BACKGROUND. The combination of gemcitabine and docetaxel has demonstrated promise in sarcomas diagnosed in adults. In the current study, the toxicity and efficacy of this combination were evaluated in pediatric sarcomas. METHODS. A retrospective case review of 22 patients with recurrent or refractory bone or soft‐tissue sarcomas who received gemcitabine (at a dose of 675 mg/m2 intravenously on Days 1 and 8) and docetaxel (at a dose of 75–100 mg/m2 intravenously on Day 8) was undertaken. RESULTS. The patients (ages 8–23 years) received a total of 109 courses of chemotherapy (median, 4 courses; range, 1–13 courses). Seventeen patients had osteosarcoma, 2 patients had Ewing sarcoma family of tumors (ESFT), 1 patient had a malignant fibrous histiocytoma (MFH), 1 patient had a chondrosarcoma, and 1 patient had an undifferentiated sarcoma. Of the 14 patients evaluable for response, the patient with an MFH achieved a complete response (CR), 3 patients with osteosarcoma achieved a partial response (PR), and 2 patients (1 with ESFT and 1 with osteosarcoma) had stable disease (SD). The overall objective response (CR + PR) rate was 29%. Median duration of response (CR + PR + SD) was 4.8 months (range, 1.6‐13 months). The toxicity was manageable and consisted primarily of thrombocytopenia and neutropenia. CONCLUSIONS. In the current study, gemcitabine in combination with docetaxel was found to be well tolerated and demonstrated antitumor activity in children and adolescents with recurrent or refractory osteosarcoma and MFH. Further evaluation of this drug combination is warranted in these patients. Cancer 2008. © 2008 American Cancer Society.

A new dual temporal resolution-based, high spatial resolution, pharmacokinetic parametric mapping method is describedimproved coverage and spatial resolution using dual injection dynamic contrast-enhanced (ICE-DICE) MRI. In a dualbolus dynamic contrast-enhanced-MRI acquisition protocol, a high temporal resolution prebolus is followed by a high spatial resolution main bolus to allow high spatial resolution parametric mapping for cerebral tumors. The measured plasma concentration curves from the dual-bolus data were used to reconstruct a high temporal resolution arterial input function. The new method reduces errors resulting from uncertainty in the temporal alignment of the arterial input function, tissue response function, and sampling grid. The technique provides high spatial resolution 3D pharmacokinetic maps (voxel size 1.0 3 1.0 3 2.0 mm 3 ) with whole brain coverage and greater parameter accuracy than that was possible with the conventional single temporal resolution methods. High spatial resolution imaging of brain lesions is highly desirable for small lesions and to support investigation of heterogeneity within pathological tissue and peripheral invasion at the interface between diseased and normal brain. The new method has the potential to be used to improve dynamic contrast-enhanced-MRI techniques in general. Magn Reson Med 68:452-462, 2012. V C 2012 Wiley Periodicals, Inc.

T hroughout the body, most arteries and veins with an internal diameter >100 μm are invested with a layer of perivascular adipose tissue (PVAT), which comprises adipocytes, inflammatory cells, and stem cells in phenotypic states that depend on the body mass of the individual and their premorbid state. Known locations of PVAT include the coronaries, aorta, and the microvascular beds of the mesentery, muscle, and kidney. [1][2][3][4][5] The fat cells were often regarded as mere repositories for excess energy and were removed before physiologists studied vascular structure and function. However, it is clear now that adipocytes are highly metabolically active and produce large numbers of substances that could influence the circulation both by paracrine and by endocrine effects. 6,7 This was demonstrated first by Soltis and Cassis,8 who reported a significantly reduced sensitivity to norepinephrine in segments of rat thoracic aorta surrounded by fat when compared with denuded vessels. Although this might be attributable to the barrier effect of the fat layer, and this is a contributory factor, 9 the effect could be corrected with desipramine plus deoxycorticosterone pretreatment implicating a sympathetic neuroeffector mechanism. Subsequently this so-called anticontractile effect of PVAT has been demonstrated in a variety of vascular beds from different species.10-14 The nature of the released adipokine(s) responsible is the subject of intense debate as are the mechanisms initiated and the picture is not complete: the vascular effects of PVAT vary depending on the anatomic location and in the case of the coronary vessels there are alternate effects on the endothelium and smooth muscle, 15,16 which are discussed in detail elsewhere in this review series. Please see http://atvb.ahajournals.org/site/misc/ ATVB_in_Focus.xhtml for all articles published in this series. Does PVAT Release Factors That Can Influence Vascular Tone?The simplest way to address this question is to stimulate a blood vessel surrounded with PVAT using a spasmogen in vitro and then expose a preconstricted artery denuded of PVAT to the organ bath solution. If there is a reduction in vascular reactivity or sensitivity, then this must be attributable to factor(s) released from PVAT. This approach has been applied to murine and human tissues, including mesenteric and subcutaneous gluteal arteries and aorta, and consistently there is an anticontractile response. [17][18][19] Furthermore, incubation and adrenergic stimulation of dissected PVAT alongside a denuded vessel further supports the secreted factor(s) hypothesis as opposed to physical blockade because vessels constrict significantly lesser than PVAT denuded counterparts. 10 What Is the Anticontractile Factor?Löhn et al 13 extended early studies and concluded that PVAT released a soluble factor that induces vasodilatation by opening smooth muscle K + channels. As a result of these reports, several candidates have been suggested as possible PVAT-mediated relaxing factors and include adiponectin, angi...

Background Sorafenib is an inhibitor of multiple kinases (e.g., VEGF receptors, PDGFR, FLT3, RET, BRAF, KIT) and is approved by FDA for treatment of two adult cancers. The activity of sorafenib was evaluated against the PPTP's in vitro and in vivo panels. Procedures Sorafenib was evaluated against the PPTP in vitro panel using 96 hour exposure at concentrations ranging from 1.0 nM to 10.0 μM. It was tested against the PPTP in vivo panels at a dose of 60 mg/kg administered by oral gavage daily for 5 days per week, repeated for 6 weeks. Results In vitro sorafenib demonstrated cytotoxic activity, with a median IC50 value of 4.3 μM. Twenty of 23 cell lines had IC50 values between 1.0 and 10.0 μM. A single cell line (Kasumi-1) with an activating KIT mutation had an IC50 value < 1.0 μM (IC50 = 0.02 μM). In vivo sorafenib induced significant differences in EFS distribution compared to control in 27 of 36 (75%) of the evaluable solid tumor xenografts and in 1 of 8 (12.5%) of the evaluable ALL xenografts. Sorafenib induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C) in 15 of 34 (44%) evaluable solid tumor xenografts. No xenografts achieved an objective response. Conclusions The primary in vitro activity of sorafenib was noted at concentrations above 1 μM, with the exception of a more sensitive cell line with an activating KIT mutation. The primary in vivo effect for sorafenib was tumor growth inhibition, which was observed across multiple histotypes.

Background-Topotecan is a small molecule DNA topoisomerase I poison, that has been successful in clinical trials against pediatric solid tumors and leukemias. Topotecan was evaluated against the PPTP tumor panels as part of a validation process for these preclinical models.