Intimal angiosarcoma masquerading as retroperitoneal fibrosis.

We present a rare case of intimal angiosarcoma arising from the iliac artery with unusual symptoms and signs mimicking retroperitoneal fibrosis (RPF). This 84-year-old male presented with constitutional symptoms, abdominal pain, increased acute-phase reactant levels, impaired renal function and a CT-documented left-sided parailiac soft-tissue mass with unilateral extrinsic ureteric obstruction. Whole-body 18F-fluorodeoxyglucose positron emission tomography scan showed highly increased FDG-uptake in a horseshoe-like pattern surrounding the left common iliac artery, but no pathologic activity elsewhere. Further diagnostic workup revealed no signs of malignancy. Because of its location, CT-guided biopsy of the mass was precluded. A tentative diagnosis of RPF was made and treatment with Tamoxifen 20 b.i.d. was started. However, his condition gradually deteriorated, eventually succumbing to severe pneumosepsis. Autopsy revealed extensive iliac intimal angiosarcoma with infiltrative expansion to the left ureter and tumor emboli in both lungs. The present case suggests that intimal angiosarcoma should be included in the differential diagnosis of suspected RPF.

18F-FDG micro-PET/CT for intra-operative margin assessment during breast-conserving surgery.

Rationale: Positive surgical margins for invasive breast cancer (BC) treated with breast-conserving surgery (BCS) are defined as ink on tumor. The rate of positive margins is approximately 20%, since a time- and cost-effective method for margin assessment is lacking. In this study, we investigated margin status by intra-operative imaging using high-resolution 18 F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) and X-ray computed tomography (CT).Methods: Twenty patients were enrolled and received 4 MBq/kg of FDG prior to surgery. Intra-operative imaging of the specimens was performed by the MOLECUBES ß-CUBE (PET) and X-CUBE (CT). Margin status was assessed by three surgeons and compared with an algorithm. The sensitivity and specificity were calculated by using histopathological assessment as a gold standard.Results: A region with high FDG uptake was visualized in all specimens. Automated analysis showed a sensitivity of 90%, a specificity of 60%, and an area under the curve (AUC) of 0.86 after ROC analysis. Margin assessment by the surgeons resulted in a mean sensitivity and specificity of 79% and 72%, respectively.Conclusions: This proof-of-concept study demonstrates that high-resolution FDG-PET/CT can facilitate intra-operative margin assessment during BCS. This technique achieves good sensitivity and specificity and may therefore reduce re-operation rates in the future.

Characterization of BAT activity in rats using invasive and non-invasive techniques.

INTRODUCTION: Brown adipose tissue (BAT) is considered as a potential target for combating obesity in humans where active BAT metabolizes glucose and fatty acids as fuel resulting in heat production. Prospective studies in humans have been set up to further study the presence and metabolic activity of BAT mostly using Positron Emission Tomography (PET) imaging in cold-stimulated conditions with the radiolabeled glucose derivative [18F]FDG. However, radiotracers beyond [18F]FDG have been proposed to investigate BAT activity, targeting various aspects of BAT metabolism. It remains questionable which tracer is best suited to detect metabolic BAT activity and to what extent those results correlate with ex vivo metabolic BAT activity. METHODS: PET and Single Photon Emission Computed Tomography (SPECT) imaging, targeting different aspects of BAT activation such as glucose metabolism, fatty acid metabolism, noradrenergic stimulation, blood perfusion and amino acid transport system, was performed immediately after injection of the tracer in rats under different temperatures: room temperature, acute cold (4 °C for 4 h) or acclimated to cold (4 °C for 6 h per day during 28 days). Furthermore, Magnetic Resonance Spectroscopy (MRS)-derived BAT temperature was measured in control and cold-acclimated rats. RESULTS: At room temperature, only [18F]FDG visualized BAT. Glucose metabolism, fatty acid metabolism, noradrenergic stimulation and blood perfusion showed a clear tracer-dependent twofold increase in BAT uptake upon cold exposure. Only the tracer for the amino acid transport system did not show BAT specific uptake under any of the experimental conditions. MRS demonstrated that cold-acclimated animals had BAT with a stronger heat-production compared to control animals. CONCLUSION: BAT activity following cold exposure in rats was visualized by several tracers, while only [18F]FDG was also able to show BAT activity under non-stimulated conditions (room temperature). The variances in uptake of the different tracers should be taken into account when developing future clinical applications in humans.

Radiation Dosimetry and Biodistribution of 18F-PSMA-11 for PET Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer. Many PSMA analog radiotracers for PET/CT prostate cancer staging have been developed, such as 68Ga-PSMA-11. This radiotracer has achieved good results in multiple clinical trials, but because of the superior imaging characteristics of 18F-fluoride, 18F-PSMA-11 was developed. The aim of this study was to evaluate the administration safety and radiation dosimetry of 18F-PSMA-11. Methods: Six patients (aged 62-68 y; mean, 66 ± 2 y) with suspected prostate cancer recurrence after previous treatment were administered 2 MBq of 18F-PSMA-11 per kilogram of body weight and then underwent low-dose PET/CT imaging at 0, 20, 50, 90, and 300 min after injection. To evaluate the safety of administration, vital parameters were monitored. To assess toxicity, full blood count and biochemical parameters were determined. According to the latest International Commission on Radiological Protection recommendations, radiation dosimetry analysis was performed using IDAC-Dose 2.1. For blood activity measurement, small samples of venous blood were collected at various time points after injection. The unbound 18F-fluoride fraction was determined in plasma at 20, 50, and 90 min after administration to evaluate the defluorination rate of 18F-PSMA-11. Results: After injection, 18F-PSMA-11 cleared rapidly from the blood. At 5 h after injection, 29.0% ± 5.9% of the activity was excreted in urine. The free 18F fraction in plasma increased from 9.7% ± 1.0% 20 min after injection to 22.2% ± 1.5% 90 min after injection. The highest tracer uptake was observed in kidneys, bladder, spleen, and liver. No study drug-related adverse events were observed. The calculated mean effective dose was 12.8 ± 0.6 µSv/MBq. Conclusion:18F-PSMA-11 can be safely administered and results in a mean effective dose of 12.8 ± 0.6 µSv/MBq. Therefore, the total radiation dose is lower than for other PSMA PET agents and in the same range as 18F-DCFPyL.

The diagnostic accuracy of imaging modalities to detect pseudarthrosis after spinal fusion-a systematic review and meta-analysis of the literature.

OBJECTIVE: The aim of the study was to determine the diagnostic accuracy of imaging modalities to detect pseudarthrosis after thoracolumbar spinal fusion, with surgical exploration as reference standard. MATERIALS AND METHODS: A systematic literature search for original studies was performed on the diagnostic accuracy of imaging as index test compared to surgical exploration as reference standard to diagnose pseudarthrosis after thoracolumbar spinal fusion. Diagnostic accuracy values were extracted and methodologic quality of studies was evaluated by the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Per modality, clinically comparable studies were included in subgroup meta-analysis and weighted odds ratios (ORs) were calculated using the random effects model. RESULTS: Fifteen studies were included. Risk of bias was classified as high/unclear in 58% of the studies. Concerns of applicability was classified as high/unclear in 40% of the studies. Four scintigraphy studies including 93 patients in total were pooled to OR = 2.91 (95% confidence interval [CI]: 0.93-9.13). Five studies on plain radiography with 398 patients in total were pooled into OR = 7.07 (95% CI: 2.97-16.86). Two studies evaluating flexion-extension radiography of 75 patients in total were pooled into OR = 4.00 (95% CI: 0.15-105.96). Two studies of 68 patients in total were pooled for CT and yielded OR = 17.02 (95% CI: 6.42-45.10). A single study reporting on polytomography, OR = 10.15 (95% CI 5.49-18.78), was also considered to be an accurate study. CONCLUSIONS: With a pooled OR of 17.02, CT can be considered the most accurate imaging modality for the detection of pseudarthrosis after thoracolumbar spinal fusion from this review.

Effect of L-arginine on energy metabolism, skeletal muscle and brown adipose tissue in South Asian and Europid prediabetic men: a randomised double-blinded crossover study.

AIMS/HYPOTHESIS: Individuals of South Asian origin are at increased risk of developing type 2 diabetes mellitus and associated comorbidities compared with Europids. Disturbances in energy metabolism may contribute to this increased risk. Skeletal muscle and possibly also brown adipose tissue (BAT) are involved in human energy metabolism and nitric oxide (NO) is suggested to play a pivotal role in regulating mitochondrial biogenesis in both tissues. We aimed to investigate the effects of 6 weeks of supplementation with L-arginine, a precursor of NO, on energy metabolism by BAT and skeletal muscle, as well as glucose metabolism in South Asian men compared with men of European descent. METHODS: We included ten Dutch South Asian men (age 46.5 ± 2.8 years, BMI 30.1 ± 1.1 kg/m2) and ten Dutch men of European descent, that were similar with respect to age and BMI, with prediabetes (fasting plasma glucose level 5.6-6.9 mmol/l or plasma glucose levels 2 h after an OGTT 7.8-11.1 mmol/l). Participants took either L-arginine (9 g/day) or placebo orally for 6 weeks in a randomised double-blind crossover study. Participants were eligible to participate in the study when they were aged between 40 and 55 years, had a BMI between 25 and 35 kg/m2 and did not have type 2 diabetes. Furthermore, ethnicity was defined as having four grandparents of South Asian or white European origin, respectively. Blinding of treatment was done by the pharmacy (Hankintatukku) and an independent researcher from Leiden University Medical Center randomly assigned treatments by providing a coded list. All people involved in the study as well as participants were blinded to group assignment. After each intervention, glucose tolerance was determined by OGTT and basal metabolic rate (BMR) was determined by indirect calorimetry; BAT activity was assessed by cold-induced [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography-computed tomography scanning. In addition, a fasting skeletal muscle biopsy was taken and analysed ex vivo for respiratory capacity using a multisubstrate protocol. The primary study endpoint was the effect of L-arginine on BAT volume and activity. RESULTS: L-Arginine did not affect BMR, [18F]FDG uptake by BAT or skeletal muscle respiration in either ethnicity. During OGTT, L-arginine lowered plasma glucose concentrations (AUC0-2 h - 9%, p < 0.01), insulin excursion (AUC0-2 h - 26%, p < 0.05) and peak insulin concentrations (-26%, p < 0.05) in Europid but not South Asian men. This coincided with enhanced cold-induced glucose oxidation (+44%, p < 0.05) in Europids only. Of note, in skeletal muscle biopsies several respiration states were consistently lower in South Asian men compared with Europid men. CONCLUSIONS/INTERPRETATION: L-Arginine supplementation does not affect BMR, [18F]FDG uptake by BAT, or skeletal muscle mitochondrial respiration in Europid and South Asian overweight and prediabetic men. However, L-arginine improves glucose tolerance in Europids but not in South Asians. Furthermore, South Asian men have lower skeletal muscle oxidative capacity than men of European descent. FUNDING: This study was funded by the EU FP7 project DIABAT, the Netherlands Organization for Scientific Research, the Dutch Diabetes Research Foundation and the Dutch Heart Foundation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02291458.

Correction: Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis-A Cohort Study in a Group of Thyroid Carcinoma Patients.

[This corrects the article DOI: 10.1371/journal.pone.0145049.].

Regional alterations of cerebral [18F]FDG metabolism in the chronic unpredictable mild stress- and the repeated corticosterone depression model in rats.

Preclinical research has been indispensable in the exploration of the neurological basis of major depressive disorder (MDD). The present study aimed to examine effects on regional brain activity of two frequently used depression models, the chronic unpredictable mild stress (CUMS)- and the chronic corticosterone (CORT) depression model. The CUMS and CORT depression model were induced by exposing male Long-Evans rats to a 4-week procedure of unpredictable mild stressors or a 3-week procedure of chronic corticosterone, respectively. Positron emission tomography with [18F]FDG was performed to determine alterations in regional brain activity. In addition, depressive- and anxiety-like behaviour was assessed via the forced swim test and the open field test, respectively. The chronic CORT administration, but not the CUMS model, significantly induced depressive-like behaviour and elevated plasma corticosterone levels. Compared to control, induction of the CORT depression model resulted in a significantly reduced glucose consumption in the insular cortex and the striatum, and a significantly elevated consumption in the cerebellum and the midbrain. Induction of the CUMS model replicated the findings with respect to the activity in the striatum region, and cerebellum, but missed significance in the insular cortex and the midbrain. Based on the alterations in behaviour and regional [18F]FDG uptake, a superior face validity and construct validity can be observed after induction of depression via chronic CORT injections, compared to the used CUMS paradigm.

Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts.

BACKGROUND: Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. METHODS: In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 µL PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 µl NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. 18F-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation). RESULTS: A T/B ≥ 3.59 on pre-treatment 18F-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B ≥ 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth. CONCLUSIONS: Tumor tissue hypoxia as measured with 18F-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.

Automated radiosynthesis of Al[18F]PSMA-11 for large scale routine use.

OBJECTIVES: We report a reproducible automated radiosynthesis for large scale batch production of clinical grade Al[18F]PSMA-11. METHODS: A SynthraFCHOL module was optimized to synthesize Al[18F]PSMA-11 by Al[18F]-chelation. Results Al[18F]PSMA-11 was synthesized within 35min in a yield of 21 ± 3% (24.0 ± 6.0GBq) and a radiochemical purity > 95%. Batches were stable for 4h and conform the European Pharmacopeia guidelines. CONCLUSIONS: The automated synthesis of Al[18F]PSMA-11 allows for large scale production and distribution of Al[18F]PSMA-11.

Added value of 18F-FDG PET/CT in diagnosing infected hip prosthesis.

Background The diagnosis of infected hip prosthesis is frequently not straightforward yet very important as it changes treatment. Purpose To retrospectively investigate the added value of 18F-FDG PET/CT to conventional tests including radiography, erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) testing, and joint aspiration, in diagnosing infected hip prosthesis. Material and Methods Seventy-eight hip prostheses of 78 patients (55% men; mean age = 66.5 years; age range = 30-85 years) with non-specific clinical presentation, i.e. no abscess or sinus tract communicating with the joint space at clinical examination, were analyzed. Cultures of intra-articular fluid and peri-implant tissues after revision surgery or clinical follow-up ≥6 months served as gold standard. Areas under the receiver operating characteristic curves (AUCs) of radiography, ESR/CRP testing, aspiration culture, and white blood cell (WBC) count without and with the addition of 18F-FDG PET/CT were compared. Results The addition of 18F-FDG PET/CT increased AUCs: for radiography with 0.212, P = 0.001; for ESR/CRP testing with 0.076, P = 0.072; for aspiration culture with 0.126, P = 0.032; and for aspiration WBC count with 0.191, P = 0.035. Conclusion This study shows that 18F-FDG PET/CT adds to individual conventional tests in diagnosing infected hip prosthesis. It may improve the preoperative planning and should therefore be considered in the diagnostic work-up. Future studies should define the exact place of 18F-FDG PET/CT in the diagnostic work-up of periprosthetic joint infection.

Variations in the practice of molecular radiotherapy and implementation of dosimetry: results from a European survey.

BACKGROUND: Currently, the implementation of dosimetry in molecular radiotherapy (MRT) is not well investigated, and in view of the Council Directive (2013/59/Euratom), there is a need to understand the current availability of dosimetry-based MRT in clinical practice and research studies. The aim of this study was to assess the current practice of MRT and dosimetry across European countries. METHODS: An electronic questionnaire was distributed to European countries. This addressed 18 explicitly considered therapies, and for each therapy, a similar set of questions were included. Questions covered the number of patients and treatments during 2015, involvement of medical specialties and medical physicists, implementation of absorbed dose planning, post-therapy imaging and dosimetry, and the basis of therapy prescription. RESULTS: Responses were obtained from 26 countries and 208 hospitals, administering in total 42,853 treatments. The most common therapies were 131I-NaI for benign thyroid diseases and thyroid ablation of adults. The involvement of a medical physicist (mean over all 18 therapies) was reported to be either minority or never by 32% of the responders. The percentage of responders that reported that dosimetry was included on an always/majority basis differed between the therapies and showed a median value of 36%. The highest percentages were obtained for 177Lu-PSMA therapy (100%), 90Y microspheres of glass (84%) and resin (82%), 131I-mIBG for neuroblastoma (59%), and 131I-NaI for benign thyroid diseases (54%). The majority of therapies were prescribed based on fixed-activity protocols. The highest number of absorbed-dose based prescriptions were reported for 90Y microsphere treatments in the liver (64% and 96% of responses for resin and glass, respectively), 131I-NaI treatment of benign thyroid diseases (38% of responses), and for 131I-mIBG treatment of neuroblastoma (18% of responses). CONCLUSIONS: There is a wide variation in MRT practice across Europe and for different therapies, including the extent of medical-physicist involvement and the implementation of dosimetry-guided treatments.

Quantitative Imaging for Targeted Radionuclide Therapy Dosimetry - Technical Review.

Targeted radionuclide therapy (TRT) is a promising technique for cancer therapy. However, in order to deliver the required dose to the tumor, minimize potential toxicity in normal organs, as well as monitor therapeutic effects, it is important to assess the individualized internal dosimetry based on patient-specific data. Advanced imaging techniques, especially radionuclide imaging, can be used to determine the spatial distribution of administered tracers for calculating the organ-absorbed dose. While planar scintigraphy is still the mainstream imaging method, SPECT, PET and bremsstrahlung imaging have promising properties to improve accuracy in quantification. This article reviews the basic principles of TRT and discusses the latest development in radionuclide imaging techniques for different theranostic agents, with emphasis on their potential to improve personalized TRT dosimetry.

Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017 report from the Internal Dosimetry Task Force.

BACKGROUND: The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented. RESULTS: A brief review of five of the most common therapy procedures is included in the current text, focused on the potential to perform patient-specific dosimetry. In the full report, 11 different therapeutic procedures are included, allowing additional considerations of effectiveness, references to specific literature on quantitative imaging and dosimetry, and existing evidence for absorbed dose-effect correlations for each treatment. Individualized treatment planning with tracer diagnostics and verification of the absorbed doses delivered following therapy is found to be scientifically feasible for almost all procedures investigated, using quantitative imaging and/or external monitoring. Translation of this directive into clinical practice will have significant implications for resource requirements. CONCLUSIONS: Molecular radiotherapy is undergoing a significant expansion, and the groundwork for dosimetry-based treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of the treatments, although must be adequately resourced.

PET imaging of zirconium-89 labelled cetuximab: A phase I trial in patients with head and neck and lung cancer.

BACKGROUND AND PURPOSE: PET imaging of cetuximab uptake may help selecting cancer patients with the highest chance of benefit. The aim of this phase I trial was to determine the safety of the tracer 89Zr-cetuximab and to assess tumour uptake. METHODS: Two dose schedules were used; two consecutive doses of 60MBq 89Zr-cetuximab or a single dose of 120MBq, both preceded by 400mg/m2 of unlabelled cetuximab. Toxicity (CTCAE 3.0) was scored twice weekly. PET-CT scans were acquired on days 4, 5 and 6 (step 1) or 5, 6, 7 (step 2). Because tumour uptake could not be assessed satisfactorily, a third step was added including EGFR overexpressing tumours. RESULTS: Nine patients were included (6 NSCLC; 3 HNC). No additional toxicity was associated with administration of 89Zr-cetuximab compared to standard cetuximab. A tumour to blood ratio (TBR)>1 was observed in all but one patient, with a maximum of 4.56. TBR was not different between dose schedules. There was a trend for higher TBR at intervals>5days after injection. CONCLUSIONS: Both presented 89Zr-cetuximab administration schedules are safe. The recommended dose for future trials is 60MBq, with a minimum time interval for scanning of 6days.

Comparison of Intraoperative γ-Probe Imaging and Postoperative SPECT/CT in Detection of Sentinel Nodes Related to the Ovary.

Tracer injection into ovarian ligaments has been shown to detect sentinel nodes (SNs) in patients with ovarian cancer. To determine the possibility that SNs are missed, this feasibility study compared their detection during surgery with their detection on postoperative SPECT/CT. METHODS: In 8 patients (with either ovarian or endometrial cancer), after a staging lymphadenectomy including resection of SNs related to the ovary, SPECT/CT was performed within 24 h. RESULTS: SPECT/CT identified hotspots in 4 patients at sites where SNs were resected. In 6 patients, additional sites were found, mainly in the pelvic region. CONCLUSION: Discrepancies between the γ-probe and SPECT/CT may be due to missed SNs during surgery, but with respect to pelvic hotspots, in most cases they are more probably related to remnants of tracer at injection sites. With respect to sites where SNs were resected, remaining hotspots may have been caused by residual lymphatic flow after resection.

UHMWPE Sublaminar Wires in Posterior Spinal Instrumentation: Stability and Biocompatibility Assessment in an Ovine Pilot Study.

STUDY DESIGN: An animal study. OBJECTIVE: To explore ultra-high molecular weight polyethylene (UHMWPE) sublaminar wires in spinal surgery and to assess stability and biocompatibility of the UHMWPE instrumentation in an ovine model. SUMMARY OF BACKGROUND DATA: Sublaminar wiring is a well-established technique in segmental scoliosis surgery. However, during introduction and/or removal of the metal sublaminar wires, neurological problems can occur. Abrasion after cutting metal wires for removal can lead to damage to the dural sac. Sublaminar wires have to withhold large forces and breakage of the wires can occur. Different types of sublaminar wires have been developed to address these problems. UHMWPE sublaminar wires can potentially substitute currently used metal sublaminar metal wires. In vivo testing and biocompatibility analysis of UHMWPE wires are recommended before clinical use in spinal surgery. MATERIALS AND METHODS: In 6 immature sheep, pedicle screws were instrumented at lumbar level L4 and attached with titanium rods to 4 thoracolumbar vertebrae using 3- and 5-mm-wide UHMWPE sublaminar wiring constructions in 5 animals. Titanium sublaminar wires were applied in 1 animal to function as a control subject. After a follow-up period of 16 weeks, the animals were sacrificed and the spines were isolated. Radiographs and computed tomography (CT) scans were made to assess stability of the instrumentation. The vertebrae were dissected for macroscopic and histologic evaluation. RESULTS: None of the wires had loosened and the instrumentation remained stable. CT scans and radiographs showed no signs of failure of the instrumentation and no neurological complications occurred. Although several bony bridges were seen on CT, growth was observed at the operated levels. Biocompatibility was assessed by macroscopical and histologic analysis, showing no signs of dural or epidural inflammation. CONCLUSIONS: This pilot animal study shows that UHMWPE sublaminar wiring is a safe technique. The UHMWPE wires are biocompatible and provide sufficient stability in spinal instrumentation. Heterotopic ossification because of periost reactions in the ovine spine led to some restrictions in this study.

Fractionated Radiotherapy with 3 x 8 Gy Induces Systemic Anti-Tumour Responses and Abscopal Tumour Inhibition without Modulating the Humoral Anti-Tumour Response.

Accumulating evidence indicates that fractionated radiotherapy (RT) can result in distant non-irradiated (abscopal) tumour regression. Although preclinical studies indicate the importance of T cells in this infrequent phenomenon, these studies do not preclude that other immune mechanisms exhibit an addition role in the abscopal effect. We therefore addressed the question whether in addition to T cell mediated responses also humoral anti-tumour responses are modulated after fractionated RT and whether systemic dendritic cell (DC) stimulation can enhance tumour-specific antibody production. We selected the 67NR mammary carcinoma model since this tumour showed spontaneous antibody production in all tumour-bearing mice. Fractionated RT to the primary tumour was associated with a survival benefit and a delayed growth of a non-irradiated (contralateral) secondary tumour. Notably, fractionated RT did not affect anti-tumour antibody titers and the composition of the immunoglobulin (Ig) isotypes. Likewise, we demonstrated that treatment of tumour-bearing Balb/C mice with DC stimulating growth factor Flt3-L did neither modulate the magnitude nor the composition of the humoral immune response. Finally, we evaluated the immune infiltrate and Ig isotype content of the tumour tissue using flow cytometry and found no differences between treatment groups that were indicative for local antibody production. In conclusion, we demonstrate that the 67NR mammary carcinoma in Balb/C mice is associated with a pre-existing antibody response. And, we show that in tumour-bearing Balb/C mice with abscopal tumour regression such pre-existing antibody responses are not altered upon fractionated RT and/or DC stimulation with Flt3-L. Our research indicates that evaluating the humoral immune response in the setting of abscopal tumour regression is not invariably associated with therapeutic effects.

Dose-Response Relationship in Differentiated Thyroid Cancer Patients Undergoing Radioiodine Treatment Assessed by Means of 124I PET/CT.

UNLABELLED: The dose-response relationship in a fixed-activity approach generally applied in the treatment of differentiated thyroid cancer was assessed using (124)I PET/CT. METHODS: Pretherapeutic (124)I PET/CT images of 47 patients scheduled for radioiodine therapy were retrospectively analyzed. (124)I PET/CT images were acquired 24 and 96 h after oral administration of approximately 28 MBq of (124)I-sodium iodide. Lesions were identified as thyroid remnants or metastases (lymph node, lung, bone). After a neoteric segmentation technique allowing accurate volume estimation down to the (124)I PET spatial resolution of 0.15 mL was applied, lesions were divided into a known-volume group and a small-volume group. For the known-volume group, average lesion-absorbed dose (AD) values were calculated, whereas for the small-volume group a minimum lesion AD was estimated. Lesion response was determined on the basis of (124)I PET/CT and (131)I SPECT/CT follow-up images. A lesion not detectable on any of the follow-up images was considered a completely responding lesion. Differences in lesion AD estimations between completely and incompletely responding lesions were evaluated by Mann-Whitney U test. Moreover, receiver-operating-characteristic curves were used to test the performance of pretherapeutic (124)I PET/CT lesion AD for prediction of complete lesion response. RESULTS: In the approach of fixed radioiodine activity (3.0 ± 1.0 GBq), 89% of thyroid remnants and 69% of metastases responded completely. Except for the small-volume groups, the lesion AD of completely responding lesions was significantly higher than that of incompletely responding lesions. Using receiver-operating-characteristic curve analysis, it was shown that for the known-volume group, pretherapeutic (124)I PET/CT lesion dosimetry can be used as a prognostic tool to predict lesion-based (131)I therapy response with an area under the curve of 0.76 for remnants and 0.97 for metastases. The corresponding lesion AD threshold value maximizing correct complete response prediction was 90 Gy for remnants and 40 Gy for metastases. CONCLUSION: In a fixed-activity approach, a statistically significant dose-response relationship for both thyroid remnants and metastases using pretherapeutic (124)I PET/CT lesion dosimetry was found. The findings may be useful in patient management.

Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans.

Recruitment of brown adipose tissue (BAT) has emerged as a potential tool to combat obesity and associated metabolic complications. Short-term cold acclimation has been shown not only to enhance the presence and activity of BAT in lean humans but also to improve the metabolic profile of skeletal muscle to benefit glucose uptake in patients with type 2 diabetes. Here we examined whether short-term cold acclimation also induced such adaptations in 10 metabolically healthy obese male subjects. A 10-day cold acclimation period resulted in increased cold-induced glucose uptake in BAT, as assessed by [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography. BAT activity was negatively related to age, with a similar trend for body fat percentage. In addition, cold-induced glucose uptake in BAT was positively related to glucose uptake in visceral white adipose tissue, although glucose uptake in visceral and subcutaneous white adipose tissue depots was unchanged upon cold acclimation. Cold-induced skeletal muscle glucose uptake tended to increase upon cold acclimation, which was paralleled by increased basal GLUT4 localization in the sarcolemma, as assessed through muscle biopsies. Proximal skin temperature was increased and subjective responses to cold were slightly improved at the end of the acclimation period. These metabolic adaptations to prolonged exposure to mild cold may lead to improved glucose metabolism or prevent the development of obesity-associated insulin resistance and hyperglycemia.