Anders Christensen

Exercise training favors increased insulin-stimulated glucose uptake in skeletal muscle in contrast to adipose tissue: a randomized study using FDG PET imaging.

Physical exercise increases peripheral insulin sensitivity, but regional differences are poorly elucidated in humans. We investigated the effect of aerobic exercise training on insulin-stimulated glucose uptake in five individual femoral muscle groups and four different adipose tissue regions, using dynamic (femoral region) and static (abdominal region) 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) PET/CT methodology during steady-state insulin infusion (40 mU·m⁻²·min⁻¹). Body composition was measured by dual X-ray absorptiometry and MRI. Sixty-one healthy, sedentary [V(O2max) 36(5) ml·kg⁻¹·min⁻¹; mean(SD)], moderately overweight [BMI 28.1(1.8) kg/m²], young [age: 30(6) yr] men were randomized to sedentary living (CON; n = 17 completers) or moderate (MOD; 300 kcal/day, n = 18) or high (HIGH; 600 kcal/day, n = 18) dose physical exercise for 11 wk. At baseline, insulin-stimulated glucose uptake was highest in femoral skeletal muscle followed by intraperitoneal visceral adipose tissue (VAT), retroperitoneal VAT, abdominal (anterior + posterior) subcutaneous adipose tissue (SAT), and femoral SAT (P < 0.0001 between tissues). Metabolic rate of glucose increased similarly (~30%) in the two exercise groups in femoral skeletal muscle (MOD 24[9, 39] μmol·kg⁻¹·min⁻¹, P = 0.004; HIGH 22[9, 35] μmol·kg⁻¹·min⁻¹, P = 0.003) (mean[95% CI]) and in five individual femoral muscle groups but not in femoral SAT. Standardized uptake value of FDG decreased ~24% in anterior abdominal SAT and ~20% in posterior abdominal SAT compared with CON but not in either intra- or retroperitoneal VAT. Total adipose tissue mass decreased in both exercise groups, and the decrease was distributed equally among subcutaneous and intra-abdominal depots. In conclusion, aerobic exercise training increases insulin-stimulated glucose uptake in skeletal muscle but not in adipose tissue, which demonstrates some interregional differences.

Staging of early lymph node metastases with the sentinel lymph node technique and predictive factors in T1/T2 oral cavity cancer: A retrospective single-center study.

The purpose of this study was to examine the diagnostic accuracy of detecting lymph node metastases and to identify predictive and prognostic clinicopathological factors in patients with oral squamous cell carcinoma (OSCC) undergoing sentinel lymph node biopsy (SLNB).

A third-generation dispersion and third-generation hydrogen bonding corrected PM6 method: PM6-D3H+.

We present new dispersion and hydrogen bond corrections to the PM6 method, PM6-D3H+, and its implementation in the GAMESS program. The method combines the DFT-D3 dispersion correction by Grimme et al. with a modified version of the H+ hydrogen bond correction by Korth. Overall, the interaction energy of PM6-D3H+ is very similar to PM6-DH2 and PM6-DH+, with RMSD and MAD values within 0.02 kcal/mol of one another. The main difference is that the geometry optimizations of 88 complexes result in 82, 6, 0, and 0 geometries with 0, 1, 2, and 3 or more imaginary frequencies using PM6-D3H+ implemented in GAMESS, while the corresponding numbers for PM6-DH+ implemented in MOPAC are 54, 17, 15, and 2. The PM6-D3H+ method as implemented in GAMESS offers an attractive alternative to PM6-DH+ in MOPAC in cases where the LBFGS optimizer must be used and a vibrational analysis is needed, e.g., when computing vibrational free energies. While the GAMESS implementation is up to 10 times slower for geometry optimizations of proteins in bulk solvent, compared to MOPAC, it is sufficiently fast to make geometry optimizations of small proteins practically feasible.

Peptide-Based Optical uPAR Imaging for Surgery: In Vivo Testing of ICG-Glu-Glu-AE105

Near infrared intra-operative optical imaging is an emerging technique with clear implications for improved cancer surgery by enabling a more distinct delineation of the tumor margins during resection. This modality has the potential to increase the number of patients having a curative radical tumor resection. In the present study, a new uPAR-targeted fluorescent probe was developed and the in vivo applicability was evaluated in a human xenograft mouse model. Most human carcinomas express high level of uPAR in the tumor-stromal interface of invasive lesions and uPAR is therefore considered an ideal target for intra-operative imaging. Conjugation of the flourophor indocyanine green (ICG) to the uPAR agonist (AE105) provides an optical imaging ligand with sufficiently high receptor affinity to allow for a specific receptor targeting in vivo. For in vivo testing, human glioblastoma xenograft mice were subjected to optical imaging after i.v. injection of ICG-AE105, which provided an optimal contrast in the time window 6–24 h post injection. Specificity of the uPAR-targeting probe ICG-AE105 was demonstrated in vivo by 1) no uptake of unconjugated ICG after 15 hours, 2) inhibition of ICG-AE105 tumor uptake by a bolus injection of the natural uPAR ligand pro-uPA, and finally 3) the histological colocalization of ICG-AE105 fluorescence and immunohistochemical detected human uPAR on resected tumor slides. Taken together, our data supports the potential use of this probe for intra-operative optical guidance in cancer surgery to ensure complete removal of tumors while preserving adjacent, healthy tissue.

A PID autotuner utilizing GPC and constraint optimization

A solution to the PID autotuning problem is presented which involves constraining the parameters of a discrete second-order discrete-time controller. The integrator is forced into the regulator by using a CARIMA model. The discrete-time regulator parameters are calculated by optimizing a generalized predictive control criterion, and the PID structure is ensured by constraining the parameters to a feasible set defined by the discrete-time Euler approximation of the ideal continuous-time PID controller. The algorithm is extended by incorporating constraints on the amplitude and slew-rate of the control signal. Simulation studies for a system of coupled tanks have indicated that the method performs well, and that signal limitations can be included in a straightforward manner.<<ETX>>

CT and MRI-based door-needle-times for acute stroke patients a quasi-randomized clinical trial

OBJECTIVESnDoor-Needle-times (DNT) of 20min are feasible when Computer Tomography (CT) is used for first-line brain-imaging to assess stroke-patients eligibility for intravenous-tissue-Plasminogen-Activator (iv-tPA), but the more time-consuming Magnetic Resonance Imaging (MRI)-based-evaluation is superior in detecting acute ischaemia.

Urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and epidermal growth factor receptor (EGFR): tumor expression patterns and prognostic value in oral cancer

BackgroundTumor-specific biomarkers are a prerequisite for the development of targeted imaging and therapy in oral squamous cell carcinoma (OSCC). urokinase-type Plasminogen Activator Receptor (uPAR), Tissue Factor (TF) and Epidermal Growth Factor Receptor (EGFR) are three biomarkers that exhibit enhanced expression in many types of cancers, and have been investigated as potential biomarkers for targeted strategies and prognostication. The aim of the study was to investigate the expression patterns of uPAR, TF and EGFR and their potential prognostic value in OSCC.MethodsImmunohistochemical expression of uPAR, TF and EGFR in tumor resection specimens from 191 patients with primary OSCC was analyzed. Overall (OS) and disease-free survival (DFS) was calculated. Associations between biomarker expression, clinicopathological factors and patient survival was analyzed using the Cox proportional hazards model for univariate and multivariate analysis, log rank and Kaplan-Meier statistics.ResultsuPAR and TF exhibited a highly tumor-specific expression pattern while EGFR also showed expression in normal tissues outside the tumor compartment. The overall positive expression rate of uPAR, TF and EGFR was 95%, 58% and 98%, respectively. High uPAR expression across the entire cohort was negatively associated with OS (pxa0=xa00.031, HRxa0=xa01.595 (95%CI 1.044–2.439)) in univariate analysis. The 5-year OS for high and low uPAR expression was 39% and 56%, respectively. The expression of TF and EGFR was not associated with survival outcome.ConclusionsThis study may suggest that uPAR and TF could potentially be attractive targets for molecular imaging and therapy in OSCC due to high positive expression rates and tumor-specific expression patterns. High uPAR expression was significantly associated with a reduced survival. uPAR seems to be a prognostic biomarker in oral cancer.

Does the Primary Imaging Modality—Computed Tomography or Magnetic Resonance Imaging—Influence Stroke Physicians' Certainty on Whether or Not to Give Thrombolysis to Randomized Acute Stroke Patients?

BACKGROUNDnDoor-to-needle time of 20 minutes to stroke patients with intravenous tissue plasminogen activator (iv-tPA) is feasible when computed tomography (CT) is used as first-line of brain imaging. Magnetic resonance imaging (MRI)-based assessment is more time-consuming but superior in detecting acute ischemia. The certainty with which stroke physicians prescribe or refrain from giving iv-tPA treatment to CT- versus MRI-examined patients has not previously been studied. The aim of the present study was to determine the effect of a primary imaging strategy of CT or MRI on clinicians certainty to prescribe or refrain from giving iv-tPA to patients with suspected acute stroke.nnnMETHODnConsecutive patients with suspected stroke were quasi-randomized to either CT- or MRI-based assessment before potential iv-tPA treatment. The influence of (1) the clinical findings and (2) the image findings, and (3) the certainty with which the stroke physician prescribed or refrained from giving iv-tPA treatment were assessed with visual analog scales (VAS). Predictors of treatment certainty were identified with a random-effect model.nnnRESULTSnFour-hundred forty-four consecutive patients were quasi-randomized. MRI influenced the final treatment decision more than CT (Pu2009=u2009.002). Compared with CT-examined patients (mean VAS score 8.6, SDu2009±1.6) stroke physicians were significantly more certain when prescribing or refraining from giving iv-tPA to MRI-examined patients (mean VAS score 9.0, SD ±1.2) (Pu2009=u2009.014). No differences in modified Rankin scale or mortality were detected at 3 months in CT- versus MRI-examined iv-tPA-treated patients.nnnCONCLUSIONSnStroke physicians were significantly more certain when prescribing iv-tPA to MRI-examined stroke patients, and MRI influences the final treatment decision significantly more compared with CT, although no difference in mortality and functional outcome at 3 months was detected between CT- and MRI-examined patients treated with iv-tPA.

Abstract IA13: Real-time near-infrared fluorescence tracer imaging to guide sentinel node biopsy and tumor detection in head and neck cancer

Introduction: Near-infrared fluorescence (NIRF) imaging is an emerging technology with several important applications in oncologic surgery. Using fluorescent dyes and dedicated camera systems, real-time intraoperative imaging is provided to guide surgical procedures and allow for instant decision-making. NIRF imaging has the potential to improve the Sentinel Node Biopsy (SNB) procedure for staging of oral cavity cancer by facilitating intraoperative visual identification of the sentinel lymph node (SN). Also, NIRF imaging may be used in the search of head and neck unknown primaries (CUP) in combination with transoral robotic surgery (TORS). The feasibility of NIRF imaging for intraoperative SN detection was investigated in a series of oral cavity cancer patients. In addition, our initial experience of using NIRF imaging during TORS for detection of oropharyngeal cancer will also be reported (ongoing study). Methods: (1) A prospective study of patients with primary oral squamous cell carcinoma (OSCC) planned for tumor resection and SNB. Thirty patients were injected peritumorally with a bimodal tracer (ICG-99mTc-Nanocoll) followed by lymphoscintigraphy (LSG) and SPECT/CT to define the SNs and their anatomical location preoperatively. SNs were detected intraoperatively with a hand-held gamma-probe and a hand-held NIRF camera. (2) In a minor prospective series of patients with oropharyngeal cancer undergoing TORS Indocyanin Green (ICG) was systematically injected preoperatively. The aim was to guide primary tumor detection using the firefly NIRF modality incorporated in the Da Vinci Si robotic system. Results: (1) In the SNB study, 29 of 30 subjects (97%), all preoperatively defined SNs could be identified intraoperatively using a combination of radioactive and fluorescence guidance. Eleven of 94 SNs (12%) could only be identified in vivo using NIRF imaging and the majority of those were located in level 1 close to the primary tumor. (2) In the pilot ICG TORS study, the additional use of ICG for primary tumor identification was varying. Conclusions: Intraoperative NIRF imaging as a tool to guide cancer surgery seems promising and further exploration of this novel technology is warranted. A combined fluorescent and radioactive tracer for SNB is feasible and the additional use of NIRF imaging may improve the accuracy of SN identification in oral cancer patients. Intraoperative fluorescence guidance seems of particular value, when SNs are located in close proximity to the injection site. Combined TORS and NIRF imaging showed with a varying quality the localization of the oropharyngeal cancer. The combined procedure may have a potential role in the diagnostic algorithm in head and neck CUP patients facilitating the detection of the primary tumor. Citation Format: Christian von Buchwald, Anders Christensen, Niclas Rubek, Karina Juhl, Birgitte Charabi, Jann Mortensen, Katalin Kiss, Andreas Kjaer. Real-time near-infrared fluorescence tracer imaging to guide sentinel node biopsy and tumor detection in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA13.

Increasing the certainty of the IV-TPA-decision potentially worsens the chances of good long-term outcome: a randomized clinical trial of CT and MRI-examination in acute stroke

Introduction: nHemiplegic shoulder pain (HSP) has a reported incidence of up to 84% on the affected side following a stroke. NICE recommends HSP should be managed according to each person’s needs.The purpose of this case study was to report findings from a patient with HSP who received problem specific treatment following real-time scanning of shoulder region with a portable diagnostic ultrasound. n nCase Description: nThe patient was a 45 year-old woman with right sided-hemiparesis resulting from a clot in December 2013. Patient was undergoing rehabilitation in a private clinic and reported shoulder pain since November 2014. On examination patient had pain (VAS 7/10) during shoulder movements. Patient was receiving the following treatment: over-arm exercises, electrical stimulation to deltoid, stretches, and Saebo exercises. Ultrasound scanning was undertaken on 23rd February 2015 to record acromion-greater tuberosity (AGT) distance (Affected AF-3.35 cm, Unaffected UAF-2.04 cm), diameter of supraspinatus in resting state (AF-1.16 cm, UAF-1.42cm) and contracted state (AF-1.14cm, UAF-1.63cm). Treatment was modified to include isometric exercises to supraspinatus muscle, and electrical stimulation was provided under ultrasound guidance. n nResults: Real time US measurement suggested reduction in AGT (2.9cm) immediately following treatment. Eight weeks later, VAS score reduced to 3/10 and patient was able to use arm more for various functional tasks. Changes in diameter of supraspinatus on the affected side (resting: 1.30 cm and contracted: 1.42cm) suggested improvements. Patient continued with modified rehabilitation programme and when seen in September had no pain. nDiscussion: Despite reduction in pain, patient continued to have GHS (2.6cm), although this was getting better with rehabilitation. n nConclusion: This case report demonstrates potential benefits of real-time ultrasound as an assessment tool to inform treatment choices for HSP in a chronic patient with stroke. Further studies using appropriate design are required to capitalise the benefits of ultrasound in the management of HSP.