/s) obtained by DWISTIR were significantly lower than those by DWISTIR+SSRF (L3: 479 ± 137 and 490 ± 148, P < 0.05, L4: 456 ± 114 and 471 ± 118, P < 0.005). Residual fat signals were more clearly observed on DWISTIR than on DWISTIR+SSRF. The ADCs of L3 obtained by DWISTIR and DWISTIR+SSRF exhibited significant positive correlations with the PDFF (r = 0.51, P < 0.0001, and r = 0.45, P < 0.0001, respectively), and the ADCs of L4 obtained by DWISTIR and DWISTIR+SSRF exhibited significantly positive correlations with the PDFF (r = 0.40, P < 0.0005, and r = 0.40, P < 0.0005, respectively). CONCLUSION: Irrespective of different fat-suppression methods, lumbar ADCs were positively correlated with the PDFF, being inconsistent with previous studies. Lumbar ADCs obtained by DWISTIR were significantly lower than those obtained by DWISTIR+SSRF, probably due to residual fat signals on DWISTIR. However, this difference (< 4%) did not explain the positive correlation between lumbar ADC and PDFF.

Utilization of Antibody Allows Rapid Clearance of Nanoparticle Probes from Blood without the Need of Probe Modifications.

Nanoparticles are attracting attention as drug carriers for realizing "theranostics". However, nanoparticles generally show long blood circulation behaviors, and the remaining nanoparticle probe in the blood is the cause of prolonged optimal time from probe injection to imaging. Recently, it has been reported that some nanoparticles activate the immune system, producing an anti-nanoparticle antibody, which can selectively detect the corresponding nanoparticle and transfer it to the liver by opsonization. Lactosome is a polymer micelle prepared from amphiphilic PNMG-block-PLLA polydepsipeptide and known to activate the immune system when administered to mice at a specific concentration. In this study, radioactive fluorine-labeled lactosome (18F-lactosome) is used as a positron emission tomography probe for tumor imaging, and anti-lactosome antibody was additionally administrated after 2 h from the probe dosage. 18F-lactosome remaining in the blood was opsonized by the anti-lactosome antibody and transferred to the liver under the antibody dose-dependent manner. Because of the probe reduction from the blood, the tumor/blood signal intensity ratio could be improved up to 50% by anti-lactosome antibody administration. There needs further improvement, but the developed method is applicable for imaging utilizing nanoparticle probes, which activate the immune system.

A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma.

Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [77Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, 77Br was used as an alternative radionuclide for 76Br. We fundamentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC50 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC50 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.

Noninvasive Measurement of [11C]PiB Distribution Volume Using Integrated PET/MRI.

A noninvasive image-derived input function (IDIF) method using PET/MRI was applied to quantitative measurements of [11C] Pittsburgh compound-B (PiB) distribution volume (DV) and compared with other metrics. Fifty-three patients suspected of early dementia (71 ± 11 y) underwent 70 min [11C]PiB PET/MRI. Nineteen of them (68 ± 11 y) without head motion during the scan were enrolled in this study and compared with 16 age-matched healthy controls (CTL: 68 ± 11 y). The dynamic frames reconstructed from listmode PET data were used for DV calculation. IDIF with metabolite correction was applied to the Logan plot method, and DV was normalized into DV ratio (DVR) images using the cerebellar reference (DVRL). DVR and standardized uptake value ratio (SUVR) images were also calculated using the reference tissue graphical method (DVRr) and the 50-70 min static data with cerebellar reference, respectively. Cortical values were compared using the 3D-T1WI MRI segmentation. All patients were assigned to the early Alzheimer's disease (eAD) group because of positive [11C]PiB accumulation. The correlations of regional values were better for DVRL vs. DVRr (r2 = 0.97) than for SUVR vs. DVRr (r2 = 0.88). However, all metrics clearly differentiated eAD from CTL with appropriate thresholds. Noninvasive quantitative [11C]PiB PET/MRI measurement provided equivalent DVRs with the two methods. SUVR images showed acceptable results despite inferior variability and image quality to DVR images.

Comparison of diagnostic accuracy between [18F]FDG PET/MRI and contrast-enhanced MRI in T staging for oral tongue cancer.

OBJECTIVE: Integrated PET/MRI with [18F]FDG is advantageous in that it enables simultaneous PET and MR imaging with higher soft-tissue contrast, multiplanar image acquisition, and functional imaging capability without using fat suppression and gadolinium-based contrast agents (GBCAs). The aims of this study were to demonstrate the feasibility of [18F]FDG PET/MRI for assessing the extent of the primary tumor (T) in oral tongue cancer (OTC) based on the 8th edition of American Joint Committee on Cancer (AJCC) cancer staging system, and to compare the diagnostic accuracy between [18F]FDG PET/MRI and contrast-enhanced MRI (ceMRI). METHODS: 18 patients with biopsy-proven operable OTC underwent preoperative regional [18F]FDG PET/MRI and ceMRI within 2 weeks. For [18F]FDG PET/MRI, rainbow-colored PET images were overlaid on the corresponding MR images. Tumor size and the depth of invasion (DOI) were visually measured on [18F]FDG PET/MRI and ceMRI. The size, DOI, and clinical T stage were evaluated using the final surgical pathology as the reference. RESULTS: Of the 18 OTCs, one was not detected by ceMRI due to metal artifacts from an artificial denture, and another due to superficial type (pathological DOI = 0 mm). Tumor sizes measured by ceMRI and [18F]FDG PET/MRI had significant positive correlations with the pathological size (r = 0.80 and r = 0.90, respectively), and DOIs measured by ceMRI and [18F]FDG PET/MRI had significant positive correlations with the pathological DOI (r = 0.74 and r = 0.64, respectively). The means ± SD of size (mm) were 20.4 ± 9.1, 22.9 ± 10.9, and 26.2 ± 10.0, and those of DOI (mm) were 7.1 ± 2.5, 6.9 ± 2.2, and 5.8 ± 3.2 for ceMRI, [18F]FDG PET/MRI, and pathology, respectively. A significant difference was observed in tumor size between ceMRI and pathology (p < 0.05), whereas no significant differences were observed between any other sizes, DOIs, or T stages. The accuracy for T status was 72% (13/18 including 2 undetectable cases) for ceMRI and 89% (16/18) for [18F]FDG PET/MRI. CONCLUSIONS: Although shallow DOIs are often overestimated, regional [18F]FDG PET/MRI without fat suppression and gadolinium enhancement is comparable to and may be substituted for ceMRI in preoperative T staging for OTC patients, reducing metal artifacts and avoiding the adverse effects of GBCAs.

Multimodal analysis using [11C]PiB-PET/MRI for functional evaluation of patients with Alzheimer's disease.

BACKGROUND: Multimodal PET/MRI image data simultaneously obtained from patients with early-stage of Alzheimer's disease (eAD) were assessed in order to observe pathophysiologic and functional changes, as well as alterations of morphology and connectivity in the brain. Fifty-eight patients with mild cognitive impairment and early dementia (29 males, 69 ± 12 years) underwent [11C]Pittsburgh compound-B (PiB) PET/MRI with 70-min PET and MRI scans. Sixteen age-matched healthy controls (CTL) (9 males, 68 ± 11 years) were also studied with the same scanning protocol. Cerebral blood flow (CBF) was calculated from the early phase PET images using the image-derived input function method. A standardized uptake value ratio (SUVr) was calculated from 50 to 70 min PET data with a reference region of the cerebellar cortex. MR images such as 3D-T1WI, resting-state functional MRI (RS-fMRI), diffusion tensor image (DTI), and perfusion MRI acquired during the dynamic PET scan were also analyzed to evaluate various brain functions on MRI. RESULTS: Twenty-seven of the 58 patients were determined as eAD based on the results of PiB-PET and clinical findings, and a total of 43 subjects' data including CTL were analyzed in this study. PiB SUVr values in all cortical regions of eAD were significantly greater than those of CTL. The PiB accumulation intensity was negatively correlated with cognitive scores. The regional PET-CBF values of eAD were significantly lower in the bilateral parietal lobes and right temporal lobe compared with CTL, but not in MRI perfusion; however, SPM showed regional differences on both PET- and MRI-CBF. SPM analysis of RS-fMRI delineated regional differences between the groups in the anterior cingulate cortex and the left precuneus. VBM analysis showed atrophic changes in the AD group in a part of the bilateral hippocampus; however, analysis of fractional anisotropy calculated from DTI data did not show differences between the two groups. CONCLUSION: Multimodal analysis conducted with various image data from PiB-PET/MRI scans showed differences in regional CBF, cortical volume, and neuronal networks in different regions, indicating that pathophysiologic and functional changes in the AD brain can be observed from various aspects of neurophysiologic parameters. Application of multimodal brain images using PET/MRI would be ideal for investigating pathophysiologic changes in patients with dementia and other neurodegenerative diseases.

Renal dysfunction can occur in advanced-stage Duchenne muscular dystrophy.

INTRODUCTION: With improved treatments, patients with Duchenne muscular dystrophy (DMD) can survive far beyond adolescence. However, advanced-stage DMD patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage DMD were analyzed. METHODS: Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups. RESULTS: Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014). DISCUSSION: Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage DMD.

No significant difference found in PET/MRI CBF values reconstructed with CT-atlas-based and ZTE MR attenuation correction.

BACKGROUND: Accurate attenuation correction (AC) is one of the most important issues to be addressed in quantitative brain PET/MRI imaging. Atlas-based MRI AC (AB-MRAC), one of the representative MRAC methods, has been used to estimate the skull attenuation in brain scans. The zero echo time (ZTE) pulse sequence is also expected to provide a better MRAC estimation in brain PET scans. The difference in quantitative measurements of cerebral blood flow (CBF) using H215O-PET/MRI was compared between the two MRAC methods, AB and ZTE. METHOD: Twelve patients with cerebrovascular disease (4 males, 43.2 ± 11.7 years) underwent H215O-PET/MRI studies with a 3-min PET scan and MRI scans including the ZTE sequence. Eleven of them were also studied under the conditions of baseline and 10 min after acetazolamide administration, and 2 of them were followed up after several months interval. A total of 25 PET images were reconstructed as dynamic data using 2 sets of reconstruction parameters to obtain the image-derived input function (IDIF), the time-activity curves of the major cerebral artery extracted from images, and CBF images. The CBF images from AB- and ZTE-MRAC were then compared for global and regional differences. RESULTS: The mean differences of IDIF curves at each point obtained from AB- and ZTE-MRAC dynamic data were less than 5%, and the differences in time-activity curves were very small. The means of CBF from AB- and ZTE-MRAC reconstructions calculated using each IDIF showed differences of less than 5% for all cortical regions. CBF images from AB-MRAC tended to show greater values in the parietal region and smaller values in the skull base region. CONCLUSION: The CBF images from AB- and ZTE-MRAC reconstruction showed no significant differences in regional values, although the parietal region tended to show greater values in AB-MRAC reconstruction. Quantitative values in the skull base region were very close, and almost the same IDIFs were obtained.

18F-FLT PET/MRI for bone marrow failure syndrome-initial experience.

BACKGROUND: Bone marrow failure syndrome (BMFS) is a heterogeneous group of disorders associated with single- or multiple-lineage cytopenia and failure of normal hematopoiesis. We assessed the feasibility of integrated PET/MRI with 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) to assess the pathophysiology of whole-body bone marrow for the diagnosis and monitoring of BMFS. Twenty-five consecutive patients with BMFS underwent a pre-treatment 18F-FLT PET/MRI scan. They included 7 patients with aplastic anemia (AA), 16 with myelodysplastic syndrome (MDS), and 2 with myeloproliferative neoplasms (MPNs), primary myelofibrosis (MF), and secondary [post-essential thrombocythemia (post-ET)] MF. Two of the seven AA patients underwent a post-treatment scan. Eight of the 16 MDS patients who exhibited decreased 18F-FLT uptake in the pelvis were considered to have hypoplastic MDS (hypo-MDS). 18F-FLT PET and diffusion-weighted imaging (DWI) were visually and quantitatively evaluated. RESULTS: The 18F-FLT uptake in the ilium was strongly correlated with bone marrow cellularity based on biopsy samples (ρ = 0.85). AA patients exhibited heterogeneously decreased uptake of 18F-FLT according to disease severity. Multiple 18F-FLT foci were observed in the proximal extremities, and they were in the central skeleton in severe AA patients. Post-treatment 18F-FLT PET scans of severe AA patients reflected the response of hematopoietic activity to treatment. MDS patients had marked 18F-FLT uptake in the central skeleton and proximal extremities, whereas hypo-MDS patients had heterogeneously decreased uptake, similar to that of non-severe AA patients. 18F-FLT PET and DWI were unable to predict the progression to leukemia for both MDS and hypo-MDS patients. A primary MF patient had slightly decreased 18F-FLT uptake in the central skeleton, but marked expansion of bone marrow activity to the distal extremities and high uptake of tracer in the extremely enlarged spleen (extramedullary hematopoiesis). In contrast, a secondary (post-ET) MF patient demonstrated marked bone marrow uptake, reflecting the hypercellular marrow with fibrosis. DWI revealed diffusely high signal intensities in both the primary and secondary MF patients. CONCLUSION: 18F-FLT PET can be used to noninvasively assess whole-body bone marrow proliferative activity and DWI may reflect the different aspects of bone marrow pathophysiology from 18F-FLT PET. 18F-FLT PET/MRI is useful for the diagnosis and monitoring of BMFS, except for the differentiation between non-severe AA and hypo-MDS, and the prediction of progression to leukemia.

Radiobrominated benzimidazole-quinoline derivatives as Platelet-derived growth factor receptor beta (PDGFRß) imaging probes.

Platelet-derived growth factor receptor beta (PDGFRß) affects in numerous human cancers and has been recognized as a promising molecular target for cancer therapies. The overexpression of PDGFRß could be a biomarker for cancer diagnosis. Radiolabeled ligands having high affinity for the molecular target could be useful tools for the imaging of overexpressed receptors in tumors. In this study, we aimed to develop radiobrominated PDGFRß ligands and evaluate their effectiveness as PDGFRß imaging probes. The radiolabeled ligands were designed by modification of 1-{2-[5-(2-methoxyethoxy)-1H- benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine (1), which shows selective inhibition profile toward PDGFRß. The bromine atom was introduced directly into C-5 of the quinoline group of 1, or indirectly by the conjugation of 1 with the 3-bromo benzoyl group. [77Br]1-{5-Bromo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([77Br]2) and [77Br]-N-3-bromobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([77Br]3) were prepared using a bromodestannylation reaction. In a cellular uptake study, [77Br]2 and [77Br]3 more highly accumulatd in BxPC3-luc cells (PDGFRß-positive) than in MCF7 cells (PDGFRß-negative), and their accumulation was significantly reduced by pretreatment with inhibitors. In biodistribution experiments, [77Br]2 accumulation was higher than [77Br]3 accumulation at 1 h postinjection. These findings suggest that [76Br]2 is more promising for positron emission tomography (PET) imaging of PDGFRß than [76Br]3.