Impact of Diabetic Hyperglycemia on Clinical Outcomes in Patients with Diabetes Mellitus Following Traumatic Brain Injury.

AIM: To identify the effect of patients with diabetes mellitus (DM) with traumatic brain injury (TBI) in Taiwan. MATERIAL AND METHODS: Data from the trauma registry in Chang Gung Memorial Hospital, Linkou, Taiwan were collected and reviewed. Several clinical characteristics and outcomes were extracted and analyzed. The trauma databank includes 3090 patient medical records, of which 475 patients were identified as having DM. Because several baseline characteristics of patients with TBI in the DM group differed from those in the non-DM group, we performed propensity score matching to eliminate confounding factors. RESULTS: After propensity score matching, 895 patients with TBI comprised the non-DM group, and no significant differences were noted in the baseline characteristics between groups. Patients in the DM group had more craniotomies, longer hospital stays, and longer ICU stays. We also segmented the DM group into two subgroups based on survival status. Compared with the survivor group, the nonsurvivor group had a significantly higher serum glucose level. Furthermore, patients with DM were divided into four subgroups according to their serum glucose level. The in-hospital mortality rate was higher in the subgroup with glucose levels greater than 200mg/dL than in the other subgroups. A receiver-operating-characteristic analysis revealed that the ability of serum glucose level to predict in-hospital mortality was modest, with an area under the curve of 0.641 and an associated optimal cutoff of 206 mg/dl. CONCLUSION: DM should be considered a risk factor for patients with TBI receiving neurosurgical intervention and a predictor of longer hospitalization and stay in an intensive care unit. Moreover, in patients with TBI with DM, higher admission serum glucose levels are associated with a higher in-hospital mortality rate.

Real-Time Intraoperative Pressure Monitoring to Avoid Surgically Induced Localized Brain Injury Using a Miniaturized Piezoresistive Pressure Sensor.

Neurosurgical procedures often cause damage to the brain tissue at the periphery from surgical manipulations. Especially during retraction, a large amount of pressure could be applied on the brain surface, which can damage it, leading to brain herniation, which can be fatal for patients. To resolve this issue, we have developed a pressure sensor that can be used to monitor the applied pressure during surgery for intraoperative care. This device was tested on a rodent model to create a superficial surgically induced damage profile for three different applied pressures (30, 50, and 70 mmHg) and compared to a standard intracranial pressure monitoring system. Magnetic resonance imaging has been performed after surgical procedures to detect the herniation caused by applied pressure. To evaluate the damage to brain cells and tissue rupture, histological analysis was performed using hematoxylin and eosin staining. A scoring system was developed to understand the severity of the surgically induced brain injury, which will help neurosurgeons to limit the pressure to an optimum point without causing damage.

DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood-Brain Barrier Permeability.

Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood-brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI.

Boron Accumulation in Brain Tumor Cells through Boc-Protected Tryptophan as a Carrier for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a binary therapeutic approach. Nonradioactive boron-10 atoms accumulated in tumor cells combining with the neutron beams produce two highly energetic particles that could eradicate the cell that takes it and the neighboring cells. Small molecules that carry boron atom, e.g. 5- and 6-boronated and 2,7-diboronated tryptophans, were assessed for their boron accumulation in U87-MG, LN229, and 3T3 for BNCT. TriBoc tryptophan, TB-6-BT, shows boron-10 at 300 ppm in both types of tumor cells with a tumor to normal ratio (T/N) of 5.19-5.25 (4 h). TB-5-BT and DBA-5-BT show boron-10 at 300 ppm (2 h) in U87-MG cells. TB-5-BT exerts a T/N of >9.66 (1 h) in LN229 compared with the current clinical boronophenyl alanine with a highest T/N of 2.3 (1 h) and accumulation concentration of <50 ppm. TB-5-BT and TB-6-BT warrant further animal study.

Comparison of Wide-Awake Local Anesthesia No Tourniquet With General Anesthesia With Tourniquet for Volar Plating of Distal Radius Fracture.

Wide-awake local anesthesia no tourniquet (WALANT) is used for various hand surgeries, but there are no reports of its use for distal radius fractures. The authors compared perioperative variables and clinical outcomes for volar plating for distal radius fractures with WALANT vs general anesthesia with tourniquet. This retrospective study included 47 patients who presented with distal radius fractures between January 2015 and February 2017. Twenty-one underwent surgical volar plating with WALANT, and 26 underwent surgical volar plating with general anesthesia with tourniquet. Patients were followed for 12 months. The 2 groups were compared regarding perioperative parameters and clinical outcomes, including perioperative field pain evaluated by visual analog scale score on postoperative day 1, range of motion 12 months postoperatively, and Mayo wrist score. The WALANT group had a lower mean visual analog scale score and a shorter mean hospitalization (both P<.001), but greater mean blood loss (P<.001). No significant differences were found regarding operative time (P=.214) or time to union (P=.180). At 12-month follow-up, no significant differences were found regarding wrist extension (P=.721), wrist flexion (P=.119), or Mayo wrist score (P=.223). Although both techniques permitted volar plating for distal radius fractures, WALANT allowed immediate intervention and led to less postoperative pain and shorter hospitalization. Although control of blood loss was worse with WALANT, blood loss was limited to a mean of 22.62 mL and did not interfere with the surgical field. [Orthopedics. 2019; 42(1):e93-e98.].

WALANT for distal radius fracture: open reduction with plating fixation via wide-awake local anesthesia with no tourniquet.

BACKGROUND: The wide-awake local anesthesia no tourniquet (WALANT) technique is applied during various hand surgeries. We investigated the perioperative variables and clinical outcomes of open reduction and internal fixation (ORIF) for distal radius fractures under WALANT. METHODS: From January 2015 to January 2017, 60 patients with distal radius fractures were treated, and 24 patients (40% of all) were treated with either a volar or a dorsal plate via WALANT procedure. Of these 24 patients, 21 radius fractures were fixed with a volar plate, and the other 3 were fixed with a dorsal plate. Radiographs; range of motions; visual analog scale (VAS); quick disabilities of the arm, shoulder, and hand (Quick DASH) questionnaire; and time to union were evaluated. RESULTS: One of the 24 patients could not tolerate the WALANT procedure and was reported as a failed attempt at WALANT. In the cohort, 23 patients successfully received distal radius ORIF under WALANT procedure. The average age is 60.9 (range, 20-88) years. The average operation time was 64.3 (range, 45-85) minutes, the average blood loss was 18.9 (range, 5-30) ml, and the average of duration of hospitalization is 1.8 (range, 1-6) days. The average postoperative day one VAS was 1.6 (range, 1-3). The average time of union was 20.7 (range, 15-32) weeks. The mean follow-up period was 15.1 (range, 12-24) months. Functional 1-year postoperative outcomes revealed an average Quick DASH score of 7.60 (range, 4.5-13.6) and an average wrist flexion and extension of 69.6° (range, 55-80°) and 57.4° (range, 45-70°). There was no wound infection, neurovascular injury, or other major complication noted. CONCLUSIONS: WALANT for distal radius fracture ORIF is a method to control blood loss by the effects of local anesthesia mixed with hemostatic agents. Without a tourniquet, the procedure prevents discomfort caused by tourniquet pain. Without sedation, patients could perform the active range of motion of the injured wrist to check if there is impingement of implants. It eliminates the need of numerous preoperative examinations, postoperative anesthesia recovery room care, and side effects of the sedation. However, patients who are not amenable to the awake procedure are contraindications.

Synthesis and evaluation of ortho-[18F] fluorocelecoxib for COX-2 cholangiocarcinoma imaging.

BACKGROUND: An 18F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development. METHODS: The in vivo uptake of celecoxib was monitored with ortho-[18F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[18F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib. RESULTS: The IC50 values were 0.039 µM and 0.024 µM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho-[18F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[18F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC50 values of 0.5 µM and 46.5 µM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30-60 min after the administration of ortho-[18F]fluorocelecoxib through the tail vein. Study of ortho-[18F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g). CONCLUSION: The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase.

Comparing morbidities of bone graft harvesting from the anterior iliac crest and proximal tibia: a retrospective study.

BACKGROUND: The anterior iliac crest (AIC) and proximal tibia (PT) are common donor sites for autologous bone graft harvesting. We compared pain levels at these harvest sites on 1 day, 5 days, 2 weeks, 4 weeks, and 8 weeks post-harvest. METHODS: We retrospectively reviewed 18 patients undergoing autologous bone grafting surgery at a level I trauma center between June 2013 and October 2014. Ten grafts were harvested from the AIC group and eight from the PT group. A standard visual analog scale (VAS) was used to rate pain at the harvest sites on postoperative day (POD) 1, 5, 14, 28, and 56 and at the recipient site on POD 1. RESULTS: There were no statistically significant differences between both groups in age (p = 0.474), gender (p = 1.00), incidence of harvest site morbidity (p = 1.00), and average VAS at the recipient site on POD 1 (p = 0.471). VAS at the harvest site on POD 1, 5, and 14 confirmed statistically that pain was more severe in the AIC group than in the PT group (p < 0.001). However, no significant difference was observed on POD 28 and 56 between both groups. Pain was significantly less on POD 1 in the PT group at the harvest site than at the recipient site (p < 0.001). CONCLUSIONS: The PT is a suitable harvest site, producing statistically less pain for at least two postoperative weeks than the AIC. Besides, patients report less postoperative pain at the PT harvest site than at the recipient site.

Single coracoclavicular suture fixation with Mersilene tape versus hook plate in the treatment of acute type V acromioclavicular dislocation: a retrospective analysis.

BACKGROUND: Here, we compared the clinical and radiographic outcomes between coracoclavicular (CC) fixation with Mersilene tape and hook plate for acute unstable acromioclavicular (AC) joint dislocation treatment. METHODS: We enrolled 49 patients with unstable acute AC dislocation who, between January 2010 and January 2014, underwent surgery with single CC suture fixation with Mersilene tape (M group, 25 cases) or clavicle hook plate (H group, 24 cases). In M and H groups, the average age was 43.7 (range 18-72) and 42.0 (range 17-84) years, the male to female ratio of each group was 15:20 and 19:5, and the injured side left to right ratio was 12:13 and 11:13, respectively. All patients were right-handed. We retrospectively compared the operation time, complication rate, visual analog scale (VAS), University of California at Los Angeles (UCLA) shoulder rating scale, Oxford shoulder scores, and the radiographic outcomes based on reduction loss of CC distance on postoperative follow-up. RESULTS: No significant difference in patient demographics between the two groups in age (p = 0.709), gender (p = 0.217), time from injury to surgery (p = 0.863), and injured side (p = 1.000). The mean follow-up was 26.2 months (range 24-35 months). Nine cases of reduction loss (36%) and one of distal clavicle osteolysis (4%) were noted in the M group. CC distance improvement in the H group was significantly superior to that in the M group at 3 months (before hook plate removal, p < 0.001) and 12 months postoperatively (after hook plate removal, p = 0.004), while subacromial erosions were revealed in nine cases (37.5%) in the H group. No significant difference in operative time (p = 0.846), complication rate (p = 1.000), VAS (p = 0.199), mean UCLA shoulder rating scale (p = 0.353), and Oxford shoulder (p = 0.224) scores between the two groups. CONCLUSIONS: Both hook plate and Mersilene tape fixations provided temporary stabilization of acute type V AC dislocation and yielded comparable clinical outcomes. The hook plate provided better maintenance of reduction of radiographic outcomes. CC suture fixation with Mersilene tape may serve as an alternative method of stabilization which provides acceptable outcome without the need of implant removal.

The titanium elastic nail serves as an alternative treatment for adult proximal radial shaft fractures: a cohort study.

BACKGROUND: To investigate whether closed reduction and internal fixation (CRIF) with titanium elastic nails (TENs) is a viable alternative treatment in proximal radial fractures. METHODS: In Kaohsiung Veterans General Hospital, from November 2013 to April 2015, five adult male patients with forearm injuries (average age 43 years; range 35-64 years) were treated for proximal radial shaft fractures. CRIF with TENs for radial shaft fractures was performed in these five patients. Radiographs; range of motions; visual analog scale (VAS); quick disabilities of the arm, shoulder, and hand (Quick DASH) questionnaire; and time to union were evaluated in our study. RESULTS: Mean follow-up period was 30 months (range 28-36 months). Average time of radius union was 7.3 months (range 6-10 months). Functional outcomes 1 year after operation revealed an average Quick DASH score of 7.92 (range 4.5-25), an average VAS of 1.5 (range 1-3), and average forearm supination and pronation of 69.2° (range 45°-75°) and 82.5° (range 80°-85°). No major complication was noted. CONCLUSIONS: CRIF with TEN for adult proximal radial fractures is a method to avoid extensive exposure or nerve injury during ORIF, especially in multiple trauma patients who require short operative time, uremia patients with ipsilateral forearm AV shunt, severe soft tissue swelling due to direct muscle contusion or strong muscularity before surgery, extensive radial fracture, and those in pursuit of cosmetic outcomes.

Dataset on the synthesis and characterization of boron fenbufen and its F-18 labeled homolog.

The data presented in this article are related to the research article entitled "Synthesis and Characterization of Boron Fenbufen and its F-18 Labeled Homolog for Boron Neutron Capture Therapy of COX-2 Overexpressed Cholangiocarcinoma". The contents of the data article include 1) the set up for performing in vitro binding assay, 2) 1H-, 13C- and 19F-NMR of compounds described in main text, 3) HPLC chromatogram of the fluorination mixtures, 4) data of in vitro stability test, cell survival assay, western blot and PCR analysis, 5) the modules for fixing the two CCA rats for BNCT, and 6) bar diagram for tumor reduction using [18F]FDG-PET 24 h post treatment with BNCT.

Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma.

Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68µM) and COX-2 (IC50=0.33±0.24µM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2-1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40-55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs.

An Intramuscular Chondrolipoma of the Scapula: A Case Report of a Rare Tumor in an Unusual Location.

INTRODUCTION: Chondrolipomas are rare benign mesenchymal tumors primarily occurring in the shoulder region. To the best of our knowledge, only one case of chondrolipoma arising from the shoulder has been reported. We herein report an intramuscular chondrolipoma located in an unusual area of the scapula. Our case is interesting because magnetic resonance imaging (MRI) that shows lipomatous tumor masses with cartilaginous nodules may mislead surgeons into not considering the possibility of chondrolipomas. CASE REPORT: A 62-year-old female, without any systemic disease, trauma, or history of surgery, presented with a unique case of a large intramuscular chondrolipoma ofthe scapula. This protruding lump over the right shoulder was present for 3 months in the patient without pain or limited range of motion. A sonographic evaluation revealed a homogeneous hypoechoic lesion in the posterior right shoulder. MRI showed that the chondrolipoma measured 7.5 x 4.6 x 3.9 cm, without remarkable bony invasion, with high signal intensity over the mass in T1- weighted images, indicating cystic changes, and mild signal enhancement within the cyst in T2-weighted images. Surgical marginal excision was performed. We identified yellowish, greasy, and firm soft tissue and two cartilaginous nodules inside the lipomatous tissue. Pathological findings revealed mature adipose tissue with a fibrous capsule and true cartilage inside. Post-operative outpatient follow-up found no recurrence after 2 years. CONCLUSION: Intramuscular chondrolipoma arising from the shoulder has been rarely reported. MRI and sonography are helpful in the diagnosis.

Altered expression of stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in cancer: will they become a new battlefield for oncotherapy?

The stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) play pivotal roles in the modulation of Ca(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes. Increasing evidence has implicated the dysregulation of STIM-ORAI and IP3Rs in tumorigenesis and tumor progression. By controlling the activities, structure, and/or expression levels of these Ca(2+)-transporting proteins, malignant cancer cells can hijack them to drive essential biological functions for tumor development. However, the molecular mechanisms underlying the participation of STIM-ORAI and IP3Rs in the biological behavior of cancer remain elusive. In this review, we summarize recent advances regarding STIM-ORAI and IP3Rs and discuss how they promote cell proliferation, apoptosis evasion, and cell migration through temporal and spatial rearrangements in certain types of malignant cells. An understanding of the essential roles of STIM-ORAI and IP3Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.

Synthesis and Biological Evaluation of an (18)Fluorine-Labeled COX Inhibitor--[(18)F]Fluorooctyl Fenbufen Amide--For Imaging of Brain Tumors.

Molecular imaging of brain tumors remains a great challenge, despite the advances made in imaging technology. An anti-inflammatory compound may be a useful tool for this purpose because there is evidence of inflammatory processes in brain tumor micro-environments. Fluorooctylfenbufen amide (FOFA) was prepared from 8-chlorooctanol via treatment with potassium phthalimide, tosylation with Ts2O, fluorination with KF under phase transfer catalyzed conditions, deprotection using aqueous hydrazine, and coupling with fenbufen. The corresponding radiofluoro product [(18)F]FOFA, had a final radiochemical yield of 2.81 mCi and was prepared from activated [(18)F]F(-) (212 mCi) via HPLC purification and concentration. The radiochemical purity was determined to be 99%, and the specific activity was shown to exceed 22 GBq/µmol (EOS) based on decay-corrected calculations. Ex-vivo analysis of [(18)F]FOFA in plasma using HPLC showed that the agent had a half-life of 15 min. PET scanning showed significant accumulation of [(18)F]FOFA over tumor loci with reasonable contrast in C6-glioma bearing rats. These results suggest that this molecule is a promising agent for the visualization of brain tumors. Further investigations should focus on tumor micro-environments.

Interleukin-15 enhances the expansion and function of natural killer T cells from adult peripheral and umbilical cord blood.

Invariant natural killer T cells (iNKT cells) are innate-like non-conventional T cells restricted by the CD1d molecule that are unique in their ability to play a pivotal role in immune regulation. Deficient iNKT function has been reported in patients receiving umbilical cord blood (UCB) transplantation. We sought to determine the effect of interleukin (IL)-15 on α-galactosylceramide (α-GalCer)-expanded iNKT cell function from UCB and adult peripheral blood (APB) mononuclear cells (MNCs). Fresh APB and UCB MNCs were cultured with IL-15 (50 ng/ml) in the presence or absence of α-GalCer (100 ng/ml) for 10 days. Cells were harvested for examination of cell yield, apoptosis, cytokine production and cytotoxic function of Vα24(+)/Vß11(+) iNKT cells. We observed that α-GalCer-expanded APB and UCB iNKT cells and such expansion was further enhanced with IL-15. The percentage of CD3(+)CD56(+) NKT-like cells in both APB and UCB MNCs was increased with IL-15 but not with α-GalCer. Apoptosis of UCB iNKT cells was ameliorated by IL-15. Although APB and UCB iNKT cells secreted lower IFN-γ, it could be enhanced with IL-15. The expression of perforin in APB iNKT cells can also be enhanced with IL-15. UCB Vα24(+)Vß11(+) iNKT cells further augmented K562 cytotoxicity mediated by IL-15. Taken together, these results demonstrated the relative functional deficiencies of α-GalCer induced UCB iNKT cells, which can be ameliorated by IL-15. Our findings suggest a therapeutic benefit of IL-15 immunotherapy during the post-UCB transplant period when iNKT function remains poor.

Investigation of brain tumors using (18)F-fluorobutyl ethacrynic amide and its metabolite with positron emission tomography.

To date, imaging of malignant glioma remains challenging. In positron emission tomography-related diagnostic imaging, differential tumor uptake of 3'-deoxy-3'-[(18)F] fluorothymidine ([(18)F]FLT) has been shown to reflect the levels of cell proliferation and DNA synthesis. However, additional biomarkers for tumors are urgently required. Aberrant levels of glutathione transferase (GST) activity have been hypothesized to constitute such a novel diagnostic marker. Here, a C6 rat glioma tumor model was used to assess the ability of the positron emission tomography tracers, [(18)F]FLT and (18)F-fluorobutyl ethacrynic amide ([(18)F]FBuEA), to indicate reactive oxygen species-induced stress responses as well as detoxification-related processes in tumors. Using a GST activity assay, we were able to demonstrate that FBuEA is more readily catalyzed by GST-π than by GST-α. Furthermore, we showed that FBuEA-GS, a metabolite of FBuEA, elicits greater cytotoxicity in tumor cells than in normal fibroblast cells. Finally, in vitro and in vivo investigation of radiotracer distribution of [(18)F]FBuEA and [(18)F] FBuEA-GS revealed preferential accumulation in C6 glioma tumor cells over normal fibroblast cells for [(18)F]FBuEA-GS but not for [(18)F]FBuEA.

18F-glutathione conjugate as a PET tracer for imaging tumors that overexpress L-PGDS enzyme.

Lipocalin-type prostaglandin D synthase (L-PGDS) has been correlated with the progression of neurological disorders. The present study aimed at evaluating the imaging potency of a glutathione conjugate of fluorine-18-labeled fluorobutyl ethacrynic amide ([18F]FBuEA-GS) for brain tumors. Preparation of [18F]FBuEA-GS has been modified from the -4-tosylate derivative via radiofluorination in 5% radiochemical yield. The mixture of nonradioactive FBuEA-GS derived from a parallel preparation has be resolved to two isomers in a ratio of 9:1 using analytic chiral reversed phase high performance liquid chromatography (RP-HPLC). The two fluorine-18-labeled isomers purified through nonchiral semipreparative RP-HPLC as a mixture were studied by assessing the binding affinity toward L-PGDS through a gel filtration HPLC, by analyzing radiotracer accumulation in C6 glioma cells, and by evaluating the imaging of radiotracer in a C6 glioma rat with positron emission tomography. The inhibition percentage of the production of PGD2 from PGH2 at the presence of 200 µM of FBuEA-GS and 4-Dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)butyl]piperidine (AT-56) were 74.1 ± 4.8% and 97.6 ± 16.0%, respectively. [18F]FBuEA-GS bound L-PGDS (16.3-21.7%) but not the isoform, microsomal prostaglandin E synthase 1. No binding to GST-alpha and GST-pi was observed. The binding strength between [18F]FBuEA-GS and L-PGDS has been evaluated using analytic gel filtration HPLC at the presence of various concentrations of the cold competitor FBuEA-GS. The contrasted images indicated that the radiotracer accumulation in tumor lesions is probably related to the overexpression of L-PGDS.

[123I]Iodooctyl fenbufen amide as a SPECT tracer for imaging tumors that over-express COX enzymes.

This study is concerned with the development of an agent for single photon emission computer tomography (SPECT) for imaging inflammation and tumor progression. [(123)I]Iodooctyl fenbufen amide ([(123)I]IOFA) was prepared from the precursor N-octyl-4-oxo-4-(4'-(trimethylstannyl)biphenyl-4-yl)butanamide with a radiochemical yield of 15%, specific activity of 37 GBq/µmol, and radiochemical purity of 95%. Analysis of the binding of [(123)I]IOFA to COX-1 and COX-2 enzymes by using HPLC and a gel filtration column showed a selectivity ratio of 1:1.3. An assay for the competitive inhibition of substrate transfer showed that IOFA exhibited a comparable IC(50) value compared to fenbufen. In the normal rat liver, a lower level and homogeneous pattern of [(123)I]IOFA radioactivity was observed by SPECT. In contrast, in the rat liver with thioacetamide-induced cholangiocarcinoma, a higher uptake and heterogeneous pattern of [(123)I]IOFA radioactivity was seen as hot spots in tumor lesions by SPECT imaging. Importantly, elevated COX-1 and COX-2 expressions from immunostaining were found in the bile ducts of tumor rats but not of normal rats. Therefore, [(123)I]IOFA was found to exhibit the potential for imaging tumors that over-express COX.