Corticobasal syndrome mimicking Foix-Chavany-Marie syndrome with suggested 4-repeat tauopathy by tau PET.

BACKGROUND: Corticobasal syndrome (CBS) is a neurodegenerative disease diagnosed based on clinical manifestations such as asymmetrical parkinsonism, limb apraxia, and speech and language impairment. The background pathology of CBS is commonly a variety of proteinopathies, but association with cerebrovascular disease has also been reported. Foix-Chavany-Marie syndrome (FCMS) is a rare neurological disorder characterized by facio-pharyngo-glossal diplegia with automatic-voluntary movement dissociation presenting with bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles. FCMS is commonly attributable to stroke. Transactive response DNA binding protein of 43 kD (TDP-43) proteinopathy is also known as the pathological background of FCMS, while the pathological background of the majority of CBS cases consists of diverse tauopathies instead of TDP-43 proteinopathy. In this report, we describe a case mimicking FCMS that was finally diagnosed as CBS with suggested 4-repeat tauopathy. CASE PRESENTATION: A 68-year-old female started experiencing difficulty speaking followed by difficulty writing, and especially texting, several years before her visit. Her impairment had been gradually worsening, and she came to our hospital. On neurological examination, she demonstrated the facial apraxia, frontal lobe dysfunction, and upper motor neuron signs. She presented some characteristics suggestive of FCMS. Her symptoms exhibited rapid progression and myoclonus, parkinsonism, and left-side dominant cortical sensory deficit occurred, resulting in the fulfillment of diagnostic criteria for CBS after 9 months. Tau PET imaging displayed notable ligand uptake in the brainstem, subthalamic nuclei, basal ganglia, and bilateral subcortical frontal lobe, suggesting that her pathological background was 4-repeat tauopathy. As a result of her progressive dysphagia, she became unable to eat and passed away after 12 months. CONCLUSION: We hereby present an atypical case of CBS showing clinical features mimicking FCMS at first presentation. TDP-43 proteinopathy was suspected based on the clinical symptoms in the early stages of the disease; however, the clinical course and imaging findings including tau PET suggested that her pathological background was 4-repeat tauopathy.

Outcomes of laparoscopic total gastrectomy in elderly patients: a propensity score matching analysis.

PURPOSE: This study evaluated the short-term outcomes and prognosis after laparoscopic total gastrectomy (LTG) in elderly patients aged ≥ 80 years in a multicenter retrospective cohort study using propensity score matching. METHODS: We retrospectively enrolled 440 patients who underwent curative LTG for gastric cancer at six institutions between January 2004 and December 2018. Patients were categorized into an elderly patient group (EG; age ≥ 80 years) and non-elderly patient group (non-EG; age < 80 years). Patients were matched using the following propensity score covariates: sex, body mass index, American Society of Anesthesiologists physical status, extent of lymph node dissection, and Japanese Classification of Gastric Carcinoma stage. Short-term outcomes and prognoses were compared. RESULTS: We identified 37 propensity score-matched pairs. The median operative time was significantly shorter, and postoperative stay was longer in the EG. In terms of postoperative outcomes, the rates of all complications were comparable. The median follow-up period of the EG and non-EG was 11.5 (1-106.4) months and 35.7 (1-110.0) months, respectively; there were significant differences in 5-year overall survival between the two groups (EG, 58.5% vs. non-EG, 91.5%; P = 0.031). However, there were no significant differences in 5-year disease-specific survival (EG, 62.1% vs. non-EG, 91.5%; P = 0.068) or 5-year disease-free survival (EG, 52.9% vs. non-EG, 60.8%; P = 0.132). CONCLUSIONS: LTG seems to be safe and feasible in elderly patients. LTG had a limited effect on morbidity, disease recurrence, and survival in elderly patients. Therefore, age should not prevent elderly patients from benefitting from LTG.

The effect of the body mass index on the short-term surgical outcomes of laparoscopic total gastrectomy: A propensity score-matched study.

PURPOSE: This study aimed to evaluate the relationship between the body mass index (BMI) and the short-term outcomes of laparoscopic total gastrectomy (LTG). SUBJECTS AND METHODS: Data of patients who underwent LTG for gastric cancer at six institutions between 2004 and 2018 were retrospectively collected. The patients were classified into three groups: low BMI (<18.5 kg/m2), normal BMI (≥18.5 and <25 kg/m2) and high BMI (≥25 kg/m2). In these patients, clinicopathological variables were analysed using propensity score matching for age, sex, the American Society of Anaesthesiologists physical state, clinical stage, surgical method, D2 lymph node dissection, combined resection of other organs, anastomosis method and jejunal pouch reconstruction. The surgical results and post-operative outcomes were compared among the three groups. RESULTS: A total of 82 patients were matched in the analysis of the low BMI and normal BMI groups. There were no differences in operative time (P = 0.693), blood loss (P = 0.150), post-operative complication (P = 0.762) and post-operative hospital stay (P = 0.448). In the analysis of the normal BMI and high BMI groups, 208 patients were matched. There were also no differences in blood loss (P = 0.377), post-operative complication (P = 0.249) and post-operative hospital stay (P = 0.676). However, the operative time was significantly longer in the high BMI group (P = 0.023). CONCLUSIONS: Despite the association with a longer operative time in the high BMI group, BMI had no significant effect on the surgical outcomes of LTG. LTG could be performed safely regardless of BMI.

Development of a novel training system for laparoscopic inguinal hernia repair.

Background: Laparoscopic inguinal hernia repair is considered technically difficult. Although a simulation-based curriculum has been developed to help trainees, access to simulation training outside North America is limited. This study aimed to develop an educational system for the transabdominal preperitoneal (TAPP) approach based on the TAPP checklist, an assessment tool we had developed and validated earlier. Material and methods: Consensus within the TAPP education working group consisting of local TAPP experts, hernia experts and a surgical educator to develop educational tools and the educational system based on the TAPP checklist. The system was piloted in several institutes, and participants were surveyed on its efficacy. Results: We systematically developed an educational video and training manual explaining each item of the TAPP checklist and conveying basic knowledge of the procedure. We integrated the training tool with evaluation and feedback to develop an educational system. In a pilot study, seven trainees at five hospitals were trained using this system and found it very useful for mastering the TAPP procedure. Conclusions: We have developed a training system for TAPP procedure and successfully implemented it in several hospitals. Further research will focus on the educational value of this tool.

Design and Synthesis of an Easily Obtainable Maleimide Reagent N-[2-(4-[18F]fluoro-N-methylbenzenesulfonamido)ethyl]maleimide ([18F]FBSEM) to Radiolabel Thiols in Proteins.

An easily obtainable thiol-selective labeling reagent [18F]FBSEM (N-[2-(4-[18F]fluoro-N-methylbenzenesulfonamido)ethyl]maleimide) was developed. The advantage of the design is that the precursor and [18F]FBSEM have the same backbone and backbone construction is not required; in contrast, known thiol-specific labeling reagents do require backbone construction, and this is thought to be the cause of their complicated synthesis. [18F]FBSEM was successfully obtained in higher yield (25%) and in a simpler way (two fluorination and deprotection steps in 65 min) than the widely used [18F]FBEM (N-[2-(4-[18F]fluorobenzamide)ethyl]maleimide). The labeling efficacy of [18F]FBSEM was confirmed by conjugation with glutathione. [18F]FBSEM is a promising labeling agent for proteins.

Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition.

A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test.

Evaluation of the delta-shaped anastomosis in laparoscopic distal gastrectomy: midterm results of a comparison with Roux-en-Y anastomosis.

BACKGROUND: Various methods of reconstruction after laparoscopic distal gastrectomy (LDG) have been developed and published, whereas only a limited number of reports are available on the utility of the delta-shaped anastomosis (Delta). This study compared Delta and Roux-en-Y anastomoses (RY), with the aim to clarify the utility of Delta. METHODS: Stage 1 gastric cancer patients who had undergone LDG with Delta (group D, n = 68) and those who had undergone LDG with RY (group RY, n = 60) were compared in terms of operative outcomes, postoperative clinical symptoms, gastrointestinal fiberscopic findings, and changes in body weight. RESULTS: Both the operative and anastomotic times were significantly shorter in group D (230 and 13 min, respectively) than in group RY (258 and 38 min, respectively) (p < 0.001). Among the complications observed at the anastomotic site, obstruction was seen in one group D patient and two group RY patients but was relieved with conservative management. Postoperative clinical symptoms were reported for 26.4% of the group D patients but had decreased to 5.9% 1 year later. Group RY yielded similar results. Upper gastrointestinal fiberscopy performed 1 year postoperatively showed no intergroup differences in the incidence of gastritis or residual retention and a significantly more frequent occurrence of bile reflux in group D. Postoperative weight changes did not differ between the two groups. CONCLUSIONS: Delta reconstruction after LDG is a safe and effective procedure that is totally laparoscopic, less time consuming, and associated with a favorable postoperative course and a better quality of life.

Synthesis and Preliminary Evaluation of an 18F-labeled Oleate Analog to Image Fatty Acid Beta-Oxidation in the Absence of Metabolic Defluorination.

PURPOSE: Fatty acid oxidation (FAO) is a key parameter for evaluating cardiovascular, oncologic, neurologic, and other metabolic diseases. Several single-photon emission computed tomography and positron emission tomography (PET) tracers have been developed to measure FAO. Among these, 18-[18F]fluoro-4-thia-oleate ([18F]FTO), first developed by DeGrado et al., is well characterized. Here, we synthesized several analogs of [18F]FTO to improve the metabolic stability of the C-18F bond, and preliminarily evaluated their performance in monkey PET studies. PROCEDURES: Several secondary 18F-fluorinated analogs, 17-[18F]fluoro-4-thia-oleate (17-[18F]FTO), 15-[18F]fluoro-4-thia-oleate (15-[18F]FTO), 12-[18F]fluoro-4-thia-oleate (12-[18F]FTO), 7-[18F]fluoro-4-thia-oleate, (7-[18F]FTO, [18F]AS3504073-00), and 6-[18F]fluoro-4-thia-oleate (6-[18F]FTO), were synthesized from tosylate or bromide precursors using similar procedures. Nucleophilic 18F fluorination on each precursor was performed using [18F]tetrabutylammonium fluoride/tetrabutylammonium hydrocarbonate, followed by hydrolysis of methylester. All synthesized 18F-labeled compounds were administered to cynomolgus monkeys, and PET measurements were performed. From the monkey PET studies, 7-[18F]FTO was selected as the best tracer and used to perform preliminary evaluations in mice. RESULTS: All five compounds had sufficient quality and stability for animal experiments. In monkey PET studies, 12-, 7-, and 6-[18F]FTO showed greater accumulation in the heart than [18F]FTO, but not 17- and 15-[18F]FTO. Only 7-[18F]FTO did not show significant accumulation in the bone. The standardized uptake values (SUVs) for 12-[18F]FTO, 7-[18F]FTO, and 6-[18F]FTO were 9.77, 9.26, and 7.25 in the heart, and 3.17, n.d., and 1.96 in the bone 1 h after administration, respectively. In mouse distribution studies, SUVs 1 h after administration of 7-[18F]FTO and [18F]FTO were 10.4 and 10.0 in the heart, and 0.37 and 3.48 in the femur, respectively. Administration of etomoxir, a carnitine palmitoyltransferase inhibitor, reduced SUVs of 7-[18F]FTO and [18F]FTO in the heart by 91% and 87%, respectively. CONCLUSIONS: We developed a novel PET tracer 7-[18F]FTO/[18F]AS3504073-00 for FAO imaging. 7-[18F]FTO had an excellent PET tracer profile, suggesting it may be a useful tracer for FAO imaging. Further evaluations of the tracer are ongoing.

Relationship between laparoscopic total gastrectomy-associated postoperative complications and gastric cancer prognosis.

This study aimed to investigate the incidence and prognosis of postoperative complications after laparoscopic total gastrectomy (LTG) for gastric cancer (GC). We retrospectively enrolled 411 patients who underwent curative LTG for GC at seven institutions between January 2004 and December 2018. The patients were divided into two groups, complication group (CG) and non-complication group (non-CG), depending on the presence of serious postoperative complications (Clavien-Dindo grade III [≥ CD IIIa] or higher complications). Short-term outcomes and prognoses were compared between two groups. Serious postoperative complications occurred in 65 (15.8%) patients. No significant difference was observed between the two groups in the median operative time, intraoperative blood loss, number of lymph nodes harvested, or pathological stage; however, the 5-year overall survival (OS; CG 66.4% vs. non-CG 76.8%; p = 0.001), disease-specific survival (DSS; CG 70.1% vs. non-CG 76.2%; p = 0.011), and disease-free survival (CG 70.9% vs. non-CG 80.9%; p = 0.001) were significantly different. The Cox multivariate analysis identified the serious postoperative complications as independent risk factors for 5-year OS (HR 2.143, 95% CI 1.165-3.944, p = 0.014) and DSS (HR 2.467, 95% CI 1.223-4.975, p = 0.011). A significant difference was detected in the median days until postoperative recurrence (CG 223 days vs. non-CG 469 days; p = 0.017) between the two groups. Serious postoperative complications after LTG negatively affected the GC prognosis. Efforts to decrease incidences of serious complications should be made that may help in better prognosis in patients with GC after LTG.

Development of a systematic telesimulation curriculum for laparoscopic inguinal hernia repair.

Purpose: Telesimulation, whereby learners telecommunicate and use simulator resources to receive education at an off-site location, has been used to educate surgical trainees about how to perform basic surgical procedures. However, it has not yet been used for advanced surgical procedures. We aimed to develop a telesimulation curriculum to teach a common laparoscopic procedure called transabdominal preperitoneal (TAPP) repair and to explore the feasibility of its use. Methods: Learning objectives were created to develop a telesimulation curriculum that included didactic telelecture and telesimulation training. Pre-tests and post-tests to assess the didactic materials were developed and assessed among surgeons with various experiences. We assessed the feasibility of the telelecture and telesimulation separately. Pre-tests, post-tests, and questionnaires were used to assess the telelectures. We created a TAPP repair telesimulation system and checked for problems during training. Trainees were assessed to determine their skill improvement using previously published assessment tools and questionnaires. Results: A didactic telelecture was developed based on the learning objectives using an expert consensus and pilot-tested among five participants. After the lecture, their test scores improved and they expressed positive opinions about the usefulness of telelectures. The TAPP repair telesimulation training was pilot-tested among three trainees. No technical problems occurred during training. All trainees improved their skills after the telesimulation training and agreed that the training was useful for learning the TAPP repair procedure. Conclusions: We systematically developed a telesimulation curriculum for the TAPP repair procedure and demonstrated its feasibility among learners.

Efficient improved extraction of tomato saponin using shock waves.

In the conventional method of mixer blending extraction, the yields of the tomato-saponin, esculeoside A, in the mini and middy tomatoes were found to be 0.043% and 0.046%, respectively. In order to improve the yields, we attempted a more efficient extraction using shock waves. The yields of esculeoside A were 0.0987% in air after 1 shock, 0.0792% in air after two shots, 0.0648% in half water after 1 or 2 shocks, and 0.0599% in water after 1 or 2 shocks. The yields obtained by the proposed method were approximately twice those of the conventional mixer blending method; therefore, this method is regarded to be very efficient. Moreover, two spirosolane glycosides, tomatine and lycoperoside A, were obtained for the first time from the ripe tomato fruit in this method. To date, these compounds have not been obtained with the mixer blending method. However, whether these glycosides are produced from esculeoside A or are newly extracted from the plant organ by the shock wave is still unclear.

Efficiency of the novel quenching-probe PCR method to detect 23S rRNA mutations in children with Mycoplasma pneumoniae infection.

An automated rapid molecular diagnostic kit (Smart Gene Myco) was recently developed for individual detection of Mycoplasma pneumoniae (MP) genes. This new testing approach requires no special equipment and skills and can be completed within 50 min. We prospectively evaluated this diagnostic kit, along with other conventional tests, for pneumonia diagnosis in children. Samples from 98 children (50 boys and 48 girls; aged 1-14 years; mean: 4.7 ± 2.1 years; median: 4 years) clinically diagnosed with pneumonia were tested for MP using real-time polymerase chain reaction (RT-PCR) as a reference method. Results from three molecular diagnostic tests, serum anti-MP antibodies, and MP culture were compared to RT-PCR data. Among the 98 children, 38 were positive for MP. All molecular diagnostic results showed complete concordance with the RT-PCR data. The sensitivity of the culture was 64%, whereas the sensitivities of the ImmunoCard Mycoplasma and SERODIA Myco II kits were lower (39% and 29%, respectively). Furthermore, a significant positive correlation was found between MP copy numbers and the culture test sensitivity (r = 0.95, p = 0.048). Macrolide-resistance mutations in the 23S ribosomal RNA gene were detected in 24 of 38 children using Smart Gene Myco based on quenching-probe PCR, which was confirmed by direct sequencing, revealing all mutations as A2063G. This is the first study to evaluate the clinical utility of the Smart Gene Myco kit, demonstrating that it is a fast and reliable method to support timely therapeutic decisions in children with MP pneumonia.

A Multicenter Retrospective Study Comparing Surgical Outcomes Between the Overlap Method and Functional Method for Esophagojejunostomy in Laparoscopic Total Gastrectomy: Analysis Using Propensity Score Matching.

BACKGROUND: This study aimed to compare the postoperative outcomes after laparoscopic total gastrectomy (LTG) with esophagojejunostomy (EJS) performed using the overlap method or the functional method in a multicenter retrospective study with propensity score matching. METHODS: We retrospectively enrolled all patients who underwent curative LTG for gastric cancer at 6 institutions between January 2004 and December 2018. Patients were categorized into the overlap group (OG) or functional group (FG) based on the type of anastomosis used in EJS. Patients in the groups were matched using the following propensity score covariates: age, sex, body mass index, American Society of Anesthesiologists physical status, extent of lymph node dissection, and Japanese Classification of Gastric Carcinoma stage. The surgical results and postoperative outcomes were compared. RESULTS: We identified 69 propensity score-matched pairs among 440 patients who underwent LTG. There was no significant between-group difference in the median operative time, intraoperative blood, or number of lymph nodes resected. In terms of postoperative outcomes, the rates of all complications [Clavien-Dindo (CD) classification ≥II; OG 13.0 vs. FG 24.6%, respectively; P=0.082], complications more severe than CD grade III (OG 8.7 vs. FG 18.8%, respectively; P=0.084), and the occurrence of EJS leakage and stenosis more severe than CD grade III (OG 7.3% vs. FG 2.9%, P=0.245; OG 1.5 vs. FG 8.7%, P=0.115, respectively) were comparable. The median follow-up period was 830 days (range, 18 to 3376 d), and there were no differences in overall survival between the 2 groups. CONCLUSIONS: There was no difference in surgical outcomes and overall survival based on the type of anastomosis used for EJS after LTG. Therefore, selection of anastomosis in EJS should be based on each surgeon's preference and experience.

Evaluation of the kappa-opioid receptor-selective tracer [(11)C]GR103545 in awake rhesus macaques.

PURPOSE: The recent development in radiosynthesis of the (11)C-carbamate function increases the potential of [(11)C]GR103545, which for the last decade has been regarded as promising for imaging the kappa-opioid receptor (kappa-OR) with PET. In the present study, [(11)C]GR103545 was evaluated in awake rhesus macaques. Separate investigations were performed to clarify the OR subtype selectivity of this compound. METHODS: Regional brain uptake kinetics of [(11)C]GR103545 was studied 0-120 min after injection. The binding affinity and opioid subtype selectivity of [(11)C]GR103545 was determined in cells transfected with cloned human opioid receptors. RESULTS: In vitro binding assays demonstrated a high affinity of GR103545 for kappa-OR (K(i) = 0.02 +/- 0.01 nM) with excellent selectivity over mu-OR (6 x 10(2)-fold) and) delta-OR (2 x 10(4)-fold). PET imaging revealed a volume of distribution (V(T)) pattern consistent with the known distribution of kappa-OR, with striatum = temporal cortex > cingulate cortex > frontal cortex > parietal cortex > thalamus > cerebellum. CONCLUSION: [(11)C]GR103545 is selective for kappa-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET.

A case of thymic basaloid carcinoma with rectal carcinoma.

INTRODUCTION: Thymic basaloid carcinoma is rare, as only about 40 reports have described it since the initial report. Thymoma and thymic carcinomas increase the risk of other malignancies, but concurrent thymic basaloid carcinoma and another malignancy has not been reported. We presented a rare case of thymic basaloid carcinoma with rectal carcinoma. CASE PRESENTATION: Computed tomography revealed an anterior mediastinal mass and rectal wall thickening, and colonoscopy identified a rectal type 2 tumor in a 68-year-old man. Total thymectomy via a median sternotomy was performed, and the thymic tumor was histopathologically confirmed as stage II thymic basaloid carcinoma. Subsequent laparoscopic low anterior resection indicated stage IIIa rectal carcinoma. Adjuvant chemotherapy was administered for the rectal cancer. DISCUSSION: Concurrent thymic and extrathymic tumors is rare condition. There are few reports of thymic basaloid carcinoma, and it is unclear whether this tumor, like common thymoma, increase the risk of extrathymic malignancies. Further studies in more patients are needed to elucidate the nature of this tumor. CONCLUSION: To our knowledge, this is the first case report of thymic basaloid carcinoma concurrent another carcinoma. Aggressive treatment including surgery should be considered aiming at radical cure.

Identifying the Essential Portions of the Skill Acquisition Process Using Item Response Theory.

OBJECTIVE: Item response theory (IRT) was originally developed to make performance assessments more accurate. However, IRT analysis of the intraoperative performance of surgical trainees could help identify the elements that the trainees find difficult during the skill acquisition process. The aim of this study was to identify the essential portions of the skill acquisition process of a surgical procedure using the IRT. DESIGN: The 24-item assessment checklist was used to evaluate a recorded intra-operative performance of a laparoscopic inguinal hernia repair. The scores were analyzed using IRT to calculate the difficulty and discrimination level of each item. SETTING: Fifteen institutes. PARTICIPANTS: Thirty surgical trainees. RESULTS: A total of 123 assessments were analyzed. The item analysis showed the procedure specific item "traction of peritoneum (difficulty: -0.45; discrimination: 19.37)" and generic items "instrument handling (difficulty: -0.59; discrimination: 3.82)" and "flow of procedure (difficulty: 0.09; discrimination: 3.27)" to be key elements in the skill acquisition process of the procedure. CONCLUSIONS: Key elements in the skill acquisition process of the procedure were quantitatively identified by applying the IRT analysis. This could lead to the use of IRT in designing and developing a more effective training curriculum.

Cancer detection using a PET tracer, 11C-glycylsarcosine, targeted to H+/peptide transporter.

UNLABELLED: H+/peptide transporter, PEPT1, is functionally expressed in some human cancer cell lines and might be a candidate molecular target for detection of cancers in vivo using PET. The aim of the present study was to establish a novel tumor-imaging technology using a PET tracer targeted to H+/peptide transporter(s). We also compared the tracer with 18F-FDG, focusing on the specificity of their accumulation between tumor and inflammatory tissues. METHODS: A dipeptide PET tracer, 11C-glycylsarcosine (11C-Gly-Sar), was injected intravenously into athymic mice transplanted with human pancreatic, prostate, and gastric cancer cells. The distribution patterns of 11C-Gly-Sar and 18F-FDG in the tumor-bearing mice, and in mice with inflammatory tissue, were assessed by imaging with a positron planar imaging system (PPIS). Tissue distributions of tracer radioactivity were also measured. The expression levels of PEPT1 and PEPT2 (PEPTs) proteins in tumor xenografts and inflammatory tissue were examined by immunohistochemical analysis. The messenger RNA expression levels of PEPTs in 58 available cancer cell lines were quantified by means of real-time polymerase chain reaction. RESULTS: All 3 tumor xenografts were well visualized with the PPIS after injection of 11C-Gly-Sar. Expression of PEPTs in those xenografts was confirmed by immunohistochemical analysis. Tumor-to-blood concentration ratios of 11C-Gly-Sar increased in a time-dependent manner and were much higher than unity. Most of the radioactivity found in the tumor tissue was recovered as the intact tracer. These results indicated that 11C-Gly-Sar was taken up by the PEPTs in tumor xenografts. It is noteworthy that 11C-Gly-Sar was minimally present in inflammatory tissues that expressed no PEPT1 or PEPT2 protein, whereas 18F-FDG was highly accumulated, with the values of the selectivity index being >25.1 and 0.72 for 11C-Gly-Sar and 18F-FDG, respectively. The mRNAs of PEPT1 and PEPT2 were expressed in 27.6% and 93.1%, respectively, of the cancer cell lines examined in the present study. CONCLUSION: The present study indicates that 11C-Gly-Sar is a promising tumor-imaging agent and is superior to 18F-FDG for distinguishing between tumors and inflammatory tissue. Because PEPTs were ubiquitously expressed in various types of tumor cells examined, 11C-Gly-Sar could be useful for the detection of many types of cancers.

Brain adenosine A2A receptor occupancy by a novel A1/A2A receptor antagonist, ASP5854, in rhesus monkeys: relationship to anticataleptic effect.

UNLABELLED: The purpose of the present study was to measure adenosine A(2A) receptor (A(2A)R) occupancy in the brain by a novel adenosine A(1)/A(2A) antagonist, 5-[5-amino-3-(4fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), and to determine the degree of receptor occupancy necessary to inhibit haloperidol-induced catalepsy in rhesus monkeys. METHODS: A(2A)R occupancy by ASP5854 (0.001-0.1 mg/kg) was examined in the striatum using an A(2A)R-specific radiotracer, (11)C-SCH442416, and PET in conscious rhesus monkeys. A(2A)R occupancy was monitored after a single intravenous administration of ASP5854 in 3 animals, and a dynamic PET scan was performed at 1, 4, and 8 h after an intravenous bolus injection of the tracer for approximately 740 MBq. Catalepsy was induced by haloperidol (0.03 mg/kg, intramuscularly) and examined for incidence and duration. RESULTS: ASP5854 dose-dependently increased A(2A)R occupancy in the striatum and showed long-lasting occupancy even after the reduction of plasma concentration. Haloperidol induced severe catalepsy at 40 min after intramuscular injection. The incidence and duration of cataleptic posture were dose-dependently reduced by ASP5854 at 1 h after oral administration, and the minimum ED(50) value was 0.1 mg/kg. Administration of a dose of 0.1 mg/kg yielded a plasma concentration of 97 +/- 16.3 ng/mL, which corresponded to 85%-90% of A(2A)R occupancy. CONCLUSION: These results showed that ASP5854 antagonized A(2A)R in the striatum, and the dissociation from A(2A)R was relatively slow. In addition, more than 85% A(2A)R occupancy by ASP5854 resulted in an inhibition of haloperidol-induced catalepsy. Thus, such a pharmacodynamic study directly demonstrates both the kinetics of a drug in the brain and the relationship between dose-dependent receptor occupancy and plasma level.