Synthesis, Anticancer Potential and Comprehensive Toxicity Studies of Novel Brominated Derivatives of Bacterial Biopigment Prodigiosin from Serratia marcescens ATCC 27117.

Prodigiosins (prodiginines) are a class of bacterial secondary metabolites with remarkable biological activities and color. In this study, optimized production, purification, and characterization of prodigiosin (PG) from easily accessible Serratia marcescens ATCC 27117 strain has been achieved to levels of 14 mg/L of culture within 24 h. Furthermore, environmentally friendly bromination of produced PG was used to afford both novel mono- and dibrominated derivatives of PG. PG and its Br derivatives showed anticancer potential with IC50 values range 0.62-17.00 µg/mL for all tested cancer cell lines and induction of apoptosis but low selectivity against healthy cell lines. All compounds did not affect Caenorhabditiselegans at concentrations up to 50 µg/mL. However, an improved toxicity profile of Br derivatives in comparison to parent PG was observed in vivo using zebrafish (Danio rerio) model system, when 10 µg/mL applied at 6 h post fertilization caused death rate of 100%, 30% and 0% by PG, PG-Br, and PG-Br2, respectively, which is a significant finding for further structural optimizations of bacterial prodigiosins. The drug-likeness of PG and its Br derivatives was examined, and the novel Br derivatives obey the Lipinski's "rule of five", with an exemption of being more lipophilic than PG, which still makes them good targets for further structural optimization.

Central osteophytes develop in cartilage with abnormal structure and composition: data from the Osteoarthritis Initiative cohort.

OBJECTIVE: To investigate the natural history of central osteophytes (COs) by analyzing the structure and matrix composition of CO-associated cartilage using 3-T MRI at and 1-3 years before the onset of COs. MATERIALS AND METHODS: Baseline, 4- and 6-year knee MRIs of 400 participants in the Osteoarthritis Initiative were screened for the appearance of new COs. Twenty-eight subjects developed 31 COs. Using MRIs at CO onset and 1-3 years before CO onset, cartilage T2 values were calculated for the local cartilage preceding COs and the surrounding cartilage. Cartilage lesions local to the site of COs and bone marrow edema like lesions (BMELs) subjacent to COs were graded using whole organ MRI scores (WORMS). Wilcoxon tests were used to compare T2 values from the local and the surrounding cartilage at each time point and to compare T2 and WORMS between time points. Knee symptoms were recorded during this period. RESULTS: All subjects showed local cartilage lesions before the development of COs. Mean cartilage WORMS increased from 1.56 ± 0.66 a period of 3 years before to 2.39 ± 0.75 with onset of COs (p = 0.008). Local T2 values in the area of the later-appearing COs were significantly higher compared with T2 values of the surrounding cartilage 3 (p = 0.044) and 2 years earlier (p = 0.031) and with the onset of COs (p = 0.025). No significant increase in symptoms was found with the onset of COs. CONCLUSION: This study provides evidence that focal cartilage structural and compositional degeneration precedes COs. No significant aggravation of knee symptoms was reported during the evolution of COs.

Tool for osteoarthritis risk prediction (TOARP) over 8 years using baseline clinical data, X-ray, and MRI: Data from the osteoarthritis initiative.

BACKGROUND: Osteoarthritis (OA), a multifactorial disease causing joint degeneration, often leads to severe disability. The rising rates of disability highlight the need for implementing preventative measures at early stages of the disease, which would especially benefit subjects at high risk for OA development. PURPOSE: To develop a risk prediction tool for moderate-severe OA (TOARP) over 8 years based on subject characteristics, knee radiographs, and MRI data at baseline using data from the Osteoarthritis Initiative (OAI). STUDY TYPE: Retrospective. SUBJECTS: 641 subjects with no/mild radiographic OA (Kellgren-Lawrence [KL] 0-2) and no clinically significant symptoms (Western Ontario and McMaster Universities Arthritis Index [WOMAC] 0-1) were selected from the OAI. FIELD STRENGTH/SEQUENCE: MR images were obtained using 3.0T. ASSESSMENT: Compartment-specific cartilage and meniscus morphology and cartilage T2 were assessed. Baseline subject demographics, risk factors, KL score, cartilage WORMS score, presence of meniscus tear, and cartilage T2 were used to predict the development of moderate/severe OA (KL = 3-4 or WOMAC pain ≥5 or total knee replacement [TKR]) over 8 years. STATISTICAL TESTS: Best subsets variable selection followed by cross-validation were used to assess which combinations of variables best predict moderate/severe OA. RESULTS: Model 1 included KL score, previous knee injury in the last 12 months, age, gender, and BMI. Model 2 included all variables in Model 1 plus presence of cartilage defects in the lateral femur and patella, and presence of a meniscal tear. Model 3 included all variables in Models 1 and 2, plus cartilage T2 in the medial tibia and medial femur. Compared to Model 1 (cross-validated AUC = 0.67), Model 3 performed significantly better (AUC = 0.72, P = 0.04), while Model 2 showed a statistical trend (AUC = 0.71, P = 0.08). DATA CONCLUSION: We established a risk calculator for the development of moderate/severe knee OA over 8 years that includes radiographic and MRI data. The inclusion of MRI-based morphological abnormalities and cartilage T2 significantly improved model performance. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1517-1526.

Intramolecular Aza-Diels-Alder Reactions of ortho-Quinone Methide Imines: Rapid, Catalytic, and Enantioselective Assembly of Benzannulated Quinolizidines.

Aza-Diels-Alder reactions (ADARs) are powerful processes that furnish N-heterocycles in a straightforward fashion. Intramolecular variants offer the additional possibility of generating bi- and polycyclic systems with high stereoselectivity. We report herein a novel Brønsted acid catalyzed process in which ortho-quinone methide imines tethered to the dienophile via the N substituent react in an intramolecular ADAR to form complex quinolizidines and oxazinoquinolines in a one-step process. The reactions proceed under very mild conditions, with very good yields and good to very good diastereo- and enantioselectivities. Furthermore, the process was extended to a domino reaction that efficiently combines substrate synthesis, ortho-quinone methide imine formation, and ADAR.

Nasal chondrocyte-based engineered autologous cartilage tissue for repair of articular cartilage defects: an observational first-in-human trial.

BACKGROUND: Articular cartilage injuries have poor repair capacity, leading to progressive joint damage, and cannot be restored predictably by either conventional treatments or advanced therapies based on implantation of articular chondrocytes. Compared with articular chondrocytes, chondrocytes derived from the nasal septum have superior and more reproducible capacity to generate hyaline-like cartilage tissues, with the plasticity to adapt to a joint environment. We aimed to assess whether engineered autologous nasal chondrocyte-based cartilage grafts allow safe and functional restoration of knee cartilage defects. METHODS: In a first-in-human trial, ten patients with symptomatic, post-traumatic, full-thickness cartilage lesions (2-6 cm2) on the femoral condyle or trochlea were treated at University Hospital Basel in Switzerland. Chondrocytes isolated from a 6 mm nasal septum biopsy specimen were expanded and cultured onto collagen membranes to engineer cartilage grafts (30 × 40 × 2 mm). The engineered tissues were implanted into the femoral defects via mini-arthrotomy and assessed up to 24 months after surgery. Primary outcomes were feasibility and safety of the procedure. Secondary outcomes included self-assessed clinical scores and MRI-based estimation of morphological and compositional quality of the repair tissue. This study is registered with ClinicalTrials.gov, number NCT01605201. The study is ongoing, with an approved extension to 25 patients. FINDINGS: For every patient, it was feasible to manufacture cartilaginous grafts with nasal chondrocytes embedded in an extracellular matrix rich in glycosaminoglycan and type II collagen. Engineered tissues were stable through handling with forceps and could be secured in the injured joints. No adverse reactions were recorded and self-assessed clinical scores for pain, knee function, and quality of life were improved significantly from before surgery to 24 months after surgery. Radiological assessments indicated variable degrees of defect filling and development of repair tissue approaching the composition of native cartilage. INTERPRETATION: Hyaline-like cartilage tissues, engineered from autologous nasal chondrocytes, can be used clinically for repair of articular cartilage defects in the knee. Future studies are warranted to assess efficacy in large controlled trials and to investigate an extension of indications to early degenerative states or to other joints. FUNDING: Deutsche Arthrose-Hilfe.

Medial femur T2 Z-scores predict the probability of knee structural worsening over 4-8 years: Data from the osteoarthritis initiative.

OBJECTIVE: The purpose of this study was to determine the probability of structural worsening of knee cartilage and whole joint degeneration over 4-8 years based on cartilage T2 Z-scores at baseline. DESIGN: Right knees with Kellgren-Lawrence (KL) grades of 0-2 in 587 participants from the Osteoarthritis Initiative were studied. 3T MR images were used to perform baseline cartilage T2 quantification and assess 4-year changes in cartilage morphology (WORMS scoring) in 5 regions. Changes in joint space narrowing (JSN) and KL were assessed over 8 years. T2 Z-scores were based on a reference database of knees without morphologic cartilage degeneration at baseline. Odds ratios for, and predicted probabilities of any worsening in WORMS cartilage, JSN and KL grade were obtained from logistic regression models. RESULTS: A one-unit increase in the baseline medial femur T2 Z-score was associated with cartilage worsening in the same region (OR = 1.59; P < 0.0001) and in any region (OR = 1.37; P < 0.0001), and with worsening JSN (OR = 1.82; P < 0.0001) and KL grades (OR = 1.69; P < 0.0001). Predicted probabilities of worsening in knees with a medial femur T2 Z-score from 2-4 were 38% for medial femur cartilage WORMS, 70% for any cartilage region, 28% for increasing JSN and 31% for increasing KL grade. CONCLUSION: Knees with elevated cartilage T2 (especially in the medial femur and those that are 2 to 4 SDs above the mean reference values) are significantly more likely to have structural worsening over 4 to 8 years. Knowing cartilage T2 Z-scores may aid in targeting prevention efforts at early stages of osteoarthritis. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1128-1136.

Evaluation of Chondrocalcinosis and Associated Knee Joint Degeneration Using MR Imaging: Data from the Osteoarthritis Initiative.

OBJECTIVES: To evaluate the ability of different MRI sequences to detect chondrocalcinosis within knee cartilage and menisci, and to analyze the association with joint degeneration. METHODS: Subjects with radiographic knee chondrocalcinosis (n = 90, age 67.7 ± 7.3 years, 50 women) were selected from the Osteoarthritis Initiative and matched to controls without radiographic chondrocalcinosis (n = 90). Visualization of calcium-containing crystals (CaC) was compared between 3D T1-weighted gradient-echo (T1GE), 3D dual echo steady-state (DESS), 2D intermediate-weighted (IW), and proton density (PD)-weighted fast spin-echo (FSE) sequences obtained with 3T MRI and correlated with a semiquantitative CaC score obtained from radiographs. Structural abnormalities were assessed using Whole-Organ MRI Score (WORMS) and logistic regression models were used to compare cartilage compartments with and without CaC. RESULTS: Correlations between CaC counts of MRI sequences and degree of radiographic calcifications were highest for GE (rT1GE = 0.73, P < 0.001; rDESS = 0.68, P < 0.001) compared to other sequences (P > 0.05). Meniscus WORMS was significantly higher in subjects with chondrocalcinosis compared to controls (P = 0.005). Cartilage defects were significantly more frequent in compartments with CaC than without (patella: P = 0.006; lateral tibia: P < 0.001; lateral femur condyle: P = 0.017). CONCLUSIONS: Gradient-echo sequences were most useful for the detection of chondrocalcinosis and presence of CaC was associated with higher prevalence of cartilage and meniscal damage. KEY POINTS: • Magnetic resonance imaging is useful for assessing burden of calcium-containing crystals (CaC). • Gradient-echo sequences are superior to fast spin echo sequences for CaC imaging. • Presence of CaC is associated with meniscus and cartilage degradation.

MR T1ρ and T2 of meniscus after acute anterior cruciate ligament injuries.

OBJECTIVE: To evaluate differences in meniscal T1ρ and T2 quantification in patients with acute anterior cruciate ligament (ACL) injuries and to determine correlations of these differences with MR morphological grading and patient-reported outcomes. DESIGN: Bilateral knees of 52 patients with acute ACL injury and 20 healthy controls were scanned using 3 T magnetic resonance imaging (MRI) T1ρ and T2 mapping in this prospective study. Quantitative analysis of the meniscus was performed in anterior and posterior horns of the lateral and medial menisci. Morphological meniscal damage was assessed using modified whole-organ MRI scores (WORMS). Measurements were compared between injured, uninjured contralateral, and control knees using a mixed-effects regression model. Correlations between meniscal T1ρ/T2, WORMS and Knee Injury and Osteoarthritis Outcome Scores (KOOS) were examined using partial correlation analysis. RESULTS: Mean meniscal T1ρ and T2 values were significantly higher in ACL-injured knees compared to control and contralateral knees. Menisci of ACL-injured knees without tears, including those limited to modified meniscal WORMS grade 0, also had significantly higher T1ρ and T2 values compared to menisci of uninjured knees. Within ACL-injured knees, T1ρ and T2 values showed significant positive associations with meniscal WORMS and significant negative associations with KOOS. CONCLUSION: Acute ACL injuries are associated with significantly increased meniscal T1ρ and T2 values in both patients with and without meniscal lesions or tears, suggesting quantitative MRI provides more sensitive measures of meniscal differences compared to traditional morphological MRI sequences. Correlation between meniscal T1ρ/T2 and KOOS suggest that quantitative MRI is reflective of the extent of patients' clinical symptoms.

Phylogeny of the Highly Divergent Echinosteliales (Amoebozoa).

Myxomycetes or plasmodial slime molds are widespread and very common soil amoebae with the ability to form macroscopic fruiting bodies. Even if their phylogenetic position as a monophyletic group in Amoebozoa is well established, their internal relationships are still not entirely resolved. At the base of the most intensively studied dark-spored clade lies the order Echinosteliales, whose highly divergent small subunit ribosomal (18S) RNA genes represent a challenge for phylogenetic reconstructions. This is because they are characterized by unusually long variable helices of unknown secondary structure and a high inter- and infraspecific divergence. Current classification recognizes two families: the monogeneric Echinosteliaceae and the Clastodermataceae with the genera Barbeyella and Clastoderma. To better resolve the phylogeny of the Echinosteliales, we obtained three new small subunit ribosomal (18S) RNA gene sequences of Clastoderma and Echinostelium corynophorum. Our phylogenetic analyses suggested the polyphyly of the family Clastodermataceae, as Barbeyella was more closely related to Echinostelium arboreum than to Clastoderma, while Clastoderma debaryanum was the earliest branching clade in Echinosteliales. We also found that E. corynophorum was the closest relative of the enigmatic Semimorula liquescens, a stalkless-modified Echinosteliales. We discuss possible evolutionary pathways in dark-spored Myxomycetes and propose a taxonomic update.

Brønsted Acid Catalyzed Addition of Enamides to ortho-Quinone Methide Imines-An Efficient and Highly Enantioselective Synthesis of Chiral Tetrahydroacridines.

The direct and highly enantioselective synthesis of tetrahydroacridines was achieved through the phosphoric acid catalyzed addition of enamides to in situ generated ortho-quinone methide imines and subsequent elimination. This novel one-step process constitutes a very efficient, elegant, and selective synthetic approach to valuable N-heterocycles with a 1,4-dihydroquinoline motif. By subsequent highly diastereoselective hydrogenation and N-deprotection the reaction products were easily converted into free hexahydroacridines with a total of three new stereogenic centers.

Metal artefact suppression at 3 T MRI: comparison of MAVRIC-SL with conventional fast spin echo sequences in patients with Hip joint arthroplasty.

OBJECTIVE: The aim of our study was to evaluate the clinical feasibility and diagnostic value of a new MRI metal artefact reduction pulse sequence called MAVRIC-SL in a 3 T MRI environment. SUBJECTS AND METHODS: Two MAVRIC-SL sequences obtained in 61 patients with symptomatic total hip replacement were compared with standard FSE-STIR sequences optimized for imaging around metal. Artefact size was measured on the slice of greatest extent. Image quality, fat saturation, image distortion, visibility of anatomical structures, and detectability of joint abnormalities were visually assessed and graded on qualitative scales. Differences between MAVRIC-SL and FSE sequences were tested with the Wilcoxon signed-rank test. RESULTS: MAVRIC-SL sequences at 3 T showed significantly smaller metal artefacts compared to FSE-STIR sequences (p < 0.0001). The general image quality of MAVRIC-SL sequences was reduced with regard to spatial resolution, noise and contrast (p = 0.001), and fat saturation (p < 0.0001). The reduction of artefact size and image distortion significantly improved visualization of joint anatomy (p < 0.0001) and diagnostic confidence regarding implant-associated abnormalities (p = 0.0075 to <0.0001). CONCLUSION: Although the image quality of MAVRIC-SL sequences is limited at 3 T, its clinical application is feasible and provides important additional diagnostic information for the workup of patients with symptomatic hip replacement through substantially reduced metal artefacts. KEY POINTS: • Metal artefacts compromise imaging of total hip replacement with MRI. • Metal artefacts are aggravated with 3 Tesla MRI. • MAVRIC-SL is a technique to suppress metal artefacts. • MAVRIC-SL effectively reduces metal artefacts at 3 Tesla and improves diagnostic quality.

Correlation of (99m) Tc-DPD SPECT/CT Scan Findings and Diagnostic Blockades of Lumbar Medial Branches in Patients with Unspecific Low Back Pain in a Randomized-Controlled Trial.

OBJECTIVE: Zygapophyseal joints are the origin of pain in up to 30% of those with unspecific chronic low back pain. Until recently, no reliable clinical tests have been found to identify the patients who would benefit from denervation of the zygapophyseal joints by medial branch blockades. DESIGN: We performed a prospective randomized placebo-controlled trial to evaluate the value of high-resolution single-photon emission computed tomography (SPECT)/computed tomography (CT) of the lumbar spine prior to any diagnostic infiltration of the medial branches. METHODS: Patients with suspected zygapophyseal joint-related pain were included in the study. After obtaining a SPECT/CT scan of the lumbar spine a set of infiltrations of the medial branches was done with local anesthetics and placebo on different days. Patients and anesthetists were blinded to the results of SPECT/CT and to the infiltrated agents. RESULTS: In a total of 29 study patients, 7 had positive and 22 negative infiltration tests, and 9 had positive and 20 negative SPECT/CT findings. Sensitivity of SPECT/CT for a positive response after diagnostic infiltration was 0.57 (95% confidence interval [CI] 0.18-0.90); specificity was 0.77 (CI 95% 0.55-0.92); odds ratio was 4.53 (CI 95% 0.75-27.40); and diagnostic accuracy was 0.72. CONCLUSION: Compared with diagnostic infiltrations SPECT/CT scans showed only a moderate sensitivity and specificity and, therefore, may not be recommended as a first line diagnostic tool prior to diagnostic infiltrations.

Metal artifact suppression at the hip: diagnostic performance at 3.0 T versus 1.5 Tesla.

PURPOSE: This work aimed to compare the diagnostic performance of a metal artifact suppression sequence (MAVRIC-SL) for imaging of hip arthroplasties (HA) at 1.5 and 3 Tesla (T) field strength. METHODS: Eighteen patients (10 females; aged 27-74) with HA were examined at 3.0 and 1.5 T within 3 weeks. The sequence protocol included 3D-MAVRIC-SL PD (coronal), 3D-MAVRIC-SL STIR (axial), FSE T1, FSE PD and STIR sequences. Anatomical structures and pathological findings were assessed independently by two radiologists. Artifact extent and technical quality (image quality, fat saturation and geometric distortion) were also evaluated. Findings at 1.5 and 3.0 T were compared using a Wilcoxon signed rank test. RESULTS: While image quality was better at 1.5 T, visualization of anatomic structures and clinical abnormalities was not significantly different using the two field strengths (p > 0.05). Fat suppression and amount of artifacts were significantly better at 1.5 T (p < 0.01). Inter- and intra-reader agreement for different anatomic details, image quality and visualization of abnormalities ranged from k = 0.62 to k = 1.00. CONCLUSION: MAVRIC-SL at 1.5 T had a comparable diagnostic performance when compared MAVRIC-SL at 3.0 T; however, the higher field strength was associated with larger artifacts, limited image quality and worse fat saturation.

Accuracy comparison of various quantitative [99mTc]Tc-DPD SPECT/CT reconstruction techniques in patients with symptomatic hip and knee joint prostheses.

BACKGROUND: There is a need for better diagnostic tools that identify loose total hip and knee arthroplasties. Here, we present the accuracy of different 99mTc-dicarboxypropandiphosphate ([99mTc]Tc-DPD) SPECT/CT quantification tools for the detection of loose prostheses in patients with painful hip and knee arthroplasties. METHODS: Quantitative reconstruction of mineral phase SPECT data was performed using Siemens xSPECT-Quant and xSPECT-Bone, with and without metal artefact reduction (iMAR) of CT-data. Quantitative data (SUVmax values) were compared to intraoperative diagnosis or clinical outcome after at least 1 year as standard of comparison. Cut-off values and accuracies were calculated using receiver operator characteristics. Accuracy of uptake quantification was compared to the accuracy of visual SPECT/CT readings, blinded for the quantitative data and clinical outcome. RESULTS: In this prospective study, 30 consecutive patients with 33 symptomatic hip and knee prostheses underwent [99mTc]Tc-DPD SPECT/CT. Ten arthroplasties were diagnosed loose and 23 stable. Mean-SUVmax was significantly higher around loose prostheses compared to stable prostheses, regardless of the quantification method (P = 0.0025-0.0001). Quantification with xSPECT-Bone-iMAR showed the highest accuracy (93.9% [95% CI 79.6-100%]) which was significantly higher compared to xSPECT-Quant-iMAR (81.8% [67.5-96.1%], P = 0.04) and xSPECT-Quant without iMAR (77.4% [62.4-92.4%], P = 0.02). Accuracies of clinical reading were non-significantly lower compared to quantitative measures (84.8% [70.6-99.1%] (senior) and 81.5% [67.5-96.1%] (trainee)). CONCLUSION: Quantification with [99mTc]Tc-DPD xSPECT-Bone-iMAR discriminates best between loose and stable prostheses of all evaluated methods. The overall high accuracy of different quantitative measures underlines the potential of [99mTc]Tc-DPD-quantification as a biomarker and demands further prospective evaluation in a larger number of prosthesis.

CT-guided robotically-assisted infiltration of foot and ankle joints.

It was our aim to describe a CT-guided robotically-assisted infiltration technique for diagnostic injections in foot and ankle orthopaedics. CT-guided mechatronically-assisted joint infiltration was performed on 16 patients referred to the orthopaedic department for diagnostic foot and ankle assessment. All interventions were performed using an INNOMOTION-assistance device on a multislice CT scanner in an image-guided therapy suite. Successful infiltration was defined as CT localization of contrast media in the target joint. Additionally, pre- and post-interventional VAS pain scores were assessed. All injections (16/16 joints) were technically successful. Contrast media deposit was documented in all targeted joints. Significant relief of pain was noted by all 16 patients (p<0.01). CT-guided robotically-assisted intervention is an exact, reliable and safe application method for diagnostic infiltration of midfoot and hindfoot joints. The high accuracy and feasibility in a clinical environment make it a viable alternative to the commonly used fluoroscopic-guided procedures.

Novel DOTA-based prochelator for divalent peptide vectorization: synthesis of dimeric bombesin analogues for multimodality tumor imaging and therapy.

Dimeric peptidic vectors, obtained by the divalent grafting of bombesin analogues on a newly synthesized DOTA-based prochelator, showed improved qualities as tumor targeted imaging probes in comparison to their monomeric analogues.

Display of dural sinuses with time-resolved, contrast-enhanced three-dimensional MR venography.

BACKGROUND: Time-resolved (TR) contrast-enhanced 3D MR angiography has recently received considerable attention for the workup of cerebrovascular diseases, foremost dural arteriovenous fistula and arteriovenous malformation, and potentially for the evaluation of dural sinus thrombosis. Thereby, the dynamic visualization of cerebral vessels is enabled similar to the principle of digital subtraction angiography. Yet, its voxel size is relatively large due to an inherent trade-off between the desired spatial and temporal resolutions. The goal of this study was to evaluate whether the limited spatial resolution of TR MR venography (MRV) is sufficient to visualize dural venous sinuses. METHODS: The prospective study included 20 patients without compromise of cerebral venous outflow. Two neuroradiologists independently graded the quality of visualization of 11 predefined dural venous sinuses on images of fast TR contrast-enhanced MRV (1.5 s/dataset; voxel size, 2 x 2 x 2.2 mm; acquisition time, 37.5 s) in comparison to time-of-flight (TOF) MRV (voxel size, 0.8 x 0.8 x 4 mm; acquisition time, 3 min 51 s) and steady-state contrast-enhanced 3D (VIBE) MRV (voxel size, 1.1 x 0.9 x 1.5 mm; acquisition time, 2 min 46 s). RESULTS: The torcular Herophili (p < 0.001), left (p < 0.001) and right (p < 0.01) transverse sinus, and right jugular bulb (p < 0.05) were visualized better at TR MRV than at TOF MRV. For visualization of the small inferior sagittal sinus, TR MRV was inferior to VIBE (p < 0.001) and TOF (p < 0.05) sequences. The visibility of all other dural sinuses was equal. CONCLUSION: Despite the inferior spatial resolution, TR MRV depicted some large dural sinuses more clearly than TOF MRV. To overcome the visualization of smaller venous structures, TR MRV can be applied complementarily with high-resolution steady-state contrast-enhanced MRV.

Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p.

PURPOSE: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. EXPERIMENTAL DESIGN: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. RESULTS: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. CONCLUSIONS: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

Increased Osseous (99m)Tc-DPD Uptake in End-Stage Ankle Osteoarthritis: Correlation Between SPECT-CT Imaging and Histologic Findings.

BACKGROUND: We analyzed the histopathologic findings in end-stage osteoarthritic ankle joint tissue that display increased uptake of bone-seeking radiotracer in single-photon emission computed tomography-computed tomography (SPECT-CT) imaging. METHODS: Six consecutive patients with end-stage osteoarthritis undergoing total ankle replacement received preoperative SPECT-CT imaging using (99m)Technetium dicarboxypropane diphosphonate ((99m)Tc-DPD). Using imaging data for stratification, osteochondral tissue sections were prepared from SPECT-positive (+) and -negative (-) areas of tibial and talar resection specimens. Histomorphometric analyses of osteoblast numbers, collagen deposition, and cartilage degeneration were performed on hematoxylin and eosin, van Gieson's and Safranin-O stained tissue sections. Osteoclast activity was visualized using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: Increased (99m)Tc-DPD uptake was observed exclusively subjacent to the subchondral bone plate of tibial and talar joint compartments. SPECT(-) tissues displayed typical fatty marrow morphology containing mainly collagen-positive blood vessels and few marrow and bone-lining cells. SPECT(+) tissues were characterized by increased numbers of active bone-lining osteoblasts depositing collagen fibers. Collagen area fraction of subchondral bone marrow was significantly increased in SPECT(+) (0.52 ± 0.21) compared with SPECT(-) (0.29 ± 0.13) tissues (P = .30). Multinucleated TRAP(+) osteoclasts were absent from bone formation sites, but associated with vascular structures invading articular cartilage through the subchondral bone plate. Increased (99m)Tc-DPD uptake was specifically and strongly correlated with increased osteoblast numbers (P = .011), and with collagen area fraction (P = .030) but not with Mankin score (P = .202), or with osteoclast number (P = .576). CONCLUSION: Subchondral bone tissues in SPECT(+) areas of end-stage ankle osteoarthritis were histologically characterized by increased osteoblast-mediated bone formation in the absence of functional osteoclasts, and increased cellularity and collagen deposition in marrow tissues. CLINICAL SIGNIFICANCE: Our findings suggest a pathologic bone-remodeling process in end-stage ankle OA areas with increased (99m)Tc-DPD uptake.