Sho Koyasu

Prostaglandin E2 acts on EP1 receptor and amplifies both dopamine D1 and D2 receptor signaling in the striatum

Dopamine is involved in multiple neural functions including motor control, reward and motivational processing, learning and reinforcement, and cognitive attention. Dopamine binds to two distinct classes of receptors, namely D1 and D2, to exert these functions. Various endogenous substances regulate dopamine signaling, although their physiological functions are not fully understood. Here, we examined the role of prostaglandin E2 (PGE2) and one of its receptors, EP1, in dopaminergic function in the striatum. EP1 was expressed in both preprodynorphin-containing D1 and preproenkephalin-containing D2 neurons, and PGE2 was produced in striatal slices in response to both D1 and D2 dopamine receptor stimulation. EP1-deficient mice exhibited significant suppression of hyperlocomotion induced by cocaine or SKF81297 (6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide), a D1 agonist, and significant attenuation of catalepsy induced by raclopride, a D2 antagonist. Despite these behavioral defects, the extracellular concentration of dopamine was not suppressed in the striatum of EP1-deficient mice, and the densities of D1 and D2 receptors in the striatum were not different between the two genotypes. Stimulation of the D1 receptor induced phosphorylation of dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34 in striatal slices, and the addition of indomethacin, a PG synthesis inhibitor, attenuated the D1 agonist-induced increase in DARPP-32–Thr34 phosphorylation. The further addition of an EP1 agonist restored the indomethacin-attenuated phosphorylation. Furthermore, both D1- and D2-mediated changes in the DARPP-32–Thr34 phosphorylation were attenuated in EP1−/− slices. These results suggest that PGE2 is formed in response to dopamine receptor stimulation in the striatum and amplifies both D1 and D2 receptor signaling via EP1.

Prognostic Value of Pretreatment 18F-FDG PET/CT Parameters Including Visual Evaluation in Patients With Head and Neck Squamous Cell Carcinoma

OBJECTIVE The purpose of this study was to determine whether pretreatment quantitative and visual parameters seen on PET/CT using (18)F-FDG add prognostic information for clinical staging in patients with head and neck cancer. MATERIALS AND METHODS We enrolled 108 patients with histologically proven oral, oropharyngeal, hypopharyngeal, and laryngeal squamous cell carcinomas who underwent FDG PET/CT before treatment and, later, definitive therapy in our study. PET/CT parameters-maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and uptake pattern (sphere-shaped or ring-shaped)-were recorded. The prognostic value of these parameters was evaluated using univariate and multivariate Cox regression analyses. RESULTS In the univariate analysis, all of the FDG PET/CT parameters--SUVmax (> 10 g/mL) of the primary tumor, MTV (> 20 cm(3)), TLG (> 70 g), and uptake pattern (ring-shaped)--were significantly associated with negative effects on disease-specific survival (DSS) and disease-free survival (DFS). In the multivariate analysis, the MTV and uptake pattern remained associated with DSS after corrections for the Union for International Cancer Control (UICC) stage and definitive therapy (p = 0.023 and < 0.001, respectively). Another multivariate model that included MTV as a continuous variable, uptake pattern, and UICC stage showed that the uptake pattern remained significantly associated with DSS, whereas the association between DSS and MTV was not significant (p < 0.001 and = 0.332, respectively). CONCLUSION Our data indicate that the pretreatment PET/CT parameters had prognostic value. In particular, a qualitative factor, uptake pattern, provided better prognostic information to the clinical staging of head and neck squamous cell carcinomas than the other PET/CT parameters.

Prognostic value of pretreatment 18F-fluorodeoxyglucose positron emission tomography/CT volume-based parameters in patients with oropharyngeal squamous cell carcinoma with known p16 and p53 status

The purpose of this study was to determine whether pretreatment 18F‐fluorodeoxyglucose‐positron emission tomography (18F‐FDG PET/CT) volume‐based parameters, such as metabolic tumor volume and total lesion glycolysis, add more prognostic information in patients with oropharyngeal squamous cell carcinoma (SCC).

Evaluation of oxygen dependence on in vitro and in vivo cytotoxicity of photoimmunotherapy using IR-700–antibody conjugates

Photoimmunotherapy (PIT) using the near-infrared-absorbing photosensitizing phthalocyanine dye, IRDye 700DX (IR-700), conjugated with a tumor-targeting antibody such as panitumumab (Pan) has shown efficacy in in vitro studies and several preclinical models in mice with promise for clinical translation. PIT results in rapid necrotic cell death in vitro and tumor shrinkage in vivo. Photochemical studies with the Pan-IR-700 conjugate showed that this agent can support generation of singlet oxygen and also generate reactive oxygen species after exposure to near-infrared (NIR) light. Moreover, in vitro studies using A431 cells, singlet oxygen scavengers abrogated the efficacy of PIT with Pan-IR-700, while oxygen depletion to undetectable levels in the exposure chamber almost completely inhibited the cellular cytotoxicity of PIT. Survival of tumor bearing mice was prolonged in PIT-treated animals but mice whose tumors were made transiently hypoxic prior to PIT had no benefit from the treatment. The results from this study support a central role for molecular oxygen-derived species in cell death caused by PIT.

Preoperative Diagnostic Strategy for Parotid Gland Tumors Using Diffusion-Weighted MRI and Technetium-99m Pertechnetate Scintigraphy: A Prospective Study

Objective Fine needle aspiration cytology (FNAC) for diagnosis of a parotid gland tumor is widely used but its sensitivity is low and non-diagnostic rate is relatively high. In contrast, core needle biopsy (CNB) has a higher sensitivity and lower rate of sampling errors but has a higher risk of injury to adjacent organs such as facial nerve than FNAC. Screening of patients with parotid gland tumors to identify cases of pleomorphic adenoma (PA) and Warthin tumor (WT) may allow CNB to be confined to patients without PA and WT. We established an algorithm for preoperative diagnosis and management of parotid gland tumor using diffusion-weighted MRI and 99mTc pertechnetate scintigraphy. This algorithm was developed with the goal of maximal reduction of the number of patients in whom CNB is required. The purpose of the study is to validate our algorithm prospectively. Methods A prospective study was conducted in 71 cases who were newly diagnosed with parotid gland tumor and 53 cases were enrolled in the study. In the algorithm, PA (high apparent diffusion coefficient (ADC) mean≥1.5×10−3 mm2/s) and non-PA (low ADCmean<1.5×10−3 mm2/s) cases are first distinguished based on the ADCmean on diffusion-weighed MRI. Second, among suspected non-PA cases, WT and non-WT are distinguished using technetium-99m pertechnetate scintigraphy. CNB is then performed only in probable non-PA and non-WT cases. Results Although CNB was only required in 40% (21/53) of all cases, we made a preoperative histopathological diagnosis with an accuracy of 87% (46/53) and we correctly diagnosed whether a tumor was benign or malignant with an accuracy of 96% (51/53). Preoperative surgical planning had to be changed during surgery in only one case (2%) Conclusions Our algorithm is valuable in terms of clinical practice with highly potential for preoperative diagnosis and with less risk of CNB procedure.

Prognostic value of fluorine-18 fludeoxyglucose positron emission tomography parameters differs according to primary tumour location in small-cell lung cancer

OBJECTIVE To investigate the prognostic value of fluorine-18 fludeoxyglucose (FDG) positron emission tomography (PET) parameters for small-cell lung cancer (SCLC), according to the primary tumour location, adjusted by conventional prognostic factors. METHODS From 2008 to 2013, we enrolled consecutive patients with histologically proven SCLC, who had undergone FDG-PET/CT prior to initial therapy. The primary tumour location was categorized into central or peripheral types. PET parameters and clinical variables were evaluated using univariate and multivariate analysis. RESULTS A total of 69 patients were enrolled in this study; 28 of these patients were categorized as having the central type and 41 patients as having the peripheral type. In univariate analysis, stage, serum neuron-specific enolase, whole-body metabolic tumour volume (WB-MTV) and whole-body total lesion glycolysis (WB-TLG) were found to be significant in both types of patients. In multivariate analysis, the independent prognostic factor was found to be stage in the central type, but WB-MTV and WB-TLG in the peripheral type. Kaplan-Meier analysis demonstrated that patients with peripheral type with limited disease and low WB-MTV or WB-TLG showed significantly better overall survival than all of the other groups (p < 0.0083). CONCLUSION The FDG-PET volumetric parameters were demonstrated to be significant and independent prognostic factors in patients with peripheral type of SCLC, while stage was the only independent prognostic factor in patients with central type of SCLC. ADVANCES IN KNOWLEDGE FDG-PET is a non-invasive method that could potentially be used to estimate the prognosis of patients, especially those with peripheral-type SCLC.

Pretreatment Mean Apparent Diffusion Coefficient Is Significantly Correlated With Event-Free Survival in Patients With International Federation of Gynecology and Obstetrics Stage Ib to IIIb Cervical Cancer

Objectives To assess the prognostic impact of the pretreatment mean apparent diffusion coefficient (ADCmean) values of tumors obtained by diffusion-weighted magnetic resonance imaging. We evaluated the prognostic value of the ADCmean for event-free survival (EFS) and overall survival (OS) among patients with uterine cervical cancer. Methods/Materials We included 171 patients diagnosed as having International Federation of Gynecology and Obstetrics stage Ib to IIIb cervical cancer by pretreatment magnetic resonance imaging scans, regardless of therapeutic methods. In all patients and in patients with squamous cell carcinoma (SCC; n = 123), the optimal cutoff values of the tumor ADCmean for EFS and for OS were determined, respectively. The prognostic significance of the ADCmean was evaluated using univariate and multivariate Cox regression analyses. Results In the univariate analyses, the ADCmean values were significantly associated with negative effects on EFS both in all patients and in patients with SCC, while not being significantly associated with OS in both groups. In the multivariate analysis, ADCmean was an independent biomarker for EFS (P < 0.05) in patients with SCC along with lymph node metastasis and definitive surgery, whereas ADCmean was not independently significant in EFS in all patients. Conclusions The pretreatment ADCmean value of the tumor was an independent prognostic factor for EFS in International Federation of Gynecology and Obstetrics stage Ib to III SCC of the uterine cervix.

Development of a composite and vascularized tracheal scaffold in the omentum for in situ tissue engineering: a canine model

OBJECTIVES We herein report on development of a composite (synthetic and biological) tracheal scaffold with vascularized autologous connective tissue in the omentum, followed by in situ tissue engineering of the composite scaffold with the pedicled omentum. In this preliminary report, we focus on development and evaluation of the vascularized autologous connective tissue in the omentum. METHODS In animal experiment 1, a polypropylene framework as a synthetic component was placed in the omental sac for 3 weeks and another was placed in the pouch of Douglas as a control in five beagle dogs. In animal experiment 2, a polypropylene framework placed in the omental sac for 3 weeks was compared with a polypropylene framework coated with porcine atelocollagen, which was also placed in the omental sac in another five dogs, to investigate whether the coating of porcine atelocollagen contributes to development of more vascularized connective tissue. Macroscopic, radiological and histological evaluations were performed for developed autologous connective tissue on the frameworks, with a focus on its thickness and capillary vessels. RESULTS In animal experiment 1, the polypropylene framework in the omentum developed a composite tracheal scaffold with homogeneous and significantly thicker (2.6 ± 0.5 vs 1.2 ± 0.4 mm, P <0.0001) connective tissue in which more capillary vessels per 10-power field of view (3.5 ± 2.2 vs 0 ± 0, P = 0.015) were identified, compared with the control in the pouch of Douglas. In animal experiment 2, the omentum developed significantly thicker connective tissue on the polypropylene framework coated with porcine atelocollagen (3.6 ± 0.7 vs 2.2 ± 0.4 mm, P <0.0001) in which not significantly more capillary vessels were identified (3.5 ± 2.2 vs 5.0 ± 2.7, P = 0.12), compared with the framework that was not coated. CONCLUSIONS Placement of the polypropylene framework in the omental sac resulted in development of homogeneous and vascularized autologous connective tissue on the polypropylene framework for a composite tracheal scaffold. The framework coated with porcine atelocollagen did not show an additional benefit in inducing vascularization. This preliminary report will be followed by the long-term evaluations of in situ tissue engineering of the composite tracheal scaffold.

Erratum to: Early diagnosis of pancreatic necrosis based on perfusion CT to predict the severity of acute pancreatitis

Yoshihisa Tsuji • Naoki Takahashi • Hiroyoshi Isoda • Koji Koizumi • Sho Koyasu • Miho Sekimoto • Yuichi Imanaka • Shujiro Yazumi • Masanori Asada • Yoshihiro Nishikawa • Hiroshi Yamamoto • Osamu Kikuchi • Tsukasa Yoshida • Tetsuro Inokuma • Shinji Katsushima • Naoki Esaka • Akihiro Okano • Chiharu Kawanami • Nobuyuki Kakiuchi • Masahiro Shiokawa • Yuzo Kodama • Ichiro Moriyama • Takafumi Kajitani • Yoshikazu Kinoshita • Tsutomu Chiba Published online: 26 April 2017 Japanese Society of Gastroenterology 2017

FDG uptake in less affected lung field provides prognostic stratification in patients with interstitial lung disease

This study evaluated the clinical significance of 18F-FDG PET/CT in patients with interstitial lung disease (ILD), by investigating the relationships between 18F-FDG PET/CT parameters and clinical indicators and by evaluating the prognostic implications of 18F-FDG PET/CT results. Methods: Ninety patients (51 men, 39 women; mean age, 55.4 y; age range, 26–78 y) with ILD who underwent 18F-FDG PET/CT were retrospectively analyzed. SUVmean was defined as the mean SUV of the less-affected lung field, SUVTF as adjusted SUVmean using tissue fraction (TF), and CTmean as the mean attenuation of the corresponding region of interest on high-resolution CT. SUVmean, SUVTF, and CTmean were compared in the 90 ILD patients and in 15 age- and sex-matched controls. Correlations of SUVmax, SUVmean, SUVTF, and CTmean with clinical indicators, including estimated percentage of forced vital capacity (%FVC), estimated percentage of diffusion capacity of the lungs for carbon monoxide (%DLco), sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), C-reactive protein (CRP), lactate dehydrogenase (LDH), and ILD-sex-age-physiology (GAP) index, were evaluated using the Spearman rank correlation test and the Tukey–Kramer test. A Cox proportional hazards model was used for univariate and multivariate analyses of factors associated with lung transplantation-free survival. Results: SUVmean, SUVTF, and CTmean were significantly higher in ILD patients than in healthy controls, except for CTmean in patients with a nonusual interstitial pneumonia pattern. SUVmean and CTmean were significantly correlated with %FVC, %DLco, KL-6, and SP-D; SUVTF was significantly correlated with %DLco, KL-6, SP-D, and LDH; and SUVmax was weakly correlated with KL-6 and CRP. Univariate analysis showed that SUVmean, SUVTF, sex, %FVC, %DLco, KL-6, and ILD-GAP index were significantly prognostic of lung transplantation-free survival; and multivariate analysis showed that SUVmean and ILD-GAP index were independently prognostic of lung transplantation-free survival. A higher SUVmean indicated a poorer prognosis, especially in patients with moderate risk based on ILD-GAP index. Conclusion: SUVmean was significantly but moderately correlated with clinical indicators, providing independent prognostic information in patients with ILD. 18F-FDG PET/CT may be helpful for monitoring and risk stratification of ILD patients.