Purpose: Change in tumor size as classified by Response Evaluation Criteria in Solid Tumors poorly correlates with histopathologic response to neoadjuvant therapy in patients with softtissue sarcomas. The aim of this study was to prospectively evaluate whether positron emission tomography with 18 F-fluorodeoxyglucose (FDG-PET) allows for a more accurate evaluation of histopathologic response. Experimental Design: From January 2005 to January 2007, 42 patients with resectable biopsy-proven high-grade soft-tissue sarcoma underwent a FDG-PET/computed tomography scan before and after neoadjuvant treatment. Relative changes in tumor FDG uptake and size from the baseline to the follow-up scan were calculated, and their accuracy for assessment of histopathologic response was compared by receiver operating characteristic curve analysis. Histopathologic response was defined as z95% tumor necrosis. Results: In histopathologic responders (n = 8; 19%), reduction in tumor FDG uptake was significantly greater than in nonresponders (P < 0.001), whereas no significant differences were found for tumor size (P = 0.24). The area under the receiver operating characteristic curve for metabolic changes was 0.93, but only 0.60 for size changes (P = 0.004). Using a 60% decrease in tumor FDG uptake as a threshold resulted in a sensitivity of 100% and a specificity of 71% for assessment of histopathologic response, whereas Response Evaluation Criteria in Solid Tumors showed a sensitivity of 25% and a specificity of 100%. Conclusion: Quantitative FDG-PET was significantly more accurate than size-based criteria at assessing histopathologic response to neoadjuvant therapy. FDG-PETshould be considered as a modality to monitor treatment response in patients with high-grade soft-tissue sarcoma.

Purpose In patients with soft-tissue sarcoma (STS), the early assessment of treatment responses is important. Using positron emission tomography/computed tomography (PET/CT) with [18F]fluorodeoxyglucose (FDG),we determined whether changes in tumor FDG uptake predict histopathologic treatment responses in high-grade STS after the initial cycle of neoadjuvant chemotherapy. Experimental Design From February 2006 to March 2008, 50 patients with resectable high-grade STS scheduled for neoadjuvant therapy and subsequent tumor resection were enrolled prospectively. FDG-PET/CT before (baseline), after the first cycle (early follow-up), and after completion of neoadjuvant therapy (late follow-up) was done. Tumor FDG uptake and changes were measured by standardized uptake values. Histopathologic examination of the resected specimen provided an assessment of treatment response. Patients with ≥95% pathologic necrosis were classified as treatment responders. FDG-PET/CT results were compared with histopathologic findings. Results At early follow-up, FDG uptake decreased significantly more in 8 (16%) responders than in the 42 (84%) nonresponders (−55% versus −23% P = 0.002). All responders and 14 of 42 nonresponders had a ≥35% reduction in standardized uptake value between baseline and early follow-up. Using a ≥35% reduction in FDG uptake as early metabolic response threshold resulted in a sensitivity and specificity of FDG-PET for histopathologic response of 100% and 67%, respectively. Applying a higher threshold at late follow-up improved specificity but not sensitivity. CT had no value at response prediction. Conclusion A 35% reduction in tumor FDG uptake at early follow-up is a sensitive predictor of histopathologic tumor response. Early treatment decisions such as discontinuation of chemotherapy in nonresponding patients could be based on FDG-PET criteria.

Measurements of tumor glucose use by 18 F-FDG PET need to be standardized within and across institutions. Various parameters are used for measuring changes in tumor glucose metabolic activity with 18 F-FDG PET in response to cancer treatments. However, it is unknown which of these provide the lowest variability between observers. Knowledge of the interobserver variability of quantitative parameters is important in sarcomas as these tumors are frequently large and demonstrate heterogeneous 18 F-FDG uptake. Methods: A total of 33 patients (16 men, 17 women; mean age, 47 6 18 y) with high-grade sarcomas underwent 18 F-FDG PET/CT scans before and after neoadjuvant chemotherapy. Two independent investigators measured the following parameters on the pretreatment and posttreatment scans: maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), SUVmean in an automatically defined volume (SUVauto), and tumor-to-background ratio (TBR). The variability of the different parameters was compared by concordance correlation coefficient (CCC), variability effect coefficient, and Bland-Altman plots. Results: Baseline SUVmax, SUVpeak, SUVmean, SUVauto, and TBR averaged 10.36, 7.78, 4.13, and 6.22 g/mL and 14.67, respectively. They decreased to 5.36, 3.80, 1.79, and 3.25 g/mL and 6.62, respectively, after treatment. SUVmax, SUVpeak, and SUVauto measurements and their changes were reproducible (CCC $ 0.98). However, SUVauto poorly differentiated between responding and nonresponding tumors. The high intratumoral heterogeneity of 18 F-FDG resulted in frequent failure of the thresholding algorithm, which necessitated manual corrections that in turn resulted in a higher interobserver variability of SUVmean (CCCs for follow-up and change were 0.96 and 0.91, respectively; P , 0.005). TBRs also showed a significantly higher variability than did SUVpeak (CCCs for follow-up and change were 0.94 and 0.86, respectively; P , 0.005). Conclusion: SUVmax and SUVpeak provided the most robust measurements of tumor glucose metabolism in sarcomas. Delineation of the whole-tumor volume by semiautomatic thresholding did not decrease the variability of SUV measurements. TBRs were significantly more observer-dependent than were absolute SUVs. These findings should be considered for standardization of clinical 18 F-FDG PET/CT trials.

1 The endocannabinoid anandamide is an emerging potential signalling molecule in the cardiovascular system. Anandamide causes vasodilatation, bradycardia and hypotension in animals and has been implicated in the pathophysiology of endotoxic, haemorrhagic and cardiogenic shock, but its vascular effects have not been studied in man. 2 Human forearm blood flow and skin microcirculatory flow were recorded using venous occlusion plethysmography and laser-Doppler perfusion imaging (LDPI), respectively. Each test drug was infused into the brachial artery or applied topically on the skin followed by a standardized pin-prick to disrupt the epidermal barrier. 3 Anandamide failed to affect forearm blood flow when administered intra-arterially at infusion rates of 0.3-300 nmol min À1. The highest infusion rate led to an anandamide concentration of approximately 1 mM in venous blood as measured by mass spectrometry. 4 Dermal application of anandamide significantly increased skin microcirculatory flow and coapplication of the transient receptor potential vanilloid 1 (TRPV 1 ) antagonist capsazepine inhibited this effect. The TRPV 1 agonists capsaicin, olvanil and arvanil all induced concentration-dependent increases in skin blood flow and burning pain when administered dermally. Coapplication of capsazepine inhibited blood flow and pain responses to all three TRPV 1 agonists. 5 This study shows that locally applied anandamide is a vasodilator in the human skin microcirculation. The results are consistent with this lipid being an activator of TRPV 1 on primary sensory nerves, but do not support a role for anandamide as a circulating vasoactive hormone in the human forearm vascular bed.

A dherence to multiple sclerosis (MS) diseasemodifying therapies, such as interferons, has been linked to improved treatment outcomes and reduced health-care costs. 1,2 Reasons for poor patient adherence to prescribed MS therapies include frequency of administration and adverse events, such as flu-like symptoms (FLSs) and injection-site reactions (ISRs), associated with interferon beta treatments. [3][4][5][6][7][8] Peginterferon beta-1a is a pegylated form of interferon beta-1a approved for the treatment of relapsing forms of MS. The safety and efficacy of peginterferon beta-1a 125 μg administered subcutaneously every 2 or 4 weeks