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10003 Background: Patients with RMS have a poor prognosis at first relapse/disease progression. VC has activity in RMS and preclinical data supports the use of bevacizumab and temsirolimus in RMS. Methods: Patients with biopsy proven RMS, 8 weeks, performance status < 2, adequate organ function and written informed consent. Patients were randomized between two regimens administered every 3 weeks for a maximum of 12 cycles: Regimen A- V 25 mg/m2 intravenously (IV) days 1 & 8, C 1.2 gms/m2 IV day 1, bevacizumab 15 mg/Kg IV day 1; b) Regimen B- VC identical to regimen A, temsirolimus 15 mg/m2 IV days 1, 8 & 15. Primary endpoint was event free survival (EFS) at 6 months. Disease response at week 6 was assessed using RECIST. The study had a phase 2 screening design and was powered to detect a 15% difference in EFS between the two regimens (α=0.2, 1-β=0.8, 2-sided test). Interim analysi...

Neutrophils (PMNs) from patients with thermal injury are dysfunctional for the CD11b/CD18-dependent functions of diapedesis, chemotaxis, and phagocytosis. The expression of CD11b/CD18 on normal PMNs is increased after an inflammatory stimulus. We proposed that CD11b/CD18 expression on burn patient PMNs would respond abnormally to inflammatory stimuli. PMNs were obtained from nonseptic burn patients during the second week after thermal injury. PMNs from burn patients incubated with lipopolysaccharide (LPS), N-formyl-methionyl-leucyl-phenylalanine, phorbol myristate acetate, or A23187 did not increase the expression of CD11b/CD18 to the same degree exhibited by normal PMNs. This inability to increase CD11b/CD18 was not due to differences in CD14 receptor expression, LPS binding, or factors present in the serum of burn patients. The upregulation of CD35 also was decreased on burn patient PMNs. Western blot analysis revealed decreased quantities of CD11b protein in burn patient PMNs compared with normal control PMNs. The deficiency in CD11b/ CD18 expression after inflammatory stimuli may explain some of the abnormalities observed in burn PMN function.

10012 Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging (computerized tomographic [CT] or magnetic resonance imaging [MRI] scan) is controversial. We previously reported no relationship between early response and failure-free survival (FFS) for patients on IRS-IV. We repeated the same analysis using an independent cohort of patients with non-metastatic, initially unresected RMS treated on a more recent clinical trial. Methods: A total of 338 patients enrolled in Children’s Oncology Group study D9803 met the following inclusion criteria for this analysis: 1) non-metastatic, initially unresected (Group III); 2) embryonal (ERMS) or alveolar (ARMS) histology; 3) documented response to induction chemotherapy (excluding progressive disease) based on anatomic imaging; and 4) documented therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR, complete resolution), partial response (PR, decrease of >= 50% of the sum of the products of maximum perpendicular diameters), or no response (NR, between 50% reduction and 25% increase in the sum of the products of maximum perpendicular diameters). FFS was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85%, with similar responses for ERMS and ARMS. FFS was similar among all patients with CR, PR, or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by histology (p=0.20 and p=0.45, respectively). Conclusions: These findings provide additional evidence that anatomic imaging assessment of early response to therapy among RMS patients does not predict outcome and should not be used to tailor subsequent therapy. Clinical trial information: NCT00003958. [Table: see text]

Nitric oxide (NO), a paracrine-acting gas enzymatically synthesized from L-arginine, is a unique biologic mediator that has been implicated in a myriad of physiologic and pathophysiologic states. It is an important regulator of vascular tone and may be the mediator of the hemodynamic changes involved in sepsis and cirrhosis. In addition, there is increasing evidence that NO is involved in coagulation, immune function, inhibitory innervation of the gastrointestinal tract, protection of gastrointestinal mucosa, and the hepatotoxicity of cirrhosis. It has already been speculated that NO may represent a point of control or intervention in a number of disease states. The purpose of this paper is to provide the surgeon with a broad overview of the scientific and clinical aspects of this important molecule.

9504 Background: The majority of intermediate risk RMS patients have gross residual disease (Group III) after their first operative procedure. In these patients local control is usually obtained wi...

The Notch pathway regulates adaptive immune responses, yet the temporal development of a specific molecular anatomy underlying the directionality of Notch signaling, central to cell-fate decisions, remains unknown. Using the development of the functional immune synapse (IS) of the human physiological T-helper lymphocyte (Th): Dendritic cell (DC) interaction as our model, we followed the temporal accumulation of Notch signaling components, unprocessed and processed, in the developing ThIS and the apposed DCIS of these cells by 2D and 3D immunofluorescense microscopy. Downstream Notch targets in both cell types were followed, as well. We demonstrate that Th-Notch1 receptor and DC-Notch ligands (Delta-like1, Jagged-1) cluster in their apposed central-supramolecular-activation-clusters (cSMAC), whereas DC-Notch1 receptor and Th-Notch ligands cluster in their apposed peripheral-SMAC in an anti-parallel arrangement to that seen in the cSMAC. The resultant accumulation in both cell types of processed nuclear Notch receptor, its ligands, as well as HES-1 and phosphorylated-STAT3, supports antiparallel, reciprocal Notch signal propagation in the DC-to-Th direction via the cSMAC and Th-to-DC direction via the pSMAC. The imposed asymmetric recruitment of the components of Notch pathway, therefore, provides a novel bi-directional route by which the partnered ThIS and DCIS regulate Notch-mediated immune responses. Our data indicate that terminally differentiated immune cells communicate bidirectionally using unidirectional Notch signaling platforms that are spatially segregated into reciprocally signaling microdomains. Significantly, our observations of bidirectional Notch signaling indicate that the heterologous Th:DC interaction is cooperative, requiring reciprocal information transfer across both cell types to mount an appropriate immune response.

8501 Background: At the end of therapy, some patients with RMS have residual masses despite receiving all planned chemotherapy and radiotherapy. For IRS IV subjects with Group III (non-metastatic, ...

8513 Background: Initial response to induction chemotherapy (CT) predicts FFS in osteosarcoma and Ewing sarcoma. Current European studies in RMS tailor therapy based on induction response. For IRS IV subjects with Group III RMS, we assessed whether reported response to induction therapy predicted FFS. Methods: We studied 453 Group III subjects who received induction CT, had response assessed at week 8 and continued with protocol therapy. Induction CT was followed by radiation therapy (RT) starting after week 9. Response to induction therapy was determined by radiographic measurement of tumor at weeks 0 and 8. Complete response (CR: complete resolution of disease), partial response (PR: ≥ 50% decrease in the sum of the products of the maximum perpendicular diameters of measurable lesions), no response (NR: 25% increase) was coded by local institutions. Results: Response rate at week 8 was 77% (CR=21%, PR=56%) but response had no influence on FFS ...

10554 Background: Age at diagnosis is a prognostic factor in patients with RMS. We sought to determine whether AYA with metastatic alveolar (ARMS) or embryonal (ERMS) RMS had a different failure-free survival (FFS) compared to younger patients, and to identify treatment related factors that may be associated with outcome. Methods: COG ARST0431 patients were reviewed. The incidence of toxicities (AE, grade3/4 using CTCAEv3) by age was determined in 4 reporting periods (RP: wks 1-6; RP2:7-19; RP3: 20-34; RP4: 35-54). The AEs in younger patients (

10015 Background: Data from a previous COG study (ARST0431) showed an early FFS improvement but no long-term survival benefit with intensive interval-compressed chemotherapy in metastatic RMS. ARST...