Quantitative and qualitative evaluation of sequential PET/MRI using a newly developed mobile PET system for brain imaging

[Purpose]To evaluate the clinical feasibility of a newly developed mobile PET system with MR-compatibility (flexible PET; fxPET), compared with conventional PET (cPET)/CT for brain imaging.[Methods]Twenty-one patients underwent cPET/CT with subsequent fxPET/MRI using 18F-FDG. As qualitative evaluation, we visually rated image quality of MR and PET images using a four-point scoring system. We evaluated overall image quality for MR, while we evaluated overall image quality, sharpness and lesion contrast. As quantitative evaluation, we compared registration accuracy between two modalities [(fxPET and MRI) and (cPET and CT)] measuring spatial coordinates. We also examined the accuracy of regional 18F-FDG uptake.[Results]All acquired images were of diagnostic quality and the number of detected lesions did not differ significantly between fxPET/MR and cPET/CT. Mean misregistration was significantly larger with fxPET/MRI than with cPET/CT. SUVmax and SUVmean for fxPET and cPET showed high correlations in the lesions (R = 0.84, 0.79; P < 0.001, P = 0.002, respectively). In normal structures, we also showed high correlations of SUVmax (R = 0.85, 0.87; P < 0.001, P < 0.001, respectively) and SUVmean (R = 0.83, 0.87; P < 0.001, P < 0.001, respectively) in bilateral caudate nuclei and a moderate correlation of SUVmax (R = 0.65) and SUVmean (R = 0.63) in vermis.[Conclusions]The fxPET/MRI system showed image quality within the diagnostic range, registration accuracy below 3 mm and regional 18F-FDG uptake highly correlated with that of cPET/CT

Evaluation of transporter-mediated hepatobiliary transport of newly developed ¹⁸F-labeled pitavastatin derivative, PTV-F1, in rats by PET imaging

Quantitative evaluations of the functions of uptake and efflux transporters directly in vivo is desired to understand an efficient hepatobiliary transport of substrate drugs. Pitavastatin is a substrate of organic anion transporting polypeptides (OATPs) and canalicular efflux transporters; thus, it can be a suitable probe for positron-emission tomography (PET) imaging of hepatic transporter functions. To characterize the performance of [¹⁸F]PTV-F1, an analogue of pitavastatin, we investigated the impact of rifampicin (a typical OATP inhibitor) coadministration or Bcrp (breast cancer resistance protein) knockout on [¹⁸F]PTV-F1 hepatic uptake and efflux in rats by PET imaging. After intravenous administration, [¹⁸F]PTV-F1 selectively accumulated in the liver, and the radioactivity detected in plasma, liver, and bile mainly derived from the parent PTV-F1 during the PET study (∼40 min). Coadministration of rifampicin largely decreased the hepatic uptake of [¹⁸F]PTV-F1 by 73%. Because of its lower clearance in rats, [¹⁸F]PTV-F1 is more sensitive for monitoring changes in hepatic OATP1B function that other previously reported OATP1B PET probes. Rifampicin coadministration also significantly decreased the biliary excretion of radioactivity by 65%. Bcrp knockout did not show a significant impact on its biliary excretion.[¹⁸F]PTV-F1 enables quantitative analysis of the hepatobiliary transport system for organic anions

A reversible lesion of the corpus callosum splenium with adult influenza-associated encephalitis/encephalopathy: a case report

<p>ABstract</p> <p>Introduction</p> <p>Influenza virus-associated encephalitis/encephalopathy is a severe childhood illness with a poor prognosis. Adult case reports are rare and, to date, there have been no reports of adults with a mild subcortical encephalopathy with reversible lesions of the corpus callosum splenium.</p> <p>Case presentation</p> <p>A previously healthy 35-year-old man presented with acute progressive tetraplegia, transcortical motor aphasia and a mild decrease in his consciousness during his recovery after receiving oseltamivir phosphate treatment, and influenza type A antiviral medication. The initial magnetic resonance imaging study at day 1 showed symmetrical diffuse lesions in the white matter and a lesion on the central portion of the corpus callosum splenium. These findings had resolved on follow-up studies at day 8 and day 146. His neurological deficits mostly recovered within 12 hours following methylprednisolone pulse therapy. The levels of interleukin-6 and interleukin-10 in his blood and cerebrospinal fluid were initially elevated, but rapidly decreased to normal levels by day 8.</p> <p>Conclusion</p> <p>It is important for clinicians to recognize that even in adulthood, the subcortical encephalopathy observed during the therapeutic treatment for influenza type A infection can occur in conjunction with a reversible lesion of the corpus callosum, which may recover quickly. In addition, the cytokine storm in the blood system and the corticospinal cavity may play an important role in the etiology of the disease process.</p

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

FDG-PET/CT assessment of misty mesentery: Feasibility for distinguishing viable mesenteric malignancy from stable conditions.

[Purpose] "Misty mesentery" is a CT appearance of mesenteric fat changes with increased attenuation often existing with swelled mesenteric lymph nodes. We evaluated diagnostic performance of FDG-PET/CT in distinguishing viable malignant disorders from benign conditions in misty mesentery. [Materials and methods] 4236 FDG-PET/CT images were reviewed to identify patients with appearances of misty mesentery. Only the initial examinations were evaluated. Patients undergoing chemotherapy and/or radiotherapy within 3 months, patients with bulky mesenteric mass, and patients without follow-up examinations were excluded. Maximum short-axis diameter of mesenteric nodules (Diam-max) and maximum standardized uptake value (SUVmax) for mesenteric abnormalities were measured, and the diagnostic performance to differentiate between viable malignancy and stable lesions was assessed by receiver-operating characteristic (ROC) analysis, based on final diagnoses obtained by histology or follow-up examinations. Their significance was assessed by multivariate logistic regression. [Results] 71 studies met the inclusion criteria with confirmed diagnoses (13 viable malignancies; 58 stable lesions). Of the 13 malignant cases, 12 were lymphoma. ROC curves indicated an optimal Diam-max cut-off value of >10 mm and SUVmax cut-off of ≥3.0, with area under the curve of 0.961 and 0.926, respectively. Using the optimal Diam-max cut-off, sensitivity and specificity were 69% and 98%, respectively. Using the optimal SUVmax cut-off, they were 85% and 98%, respectively. The combination of either Diam-max > 10 mm or SUVmax ≥ 3.0 had a sensitivity of 92%. Both Diam-max and SUVmax were significant independent factors for predicting malignancy. [Conclusions] FDG-PET/CT is feasible for identifying viable malignancy in misty mesentery

Evaluation of [¹⁸F]pitavastatin as a positron emission tomography tracer for in vivo organic transporter polypeptide function

Introduction: To understand the pathways involved in drug clearance from the body, quantitative evaluations of the hepatobiliary transport of drugs are important. The organic anion transporting polypeptide (OATP) family transporter, particularly OATP1B1 and 1B3, are considered to play an important role in hepatic uptake of organic anion compounds. Pitavastatin is a substrate of OATP, and it includes a fluorine group. Therefore, it represents an acceptable positron-emission tomography (PET) tracer using fluorine-18 to image in vivo hepatic transporter functions. Method: [¹⁸F]Pitavastatin was synthesized using the method we previously reported. To evaluate the potential of [¹⁸F]pitavastatin in PET imaging of in vivo OATP functions, we investigated the hepatic uptake with/without rifampicin as an OATP inhibitor after administration in normal SD rats. [¹⁸F]Pitavastatin metabolite was evaluated using reverse-phase thin-layer chromatography (TLC) autoradiography. We subsequently analyzed the PET image results and demonstrated that [¹⁸F]pitavastatin selectively accumulated in the liver post-administration. Result and discussion: In metabolite analysis using reverse-phase TLC, we found that the radioactivity detected in the plasma, liver (>90% intact), and bile mostly originated from the parent pitavastatin of the PET study (~40 min). [¹⁸F]pitavastatin's hepatic uptake decreased (approximately 76%) with rifampicin co-administration in PET analysis. Because [¹⁸F]pitavastatin has lower clearance in rats than other previously reported OATP1B PET s, it holds the potential of an imaging tracer that has a higher sensitivity in monitoring hepatic OATP1B function's changes. Conclusion: Compared with the previously reported OATP imaging tracers, [¹⁸F]pitavastatin is more suitable for the sensitive detection of functional changes in OATP transporters. We believe that [¹⁸F]pitavastatin enables quantitative analysis of the hepatobiliary transport system for organic anion compounds

Additional information gained by positron emission tomography with (68)Ga-DOTATOC for suspected unknown primary or recurrent neuroendocrine tumors.

[Objective]Positron emission tomography (PET)/computed tomography (CT) using 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-D-Phe1-Tyr3-octreotide (DOTATOC) has been used to detect neuroendocrine tumors (NETs). The purpose of this study was to investigate the clinical efficacy of DOTATOC-PET/CT for detecting clinically suspected NETs when conventional imaging modalities were negative or inconclusive, in terms of additional value. [Methods]A total of 46 patients were analyzed retrospectively. Among them, 14 patients underwent a DOTATOC-PET/CT scan for detecting unknown primary tumors after histopathological confirmation of a NET at metastatic sites (group A): 7 patients for detecting metastasis or recurrence after surgery for NET because of their high hormone levels but with no recurrence detected by other imaging modalities (group B); the remaining 25 patients for detecting suspected NETs because their hormone levels were high with no history of histopathologically proven NET (group C). Additional information was assessed, according to each situation. [Results]In group A, unknown primary tumors were suspected by DOTATOC-PET/CT in 8 of 14 patients (gastrointestinal/pancreatic NET in 7 patients, prostatic cancer in 1 patient), but prostatic cancer was not confirmed by histopathology (i.e., false positive). In group B, DOTATOC-PET/CT depicted lesions in six of seven patients, including nodal metastasis (n = 5) and liver metastasis (n = 1). In group C, DOTATOC-PET/CT did not demonstrate any abnormal foci except in one case of pancreatic NET. Additional information was obtained in 50, 86, and 4 % of cases, in groups A, B, and C, respectively. [Conclusions]DOTATOC-PET/CT was useful for detecting NETs, especially when recurrence or metastases were suspected because of high hormone levels after surgery for a NET. It is unlikely, however, that additional information can be acquired in patients with no history of NET simply based on high hormone levels

FDG uptake observed around the lumbar spinous process: relevance to Baastrup disease.

First online: 14 July 2015[Objective] In positron emission tomography (PET) with F-18-fluorodeoxyglucose (FDG), non-tumorous focal uptake is often observed around the lumbar spinous processes (LSPs). Close approximation of LSPs with sclerosis is often seen, which is called Baastrup disease. The aim of this study was to characterize this finding in terms of location and subjects’ age and investigate the relation between PET and CT findings. [Methods] The PET/CT scans of 40 patients each in the fifth, sixth, seventh, eighth, and ninth decades were screened for FDG uptake around the LSPs from L1–2 through L5–S1. Patients with metastasis to the lumbar spine or recent chemotherapy or rheumatoid arthritis-related disease were excluded. Focal uptake greater than blood pool activity was considered positive. Positive uptake was compared among the ages and locations. We also evaluated the relationship between FDG uptake and CT morphology. [Results] Overall, focal uptake was observed in 122 LSPs in 71 patients. At least one positive uptake was seen in 9, 21, 15, 12, and 14 of 40 patients (16, 30, 30, 20, and 26 of 200 regions) in each age group of 40s through 80s, respectively (p = 0.12). As for the location, uptake around L1–2, L2–3, L3–4, L4–5, and L5–S1 was observed in 19, 22, 39, 35, and 7 regions, respectively (p < 0.01). There was no statistically significant difference in PET positivity among the five age groups, but positive uptake was predominantly seen in L3–4. Degeneration on CT was apparent in 58, 74, 108, 123, and 144 regions in each age group, respectively (p < 0.01), and in 38, 79, 131, 151, and 108 regions in each location, respectively (p < 0.01). The PET positive ratio was higher in CT positive group than in CT negative group (14 vs. 10 %, p < 0.05), but there was no significant difference of quantitative values (p = 0.10). Of 42 regions in 27 patients who had serial PET/CT scans that were initially PET-positive, 35 regions (83 %) turned negative on a later PET-scan. [Conclusions] Focal uptake around the LSPs was commonly seen in the mid-lumbar vertebrae, independent of age, and was not always correlated with morphological changes. This uptake should not be assumed to represent osseous metastasis